NZ770256B2 - N-((het)arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors - Google Patents
N-((het)arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors Download PDFInfo
- Publication number
- NZ770256B2 NZ770256B2 NZ770256A NZ77025615A NZ770256B2 NZ 770256 B2 NZ770256 B2 NZ 770256B2 NZ 770256 A NZ770256 A NZ 770256A NZ 77025615 A NZ77025615 A NZ 77025615A NZ 770256 B2 NZ770256 B2 NZ 770256B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- phenyl
- pyrazolecarboxamide
- alkyl
- oxopyridin
- Prior art date
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- 108090000113 Plasma kallikrein Proteins 0.000 title claims abstract description 57
- 102000003827 Plasma kallikrein Human genes 0.000 title claims abstract description 57
- 125000005002 aryl methyl group Chemical group 0.000 title abstract 2
- 230000002401 inhibitory effect Effects 0.000 title description 49
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- 125000001424 substituent group Chemical group 0.000 claims description 89
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- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 5
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
The present invention provides N-((het)arylmethyl)-heteroary-carboxyamide compounds of formula (I), compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, A, B, W, X, Y and Z are as defined herein. The use of such compounds are particularly useful in therapy, such as in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated, for example retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema, hereditary angioedema and the like. nd methods of treating patients with such compounds; wherein R5, R6, R7, A, B, W, X, Y and Z are as defined herein. The use of such compounds are particularly useful in therapy, such as in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated, for example retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema, hereditary angioedema and the like.
Description
N-((HET)ARYLMETHYL)-HETEROARYL-CARBOXAMIDES COMPOUNDS AS PLASMA KALLIKREIN
INHIBITORS
This invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein and to pharmaceutical
compositions containing and the uses of, such inhibitors.
Background to the Invention
The heterocyclic derivatives of the present invention are inhibitors of plasma kallikrein and have a
number of therapeutic applications, particularly in the treatment of retinal vascular permeability
associated with diabetic retinopathy and diabetic macular edema.
Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see K. D.
Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et
al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular
and haematological agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et al.,
Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, "Towards understanding the kallikrein-kinin
system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological
Research 2000, 33, 665-677). It is an essential member of the intrinsic blood coagulation cascade
although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage.
Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by
hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a heterodimer complex
bound to high molecular weight kininogen which is activated to give the active plasma kallikrein. Kinins
are potent mediators of inflammation that act through G protein-coupled receptors and antagonists of
kinins (such as bradykinin antagonists) have previously been investigated as potential therapeutic agents
for the treatment of a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery,
2004, 3, 845-852).
Plasma kallikrein is thought to play a role in a number of inflammatory disorders. The major inhibitor of
plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a genetic deficiency in C1
esterase inhibitor suffer from hereditary angioedema (HAE) which results in intermittent swelling of
face, hands, throat, gastro-intestinal tract and genitals. Blisters formed during acute episodes contain
high levels of plasma kallikrein which cleaves high molecular weight kininogen liberating bradykinin
306761NZDIV
leading to increased vascular permeability. Treatment with a large protein plasma kallikrein inhibitor has
been shown to effectively treat HAE by preventing the release of bradykinin which causes increased
vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment
of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert
Opin. Biol. Ther. 8, p1187-99).
The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular
edema. It has been recently published that plasma kallikrein contributes to retinal vascular dysfunctions
in diabetic rats (A. Clermont et al. "Plasma kallikrein mediates retinal vascular dysfunction and induces
retinal thickening in diabetic rats" Diabetes, 2011, 60, p1590-98). Furthermore, administration of the
plasma kallikrein inhibitor ASP-440 ameliorated both retinal vascular permeability and retinal blood flow
abnormalities in diabetic rats. Therefore a plasma kallikrein inhibitor should have utility as a treatment
to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular
edema.
Other complications of diabetes such as cerebral haemorrhage, nephropathy, cardiomyopathy and
neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a
plasma kallikrein inhibitor.
Synthetic and small molecule plasma kallikrein inhibitors have been described previously, for example
by Garrett et al. ("Peptide aldehyde…." J. Peptide Res. 52, p62-71 (1998)), T. Griesbacher et al.
("Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated
by endogenous kinins in acute pancreatitis in rats" British Journal of Pharmacology 137, p692-700
(2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03/076458), Szelke et al. ("Kininogenase
inhibitors" WO92/04371), D. M. Evans et al. (Immunolpharmacology, 32, p115-116 (1996)), Szelke et al.
("Kininogen inhibitors" WO95/07921), Antonsson et al. ("New peptides derivatives" WO94/29335), J.
Corte et al. (”Six membered heterocycles useful as serine protease inhibitors” WO2005/123680), J.
Stürzbecher et al. (Brazilian J. Med. Biol. Res 27, p1929-34 (1994)), Kettner et al. (US 5,187,157), N. Teno
et al. (Chem. Pharm. Bull. 41, p1079-1090 (1993)), W. B. Young et al. ("Small molecule inhibitors of
plasma kallikrein" Bioorg. Med. Chem. Letts. 16, p2034-2036 (2006)), Okada et al. ("Development of
potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity
relationship" Chem. Pharm. Bull. 48, p1964-72 (2000)), Steinmetzer et al. ("Trypsin-like serine protease
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inhibitors and their preparation and use" WO08/049595), Zhang et al. ("Discovery of highly potent small
molecule kallikrein inhibitors" Medicinal Chemistry 2, p545-553 (2006)), Sinha et al. ("Inhibitors of
plasma kallikrein" WO08/016883), Shigenaga et al. (“Plasma Kallikrein Inhibitors” WO2011/118672), and
Kolte et al. (“Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor”, British
Journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer et al. (“Serine protease
inhibitors” WO2012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin
and plasma kallikrein.
To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. The
molecules described in the known art suffer from limitations such as poor selectivity over related
enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. The large protein
plasma kallikrein inhibitors present risks of anaphylactic reactions, as has been reported for Ecallantide.
Thus there remains a need for compounds that selectively inhibit plasma kallikrein, that do not induce
anaphylaxis and that are orally available. Furthermore, the vast majority of molecules in the known art
feature a highly polar and ionisable guanidine or amidine functionality. It is well known that such
functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has
been reported by Tamie J. Chilcote and Sukanto Sinha (“ASP-634: An Oral Drug Candidate for Diabetic
th th
MacularEdema”, ARVO 2012 May 6 – May 9 , 2012, Fort Lauderdale, Florida, Presentation 2240) that
ASP-440, a benzamidine, suffers from poor oral availability. It is further reported that absorption may be
improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs can suffer
from several drawbacks, for example, poor chemical stability and potential toxicity from the inert carrier
or from unexpected metabolites. In another report, indole amides are claimed as compounds that might
overcome problems associated with drugs possessing poor or inadequate ADME-tox and
physicochemical properties although no inhibition against plasma kallikrein is presented or claimed
(Griffioen et al, “Indole amide derivatives and related compounds for use in the treatment of
neurodegenerative diseases”, WO2010, 142801).
BioCryst Pharmaceuticals Inc. have reported the discovery of the orally available plasma kallikrein
inhibitor BCX4161 (“BCX4161, An Oral Kallikrein Inhibitor: Safety and Pharmacokinetic Results Of a
Phase 1 Study In Healthy Volunteers”, Journal of Allergy and Clinical Immunology, Volume 133, Issue 2,
Supplement, February 2014, page AB39 and “A Simple, Sensitive and Selective Fluorogenic Assay to
Monitor Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma”, Journal of Allergy and
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Clinical Immunology, Volume 133, Issue 2, Supplement February 2014, page AB40). However, human
doses are relatively large, currently being tested in proof of concept studies at doses of 400 mg three
times daily.
There are only few reports of plasma kallikrein inhibitors that do not feature guanidine or amidine
functionalities. One example is Brandl et al. (“N-((6-amino-pyridinyl)methyl)-heteroaryl-carboxamides
as inhibitors of plasma kallikrein” WO2012/017020), which describes compounds that feature an amino-
pyridine functionality. Oral efficacy in a rat model is demonstrated at relatively high doses of 30 mg/kg
and 100 mg/kg but the pharmacokinetic profile is not reported. Thus it is not yet known whether such
compounds will provide sufficient oral availability or efficacy for progression to the clinic. Other
examples are Brandl et al. (“Aminopyridine derivatives as plasma kallikrein inhibitors” WO2013/111107)
and Flohr et al. (“5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors”
WO2013/111108). However, neither of these documents report any in vivo data and therefore it is not
yet known whether such compounds will provide sufficient oral availability or efficacy for progression to
the clinic. Another example is Allen et al. “Benzylamine derivatives” WO2014/108679.
Therefore there remains a need to develop new plasma kallikrein inhibitors that will have utility to treat
a wide range of disorders, in particular to reduce retinal vascular permeability associated with diabetic
retinopathy and diabetic macular edema. Preferred compounds will possess a good pharmacokinetic
profile and in particular will be suitable as drugs for oral delivery.
Summary of the Invention
The present invention relates to a series of heterocyclic derivatives that are inhibitors of plasma
kallikrein. These compounds demonstrate good selectivity for plasma kallikrein and are potentially
useful in the treatment of impaired visual acuity, diabetic retinopathy, macular edema, hereditary
angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy,
inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory
distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and
bleeding from post operative surgery. The invention further relates to pharmaceutical compositions of
the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using
these compositions.
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In a first aspect, the present invention provides compounds of formula I
Formula (I)
wherein
B is phenyl substituted with 1 to 4 substituents selected from alkyl , alkoxy, OH, halo, CN, heteroaryl,
COOR8, NHCOR8, CONR8R9, OCF and CF ;
3, 3
or B is selected from benzothiophenyl, benzofuranyl, benzomorpholinyl, and a 5 or 6 membered
heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein said 5 or 6
membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said
benzofuranyl, said benzomorpholinyl or said 5 or 6 membered heterocyclic ring is substituted with 1 to 3
substituents selected from alkyl , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9,
OCF and CF ;
W is C and X, Y and Z are independently selected from C, N, O and S, such that the ring containing W, X,
Y and Z is a five membered aromatic heterocycle;
R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, alkoxy, halo,
OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked
piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9 and CF ; wherein at least one of R5 and R6 is
present and is not H;
R7 is H;
A is selected from aryl and heteroaryl; wherein aryl is substituted with 1, 2 or 3 substituents
independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, -
b b b
(CH ) -O-heteroaryl, aryl , -O-aryl , -(CH ) -aryl , -(CH ) -heteroaryl, -COOR10, -CONR10R11, -(CH ) -
2 0-3 2 1-3 2 1-3 2 0-3
NR10R11, OCF and CF ; and heteroaryl is substituted with 1, 2 or 3 substituents independently selected
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from alkyl, alkoxy, OH, OCF , halo, CN, aryl, -(CH ) -aryl, -(CH ) -NR10R11, heteroaryl , -COOR10, -
3 2 1-3 2 0-3
CONR10R11 and CF ;
R8 and R9 are independently selected from H and alkyl;
alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C -C ) or a branched saturated
1 10
hydrocarbon of between 3 and 10 carbon atoms (C -C ); alkyl may optionally be substituted with 1 or 2
3 10
substituents independently selected from (C -C )alkoxy, OH, CN, CF , COOR10, CONR10R11, fluoro and
1 6 3
NR10R11;
alkyl is a linear saturated hydrocarbon having up to 6 carbon atoms or a branched saturated
hydrocarbon of between 3 and 6 carbon atoms (C ); alkyl may optionally be substituted with 1 or 2
substituents independently selected from (C -C )alkoxy, OH, CN, CF , COOR10, CONR10R11 and fluoro;
1 6 3
cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6 carbon atoms;
alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C -C ) or a branched O-linked
hydrocarbon of between 3 and 6 carbon atoms (C3-C6); alkoxy may optionally be substituted with 1 or 2
substituents independently selected from OH, CN, CF , COOR10, CONR10R11, fluoro and NR10R11;
aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents
independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, -
b b b
(CH ) -O-heteroaryl, aryl , -O-aryl , -(CH ) -aryl , -(CH ) -heteroaryl, -COOR10, -CONR10R11, -(CH ) -
2 0-3 2 1-3 2 1-3 2 0-3
NR10R11, OCF and CF ;
aryl is phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents
independently selected from alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF and NR10R11;
heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2,
3 or 4 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally
substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF , halo, CN,
aryl, -(CH ) -aryl, -(CH ) -NR10R11, heteroaryl , -COOR10, -CONR10R11 and CF ;
2 1-3 2 0-3 3
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heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2
or 3 ring members independently selected from N, NR8, S and O; wherein heteroaryl may be optionally
substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, aryl, -
(CH ) -aryl, -COOR10, -CONR10R11, CF and NR10R11;
2 1-3 3
R10 and R11 are independently selected from H, alkyl, aryl and heteroaryl or R10 and R11 together
with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered
heterocylic ring, optionally containing an additional heteroatom selected from N, S and O, which may be
saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted
with substituents selected from oxo, alkyl, alkoxy, OH, halo and CF3;
and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and
scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect the present invention provides a prodrug of a compound of formula (I) as herein
defined, or a pharmaceutically acceptable salt thereof.
In yet another aspect the present invention provides an N-oxide of a compound of formula (I) as herein
defined, or a prodrug or pharmaceutically acceptable salt thereof.
It will be understood that certain compounds of the present invention may exist in solvated, for example
hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all
such solvated forms.
In a further aspect, also provided are compounds of formula (I), wherein:
B is selected from phenyl, thiophenyl, benzothiophenyl and pyridyl, each substituted with 1 to 3
substituents selected from alkyl , alkoxy, halo, CN, COOR8, CONR8R9, OCF and CF ; wherein alkyl ,
alkoxy, R8 and R9 are as defined above;
W is C and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and
Z is a five membered aromatic heterocycle;
R5 and R6 are independently absent or independently selected from H, CH OCH , cycloalkyl, -NR8R9, -
NR8COR9 and CF ; wherein at least one of R5 and R6 is present and is not H;
R7 is H;
306761NZDIV
A is selected from:
, , and ;
wherein alkyl, cycloalkyl, alkoxy, R8 and R9 are as defined above;
and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and
scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
In a further aspect, also provided are compounds of formula (I), wherein:
B is selected from phenyl and pyridyl, each substituted with 1 to 3 substituents selected from methyl,
ethyl, methoxy, ethoxy, CF , CN and F;
W is C, X is N and Y and Z are selected from C and N;
R7 is H and R5 and R6 are independently absent or independently selected from H,
CH OCH ,cyclopropyl, NH and CF ; wherein at least one of R5 and R6 is present and is not H.;
2 3 2 3
A is selected from:
, , and ;
and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and
scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
306761NZDIV
The aspects of the invention described above may also comprise the following features:
• B is phenyl substituted with 1 to 4 substituents selected from alkyl , alkoxy, OH, halo, CN,
heteroaryl, COOR8, NHCOR8, CONR8R9, OCF , and CF ; or B is selected from benzothiophenyl,
benzofuranyl, benzomorpholinyl, and a 5 or 6 membered heterocyclic ring containing one or two
heteroatoms selected from N, O and S; wherein said 5 or 6 membered heterocyclic ring may be
aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl, said
benzomorpholinyl or said 5 or 6 membered heterocyclic ring is substituted with 1 to 3 substituents
selected from alkyl , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF and
CF ;
• B is phenyl substituted with 1 to 4 substituents selected from alkyl , alkoxy, OH, halo, CN,
heteroaryl, COOR8, NHCOR8, CONR8R9, OCF and CF ; or B is selected from benzothiophenyl,
3, 3
benzofuranyl, and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected
from N, O and S; wherein said 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic;
and wherein said benzothiophenyl, said benzofuranyl or said 5 or 6 membered heterocyclic ring is
substituted with 1 to 3 substituents selected from alkyl , alkoxy, OH, oxo, halo, CN, heteroaryl,
COOR8, NHCOR8, CONR8R9, OCF and CF ; wherein alkyl , alkoxy, R8 and R9 are as defined above.
• B is selected from phenyl, pyridyl, pyrimidone, pyrimidine, thiazolyl, isothiazolyl, pyrazolyl,
imidazolyl, isoxazolyl, oxazolyl, thiophenyl, benzothiophenyl and furanyl, each substituted, when
possible, with 1 to 3 substituents selected from alkyl , alkoxy, OH, oxo, halo, CN, COOR8, CONR8R9,
OCF and CF ; wherein alkyl , alkoxy, R8 and R9 are as defined above.
• B is selected from phenyl, pyridyl, pyrimidone, thiazolyl, pyrazolyl, isoxazolyl, thiophenyl,
benzothiophenyl and furanyl, each substituted, when possible, with 1 to 3 substituents selected
from alkyl , alkoxy, OH, oxo, halo, CN, COOR8, CONR8R9, OCF and CF ; wherein alkyl , alkoxy, R8
and R9 are as defined above.
• B is selected from phenyl, thiophenyl, benzothiphenyl and pyridyl, each substituted with 1 to 3
substituents selected from alkyl , alkoxy, halo, CN, COOR8, CONR8R9, OCF and CF ; wherein alkyl ,
alkoxy, R8 and R9 are as defined above.
• B is selected from phenyl and pyridyl, each substituted with 1 to 3 substituents selected from alkyl ,
alkoxy, CN, CF and halo; wherein alkyl and alkoxy are as defined above.
• B is selected from phenyl and pyridyl, each substituted with 1 to 3 substituents selected from alkyl ,
alkoxy, CF and halo; wherein alkyl and alkoxy are as defined above.
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• B is selected from phenyl and pyridyl, each substituted with 1 to 3 substituents selected from
methyl, ethyl, methoxy, ethoxy, CF , CN and F.
• B is selected from phenyl and pyridyl, each substituted with 1 to 3 substituents selected from
methyl, ethyl, methoxy, ethoxy, CF , Cl, CHF and F.
• B is selected from phenyl substituted with 1 to 3 substituents selected from methyl, ethyl, methoxy,
ethoxy, CN, CF , Cl, CHF and F.
• B is selected from phenyl substituted with 1 to 3 substituents selected from methyl, ethyl, methoxy,
ethoxy, CF , Cl, CHF and F.
• W is C and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y
and Z is a five membered aromatic heterocycle.
• W is C and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y
and Z is selected from pyrrole, pyrazole, imidazole and 1, 2, 3-triazole.
• W is C and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y
and Z is selected from pyrazole and imidazole.
• W is C.
• X is N.
• W is C, X is N and Y and Z are selected from C and N.
• W is C, X is N, Y is N and Z is C.
• W is C, X is N, Y is C and Z is N.
• R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, alkoxy,
halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked
piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9 and CF ; wherein at least one of R5 and R6 is
present and is not H; wherein alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, R8 and R9 are as defined
above.
• R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, -NR8R9, CN,
-NR8COR9 and CF3; wherein at least one of R5 and R6 is present and is not H; wherein alkyl,
cycloalkyl, R8 and R9 are as defined above.
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• R5 and R6 are independently absent or independently selected from H, CH OCH , cycloalkyl, CN, -
NR8R9, -NR8COR9 and CF ; wherein at least one of R5 and R6 is present and is not H; wherein
cycloalkyl, R8 and R9 are as defined above.
• R5 and R6 are independently absent or independently selected from H, cycloalkyl, CN,
-NR8R9, -NR8COR9 and CF ; wherein at least one of R5 and R6 is present and is not H; wherein
cycloalkyl, R8 and R9 are as defined above.
• R5 and R6 are independently absent or independently selected from H, CH OCH , cycloalkyl, CN,
NR8R9 and CF ; wherein R8 and R9 are H and cycloalkyl is as defined above; and, wherein at least
one of R5 and R6 is present and is not H.
• R7 is H.
• R7 is H and R5 and R6 are independently absent or independently selected from H, CH2OCH3,
cyclopropyl, CN, NH and CF ; wherein at least one of R5 and R6 is present and is not H.
• R7 is H and R5 and R6 are independently absent or independently selected from H,
CH OCH ,cyclopropyl, NH , CN and CF ; wherein at least one of R5 and R6 is present and is not H.
2 3 2 3
• R7 is H and R5 and R6 are independently absent or independently selected from H,
CH OCH ,cyclopropyl, NH and CF ; wherein at least one of R5 and R6 is present and is not H.
2 3 2 3
• R7 is H, R6 is absent and R5 is selected from CH OCH , cyclopropyl, NH and CF .
2 3 2 3
• R7 is H, R6 is absent and R5 is CH OCH .
• W is C, X is N, Y and Z are selected from C and N, R7 is H and R5 and R6 are independently absent or
independently selected from H, CH OCH , cycloalkyl, NR8R9 and CF ; wherein R8 and R9 are H and
2 3 3
cycloalkyl is as defined above.
• W is C, X is N, Y is N, Z is C, R7 is H, R6 is absent and R5 is selected from CH OCH , cyclopropyl, NH
2 3 2
and CF .
• A is selected from aryl and heteroaryl, each substituted as specified above.
• A is phenyl, pyridyl, thiophenyl or quinolinyl, each substituted with 1, 2 or 3 substituents
independently selected from alkyl, alkoxy, halo, CN, aryl , -(CH ) -aryl , -(CH ) -heteroaryl, -(CH )
2 1-3 2 1-3 2 0-
-NR10R11 and CF ; wherein alkyl, alkoxy, heteroaryl, aryl , R10 and R11 are as defined above.
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• A is phenyl or pyridyl, each substituted with 1, 2 or 3 substituents independently selected from alkyl,
alkoxy, halo, -(CH ) -aryl , -(CH ) -heteroaryl, CF and -(CH ) -NR10R11; wherein alkyl, alkoxy,
2 1-3 2 1-3 3 2 0-3
heteroaryl, aryl , R10 and R11 are as defined above.
• A is pyridyl substituted with 1, 2 or 3 substituents independently selected from alkyl, halo,
heteroaryl , CF and -NR10R11; wherein alkyl, heteroaryl , R10 and R11 are as defined above.
• A is pyridyl substituted with heteroaryl or -NR10R11 and, optionally, 1 or 2 additional substituents
independently selected from alkyl, halo and CF ; wherein alkyl, heteroaryl , R10 and R11 are as
defined above.
• A is phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl, halo,
-(CH ) -heteroaryl, CF and -(CH ) -NR10R11; wherein alkyl, heteroaryl, R10 and R11 are as
2 1-3 3 2 1-3
defined above.
• A is phenyl substituted with -(CH ) -heteroaryl or -(CH ) -NR10R11 and, optionally, 1 or 2
2 1-3 2 1-3
additional substituents independently selected from alkyl, halo and CF ; wherein alkyl, heteroaryl,
R10 and R11 are as defined above.
• A is selected from:
, ,
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, , ,
, , ,
, and
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• A is selected from:
, ,
, ,
, and .
• A is selected from:
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, ,
, and .
• A is selected from:
and .
• A is:
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• A is:
• R8 and R9 are independently selected from H and alkyl; wherein alkyl is defined above.
• R8 and R9 are independently selected from H and methyl, ethyl, n-propyl and isopropyl.
• R8 and R9 are independently selected from H and methyl.
• R10 and R11 are independently selected from H, alkyl, aryl and heteroaryl or R10 and R11 together
with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-
membered heterocylic ring, optionally containing an additional heteroatom selected from N, S and
O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally
mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, halo and CF ;
wherein alkyl, alkoxy, aryl and heteroaryl are as defined above.
• R10 and R11 are independently selected from H and alkyl or R10 and R11 together with the nitrogen
atom to which they are attached form a carbon-containing 5- or 6-membered heterocylic ring,
optionally containing an addition N atom, which may be saturated or unsaturated with 1 or 2 double
bonds and which may be optionally mono- or di-substituted with substituents selected from oxo,
alkyl, alkoxy, OH, Cl, F and CF ; wherein alkyl and alkoxy are as defined above.
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• R10 and R11 are independently selected from H and alkyl or R10 and R11 together with the nitrogen
atom to which they are attached form a 5- or 6-membered carbon containing heterocylic ring,
optionally containing an addition N atom, which may be saturated or unsaturated with 1 or 2 double
bonds, and optionally mono- or di-substituted with substituents selected from oxo, methyl, Cl and F;
wherein alkyl is as defined above.
• R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered
carbon containing heterocylic ring, optionally containing an addition N atom, which may be
saturated or unsaturated with 1 or 2 double bonds, and optionally mono- or di-substituted with
substituents selected from oxo, methyl, Cl and F.
• R10 and R11 together with the nitrogen atom to which they are attached form a 6-membered
carbon containing heterocylic ring, optionally containing an addition N atom, which may be
saturated or unsaturated with 1 or 2 double bonds, and optionally may be oxo substituted.
• R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing
- or 6-membered saturated heterocylic ring.
• R10 and R11 are independently selected from H and alkyl ; wherein alkyl is as defined above.
The present invention also encompasses, but is not limited to, the compounds listed below:
N-(3,5-Dimethoxybenzyl)(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-
1H-pyrazolecarboxamide;
3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 2-
fluoromethoxy-benzylamide;
1-(7-Chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid 2-fluoro-
3-methoxy-benzylamide;
N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(3-methoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(3-ethoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
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1-({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-N-{[3-
(trifluoromethoxy)phenyl]methyl}(trifluoromethyl)pyrazolecarboxamide;
N-[(4-methylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(2,4-dimethoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-{[4-methoxy(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(2,6-difluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(2-chlorofluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide;
N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(4-chloro-2,6-difluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(4-chlorofluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide;
N-[(3-chloro-2,6-difluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(3-chlorofluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide;
N-[(5-chlorofluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide;
N-{[3-chlorofluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
306761NZDIV
N-[(2,6-dichlorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-{[5-chloro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(2,4-dimethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(2,6-dimethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
1-({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)(trifluoromethyl)-N-[(2,4,6-
trimethylphenyl)methyl]pyrazolecarboxamide;
N-[(3-fluoromethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide;
N-[(2-fluoromethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide;
N-[(3-fluoropyridinyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(4-chloropyridinyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[4-
(trifluoromethyl)pyridinyl]methyl}pyrazolecarboxamide;
3-(methoxymethyl)-N-[(6-methylpyridinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(4-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(4-acetamidopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[4-fluoro(trifluoromethyl)pyridinyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[2-
(trifluoromethyl)pyridinyl]methyl}pyrazolecarboxamide;
306761NZDIV
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[4-
(trifluoromethyl)pyridinyl]methyl}pyrazolecarboxamide;
N-[(4-fluoropyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(methoxymethyl)-N-[(6-methylpyridinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(methoxymethyl)-N-[(6-methoxypyridinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-chlorothiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-chloromethylthiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl){[6-(pyrrolidin
yl)pyridinyl]methyl}pyrazolecarboxamide;
N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl)({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-carbamoylphenyl)methyl]cyclopropyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-carbamoylphenyl)methyl]cyclopropyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(4-carbamoylphenyl)methyl]cyclopropyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
306761NZDIV
3-cyclopropyl-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoro-3,6-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methylamino)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(ethylamino)-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](isopropylamino)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[4-
(trifluoromethoxy)phenyl]methyl}pyrazolecarboxamide;
3-(dimethylamino)-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methylamino)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[2-
(trifluoromethyl)phenyl]methyl}pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
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N-[(3-chloromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-acetamido-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](N-methylacetamido)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-chloro-2,6-difluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(5-chlorocyanophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[3-methoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[5-methoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
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N-{[6-(difluoromethyl)fluoromethoxyphenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)fluoromethoxyphenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-chloromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-carbamoylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-carbamoylmethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
2-({[3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazol
yl]formamido}methyl)benzoic acid
N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[3-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[3-(difluoromethoxy)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)fluoromethylphenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,5-difluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,5-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
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N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(5-chlorofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(6-chlorofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-fluoromethoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-fluoromethyl(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[4-chlorofluoro(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-cyano-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluorohydroxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-[(2-fluorohydroxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
methyl 2-({[3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazol
yl]formamido}methyl)benzoate
N-[(3-ethylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyrazin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(4-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(4-methyl
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
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1-({4-[(5-fluorooxopyridinyl)methyl]phenyl}methyl)-N-[(2-fluoro
methoxyphenyl)methyl](methoxymethyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(5-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(4-ethoxyoxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]({4-[(5-methoxymethylpyrazol
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[5-(2-oxopyridin
yl)thiophenyl]methyl}pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin
yl)methyl]thiophenyl}methyl)pyrazolecarboxamide;
3-amino-N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-methoxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic
acid 6-cyanofluoromethoxy-benzylamide;
3-methoxymethyl(2-pyrrolidinyl-pyrimidinylmethyl)-1H-pyrazolecarboxylic acid
6-cyanofluoromethoxy-benzylamide;
1-(2-pyrrolidinyl-pyrimidinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid
6-cyanofluoromethoxy-benzylamide;
N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide;
1-({4-[(2-chlorooxopyridinyl)methyl]phenyl}methyl)-N-[(2-fluoro
methoxyphenyl)methyl](methoxymethyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({2-
[(methylamino)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl){[2-
(methylamino)pyridinyl]methyl}pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[2-(2,2,2-
trifluoroethyl)phenyl]methyl}pyrazolecarboxamide;
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N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[2-
(trifluoromethoxy)phenyl]methyl}pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]methyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide;
2-amino-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide;
2-cyclopropyl-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridinyl)methyl]phenyl}methyl)
(trifluoromethyl)imidazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]{[6-(pyrrolidinyl)pyridinyl]methyl}
(trifluoromethyl)pyrazolecarboxamide;
3-amino-N-[(2-fluoromethoxyphenyl)methyl]{[6-(pyrrolidinyl)pyridin
yl]methyl}pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[6-(pyrrolidinyl)pyridin
yl]methyl}pyrazolecarboxamide;
3-methoxymethyl(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid 6-
cyanofluoromethoxy-benzylamide;
1-(6-pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 6-
cyanofluoromethoxy-benzylamide;
3-amino-N-[(7-chloromethyl-2,3-dihydro-1,4-benzoxazinyl)methyl]({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
and pharmaceutically acceptable salts and solvates thereof.
The present invention also encompasses, but is not limited to, the compounds listed below:
3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 2-fluoro
methoxy-benzylamide;
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N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(4-chloro-2,6-difluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide;
N-{[3-chlorofluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
N-[(2-fluoromethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide;
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
3-cyclopropyl-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoro-3,6-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(dimethylamino)-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
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N-{[2-(difluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-acetamido-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-chloro-2,6-difluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(5-chlorocyanophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[5-methoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)fluoromethoxyphenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-carbamoylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-carbamoylmethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[3-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,5-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
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N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(6-chlorofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-[(2-fluorohydroxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(3-ethylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(4-methyloxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(5-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]methyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridinyl)methyl]phenyl}methyl)
(trifluoromethyl)imidazolecarboxamide;
3-amino-N-[(7-chloromethyl-2,3-dihydro-1,4-benzoxazinyl)methyl]({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
and pharmaceutically acceptable salts and solvates thereof.
The present invention also encompasses, but is not limited to, the compounds listed below:
3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 2-fluoro
methoxy-benzylamide;
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide;
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3-cyclopropyl-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoro-3,6-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(dimethylamino)-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(5-chlorocyanophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[5-methoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
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N-{[2-(difluoromethyl)fluoromethoxyphenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-carbamoylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2-carbamoylmethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-{[2-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,5-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(6-chlorofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide;
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(5-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide;
N-[(2-fluoromethoxyphenyl)methyl]methyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide;
3-amino-N-[(7-chloromethyl-2,3-dihydro-1,4-benzoxazinyl)methyl]({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide;
3-amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
and pharmaceutically acceptable salts and solvates thereof.
Therapeutic Applications
As previously mentioned, the compounds of the present invention are potent and selective inhibitors of
plasma kallikrein. They are therefore useful in the treatment of disease conditions for which over-
activity of plasma kallikrein is a causative factor.
Accordingly, the present invention provides a compound of formula (I) for use in medicine.
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The present invention also provides for the use of a compound of formula (I) in the manufacture of a
medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity
is implicated.
The present invention also provides a compound of formula (I) for use in the treatment or prevention of
a disease or condition in which plasma kallikrein activity is implicated.
The present invention also provides a method of treatment of a disease or condition in which plasma
kallikrein activity is implicated comprising administration to a subject in need thereof a therapeutically
effective amount of a compound of formula (I).
In one aspect, the disease or condition in which plasma kallikrein activity is implicated is selected from
impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes,
pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel
disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome,
disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post
operative surgery.
In a preferred aspect, the disease or condition in which plasma kallikrein activity is implicated is retinal
vascular permeability associated with diabetic retinopathy and diabetic macular edema.
Combination Therapy
The compounds of the present invention may be administered in combination with other therapeutic
agents. Suitable combination therapies include a compound of formula (I) combined with one or more
agents selected from agents that inhibit platelet-derived growth factor (PDGF), endothelial growth
factor (VEGF), integrin alpha5beta1, steroids, other agents that inhibit plasma kallikrein and other
inhibitors of inflammation. Specific examples of therapeutic agents that may be combined with the
compounds of the present invention include those disclosed in EP2281885A and by S. Patel in Retina,
2009 Jun;29(6 Suppl):S45-8.
When combination therapy is employed, the compounds of the present invention and said combination
agents may exist in the same or different pharmaceutical compositions, and may be administered
separately, sequentially or simultaneously.
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In another aspect, the compounds of the present invention may be administered in combination with
laser treatment of the retina. The combination of laser therapy with intravitreal injection of an inhibitor
of VEGF for the treatment of diabetic macular edema is known (Elman M, Aiello L, Beck R, et al.
“Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt
laser for diabetic macular edema” .Ophthalmology. 27 April 2010).
Definitions
The term "alkyl" includes saturated hydrocarbon residues including:
- linear groups up to 10 carbon atoms (C -C ), or of up to 6 carbon atoms (C -C ), or of up to 4 carbon
1 10 1 6
atoms (C1-C4). Examples of such alkyl groups include, but are not limited, to C1 - methyl, C2 - ethyl, C3
- propyl and C - n-butyl.
- branched groups of between 3 and 10 carbon atoms (C -C ), or of up to 7 carbon atoms (C -C ), or of
3 10 3 7
up to 4 carbon atoms (C -C ). Examples of such alkyl groups include, but are not limited to, C - iso-
3 4 3
propyl, C - sec-butyl, C - iso-butyl, C - tert-butyl and C - neo-pentyl.
4 4 4 5
each optionally substituted as stated above.
Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms, or between 3 and 6
carbon atoms, or between 3 and 5 carbon atoms. Optionally, cycloalkyl may be substituted with a
substituent selected from alkyl, alkoxy and NR12R13; wherein R12 and R13 are independently selected
from H and alkyl or R12 and R13 together with the nitrogen to which they are attached form a 4-, 5-, 6-
or 7-membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds and
which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH,
F and CF . Cycloalkyl groups may contain from 3 to 7 carbon atoms, or from 3 to 6 carbon atoms, or
from 3 to 5 carbon atoms, or from 3 to 4 carbon atoms. Examples of suitable monocyclic cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "alkoxy" includes O-linked hydrocarbon residues including:
- linear groups of between 1 and 6 carbon atoms (C -C ), or of between 1 and 4 carbon atoms (C -C ).
1 6 1 4
Examples of such alkoxy groups include, but are not limited to, C - methoxy, C - ethoxy, C - n-
1 2 3
propoxy and C - n-butoxy.
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- branched groups of between 3 and 6 carbon atoms (C -C ) or of between 3 and 4 carbon atoms (C -
3 6 3
C ). Examples of such alkoxy groups include, but are not limited to, C - iso-propoxy, and C - sec-
4 3 4
butoxy and tert-butoxy.
each optionally substituted as stated above.
Unless otherwise stated, halo is selected from Cl, F, Br and I.
Aryl is as defined above. Typically, aryl will be optionally substituted with 1, 2 or 3 substituents.
Optional substituents are selected from those stated above. Examples of suitable aryl groups include
phenyl and naphthyl (each optionally substituted as stated above). Preferably aryl is selected from
phenyl, substituted phenyl (wherein said substituents are selected from those stated above) and
naphthyl.
Heteroaryl is as defined above. Typically, heteroaryl will be optionally substituted with 1, 2 or 3
substituents. Optional substituents are selected from those stated above. Examples of suitable
heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinolinyl (optionally substituted as stated
above).
The term "N-linked", such as in "N-linked pyrrolidinyl", means that the heterocycloalkyl group is joined
to the remainder of the molecule via a ring nitrogen atom.
The term "O-linked", such as in "O-linked hydrocarbon residue", means that the hydrocarbon residue is
joined to the remainder of the molecule via an oxygen atom.
In groups such as -(CH ) -aryl, "-" denotes the point of attachment of the substituent group to the
2 1-3
remainder of the molecule.
"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes,
when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable
acid addition salts. For example (i) where a compound of the invention contains one or more acidic
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groups, for example carboxy groups, pharmaceutically acceptable base addition salts that can be formed
include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such
as, diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii)
where a compound of the invention contains a basic group, such as an amino group, pharmaceutically
acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates,
phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates,
tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates,
camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates,
ascorbates, oleates, bisulfates and the like.
Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by
Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
“Prodrug” refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis,
reduction or oxidation) to a compound of the invention. Suitable groups for forming prodrugs are
described in ‘The Practice of Medicinal Chemistry, 2 Ed. pp561-585 (2003) and in F. J. Leinweber, Drug
Metab. Res., 1987, 18, 379.
The compounds of the invention can exist in both unsolvated and solvated forms. The term 'solvate' is
used herein to describe a molecular complex comprising the compound of the invention and a
stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example,
ethanol. The term 'hydrate' is employed when the solvent is water.
Where compounds of the invention exist in one or more geometrical, optical, enantiomeric,
diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms,
R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular
compound includes all such isomeric forms, including racemic and other mixtures thereof. Where
appropriate such isomers can be separated from their mixtures by the application or adaptation of
known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate
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such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric
synthesis).
Unless otherwise stated, the compounds of the invention include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example, compounds wherein hydrogen is
13 14
replaced by deuterium or tritium, or wherein carbon is replaced by C or C, are within the scope of the
present invention. Such compounds are useful, for example, as analytical tools or probes in biological
assays.
In the context of the present invention, references herein to "treatment" include references to curative,
palliative and prophylactic treatment.
General Methods
The compounds of formula (I) should be assessed for their biopharmaceutical properties, such as
solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate
dosage form and route of administration for treatment of the proposed indication. They may be
administered alone or in combination with one or more other compounds of the invention or in
combination with one or more other drugs (or as any combination thereof). Generally, they will be
administered as a formulation in association with one or more pharmaceutically acceptable excipients.
The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the
invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-
functional (i.e., processing aid or diluent) characteristic to the formulations. The choice of excipient will
to a large extent depend on factors such as the particular mode of administration, the effect of the
excipient on solubility and stability, and the nature of the dosage form.
Compounds of the invention intended for pharmaceutical use may be administered as a solid or liquid,
such as a tablet, capsule or solution. Pharmaceutical compositions suitable for the delivery of
compounds of the present invention and methods for their preparation will be readily apparent to those
skilled in the art. Such compositions and methods for their preparation may be found, for example, in
Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
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Accordingly, the present invention provides a pharmaceutical composition comprising a compound of
formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
For the treatment of conditions such as retinal vascular permeability associated with diabetic
retinopathy and diabetic macular edema, the compounds of the invention may be administered in a
form suitable for injection into the ocular region of a patient, in particular, in a form suitable for intra-
vitreal injection. It is envisaged that formulations suitable for such use will take the form of sterile
solutions of a compound of the invention in a suitable aqueous vehicle. The compositions may be
administered to the patient under the supervision of the attending physician.
The compounds of the invention may also be administered directly into the blood stream, into
subcutaneous tissue, into muscle, or into an internal organ. Suitable means for parenteral
administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular,
intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices
for parenteral administration include needle (including microneedle) injectors, needle-free injectors and
infusion techniques.
Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous,
excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts,
carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they
may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in
conjunction with a suitable vehicle such as sterile, pyrogen-free water.
Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e.,
polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate),
polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into
the subcutaneous tissue, muscular tissue or directly into specific organs.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may
readily be accomplished using standard pharmaceutical techniques well known to those skilled in the
art.
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The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be
increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents
and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
In one embodiment, the compounds of the invention may be administered orally. Oral administration
may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual,
or sublingual administration by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and
liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing
multi- or nano-particulates, liquids, emulsions or powders; lozenges (including liquid-filled); chews; gels;
fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
Formulations suitable for oral administration may also be designed to deliver the compounds of the
invention in an immediate release manner or in a rate-sustaining manner, wherein the release profile
can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner
which optimises the therapeutic efficacy of the said compounds. Means to deliver compounds in a rate-
sustaining manner are known in the art and include slow release polymers that can be formulated with
the said compounds to control their release.
Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be
used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
Examples of rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose,
methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl
pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
Liquid (including multiple phases and dispersed systems) formulations include emulsions, solutions,
syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for
example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example,
water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more
emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the
reconstitution of a solid, for example, from a sachet.
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The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms
such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman
and L. Lachman (Marcel Dekker, New York, 1980).
For administration to human patients, the total daily dose of the compounds of the invention is typically
in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg
depending, of course, on the mode of administration.
The total dose may be administered in single or divided doses and may, at the physician's discretion, fall
outside of the typical range given herein. These dosages are based on an average human subject having
a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects
whose weight falls outside this range, such as infants and the elderly.
Synthetic Methods
The compounds of the present invention can be prepared according to the procedures of the following
schemes and examples, using appropriate materials, and are further exemplified by the specific
examples provided herein below. Moreover, by utilising the procedures described herein, one of
ordinary skill in the art can readily prepare additional compounds that fall within the scope of the
present invention claimed herein. The compounds illustrated in the examples are not, however, to be
construed as forming the only genus that is considered as the invention. The examples further illustrate
details for the preparation of the compounds of the present invention. Those skilled in the art will
readily understand that known variations of the conditions and processes of the following preparative
procedures can be used to prepare these compounds.
The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts,
such as those described previously herein above.
It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in
intermediates used in the preparation of compounds of the invention to avoid their unwanted
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participation in a reaction leading to the formation of the compounds. Conventional protecting groups,
for example those described by T. W. Greene and P. G. M. Wuts in “Protective groups in organic
chemistry” John Wiley and Sons, 4 Edition, 2006, may be used. For example, a common amino
protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by
treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as
dichloromethane. Alternatively the amino protecting group may be a benzyloxycarbonyl (Z) group
which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere or 9-
fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of secondary organic
amines such as diethylamine or piperidine in an organic solvent. Carboxyl groups are typically protected
as esters such as methyl, ethyl, benzyl or tert-butyl which can all be removed by hydrolysis in the
presence of bases such as lithium or sodium hydroxide. Benzyl protecting groups can also be removed
by hydrogenation with a palladium catalyst under a hydrogen atmosphere whilst tert-butyl groups can
also be removed by trifluoroacetic acid. Alternatively a trichloroethyl ester protecting group is removed
with zinc in acetic acid. A common hydroxy protecting group suitable for use herein is a methyl ether,
deprotection conditions comprise refluxing in 48% aqueous HBr for 1-24 hours, or by stirring with
borane tribromide in dichloromethane for 1-24 hours. Alternatively where a hydroxy group is protected
as a benzyl ether, deprotection conditions comprise hydrogenation with a palladium catalyst under a
hydrogen atmosphere.
Examples of synthetic methods that may be used to prepare 4-carboxyimidazoles are described in EP
1426364 A1 (“Imidazole-derivatives as factor Xa inhibitors”, p27-28).
The compounds according to general formula I can be prepared using conventional synthetic methods
for example but not limited to, the route outlined in Scheme 1. The amine 2 is coupled to an acid 1 to
give the compound 3. This coupling is typically carried out using standard coupling conditions such as
hydroxybenzotriazole and a carbodiimide, such as water soluble carbodiimide, in the presence of an
organic base. Other standard coupling methods include the reaction of acids with amines in the
presence of 2-(1H-benzotriazoleyl)-1,1,3,3-tetramethylaminium hexafluorophosphate, 2-(3H-
[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V),
benzotriazoleyl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphate or bromo-trispyrolidino-
phosphoium hexafluorophosphate in the presence of organic bases such as triethylamine,
diisopropylethylamine or N-methylmorpholine. Alternatively the amide formation can take place via an
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acid chloride in the presence of an organic base. Such acid chlorides can be formed by methods well
known in the literature, for example reaction of the acid with oxalyl chloride or thionyl chloride.
R7 R7
OH N
Y Z Y Z
R6 R6
R5 R5
1 2 3
Scheme 1
Alternatively compounds according to general formula I can be prepared using the route outlined in
Scheme 2a. The acid 4 can be coupled to an amine 2 using suitable coupling methods as previously
described to give compound 5. In a typical second step the nitrogen of the heterocyclic ring is alkylated
with compound 6 to give compound 7. The alkylation can be carried out in the presence of a base such
as potassium carbonate, cesium carbonate, sodium carbonate or sodium hydride in which case the
leaving group is a halide or sulphonate. Alternatively the alkylation may be carried out using an alcohol
under Mitsunobu conditions in the presence of triphenylphosphine.
R7 R7
HN HN
OH N
Y Z Y Z
R6 R6
R5 R5
4 2 5
A LG
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Scheme 2a
In a variation of Scheme 2a compounds according to general formula I can be prepared using the route
outlined in Scheme 2b. Scheme 2b differs from Scheme 2a in that the moiety Y is equal to N therefore a
protecting group strategy may be employed and the synthetic steps carried out in a different order. The
pyrazole carboxylic acid, protected as an ester (PG) as described previously, compound 8, is alkylated
with compound 6. The alkylation can be carried out in the presence of a base such as potassium
carbonate, cesium carbonate, sodium carbonate or sodium hydride in which case the leaving group is a
halide or sulphonate. Alternatively the alkylation may be carried out using an alcohol under Mitsunobu
conditions in the presence of triphenylphosphine. In this case there are two possible nitrogens for the
alkylation to occur at therefore there is the possibility of two regioisomers 9 and 10 being formed.
Compounds 9 and 10 may be separated at this stage or at a subsequent stage in the synthesis using
separation methods well known to those skilled in the art, for example by chromatography or by
fractional crystallisation. The protecting group of compound 9 is removed by hydrolysis to give the
corresponding acid 11 using standard methods as described previously. Compound 11 can be coupled to
an amine 2 using suitable coupling methods as previously described to give compound 12.
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W O O
1 + 1
N Z N Z
A LG
8 6 10
Scheme 2b
Alternatively compounds according to general formula I can be prepared using the route outlined in
Scheme 3. The pyrrole 17 can be formed in two steps the first of which involves reaction of the sodium
salt of an alkyl ketoacetate 13, typically protected with a protecting group (PG) as described previously,
with a chloroketone 14 in the presence of a base such as potassium carbonate to give compound 15
which in a typical second step is reacted with the amine 16 in the presence of an acid such as but not
limited to sulphonic acid derivatives e.g. p-toluenesulphonic acid to yield compound 17 which in a
typical third step is subsequently hydrolysed to the corresponding acid 18 using standard methods as
described previously. In a typical fourth step the acid 18 can be coupled to an amine 2 using suitable
coupling methods as previously described to give compound 19.
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O OPG
O OPG
R7 O
R7 O
13 14 15
A NH
Scheme 3
The amine, compound 2 can be prepared using conventional synthetic methods for example, but not
limited to, the routes outlined in Scheme 4. The nitrile of compound 20 is reduced by standard reducing
agents including but not limited to lithium aluminium hydride, sodium borohydride, sodium borohydride
and nickel chloride, sodium borohydride and cobalt chloride, borane, and catalytic hydrogenation over a
catalyst such as palladium, platinum or Raney nickel. In some cases, for example when the reducing
agent is sodium borohydride or catalytic hydrogenation is employed, it is possible to carry out in situ
protection of the resulting amino group, for example resulting in the carbamate 21, for example tert-
butoxy carbamate. This may be helpful to enable for example purification by chromatography of the
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intermediate compound 21. The protecting group is subsequently removed using standard conditions as
described previously to give compound 2.
Scheme 4
Examples
The invention is illustrated by the following non-limiting examples in which the following abbreviations
and definitions are used:
aq Aqueous solution
DCM Dichloromethane
DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
EtOAc Ethyl Acetate
2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium
HATU
hexafluorophosphate(V)
hrs Hours
HOBt Hydroxybenzotriazole
LCMS Liquid chromatography mass spectrometry
Me Methyl
MeCN Acetonitrile
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MeOH Methanol
Min Minutes
MS Mass spectrum
Nuclear magnetic resonance spectrum – NMR spectra were recorded at a
frequency of 400MHz unless otherwise indicated
Pet. Ether Petroleum ether fraction boiling at 60-80 C
Ph Phenyl
SWFI Sterile water for injection
rt room temperature
THF Tetrahydrofuran
TFA Trifluoroacetic acid
All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.
H NMR spectra were recorded on a Bruker (400MHz) spectrometer with reference to deuterium solvent
and at rt.
Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e
column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCO H/MeCN into 0.1% HCO H/H O over
2 2 2
13 min, flow rate 1.5 mL/min, or using Agilent, X-Select, acidic, 5-95% MeCN/water over 4 min. Data was
collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in
conjunction with a Thermofinnigan Surveyor LC system.
Where products were purified by flash chromatography, ‘silica’ refers to silica gel for chromatography,
0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen up
to 10 p.s.i accelerated column elution. Reverse phase preparative HPLC purifications were carried out
using a Waters 2525 binary gradient pumping system at flow rates of typically 20 mL/min using a Waters
2996 photodiode array detector.
All solvents and commercial reagents were used as received.
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Chemical names were generated using automated software such as the Autonom software provided as
part of the ISIS Draw package from MDL Information Systems or the Chemaxon software provided as a
component of MarvinSketch or as a component of the IDBS E-WorkBook.
A. 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone
4-(Chloromethyl)benzylalcohol (5.0 g, 31.93 mmol) was dissolved in acetone (150 mL). 2-hydroxypyridine
(3.64 g, 38.3 mmol) and potassium carbonate (13.24 g, 95.78 mmol) were added and the reaction mixture
was stirred at 50 °C for 3 hrs after which time the solvent was removed in vacuo and the residue taken up
in chloroform (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (Na SO ) and
evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH / 97%
CHCl3, to give a white solid identified as 1-(4-hydroxymethyl-benzyl)-1H-pyridinone (5.30g, 24.62mmol,
77% yield).
[M+Na] = 238
B1. 1-(4-Chloromethyl-benzyl)-1H-pyridinone
1-(4-Hydroxymethyl-benzyl)-1H-pyridinone (8.45 g, 39.3 mmol), dry DCM (80 mL) and triethylamine
(7.66 ml, 55.0 mmol) were cooled in an ice bath. Methanesulfonyl chloride (3.95 ml, 51.0 mmol) was
added and stirred in ice bath for 15 min. The ice bath was removed and stirring continued at rt
temperature overnight. The reaction mixture was partitioned between DCM (100 mL) and saturated
aqueous NH Cl solution (100 mL). The aqueous layer was extracted with further DCM (2 x 50 mL) and the
combined organics washed with brine (50 mL), dried over Na SO , filtered and concentrated to give 1-(4-
chloromethyl-benzyl)-1H-pyridinone (8.65 g, 36.6 mmol, 93 % yield) as a pale yellow solid.
[MH] = 234.1
B2. 1-(4-Bromomethyl-benzyl)-1H-pyridinone
1-(4-Hydroxymethyl-benzyl)-1H-pyridinone (2.30 g, 6.97 mmol) was dissolved in DCM (250 mL). To this
solution was added phosphorous tribromide (5.78 g, 21.37 mmol). The reaction mixture was stirred at rt
for 18 hrs and diluted with CHCl (250 mL). The filtrate was washed with sat. NaHCO (aq) (30 mL), water
(30 mL), brine (30 mL), dried (Na SO ) and evaporated in vacuo to give a white solid which was identified
as 1-(4-bromomethyl-benzyl)-1H-pyridinone (2.90 g, 10.43 mmol, 98%).
[M+H] = 277.7
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C. Methyl 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylate
Potassium carbonate (519 mg, 3.76 mmol) was added to a solution of methyl 3-(methoxymethyl)-1H-
pyrazolecarboxylate (320 mg, 1.88 mmol; CAS no. 3184961 (synthesised according to the method
described in )) and 1-(4-(chloromethyl)benzyl)pyridin-2(1H)-one (527 mg, 2.26 mmol) in
DMF (5 mL) and heated at 60 °C overnight. The reaction mixture was diluted with EtOAc (50 mL) and
washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered and reduced in vacuo. The crude
product was purified by flash chromatography (40 g column, 0-100% EtOAc in isohexanes) to afford two
regioisomers. The second isomer off the column was collected to afford methyl 3-(methoxymethyl)(4-
((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylate (378 mg, 1.01 mmol, 53.7 % yield) as a
colourless gum.
[MH] = 368.2
D. 3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid
To methyl 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylate
(3.77 g, 10.26 mmol) in THF (5 mL) and MeOH (5 mL) was added 2M NaOH solution (15.39 ml, 30.8 mmol)
and stirred at rt overnight. 1M HCl (50 mL) was added and extracted with EtOAc (50 mL). The organic layer
was washed with brine (50 mL), dried over magnesium sulfate, filtered and reduced in vacuo to give 3-
(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (1.22 g, 3.45
mmol, 33.6 % yield) as a white powder.
[MH] = 354.2
G. [4-(4-Methyl-pyrazolylmethyl)-phenyl]-methanol
4-(Chloromethyl)benzylalcohol (5.47 g, 34.9 mmol) was dissolved in acetone (50 mL). 4-Methylpyrazole
(2.86 g, 34.9 mmol) and potassium carbonate (5.07 g, 36.7 mmol) were added and the reaction mixture
was stirred at rt for 18 hrs and at 60 °C for 30 hrs after which time the solvent was removed in vacuo and
the residue taken up in EtOAc (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried
(MgSO ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent
gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white
solid identified as [4-(4-methyl-pyrazolylmethyl)-phenyl]-methanol (3.94 g, 18.90 mmol, 54% yield).
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[MH] = 203
H. 1-(4-Chloromethyl-benzyl)methyl-1H-pyrazole
[4-(4-Methyl-pyrazolylmethyl)-phenyl]-methanol (2.03 g, 10.04 mmol) and triethylamine (1.13 g, 11.54
mmol) was dissolved in DCM (40 mL). To this solution was added methanesulphonyl chloride (1.26 g, 11.04
mmol) dropwise. The reaction mixture was stirred at rt for 18 hrs and diluted with CHCl (250 mL). The
mixture was washed with saturated NH Cl (30 mL), water (30 mL), brine (30 mL), dried (Na SO ) and
4 2 4
evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 0 to
60% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as
1-(4-chloromethyl-benzyl)methyl-1H-pyrazole (1.49 g, 6.62 mmol, 60% yield).
[MH] = 221, 223
M. 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester
1-(4-Bromomethyl-benzyl)-1H-pyridinone (850 mg, 3.06 mmol) was dissolved in DMF (10 mL). 5-
Amino-1H-pyrazolecarboxylic acid ethyl ester (522 mg, 3.36 mmol) and cesium carbonate (1.99 g,
6.11 mmol) were added and the reaction mixture was stirred at 50 °C for 18 hrs after which time the
reaction mixture was diluted with EtOAc (100 mL). This solution was washed with water (30 mL), brine
(30 mL), dried (Na SO ) and evaporated in vacuo. The residue was purified by flash chromatography
(silica), eluent gradient from 30% Pet Ether / 70% EtOAc to 100% EtOAc, to afford two regioisomers.
The second isomer off the column was collected to afford 3-amino[4-(2-oxo-2H-pyridinylmethyl)-
benzyl]-1H-pyrazolecarboxylic acid ethyl ester (480 mg, 1.36mmol, 45% yield) as a white solid.
[MH] = 353.1
N. 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid
3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester (480 mg,
1.36 mmol) was dissolved in THF (50 mL) and water (5 mL). Lithium hydroxide (16 3mg, 6.81 mmol) was
added. The reaction mixture was stirred at 50 °C for 18 hrs after which time the volatiles were removed
in vacuo and the aqueous residue washed with CHCl (150 mL). The aqueous layer was acidified with 1M
HCl to pH7 and extracted with CHCl (3 x 50 mL). The combined extracts were washed with water (30 mL),
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brine (30 mL), dried (Na SO ) and evaporated in vacuo to give a white solid identified as 3-amino[4-(2-
oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (370 mg, 1.14mmol, 84% yield).
[MH] = 325.2
P. (2-Fluoromethoxy-benzyl)-carbamic acid tert-butyl ester
2-Fluoromethoxybenzonitrile (500 mg, 3.31 mmol) was dissolved in methanol (40 mL). This solution
was cooled to 0 °C. Nickel (II) chloride hexahydrate (79 mg, 0.33 mmol) and di-tertbutyl dicarbonate
(1.44g, 6.62mmol) were added followed by sodium borohydride (876 mg, 23.16 mmol) portionwise. The
reaction mixture was stirred, allowed to warm to rt and stirred for 3 days. The MeOH was removed in
vacuo. The residue was dissolved in CHCl (150 mL), washed with sat NaHCO (aq) (50 mL), water (50mL),
brine (50mL), dried (Na SO ) and evaporated in vacuo. The residue was purified by chromatography
(silica), eluent 20% EtOAc / 80% Pet. Ether, to give a white solid identified as (2-fluoromethoxy-benzyl)-
carbamic acid tert-butyl ester (540 mg, 0.2 mmol, 64% yield).
[MH] = 255.8
Q. 2-Fluoromethoxy-benzylamine hydrochloride
(2-Fluoromethoxy-benzyl)-carbamic acid tert-butyl ester (600 mg, 2.35 mmol) was dissolved in 4M HCl
in dioxan (40 mL). After 2 hrs at rt the solvent was removed in vacuo to give a pale yellow solid identified
as 2-fluoromethoxy-benzylamine hydrochloride (414 mg, 2.17 mmol, 92% yield).
[MH] = 155.9
T. 1-tert-Butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate
To 5-amino-1H-pyrazolecarboxylic acid ethyl ester (250 mg, 1.61 mmol) in DCM (10 mL) was added di-
tert-butyl dicarbonate (352 mg, 1.61 mmol) and diisopropylethylamine (702 µL, 521 mg, 4.03 mmol) and
the reaction stirred at rt overnight. Reaction mixture was diluted with DCM, water added, separated,
washed with brine, dried (MgSO ), filtered and concentrated in vacuo. Flash chromatography afforded 1-
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tert-butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate as a white solid (122 mg, 30% yield).
[MH] = 256.2
U. Ethyl 3-acetamido-1H-pyrazolecarboxylate
A mixture of 1-tert-butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate and acetyl chloride was stirred at 0
°C then heated at reflux for 2 hrs. The excess acetyl chloride was removed in vacuo. Water was added
and the resulting mixture stirred for 18 hrs at rt. The precipitate was collected by vaccum filtration and
dried to afford ethyl 3-acetamido-1H-pyrazolecarboxylate as a white solid (46 mg). The aqueous filtrate
was extracted with DCM (4 x 15 mL) and the combined organic layers were dried (MgSO ), filtered and
concentrated in vacuo to afford a further crop of ethyl 3-acetamido-1H-pyrazolecarboxylate (48 mg)
(overall yield 94 mg, 99 %).
[MH] = 197.8
V. 5-Dimethylamino-1H-pyrazolecarboxylic acid ester
5-Amino-1H-pyrazolecarboxylic acid ester (1.0 g, 6.45 mmol) was dissolved in methanol (200 mL) and
the solution purged with nitrogen. Formaldehyde (37% by weight, 4.5 mL, 21.18 mmol) was added
followed by 10% Pd/C (1.0 g). The reaction mixture was shaked on a Parr hydrogenator at 10 psi for
18hrs. The reaction mixture was filtered through celite to remove the catalyst and the residue washed
with methanol (200 mL) and water (20 mL). The combined filtrates were evaporated in vacuo. The crude
residue was triturated with methanol/diethyl ether and the filtrate concentrated to afford a colourless
oil identified as the title compound (1.1 g, 6.00 mmol, 93% yield).
[MH] = 183.7
Example 1
N-(3,5-Dimethoxybenzyl)(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-
pyrazolecarboxamide
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To a mixture of 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic
acid (80 mg, 0.226 mmol), (3,5-dimethoxyphenyl)methanamine (45.4 mg, 0.272 mmol) and HATU (95 mg,
0.249 mmol) in anhydrous DCM (1.5 mL) and anhydrous DMF (0.3 mL) was added N,N-
diisopropylethylamine (99 µl, 0.566 mmol) and the mixture allowed to stir at rt overnight. The reaction
was concentrated in vacuo and the residue purified by flash chromatography loading in DCM, eluting with
a gradient of 1 to 10% MeOH (containing 0.3% NH3)/DCM to afford a gum. This was dissolved in
acetonitrile (0.5 mL) and water (3 mL) added, forming a precipitate. This was sonicated, then filtered and
dried under vacuum to afford N-(3,5-dimethoxybenzyl)(methoxymethyl)(4-((2-oxopyridin-1(2H)-
yl)methyl)benzyl)-1H-pyrazolecarboxamide (76 mg, 0.150 mmol, 66.1 % yield) as a sticky pale yellow
solid.
NMR (d6-DMSO) δ: 3.20 (3H, s), 3.71 (6H, s), 4.32 (2H, d, J = 5.8Hz), 4.53 (2H, s), 5.07 (2H, s), 5.28 (2H, s),
6.22 (1H, td, J = 6.7, 1.4Hz), 6.37 (1H, t, J = 2.3Hz), 6.40 (1H, dd, J = 9.2, 1.4Hz), 6.44 (2H, d, J = 2.3Hz), 7.20-
7.29 (4H, m), 7.41 (1H, ddd, J = 9.1, 6.6, 2.1Hz), 7.76 (1H, dd, J = 6.8, 2.1Hz), 8.24 (1H, s), 8.32 (1H, t, J =
5.9Hz).
[MH] = 503.3
Example 2
3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 2-fluoro
methoxy-benzylamide
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3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (75 mg, 0.23 mmol)
was dissolved in DCM (20 mL) and DMF (1 ml). This solution was cooled to 0 °C. 2-Fluoromethoxy-
benzylamine hydrochloride (53 mg, 0.28 mmol) was added followed by HOBt (34 mg, 0.25 mmol) and
triethylamine (70 mg, 0.69 mmol). Water soluble carbodiimide (53 mg, 0.28 mmol) was then added. The
reaction mixture was stirred, allowed to warm to rt and stirred for 3 days. The mixture was diluted with
chloroform (200 mL) and washed with NaHCO (aq) (50mL), water (50mL) and brine (50mL), dried (Na SO )
3 2 4
and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 4% MeOH /
96% CHCl , to give a white solid identified as 3-amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-
pyrazolecarboxylic acid 2-fluoromethoxy-benzylamide (92 mg, 0.20 mmol, 86% yield).
[MH] = 462.2
H NMR: (d6-DMSO) δ: 3.82 (3H, s), 4.36 (2H, d, J = 5.7Hz), 5.04 (2H, s), 5.07 (2H, s), 5.38 (2H, s), 6.21-6.24
(1H, m), 6.39 (1H, t, J = 0.7Hz), 6.86-6.87 (1H, m), 7.04-7.07 (2H, m), 7.20 (2H, d, J = 8.1Hz), 7.26 (2H, d, J
= 8.1Hz), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 6.6, 1.6Hz), 8.00 (1H, s), 8.27 (1H, t, J = 5.9Hz).
Example 3
1-(7-Chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid 2-fluoromethoxy-
benzylamide
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(7-Chloro-quinolinyl)-methanol
7-Chloroquinolinecarboxylic acid (500 mg, 2.4 mmol) was dissolved in anhydrous THF (20 mL) and
cooled to -20 °C. To this solution was added triethylamine (1.0 mL, 7.23 mmol) and isobutyl chloroformate
(0.38 mL, 2.9 mmol). The reaction mixture was stirred at -20 °C for 20 min and then poured into a solution
of sodium borohydride (731 mg, 19 mmol) in water (2 mL) at 0 °C. The reaction mixture was allowed to
warm to rt and stirred for 18 hours. The mixture was diluted with EtOAc (50 mL) and the layers separated.
The organic layer was washed with water (20 mL), brine (20 mL), dried (Na SO ), filtered and evaporated
in vacuo to give a yellow solid. The solid was purified by chromatography on silica, eluting with EtOAc/Pet
Ether to afford (7-chloro-quinolinyl)-methanol as an off white solid, 134 mg, 29% yield.
[MH] = 194.1
3-Bromomethylchloro-quinoline
(7-Chloro-quinolinyl)-methanol (134 mg, 0.692 mmol) was dissolved in DCM (5 mL). PBr (65 µL, 0.692
mmol) was added and the reaction stirred for 3 hrs at rt. Upon completion, the reaction mixture was
quenched with dilute NaHCO (aq) (10mL). The layers were separated and the organic washed with water
(10 mL) and brine (10 mL). The organic layer was dried (MgSO ), filtered and concentrated in vacuo to
afford a yellow solid identified as 3-bromomethylchloro-quinoline (78mg, 44% yield).
[MH] = 257.6
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1-(7-Chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid methyl ester
Methyl 3-(methoxymethyl)-1H-pyrazolecarboxylate (51 mg, 0.304 mmol; CAS no. 3184961
(synthesised according to the method described in )) was taken up in DMF (2 mL) and
treated with potassium carbonate (84 mg, 0.608 mmol) and 3-bromomethylchloro-quinoline (78 mg,
0.304 mmol). The reaction was stirred overnight at rt. EtOAc (60 mL) and water (20 mL) were added and
the layers separated. The organic layer was washed with water (3 x 10 mL), brine (10 mL), dried (MgSO ),
filtered and evaporated in vacuo. The residue was purified by chromatography, eluting with EtOAc /
Pet.Ether to afford two isomeric products. The faster running product was identified as the undesired
regioisomer. The slower running product afforded a yellow oil and was identified as 1-(7-chloro-quinolin-
3-ylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid methyl ester (53 mg, 50% yield).
[MH] = 345.8
1-(7-Chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid
To 1-(7-chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid methyl ester (53 mg,
0.153 mmol) in ethanol (10 mL) was added sodium hydroxide (61 mg, 1.53 mmol) and the reaction was
heated at vigorous reflux for 4.5 hrs. The mixture was cooled and concentrated in vacuo. The residue was
diluted with water (5 mL), adjusted to pH 3.6 with 2M HCl and extracted with 90% chlorofrom / 10% iso-
propyl alcohol (6 x 15 mL). The combined organic layers were dried (Na SO ), filtered and concentrated in
vacuo to give 1-(7-chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid as a pale
yellow solid (50 mg, 98% yield).
[MH] = 332
1-(7-Chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid 2-fluoromethoxy-
benzylamide
1-(7-Chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid (25 mg, 0.075 mmol)
was taken up in DCM (5 mL) at 0 °C. To the solution was added triethylamine (52 µL, 0.377 mmol), HOBt
(12 mg, 0.09 mmol) and water soluble carbodiimide (20 mg, 0.106 mmol). After 15 min, 2-fluoro
methoxy-benzylamine hydrochloride (14 mg, 0.075 mmol) was added and the reaction allowed to warm
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to rt and stirred for over the weekend. The reaction was diluted with CHCl (50 ml) and washed with sat.
aq. NaHCO (20 ml) followed by water (20 mL) and brine (20 mL). The organic layer was dried (MgSO ),
filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with 6%
Methanol / 94% DCM to give a white solid (16 mg, 45% yield) identified as 1-(7-chloro-quinolin
ylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid 2-fluoromethoxy-benzylamide.
[MH] = 469
1H NMR (DMSO): 3.20 (3H, s), 3.82 (3H, s), 4.41 (2H, d, J = 5.8 Hz), 4.54 (2H, s), 5.57 (2H, s), 6.87-6.91 (1H,
m), 7.03-7.09 (2H, m), 7.67 (1H, dd, J = 8.8, 2.1 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 1.9 Hz), 8.30
(1H, d, J = 1.7 Hz), 8.37 (1H, s), 8.39 (1H, t, J = 5.8 Hz), 8.92 (1H, d, J = 2.2 Hz)
Example 41
3-Fluoromethoxy-pyridinecarbonitrile
To a large microwave vial, cyanocopper (1.304 g, 14.56 mmol) was added to a solution of 2-bromo
fluoromethoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The reaction vial was sealed and heated to 100
°C for 16 hrs. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension
was sonicated and required additional water (40 mL) and EtOAc (2 x 50 mL) with sonication to break-up
the solid precipitated. The combined layers were filtered through a plug of celite and the organic layer
isolated, washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvent removed
under reduced pressure to give a pale green solid identified as the desired compound 3-fluoromethoxy-
pyridinecarbonitrile (100 mg, 0.578 mmol, 12 % yield)
(3-Fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester
3-Fluoromethoxy-pyridinecarbonitrile (100 mg, 0.578 mmol) was dissolved in anhydrous methanol
(10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added followed by di-tert-
butyl dicarbonate (255 mg, 1.157 mmol). The resulting pale green solution was cooled in an ice-salt bath
to -5 °C and then sodium borohydride (153 mg, 4.05 mmol) was added portionwise maintaining the
reaction temperature ~0 °C. The deep brown solution was left to stir at 0 °C and slowly allowed to warm
to rt and then left to stir at rt for 3 hrs. The reaction mixture was evaporated to dryness at 40 °C to afford
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a black residue which was diluted with DCM (10 mL) and washed with sodium hydrogen carbonate (10
mL). An emulsion formed so the organics were separated via a phase separating cartridge and
concentrated. The crude liquid was purified by chromatography eluting with EtOAc / iso-Hexane to afford
the title compound, (3-fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester as a clear
yellow oil (108 mg, 62 % yield)
[MH] = 257
C-(3-Fluoromethoxy-pyridinyl)-methylamine hydrochloride salt
(3-Fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester (108mg, 0.358mmol) was taken
up in iso-propyl alcohol (1 mL) and then HCl (6N in iso-propyl alcohol) (1 mL, 0.578 mmol) was added at rt
and left to stir at 40 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and
then triturated with ether, sonicated and then decanted to give a cream coloured solid (75 mg, 55% yield)
identified as C-(3-fluoromethoxy-pyridinyl)-methylamine hydrochloride salt.
[MH] = 157
3-Methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (3-fluoro-
4-methoxy-pyridinylmethyl)-amide
3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (75 mg,
0.212 mmol), C-(3-Fluoromethoxy-pyridinyl)-methylamine hydrochloride salt (49 mg, 0.212 mmol)
and HATU (89 mg, 0.233 mmol) were suspended in anhydrous DCM (3 mL) to which triethylamine (177
µL, 1.270 mmol) was added, sonicated and then left to stir at rt for 4 hours. The solvent was removed
under reduced pressure and the resulting residue was quenched with ammonium chloride solution (5 mL).
An off white solid resulted which was sonicated, filtered under reduced pressure washed with water and
then placed in the vac oven at 40 °C overnight. The crude material was purified by chromatography eluting
with (1% ammonia-methanol) /DCM to afford the 3-methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-
benzyl]-1H-pyrazolecarboxylic acid (3-fluoromethoxy-pyridinylmethyl)-amide as a white solid (67
mg, 64% yield)
[MH] = 492
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NMR (d -DMSO) δ: 3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J =
1.4, 6.7Hz), 6.39 (1H, ddd, J = 0.7, 1.4, 9.2Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.75
(1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J = 5.4Hz)
Example 77
6-Bromofluoromethoxy-benzoic acid
To a suspension of 2-fluoromethoxybenzoic acid (10 g, 58.8 mmol) in acetic acid (50 mL) and water (50
mL) at rt was added bromine (6.06 mL, 118 mmol) dropwise. The reaction was then heated to 60 °C for 1
hr. The reaction was cooled to room temperature and the white precipitate was filtered. The solid was
washed with water (200 mL) and iso-Hexane (50 mL) to give 6-bromofluoromethoxy-benzoic acid as
white solid, 12.098 g, 82 % yield.
[MH] = 249/251
(6-Bromofluoromethoxy-phenyl)-methanol
To a stirred solution of 6-bromofluoromethoxy-benzoic acid (4.13 g, 16.58 mmol) in THF (20 mL) was
added 4-methylmorpholine (1.914 mL, 17.41 mmol) and then isobutyl chloroformate (2.15 mL, 16.58
mmol). After 1 hour the reaction mixture was filtered to remove any salts generated, the solid was washed
with additional THF (10 mL). The filtrate and washings were combined and cooled to 0 °C in an ice bath
and then NaBH (0.659 g, 17.41 mmol) in cold water (10 mL) was added in one portion (gas evolved), then
allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched by
careful addition of 1M HCl (30 mL) until acidic pH was obtained. The product was extracted into diethyl
ether (150 mL). The organic layer was then washed with 2M NaOH (2 x 100 mL) to removed starting
carboxylic acid, then acidified by washing with 1M HCl (100 mL), followed by brine (100 mL), dried over
magnesium sulfate, filtered and solvent removed in vacuo. The crude product was purified by
chromatography eluting with 0-50% EtOAc / iso-Hexane to afford (6-bromofluoromethoxy-phenyl)-
methanol as a colourless oil, 1.37g, 50% yield.
[MH] = 217/219
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1-Bromochloromethylfluoromethoxy-benzene
A solution of (6-bromofluoromethoxy-phenyl)-methanol (500 mg, 2.127 mmol) in anhydrous DCM
(4 mL) was treated with triethylamine (415 µL, 2.98 mmol), followed by methanesulfonyl chloride (214
µL, 2.77 mmol). The mixture was allowed to stir at ambient temperature overnight. The reaction mixture
was partitioned between DCM (50 mL) and sat. aq. NH Cl (40 mL). The organic layer was collected and the
aqueous layer extracted with further DCM (40 mL). The combined organics were washed with water (40
mL), brine (40 mL), dried (Na SO ), filtered and concentrated. The crude material was purified by
chromatography eluting with a gradient of 0 to 30% EtOAc/iso-Hexane to afford 1-bromochloromethyl-
3-fluoromethoxy-benzene (468 mg, 86% yield) as a white solid.
2-(6-Bromofluoromethoxy-benzyl)-isoindole-1,3-dione
To a solution of 1-bromochloromethylfluoromethoxy-benzene (460 mg, 1.815 mmol) in
anhydrous DMF (5 mL) was added potassium phthalimide (403 mg, 2.178 mmol) and the mixture heated
at 90 °C overnight. The mixture was diluted with EtOAc (75 mL) and washed with water (3 x 35 mL), brine
(35 mL), dried (Na SO ), filtered and concentrated to a yellow solid. The crude material was purified by
flash chromatography, eluting with a gradient of 0 to 50% EtOAc / iso-Hexane. The desired product 2-(6-
bromofluoromethoxy-benzyl)-isoindole-1,3-dione was isolated as white needles, 372 mg, 56% yield.
[MH] = 364.0/366.0
6-Bromofluoromethoxy-benzylamine
A suspension of 2-(6-bromofluoromethoxy-benzyl)-isoindole-1,3-dione (0.368 g, 1.011 mmol) in
methanol (7.5 mL) was treated with hydrazine hydrate (0.064 mL, 1.314 mmol) and the reaction mixture
heated at reflux for 5 hrs. The crude mixture was loaded directly onto an SCX column (8 g), washed with
MeOH and eluted with 1% NH /MeOH to afford 6-bromofluoromethoxy-benzylamine (204 mg, 85 %
yield) as a yellow oil
[MH] = 233.9/235.9
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3-Methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-bromo-
2-fluoromethoxy-benzylamide
A 25 mL flask was charged with 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-
pyrazolecarboxylic acid (130 mg, 0.368 mmol), (6-bromofluoromethoxy-benzylamine (86 mg,
0.368 mmol), HATU (154 mg, 0.405 mmol), anhydrous DCM (3 mL) and anhydrous DMF (0.5 mL). N,N-
Disopropylethylamine (160 µL, 0.920 mmol) was added and the mixture allowed to stir at ambient
temperature overnight. The reaction was concentrated under vacuum and redissolved in MeOH (4 mL)
then purified by SCX, washing with MeOH, eluting with 1% NH /MeOH. The residue was further purified
chromatography eluting with a gradient of 0 to 10% MeOH (containing 0.3% NH ) / DCM to afford 3-
methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-bromo
fluoromethoxy-benzylamide (191 mg, 89 % yield) as a white foam.
[MH] = 569.2/571.2
3-Methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-cyano
fluoromethoxy-benzylamide
To a degassed solution of dicyanozinc (24.13 mg, 0.205 mmol) and 3-methoxymethyl[4-(2-oxo-2H-
pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-bromofluoromethoxy-benzylamide (90
mg, 0.158 mmol) in dimethylacetamide (1.2 mL) was added tetrakis(triphenylphosphine)palladium(0)
(18.26 mg, 0.016 mmol) and the mixture heated to 110 °C overnight. The mixture was purified by
chromatography eluting with a gradient of 0 to 10% (0.3% NH /MeOH) / DCM to give 3-methoxymethyl-
1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-cyanofluoromethoxy-
benzylamide as a pale yellow foam, 21 mg, 25% yield.
[MH] = 516.3
H NMR (d -DMSO) δ: 3.21 (3H, s), 3.92 (3H, s), 4.47-4.55 (4H, m), 5.06 (2H, s), 5.27 (2H, s), 6.21 (1H, td, J
= 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 7.17-7.31 (5H, m), 7.40 (1H, ddd, J = 8.9, 6.6, 2.1Hz), 7.67 (1H, dd, J =
8.6, 1.5Hz), 7.75 (1H, dd, J = 6.8, 2.1Hz), 8.20 (1H, s), 8.40 (1H, t, J = 5.2Hz)
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Example 83
2-Chlorofluoromethoxy-benzaldehyde
To an ice-salt cooled flask containing methanol (8 mL, 198 mmol) was slowly added sodium hydride (1.318
g, 33.0 mmol). Once the addition was complete the cooling bath was removed and then allowed to warm
to rt. In a second vessel (250 mL flask), 2-chloro-3,6-difluorobenzaldehyde (5 g, 27.5 mmol) was dissolved
in a mixture of anhydrous methanol (60 mL, 1483 mmol) and THF (25 mL, 305 mmol) and warmed to 60
°C. Whilst at 60 °C the sodium methoxide solution was slowly added to the reaction mixture. Once the
addition was complete the reaction mixture was left to heat at 60 °C overnight. The solvent was removed
under reduced pressure to give a bright yellow solid which was quenched with water (100 mL), sonicated
and then left to stir for 30 min. The resulting yellow solid was filtered, washed with water and then left to
dry under reduced pressure before transferring to a vacuum oven at 40 °C overnight. The crude was
purified by chromatography eluting with EtOAc / iso-Hexane to afford the desired compound 2-chloro
fluoromethoxy-benzaldehyde as an off white solid, 3.19 g, 61% yield.
[MH] = 189/191
2-Chlorodifluoromethylfluoromethoxy-benzene
2-Chlorofluoromethoxy-benzaldehyde (2 g, 10.61 mmol) was dissolved in anhydrous DCM (30 mL,
466 mmol) under a nitrogen filled balloon and cooled in a salt-ice bath. To the solution diethylaminosulfur
trifluoride (4.20 mL, 31.8 mmol) was added dropwise to form a yellow solution. The reaction was stirred
at 0 °C for 5 min and then the cooling bath was removed and the reaction allowed to warm to rt overnight.
The reaction mixture was slowly quenched into saturated sodium hydrogen carbonate (100 mL), the
organic layer was separated, washed with brine (100 mL) and dried using a phase separating cartridge.
The solvent was removed under reduced pressure to give an orange oil, which was purified by
chromatography eluting with EtOAc / iso-Hexane. 2-Chlorodifluoromethylfluoromethoxy-
benzene (1.0g, 43% yield) was isolated as a pale yellow oil which solidified on standing.
2-Difluoromethylfluoromethoxy-benzonitrile
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2-Chlorodifluoromethylfluoromethoxy-benzene (1g, 4.75 mmol) was dissolved in anhydrous
dimethylacetamide (7 mL, 74.7 mmol) to which dicyanozinc (0.558 g, 4.75 mmol) was added. Nitrogen
was bubbled into the reaction mixture for 20 min then, tris(dibenzylideneacetone)dipalladium(0) (0.087
g, 0.095 mmol) and [1,1’bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with
dichloromethane (0.139 g, 0.190 mmol) were added. The reaction mixture was heated at 150 °C overnight
under an atmosphere of nitrogen. The reaction mixture was quenched into water (100 mL) and then
extracted with EtOAc (3 x 200 mL). The combined organics were washed with brine (3 x 200 mL), dried
over magnesium sulphate, filtered and evaporated under reduced pressure to give a dark brown oil. The
crude product was purified by chromatography eluting with EtOAc / iso-Hexane to afford 2-
difluoromethylfluoromethoxy-benzonitrile (182 mg, 17 % yield) as a brown solid.
[MH] = 202.1
(2-Difluoromethylfluoromethoxy-benzyl)-carbamic acid tert-butyl ester
2-(Difluoromethyl)fluoromethoxy-benzonitrile (182 mg, 0.778 mmol) was dissolved in anhydrous
methanol (5 mL, 124 mmol) to which Nickel Chloride hexahydrate (19 mg, 0.078 mmol) was added
followed by di-tert-butyl dicarbonate (343 mg, 1.556 mmol). The resulting pale green solution was cooled
in an ice-salt bath to -5 °C and then sodium borohydride (206 mg, 5.45 mmol) was added portionwise,
maintaining the reaction temperature ~0 °C. The deep brown solution was left to stir at 0 °C and slowly
allowed to warm to rt overnight. The solvent was removed under reduced pressure and then partitioned
between DCM (10 mL) and water (10 mL). The aqueous was re-extracted with DCM (2 x 10 mL). The
combined organics were washed brine (10 mL), dried using a phase separating cartridge and concentrated
in vacuo. The crude product was purified by chromatography eluting with EtOAc / iso-Hexane to give (2-
difluoromethylfluoromethoxy-benzyl)-carbamic acid tert-butyl ester as a white waxy solid (158 mg,
63% yield).
[MNa] = 328
2-Difluoromethylfluoromethoxy –benzylamine hydrochloride
(2-Difluoromethylfluoromethoxy-benzyl)-carbamic acid tert-butyl ester (158 mg, 0.492 mmol) was
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taken up in iso-propyl alcohol (1 mL) and then HCl (6N in iso-propyl alcohol) (1 mL, 0.778 mmol) was added
and stirred at 40 °C for 1 hour. An off white precipitate formed and was collected via vacuum filtration
and washed with iso-propyl alcohol (1 mL) to give the desired product 2-difluoromethylfluoro
methoxy–benzylamine hydrochloride as an off white solid (43 mg, 22% yield).
[MH] = 206
3-Methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 2-
difluoromethylfluoromethoxy-benzylamide
3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (58 mg,
0.162 mmol), 2-difluoromethylfluoromethoxy–benzylamine hydrochloride salt (40.2 mg, 0.163
mmol) and HATU (68.3 mg, 0.180 mmol) were suspended in anhydrous DCM (3 mL) to which triethylamine
(91 µL, 0.653 mmol) was added, sonicated and then left to stir at rt for 3 hrs. The solvent was removed
under reduced pressure and the residue quenched with ammonium chloride solution (5 mL), resulting in
a pale brown solid which was left to stir rt over the weekend. The solid was filtered under reduced
pressure washed with water, dried under reduced pressure and then placed in the desiccator at 50 °C for
3 hours. The desired product, 3-,ethoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazole
carboxylic acid 2-difluoromethylfluoromethoxy-benzylamide (74 mg, 83 % yield) was isolated as a
free flowing cream solid.
[MH] = 541.2
NMR (d -DMSO) δ 3.12 (3H, s), 3.83 (3H, s), 4.43 (2H, s), 4.52-4.59 (2H, m), 5.05 (2H, s), 5.25 (2H, s), 6.21
(1H, td, J = 1.4, 6.7Hz), 6.39 (1H, dt, J = 1.0, 9.2Hz), 7.15-7.44 (8H, m), 7.75 (1H, ddd, J = 0.7, 2.1, 6.8Hz),
8.08 (1H, t, J = 4.9Hz), 8.22 (1H, s)
Example 126
5-Bromomethylfluoro-pyridine
2-Fuoromethylpyridine (5.0 g, 45 mmol) was dissolved in 1,2-dichloroethane (120 mL). To this solution
was added N-bromosuccinimide (9.61 g, 54 mmol) and azobisisobutyronitrile (739 mg, 4.5 mmol). The
306761NZDIV
reaction was stirred at reflux (95 °C) for 5 hours then the reaction was cooled to rt. The reaction mixture
was diluted with CHCl (50 mL) and was washed with sat. NaHCO (1 x 20 mL), water (1 x 20 mL), followed
by brine (1 x 20 mL), dried (Na SO ) and filtered through PS paper and evaporated in vacuo. The residue
was purified by chromatography (silica), eluting with 10% EtOAc, 90% Pet. Ether, to give a colourless oil
identified as 5-bromomethylfluoro-pyridine, 5.9g, 69% yield.
[MH] = 191.76
NMR (CDCl3): 4.46 (2H, s), 6.93 (1H, dd, J = 8.4, 3.0 Hz), 7.84 (1H, td, J = 7.8, 2.6 Hz), 8.23 (1H, d, J = 2.2
1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester
Ethyl 3-trifluoromethyl-1H-pyrazolecarboxylate (1.57g, 7.53mmol) was dissolved in DMF (20 mL), 5-
Bromomethylfluoro-pyridine (1.3g, 6.84mmol) and cesium carbonate (6.69g, 20.53mmol) were added.
The reaction mixture was stirred at 50 °C for 18 hours after which time the reaction mixture was diluted
with EtOAc (100 mL), this solution was washed with water (1 x 30 mL), brine (1 x 30 mL), dried (Na SO )
and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography
(silica), eluting with 85% Pet. Ether, 15% EtOAc to give a white foamy solid (1.26 g, 58% yield) identified
as 1-(6-fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester.
[MMeCN] = 358.75
1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid
1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (1.26 g, 3.97
mmol) was dissolved in THF (50 mL) and water (5 mL) then lithium hydroxide (476 mg, 19.86 mmol) were
added. The reaction mixture was stirred at 50 °C for 18 hrs after which time the solvent was concentrated
in vacuo and the residue taken up in EtOAc (50 mL). The aqueous layer was extracted and acidified with
1M HCl to pH2 and extracted with CHCl (3 x 50 mL). The combined extracts were washed with water (1 x
mL) followed by brine (1 x 30 mL), dried (Na SO ) and filtered through PS paper and evaporated in
vacuo. The residue was purified by chromatography (silica), eluting with 3%MeOH, 97% CHCl , to give a
306761NZDIV
colourless oil identified as 1-(6-fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic
acid, 946 mg, 82% yield.
[MH] = 289.82
1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid
1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (300 mg, 1.04
mmol) was dissolved in dioxane (25 mL) and pyrrolidine (2 mL) and the reaction mixture was stirred at 80
°C for 18 hrs. Upon completion the reaction mixture was diluted with EtOAc (100 mL), this solution was
washed with water (1 x 30 mL), brine (1 x 30 mL), dried (Na SO ) and filtered through PS paper and
evaporated in vacuo. The residue was purified by chromatography eluting with 1% AcOH, 9% MeOH, 90%
CHCl to give a white foamy solid (267 mg, 76% yield) identified as 1-(6-pyrrolidinyl-pyridinylmethyl)-
3-trifluoromethyl-1H-pyrazolecarboxylic acid.
MH] = 340.72
1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 2-fluoro
methoxy-benzylamide
2-Fluoromethoxy-benzylamine hydrochloride (56 mg, 0.294 mmol) and 1-(6-pyrrolidinyl-pyridin
ylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (100 mg, 0.294 mmol) were combined and
taken up in DCM (10 mL) at 0 °C. To the solution was added HOBt (48 mg, 0.353 mmol), triethylamine (205
µL, 1.469 mmol) and water soluble carbodiimide (79 mg, 0.411 mmol). The reaction was allowed to warm
to rt and stirred for 3 days. The reaction was diluted with CHCl (50 mL) and sat. aq. NaHCO (20 mL) was
added. The organic layer was separated, dried (MgSO ), filtered and concentrated. The crude product was
purified by chromatography eluting with MeOH / DCM to afford the desired product 1-(6-pyrrolidinyl-
pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 2-fluoromethoxy-benzylamide as
a white solid, 95 mg, 68% yield.
[MH] = 478.0
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H NMR (DMSO) δ: 1.90-1.94 (4H,m), 3.31-3.37 (4H, m), 3.82 (3H, s), 4.39 (2H, d, J = 5.6Hz), 5.26 (2H, s),
6.44 (1H, d, J = 8.6Hz), 6.85-6.90 (1H, m), 7.03-7.10 (2H, m), 7.50 (1H, dd, J = 8.8, 2.4Hz), 8.14 (1H, d, J =
2.3Hz), 8.36 (1H, d, J = 0.6Hz), 8.74 (1H, t, J = 5.8Hz)
Table 1
Example Free Base
[M+H]
R14 R15 R16 R17 18
number MW
4 501.5 501.8
F OMe H H H
483.5 484.1
H OMe H H H
6 497.5 497.6
H OEt H H H
7 537.5 537.8
H OCF H H H
8 467.5 468.1
H H Me H H
9 501.5 501.9
H OMe H H F
513.5 513.8
OMe H OMe H H
11 519.5 520.0
F H OMe H F
12 551.5 551.8
CF3 H OMe H H
13 489.4 490.0
F H H H F
14 505.9 506.0
F H H H Cl
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Example Free Base
[M+H]
R14 R15 R16 R17 18
number MW
539.4 540.0
F H H H CF
16 523.9 523.9
F H Cl H F
17 505.9 506.0
F H Cl H H
18 523.9 523.9
F Cl H H F
19 505.9 505.9
F Cl H H H
505.9 505.8
F H H Cl H
21 573.9 573.8
F Cl H H CF
22 522.4 593.9
Cl H H H Cl
23 555.9 555.8
H H Cl H CF
24 481.5 481.9
Me H Me H H
481.5 481.9
Me H H H Me
26 495.5 496.1
Me H Me H Me
27 485.5 485.9
Me F H H H
28 485.5 486.1
F H Me H H
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Table 2
Example Free Base
R14 R15 [M+H]
number MW
29 472.4 472.9
488.9 488.9
H Cl
Table 3
Free Base
Example number R14 R15 R16 R18 [M+H]
31 511.5 512.0
CF H H H
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Free Base
Example number R14 R15 R16 R18 [M+H]
32 457.5 458.3
H H Me H
33 491.5
F OMe H H
34 500.5
NHCOMe H H H
529.5
F H H CF
36 511.5
H H H CF 512.3
37 511.5
CF H H H 512.0
38 461.5
F H H H
39 457.5 458.3
H H Me H
Table 4
Example
R14 R15 R17 Free Base MW [M+H]
number
40 473.5
H H OMe 474.0
41 491.5 492.0
F OMe H
42 491.5
F H OMe 492.3
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Table 5
Example number R14 R16 Free Base MW
43 483.0
Cl H
44 497.0
Cl Me
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Table 6
Example
A Free Base MW [M+H]
number
45 533.0 533.0
46 496.0 495.9
47 520.0 520.0
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Table 7
Example
R5 R14 R15 R16 R17 R18 Free Base MW [M+H]
number
48 481.5 482.0
CONH H H H H
49 481.5 481.6
H CONH H H H
50 481.5 481.7
H H CONH H H
51 CF3 F H H H CF3 552.4 552.9
52 486.5 486.8
F OMe H H H
53 490.5 491.0
CH OMe F OMe H H H
54 520.6 521.2
CH OMe F OMe H H OMe
55 475.5
NHMe F OMe H H H
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Example
R5 R14 R15 R16 R17 R18 Free Base MW [M+H]
number
56 489.5
NHCH CH F OMe H H H
57 503.6
NHCH(Me) F OMe H H H
58 497.5 497.6
NH H H OCF H H
59 489.5 490.2
NMe F OMe H H H
60 479.5
NH F OMe H H F
61 493.5
NHMe F OMe H H F
62 460.5 461.2
CH OMe F H H H H
63 510.5 511.3
CH OMe CF H H H H
64 490.5 491.3
CH OMe F H H OMe H
65 474.5 475.3
CH OMe F H Me H H
66 508.5 509.0
CH OMe F OMe H H F
67 507.0 507.0
CH OMe H Cl H OMe H
68 492.5 493.0
CH OMe CHF H H H H
69 522.5 523.0
CH OMe CHF OMe H H H
70 499.5 500.0
NH F H H H CF
71 503.5 504.0
NHCOMe F OMe H H H
72 517.6 518.0
NMeCOMe F OMe H H H
73 512.9
513.2
CH OMe F Cl H H F
74 504.6
CH OMe F OMe Me H H
75 497.5
CH OMe CN H H OMe H
76 502.0 502.2
CH OMe CN H H Cl H
77 515.5 516.3
CH OMe F OMe H H CN
78 540.5 541.1
CH OMe CF OMe H H H
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Example
R5 R14 R15 R16 R17 R18 Free Base MW [M+H]
number
79 540.5 541.1
CH OMe CF H H OMe H
80 510.5 511.2
CH OMe CHF H H H F
81 522.5 523.1
CH OMe CHF H H OMe H
82 540.5
CH OMe CHF H H OMe F
83 540.5
541.2
CH OMe CHF OMe H H F
84 507.0
CH OMe Cl H H OMe H
85 503.5 504.3
CH OMe CONH H H H F
86 515.6 516.3
CH2OMe CONH2 H H OMe H
87 486.5 487.1
CH OMe COOH H H H H
88 528.5
CH OMe H H H F
89 528.5
CH OMe H H H F
90 526.5 527.2
CH OMe F OCHF H H H
91 508.5 509.2
CH OMe H OCHF H H H
92 526.5 527.3
CH OMe F H H H OCHF
93 524.5
CH OMe F H Me H CHF
94 478.5 479.0
CH OMe F H H F H
95 490.5 491.3
CH OMe H OMe H F H
96 508.5 509.0
CH OMe F OMe H F H
97 474.5 475.0
CH OMe F H H H Me
98 525.0
CH OMe F OMe H Cl H
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Example
R5 R14 R15 R16 R17 R18 Free Base MW [M+H]
number
99 525.0 525.0
CH OMe F OMe H H Cl
100 558.5
CH OMe F OMe H H CF3
101 542.5
CH OMe F H Me H CF3
102 562.9
CH OMe F H Cl H CF3
103 471.5
CN F OMe H H H
129 476.5 477.0
CH OMe F OH H H H
130 447.5 447.9
NH F OH H H H
131 500.6 501.1
CH OMe COOMe H H H H
132 488.6 489.3
CH OMe F CH Me H H H
133 472.5 473.1
CH OMe H OMe H H H
Table 8
Free
Example
A R5 R18 Base [M+H]
number
104 491.5
CH OMe H 492.0
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Free
Example
A R5 R18 Base [M+H]
number
105 526.5
CH OMe F
106 522.5
CH OMe F 523.0
107 508.5
CH OMe H
108 526.5
CH OMe F 527.0
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Free
Example
A R5 R18 Base [M+H]
number
109 552.6
CH OMe F 553.0
110 507.6
CH OMe H
111 482.5
CH OMe H
112 496.6
CH OMe H
113 448.5
NH H
134 502.5
CH OMe CN
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Free
Example
A R5 R18 Base [M+H]
number
135 479.5
CH OMe CN
136 503.5
CF CN
114 508.5
CH OMe H
115 525.0
CH OMe H
116 444.5
CH2OMe F
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Free
Example
A R5 R18 Base [M+H]
number
117 431.4
CH OMe H
118 465.4
CH OMe H
119 467.4
CH OMe H
306761NZDIV
Table 9
Example Free Base
R5 [M+H]
number MW
121 460.5 461.0
122 461.5
123 486.5
124 514.5 515.0
125 490.5
CH OMe
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Table 10
Example
R5 R18 Free Base MW [M+H]
number
126 H 477.5 478.0
127 H 424.5
128 H 453.5
CH OMe
137 CN 478.5
CH2OMe
138 CN 502.5
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Table 11
Example
T Free Base MW [M+H]
number
139 519.0 519.1
140 505.0 505.1
Table 12: Compound names
Example
Name
Number
N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(3-methoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide
N-[(3-ethoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide
1-({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-N-{[3-
(trifluoromethoxy)phenyl]methyl}(trifluoromethyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
N-[(4-methylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)
(trifluoromethyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(2,4-dimethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-{[4-methoxy(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(2,6-difluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide
N-[(2-chlorofluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(4-chloro-2,6-difluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(4-chlorofluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(3-chloro-2,6-difluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(3-chlorofluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(5-chlorofluorophenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-{[3-chlorofluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
N-[(2,6-dichlorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide
N-{[5-chloro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(2,4-dimethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide
N-[(2,6-dimethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide
1-({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)(trifluoromethyl)-N-[(2,4,6-
trimethylphenyl)methyl]pyrazolecarboxamide
N-[(3-fluoromethylphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(2-fluoromethylphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
N-[(3-fluoropyridinyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide
N-[(4-chloropyridinyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazolecarboxamide
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[4-
(trifluoromethyl)pyridinyl]methyl}pyrazolecarboxamide
3-(methoxymethyl)-N-[(6-methylpyridinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(4-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(4-acetamidopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[4-fluoro(trifluoromethyl)pyridinyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[2-
(trifluoromethyl)pyridinyl]methyl}pyrazolecarboxamide
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[4-
(trifluoromethyl)pyridinyl]methyl}pyrazolecarboxamide
N-[(4-fluoropyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-(methoxymethyl)-N-[(6-methylpyridinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-(methoxymethyl)-N-[(6-methoxypyridinyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-chlorothiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-chloromethylthiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl){[6-(pyrrolidin
yl)pyridinyl]methyl}pyrazolecarboxamide
N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl)({4-[(4-
methylpyrazolyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-carbamoylphenyl)methyl]cyclopropyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-carbamoylphenyl)methyl]cyclopropyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
N-[(4-carbamoylphenyl)methyl]cyclopropyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide
3-cyclopropyl-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoro-3,6-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methylamino)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-(ethylamino)-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](isopropylamino)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-amino({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[4-
(trifluoromethoxy)phenyl]methyl}pyrazolecarboxamide
3-(dimethylamino)-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl](methylamino)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[2-
(trifluoromethyl)phenyl]methyl}pyrazolecarboxamide
306761NZDIV
Example
Name
Number
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-chloromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-(difluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
3-amino-N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-acetamido-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](N-methylacetamido)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-chloro-2,6-difluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethoxymethylphenyl)methyl](methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(5-chlorocyanophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
N-{[3-methoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[5-methoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-(difluoromethyl)fluorophenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[6-(difluoromethyl)fluoromethoxyphenyl]methyl}(methoxymethyl)({4-
[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-(difluoromethyl)fluoromethoxyphenyl]methyl}(methoxymethyl)({4-
[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-chloromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-carbamoylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-carbamoylmethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
2-({[3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazol
yl]formamido}methyl)benzoic acid
N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[3-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[3-(difluoromethoxy)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
N-{[2-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-(difluoromethyl)fluoromethylphenyl]methyl}(methoxymethyl)({4-
[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2,5-difluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(3-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2,5-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin-
1-yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(5-chlorofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(6-chlorofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-fluoromethoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-
[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[2-fluoromethyl(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-
[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
N-{[4-chlorofluoro(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-
[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
3-cyano-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluorohydroxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-amino-N-[(2-fluorohydroxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
methyl 2-({[3-(methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolyl]formamido}methyl)benzoate
N-[(3-ethylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyrazin
yl)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(4-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(4-methyl
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
1-({4-[(5-fluorooxopyridinyl)methyl]phenyl}methyl)-N-[(2-fluoro
methoxyphenyl)methyl](methoxymethyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(5-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(4-ethoxyoxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl]({4-[(5-methoxymethylpyrazol
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[5-(2-oxopyridin
yl)thiophenyl]methyl}pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin
yl)methyl]thiophenyl}methyl)pyrazolecarboxamide
3-amino-N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazol
yl)methyl]phenyl}methyl)pyrazolecarboxamide
3-methoxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazole
carboxylic acid 6-cyanofluoromethoxy-benzylamide
306761NZDIV
Example
Name
Number
3-methoxymethyl(2-pyrrolidinyl-pyrimidinylmethyl)-1H-pyrazole
carboxylic acid 6-cyanofluoromethoxy-benzylamide
1-(2-pyrrolidinyl-pyrimidinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic
acid 6-cyanofluoromethoxy-benzylamide
N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-fluorooxopyridin
yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide
1-({4-[(2-chlorooxopyridinyl)methyl]phenyl}methyl)-N-[(2-fluoro
methoxyphenyl)methyl](methoxymethyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({2-
[(methylamino)methyl]phenyl}methyl)pyrazolecarboxamide
N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl){[2-
(methylamino)pyridinyl]methyl}pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[2-(2,2,2-
trifluoroethyl)phenyl]methyl}pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[2-
(trifluoromethoxy)phenyl]methyl}pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl]methyl({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide
2-amino-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide
2-cyclopropyl-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)(trifluoromethyl)imidazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin
yl)methyl]phenyl}methyl)imidazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl]{[6-(pyrrolidinyl)pyridinyl]methyl}
(trifluoromethyl)pyrazolecarboxamide
306761NZDIV
Example
Name
Number
3-amino-N-[(2-fluoromethoxyphenyl)methyl]{[6-(pyrrolidinyl)pyridin
yl]methyl}pyrazolecarboxamide
N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl){[6-(pyrrolidin
yl)pyridinyl]methyl}pyrazolecarboxamide
3-methoxymethyl(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic
acid 6-cyanofluoromethoxy-benzylamide
1-(6-pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic
acid 6-cyanofluoromethoxy-benzylamide
3-amino-N-[(7-chloromethyl-2,3-dihydro-1,4-benzoxazinyl)methyl]({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
3-amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazinyl)methyl]({4-[(2-
oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide
Table 13: NMR data of examples (solvent d6 DMSO)
Example
Chemical shift
Number
1.98 (3H, s), 3.82 (3H, s), 4.39 (2H, d, J = 5.7Hz), 5.22 (2H, s), 5.40 (2H, s), 6.86-6.90
4 (1H, m), 7.04-7.10 (2H, m), 7.19-7.29 (5H, m), 7.53 (1H, s), 8.43 (1H, s), 8.74 (1H, t, J =
.7Hz)
1.87 (3H, s), 3.72 (3H, s), 4.35 (2H, d, J =5.9Hz), 5.22 (2H, s), 5.41 (2H, s), 6.80-6.86 (3H,
m), 7.20 (2H, d, J =8.2Hz), 7.23-7.29 (4H, m), 7.53 (1H, s), 8.42 (1H, s), 8.75 (1H, br. s)
306761NZDIV
Example
Chemical shift
Number
1.30 (3H, t, J = 6.9Hz), 1.98 (3H, s), 3.99 (2H, q, J = 7.0Hz), 4.34 (2H, d, J = 5.9Hz), 5.22
6 (2H, s), 5.41 (2H, s), 6.78-6.84 (3H, m), 7.19-7.27 (6H, m), 7.53 (1H, s), 8.43 (1H, s), 8.75
(1H, t, J = 5.8Hz)
1.98 (3H, s), 4.42 (2H, d, J = 6.0Hz), 5.22 (2H, s), 5.41(2H, s), 7.19-7.33 (8H,m), 7.46
(1H, t, J = 7.7Hz), 7.53 (1H, s), 8.43 (1H, s), 8.86 (1H, t, J = 5.9Hz)
1.98 (3H, s), 2.27 (3H, s), 4.32 (2H, d, J = 5.8 Hz), 5.22 (2H, s), 5.40 (2H, s), 7.11-7.23
(9H, m), 7.54 (1H, s), 8.42 (1H, s), 8.75 (1H, t, J = 5.9 Hz)
1.98 (3H, s), 3.70 (3H, s), 4.37 (2H, d , J = 5.7Hz), 5.23 (2H, s), 5.41 (2H, s), 6.84-6.87
9 (2H, m), 7.09-7.13 (1H, m), 7.21-7.29 (5H, m), 7.54 (1H, s), 8.44 (1H, s), 8.77 (1H, t, J =
.7Hz)
1.98 (3H, s), 3.74 (3H, s), 3.78 (3H, s), 4.25 (2H, d, J = 5.6Hz), 5.23 (2H, s), 5.40 (2H, s),
6.47 (1H, dd, J = 8.4, 2.4Hz), 6.54 (1H, d, J = 2.3Hz), 7.09 (1H, d, J = 8.3Hz), 7.20 (2H, d, J
= 8.2Hz), 7.24 (1H, s), 7.28 (2H, d, J = 8.1Hz), 7.54 (1H, s), 8.44 (1H, d, J = 0.6), 8.51 (1H,
t, J = 5.6Hz)
1.98 (3H, s), 3.77 (3H, s), 4.33 (2H, d, J= 5.0Hz), 5.22 (2H, s), 5.38 (2H, s), 6.74 (2H, d, J=
11 9.7Hz), 7.19 (2H, d, J = 8.1Hz), 7.24 (2H, d, J = 3.7Hz), 7.26 (1H, s), 7.54 (1H, s), 8.37
(1H, s), 8.55 (1H, t, J = 5.0Hz)
1.98 (3H, s), 3.81 (3H, s), 4.47 (2H, d, J = 5.2Hz), 5.23 (2H, s), 5.42 (2H, s), 7.20-7.24
12 (5H, m), 7.29 (2H, d, J = 8.0Hz), 7.44 (1H, d, J = 8.2Hz), 7.54 (1H, s), 8.46 (1H, s), 8.78
(1H, t, J = 4.8Hz)
1.98 (3H, s), 4.42 (2H, d, J = 5.1Hz), 5.22 (2H, s), 5.38 (2H, s), 7.06-7.09 (2H, m), 7.10-
13 7.13 (2H, m), 7.18-7.26 (3H, m), 7.37-7.44 (1H, m), 7.54 (1H, s), 8.38 (1H, s), 8.65 (1H, t,
J = 5.1Hz)
1.98 (3H, s), 4.49-4.50 (2H, m), 5.21 (2H, s), 5.38 (2H, s), 7.18 (2H, d, J = 8.2Hz), 7.23-
7.27 (4H, m), 7.34-7.43 (2H, m), 7.54 (1H, s), 8.38 (1H, s), 8.55 (1H, t, J = 4.8Hz)
1.98 (3H, s), 4.52 (2H, d, J = 3.9Hz), 5.21 (2H,s), 5.38 (2H, s), 7.18 (2H, d, J = 8.1Hz),
7.23-7.25 (3H, m), 7.53 (1H, s), 7.58-7.63 (3H, m), 8.35 (1H, s), 8.51 (1H, t, J= 4.3Hz)
1.98 (3H, s), 4.38 (2H, d, J = 5.1Hz), 5.22 (2H, s), 5.39 (2H, s), 7.18 (1H, s), 7.20 (1H, s),
16 7.24 (2H, d, J = 4.5Hz), 7.27 (1H, s), 7.38 (2H, d, J = 7.4Hz), 7.54 (1H, s), 8.36 (1H, s),
8.67 (1H, t, J = 5.1Hz)
306761NZDIV
Example
Chemical shift
Number
1.98 (3H, s), 4.38 (2H, d, J = 5.6Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19 (1H, s), 7.21 (1H, s),
17 7.24 (1H, s), 7.26-7.29 (3H, m), 7.37 (1H, t, J = 8.2Hz), 7.43 (1H, dd, J = 10.0, 2.0Hz),
7.55 (1H, s), 8.44 (1H, s), 8.82 (1H, t, J = 5.8Hz)
1.98 (3H, s), 4.44 (2H, d, J = 5.2 Hz), 5.22 (2H, s), 5.39 (2H, s), 7.18-7.27 (6H, m), 7.53
(1H, s), 7.58-7.62 (1H, m), 8.46 (1H, s), 8.71 (1H, t, J = 5.2Hz)
1.98 (3H, s), 4.44 (2H, d, J = 5.6Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19-7.23 (4H, m), 7.27-
7.32 (3H, m), 7.47-7.51 (1H, m), 7.53 (1H, s), 8.44 (1H,s), 8.82 (1H, t, J= 5.6Hz)
1.98 (3H, s), 4.39 (2H, d, J = 5.7Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19-7.30 (6H, m), 7.36-
7.40 (2H, m), 7.54 (1H, s), 8.45 (1H, s), 8.80 (1H, t, J = 5.7Hz)
1.98 (3H, s), 4.56 (2H, d, J = 3.7 Hz), 5.21 (2H, s), 5.39 (2H, s), 7.19 (2H, d, J = 8.1Hz),
21 7.24 (2H, d, J = 2.8Hz), 7.26 (1H, s), 7.53 (1H, s), 7.65 (1H, d, J = 8.6Hz), 7.82 (1H, t, J =
7.8Hz), 8.35 (1H, s), 8.54 (1H, t, J = 4.2Hz)
1.98 (3H, s), 4.61 (2H, d, J = 4.4Hz), 5.21 (2H, s), 5.38 (2H, s), 7.18 (2H, d, J = 8.2Hz),
22 7.22-7.26 (3H, m), 7.38-7.40 (1H, m), 7.49-7.53 (3H, m), 8.38 (1H, s), 8.45 (1H, t, J=
4.3Hz)
1.98 (3H, s), 4.54 (2H, d, J = 5.6Hz), 5.23 (2H, s), 5.44 (2H, s), 7.20-7.24 (3H, m), 7.30
23 (2H, d, J = 8.1Hz), 7.53 (2H, d, J = 5.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.77 (1H, d, J = 8.4Hz),
8.49 (1H, s), 8.90 (1H, t, J = 5.8Hz)
1.98 (3H, s), 2.24 (6H, s), 4.31 (2H, d, J = 5.6 Hz), 5.22 (2H, s), 5.40 (2H, s), 6.95 (1H, d, J
24 = 7.7 Hz), 6.98 (1H, s), 7.10 (1H, d, J = 7.6 Hz), 7.18-7.29 (5H, m), 7.54 (1H, s), 8.44 (1H,
s), 8.60 (1H, t, J = 5.6 Hz)
1.97 (3H, s), 2.31 (6H, s), 4.38 (2H, d, J = 4.7 Hz), 5.21 (2H, s), 5.36 (2H, s), 7.01 (1H, s),
7.03 (1H, s), 7.07-7.11 (1H, m), 7.16 (1H, s), 7.18 (1H, s), 7.23 (2H, d, J = 3.5 Hz), 7.25
(1H, s), 7.53 (1H, s), 8.26 (1H, t, J = 5.0 Hz), 8.38 (1H, s)
1.97 (3H, s), 2.20 (3H, s), 2.26 (6H, s), 4.34 (2H, d, J = 4.8Hz), 5.21 (2H, s), 5.36 (2H, s),
26 6.84 (2H, s), 7.17 (2H, d, J = 8.1Hz), 7.23-7.25 (3H, m), 7.53 (1H, s), 8.20 (1H, t, J =
4.7Hz), 8.38 (1H, s)
1.98 (3H, s), 2.19 (3H, d, J = 1.7Hz), 4.38 (2H, d, J = 5.6Hz), 5.22 (2H, s), 5.40 (2H, s),
7.04-7.09 (2H, m), 7.16-7.29 (6H, m), 7.53 (1H, s), 8.44 (1H, s), 8.68 (1H, t, J = 5.2Hz)
306761NZDIV
Example
Chemical shift
Number
1.98 (3H, s), 2.29 (3H, s), 4.35 (2H, d, J = 5.7 Hz), 5.23 (2H, s), 5.40 (2H, s), 6.98 (1H, d, J
28 = 8.1 Hz), 7.01 (1H, d, J = 11.6 Hz), 7.19-7.22 (3H, m), 7.24 (1H, s), 7.27 (1H s), 7.29 (1H,
s), 7.55 (1H, s), 8.44 (1H, s), 8.75 (1H, t, J = 5.7 Hz)
1.99 (3H, s), 4.55 (2H, dd, J = 5.5, 1.4Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19-7.24 (3H, m),
29 7.28 (2H, d, J= 8.2Hz), 7.38-7.43 (1H, m), 7.54 (1H, s), 7.67-7.72 (1H, m), 8.36-8.38 (1H,
m), 8.44 (1H, s), 8.76 (1H, t, J = 4.2Hz)
1.99 (3H, s), 4.49 (2H, d, J = 5.9Hz), 5.24 (2H, s), 5.43 (2H, s), 7.20-7.25 (3H, m), 7.30-
7.31 (2H, m), 7.49-7.50 (2H, m), 7.55 (1H, s), 8.52 (2H, d, J = 5.8Hz), 8.97 (1H, d, J=
.9Hz)
3.20 (3H, m), 4.53 (2H, d, J = 2.9Hz), 4.59 (2H, d, J = 5.2Hz), 5.06 (2H, s), 5.30 (2H, s),
31 6.19-6.27 (1H, m), 6.40 (1H, d, J = 9.2Hz), 7.18-7.34 (4H, m), 7.36-7.47 (1H, m), 7.76
(2H, t, J = 6.4Hz), 8.24-8.37 (1H, s), 8.54 (1H, s), 8.74-8.86 (2H, m)
2.73 (3H, s), 3.22 (3H, s), 4.46 - 4.58 (4H, m), 5.08 (2H, s), 5.30 (2H, s), 6.20 - 6.27 (1H,
m), 6.40 (1H, d, J = 9.1Hz), 7.20 - 7.32 (4H, m), 7.42 (1H, ddd, J = 2.1, 6.6, 8.8Hz), 7.78
(1H, dd, J = 1.5, 6.8Hz), 7.88 (1H, d, J = 8.3Hz), 8.30 (1H, s), 8.39 (1H, dd, J = 2.0, 8.3Hz),
8.64 - 8.76 (2H, m)
3.21 (3H, s), 4.54 (2H, s), 4.58 (2H, d, J = 5.7Hz), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H, td, J
= 6.7, 1.4Hz), 6.39 (1H, d, J = 9.2Hz), 7.20-7.31 (4H, m), 7.41 (1H, ddd, J = 8.9, 6.6,
2.1Hz), 7.70 (1H, dd, J = 7.9, 4.7Hz), 7.76 (1H, dd, J = 6.8, 2.1Hz), 7.97 (1H, d, J = 7.8Hz),
8.28 (1H, s), 8.50 (1H, t, J = 5.8Hz), 8.62 (1H, d, J = 4. 9Hz)
3.20 (3H, m ), 4.53 (2H, d, J = 2.9Hz), 4.59 (2H, d, J = 5.2Hz), 5.06 (2H, s), 5.30 (2H, s),
37 6.19-6.27 (1H, m), 6.40 (1H, d, J = 9.2Hz), 7.18-7.34 (4H, m), 7.36-7.47 (1H, m), 7.76
(2H, t, J = 6.4Hz), 8.24-8.37 (1H, s), 8.54 (1H, s), 8.74-8.86 (2H, m)
2.73 (3H, s), 3.22 (3H, s), 4.46 - 4.58 (4H, m), 5.08 (2H, s), 5.30 (2H, s), 6.20 - 6.27 (1H,
m), 6.40 (1H, d, J = 9.1Hz), 7.20 - 7.32 (4H, m), 7.42 (1H, ddd, J = 2.1, 6.6, 8.8Hz), 7.78
(1H, dd, J = 1.5, 6.8Hz), 7.88 (1H, d, J = 8.3Hz), 8.30 (1H, s), 8.39 (1H, dd, J = 2.0, 8.3Hz),
8.64 - 8.76 (2H, m)
3.21 (3H, s), 3.83 (3H, s), 4.40 (2H, d, J = 5.8Hz), 4.55 (2H, s), 5.07 (2H, s), 5.30 (2H, s),
6.22 (1H, dt, J = 1.4, 6.6Hz), 6.40 (1H, ddd, J = 0.7, 1.4, 9.1Hz), 6.67 (1H, dd, J = 0.8,
40 8.2Hz), 6.88 (1H, dd, J = 0.8, 7.3Hz), 7.22-7.29 (4H, m), 7.41 (1H, ddd, J = 2.1, 6.6,
9.2Hz), 7.65 (1H, dd, J = 7.3, 8.2Hz), 7.76 (1H, ddd, J = 0.8, 2.1, 6.8Hz), 8.28 (1H, s),
8.42 (1H, t, J = 5.8Hz)
306761NZDIV
Example
Chemical shift
Number
3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J =
1.4, 6.7 Hz), 6.39 (1H, ddd, J = 0.7, 1.4, 9.2 Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J =
2.1, 6.6, 8.9 Hz), 7.75 (1H, ddd, J = 0.7, 2.1, 6.8 Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J =
.4 Hz)
3.21 (3H, s), 3.79 (3H, s), 4.49 (2H, dd, J = 2.0, 5.5Hz), 4.54 (2H, s), 5.07 (2H, s), 5.29
(2H, s), 6.23 (1H, td, J = 1.4, 6.7Hz), 6.38 - 6.43 (1H, m), 6.77 (1H, dd, J = 3.0, 8.9Hz),
7.20 - 7.25 (2H, m), 7.25 - 7.30 (2H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.65 (1H, t, J
= 8.9Hz), 7.76 (1H, dd, J = 1.5, 6.8Hz), 8.26 (1H, s), 8.31 (1H, t, J = 5.5Hz)
3.17 (3H, s), 4.53 (2H, s), 4.61 (2H, d, J = 5.7Hz), 5.06 (2H, s), 5.27 (2H, s), 6.21 (1H, dt, J
= 6.8, 1.3Hz), 6.39 (1H, d, J = 9.3Hz), 7.22 (2H, d, J = 8.2Hz), 7.26 ( 2H, d, J = 8.3Hz),
7.38-7.42 (2H, m), 7.69 (1H, s), 7.75 (1H, dd, J = 6.8, 1.8Hz), 7.99 (1H, d, J = 2.0Hz), 8.02
(1H, d, J = 8.6Hz), 8.22 (1H, s), 8.36-8.43 (1H, m)
1.91-1.93 (4H, m), 3.19 ( 3H, s), 3.31-3.36 (4H, m), 4.54 (2H, s), 4.61 (2H, d, J = 5.7Hz),
.12 (2H, s), 6.40 (1H, d, J = 8.7Hz), 7.40 (1H, dd, J = 8.6, 2.0Hz), 7.43 (1H, dd, J = 8.7,
2.4Hz), 7.68 (1H, s), 7.98 (1H, d, J = 2.0Hz), 8.01 (1H, s), 8.03 (1H, s), 8.08 (1H, d, J =
2.2Hz), 8.14 (1H, s), 8.38 (1H, t, J = 5.2Hz)
1.98 (3H, s), 3.17 (3H, s), 4.53 (2H, s), 4.61 (2H, d, J = 5.6Hz), 5.20 (2H, s), 5.27 (2H, s),
7.17 (2H, d, J = 8.2Hz), 7.21 (2H, d, J = 8.2Hz), 7.22 (1H, s), 7.41 (1H, dd, J = 8.6, 2.0Hz),
7.52 (1H, s), 7.69 (1H, s), 7.99 (1H, d, J = 2.0Hz), 8.03 (1H, d, J = 8.6Hz), 8.22 (1H, s),
8.40 (1H, t, J = 5.7Hz)
0.72-0.75 (2H, m), 0.80-0.84 (2H, m), 2.50-2.55 (1H, m), 4.52 (2H, d, J = 5.9Hz), 5.06
(2H, s), 5.19 (2H, s), 6.21-6.25 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.18 (2H, d, J = 8.2Hz),
7.25 (2H, d, J = 8.2Hz), 7.27-7.30 (1H, m), 7.35-7.49 (4H, m), 7.77 (1H, dd, J = 1.9,
6.8Hz), 7.80 (1H, s), 7.98 (1H, s), 8.14 (1H, s), 8.31 (1H, t, J = 6.0Hz)
0.72-0.76 (2H, m), 0.79-0.84 (2H, m), 2.52-2.64 (1H, m), 4.40 (2H, d, J = 5.9Hz), 5.06
(2H, s), 5.19 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 8.8Hz), 7.18 (2H, d, J = 8.2Hz),
7.25 (2H, d, J = 8.1Hz), 7.38-7.44 (4H, m), 7.72-7.77 (2H, m), 7.80 (1H, s), 7.95 (1H, s),
8.11 (1H, s), 8.40 (1H, t, J = 5.9Hz)
0.73-0.76 (2H, m), 0.79-0.84 (2H, m), 2.57-2.62 (1H, m), 4.41 (2H, d, J = 5.9Hz), 5.07
(2H, s), 5.19 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, d, J = 8.8Hz), 7.18 (2H, d, J = 8.2Hz),
7.25 (2H, d, J = 8.1Hz), 7.27-7.35 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 1.9,
6.5Hz), 7.81 (1H, d, J = 8.2Hz), 7.91 (1H, s), 8.11 (1H, s), 8.20 (1H, t, J = 6.0Hz)
306761NZDIV
Example
Chemical shift
Number
4.52 (2H, d, J = 3.9Hz), 5.06 (2H, s), 5.31 (2H, s), 6.20-6.24 (1H, m), 6.38 (1H, t, J =
51 9.0Hz), 7.26 (4H, s), 7.39-7.45 (1H, m), 7.63 (3H, t, J = 2.0Hz), 7.76 (1H, dd J = 4.8,
1.9Hz), 8.35 (1H, s), 8.51 (1H, t, J = 4.5Hz)
0.72-0.75 (2H, m), 0.79-0.82 (2H, m), 2.56-2.62 (1H, m), 3.82 (3H, s), 4.39 (2H, d, J =
.7Hz), 5.06 (2H, s), 5.18 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, d, J = 8.9Hz), 6.86-6.90
(1H, m), 7.04-7.07 (2H, m), 7.18 (2H, d, J = 8.1Hz), 7.25 (2H, d, J = 8.1Hz), 7.39-7.43
(1H, m), 7.76 (1H, q, J = 5.1Hz), 8.12 (1H, s), 8.35 (1H, t, J = 5.9Hz)
3.2 (3H, s), 3.82 (3H, s), 4.41 (2H, d, J = 5.6Hz), 4.52 (2H, s), 5.07 (2H, s), 5.28 (2H, s),
6.22 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.8Hz), 6.86-6.90 (1H, m), 7.05-7.10 (2H,
m), 7.22-7.27 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 6.8, 1.9Hz), 8.24 (1H, s), 8.34
(1H, t, J = 5.7Hz)
3.16 (3H, s), 3.77 (6H, d, J = 1.8Hz), 4.39 (2H, dd, J = 1.6, 5.2Hz), 4.45 (2H, s), 5.05 (2H,
s), 5.25 (2H, s), 6.21 (1H, td, J = 1.4, 6.7Hz), 6.36-6.40 (1H, m), 6.76 (1H, dd, J = 1.7, 9.1
Hz), 7.05 (1H, t, J = 9.4Hz), 7.17-7.27 (4H, m); 7.40 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.74
(1H, dd, J = 2.1, 6.8Hz), 7.95 (1H, t, J = 5.1Hz), 8.21 (1H, s)
4.36 (2H, d, J = 5.9Hz), 5.04 (2H, s), 5.07 (2H, s), 5.37 (2H, s), 6.21-6.24 (1H, m), 6.39
58 (1H, d, J = 9.1Hz), 7.20 (2H, d, J = 8.1Hz), 7.26 (2H, d, J = 8.1Hz), 7.27-7.31 (2H, m),
7.38-7.43 (3H, m), 7.76 (1H, dd, J = 2.0, 6.8Hz), 7.97 (1H, s), 8.35 (1H, t, J = 5.9Hz)
2.72 (6H, s), 3.82 (3H, s), 4.41 (2H, d, J = 5.6Hz), 5.07 (2H, s), 5.17 (2H, s), 6.21-6.25 (1H,
59 m), 6.40 (1H, d, J = 8.8Hz), 6.86-6.89 (1H, m), 7.04-7.07 (2H, m), 7.21-7.25 (4H, m),
7.39-7.41 (1H, m), 7.76 (1H, dd, J = 6.9, 1.6Hz), 8.07 (1H, s), 8.35 (1H, t, J = 5.8Hz)
3.20 (3H, s), 4.42 (2H, J = 5.7Hz), 4.53 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J =
62 6.7, 1.4Hz), 6.39 (1H, d, J = 9.2Hz), 7.13-7.38 (8H, m), 7.41 (1H, ddd, J = 8.9, 6.6, 2.1Hz),
7.76 (1H, dd, J = 6.8, 2.1Hz), 8.25 (1H, s), 8.35 (1H, t, J = 5.8Hz)
3.20 (3H, s), 4.53 (2H, s), 4.57 (2H, d, J = 5.7Hz), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H, td, J
= 6.7, 1.4Hz), 6.40 (1H, d, J = 9.1Hz), 7.22-7.31 (4H, m), 7.41 (1H, ddd, J = 8.9, 6.5,
2.1Hz), 7.47 (1H, t, J = 7.6Hz), 7.54 (1H, d, J = 7.7Hz), 7.65 (1H, t, J = 7.6Hz), 7.72 (1H, d,
J = 7.7Hz), 7.76 (1H, dd, J = 6.8, 2.1Hz), 8.29 (1H, s), 8.43 (1H, t, J = 5.8Hz)
3.20 (3H, s), 3.70 (3H, s), 4.38 (2H, d, J = 5.7Hz), 4.52 (2H, s), 5.07 (2H, s), 5.28 (2H, s),
6.22 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 6.80-6.81 (2H, m), 7.10 (1H, dd, J =
9.6, 8.9Hz), 7.20-7.30 (4H, m), 7.41 (1H, ddd, J = 9.2, 6.6, 2.1Hz), 7.76 (1H, dd, J = 6.8,
2.1Hz), 8.25 (1H, s), 8.33 (1H, t, J = 5.7Hz)
306761NZDIV
Example
Chemical shift
Number
2.28 (3H, s), 3.20 (3H, s), 4.37 (2H, d, J = 5.7Hz), 4.52 (2H, s), 5.06 (2H, s), 5.28 (2H, s),
6.22 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 6.93-7.04 (2H, m), 7.18-7.30 (5H,
m), 7.41 (1H, ddd, J = 9.2, 6.6, 2.1Hz), 7.75 (1H, dd, J = 6.8, 2.1Hz), 8.24 (1H, s), 8.30
(1H, t, J = 5.7Hz),
3.20 (3H, s), 3.81 (3H, s), 4.43 (2H, d, J = 5.3Hz), 4.49 (2H, s), 5.06 (2H, s), 5.26 (2H, s),
6.21 (1H, dt, J = 1.4, 6.7Hz), 6.39 (1H, ddd, J = 0.7, 1.4, 9.1Hz), 7.02 (1H, dt, J = 1.9,
9.2Hz), 7.12 (1H, dt, J = 5.3, 9.3Hz), 7.18-7.27 (4H, m), 7.40 (1H, ddd, J = 2.1, 6.6,
9.2Hz), 7.75 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.21 (1H, s), 8.24 (1H, t, J = 5.3Hz)
3.21 (3H, s), 3.75 (3H, s), 4.35 (2H, d, J = 5.9Hz), 4.54 (2H, s), 5.07 (2H, s), 5.29 (2H, s),
6.22 (1H, dt, J = 1.4, 6.7Hz), 6.40 (1H, ddd, J = 0.7, 1.4, 9.2Hz), 6.82 (1H, dd, J = 1.4,
2.4Hz), 6.87-6.93 (2H, m), 7.21-7.31 (4H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 9.2Hz), 7.76
(1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.24 (1H, s), 8.39 (1H, t, J = 5.9Hz)
3.18 (3H, d, J = 0.7Hz), 4.53 (4H, d, J = 8.8Hz), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, tt, J =
68 1.0, 6.7Hz), 6.39 (1H, d, J = 9.2Hz), 7.13-7.45 (8H, m), 7.51 (1H, t, J = 7.5Hz), 7.58 (1H,
d, J = 7.7Hz), 7.76 (1H, dd, J = 2.0, 6.8Hz), 8.25 (1H, s), 8.39 (1H, t, J = 5.9Hz)
3.19 (3H, s), 3.83 (3H, s), 4.52 (2H, s), 4.59 (2H, d, J = 5.8 Hz), 5.07 (2H, s), 5.29 (2H, s),
6.22 (1H, td, J = 1.4, 6.7Hz), 6.39 (1H, dt, J = 1.0, 9.1Hz), 7.01 (1H, d, J = 7.8Hz), 7.06
(1H, d, J = 8.4Hz), 7.14-7.48 (7H, m), 7.76 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.27 (1H, s),
8.34 (1H, t, J = 5.9Hz)
4.14 (2H, d, J = 6.2Hz), 4.55 (2H, br.s), 5.04 (2H, s), 6.20 (1H, td, J = 6.7, 1.3Hz), 6.38
70 (1H, d, J = 9.2Hz), 7.20-7.29 (4H, m), 7.37-7.42 (1H, m), 7.57 (1H, d, J = 3.8Hz), 7.60 (3H,
br.s), 7.74 (2H, dd, J = 6.7, 1.9Hz), 8.40 (1H, br.s), 12.01 -12.19 (1H, m)
1.98 (3H, s), 3.83 (3H, s), 4.41 (2H, d, J = 5.8Hz), 5.04 (2H, s), 5.59 (2H, s), 6.22 (1H, td, J
= 6.7, 1.4Hz), 6.39 (1H, dd, J = 9.1, 0.5Hz), 6.79-6.83 (1H, m), 7.03-7.05 (2H, m), 7.08-
7.10 (2H, m), 7.19 (1H, s), 7.21 (1H, s), 7.22 (1H, s), 7.39-7.43 (1H, m), 7.74 (1H, dd, J =
6.7, 1.9Hz), 9.13 (1H, t, J = 5.9Hz), 10.53 (1H, s)
1.93 (3H, s), 3.10 (3H, s), 3.83 (3H, s), 4.42 (2H, d, J = 4.8Hz), 5.05 (2H, s), 5.64 (2H, s),
6.22 (1H, td, J = 6.7, 1.3Hz), 6.40 (1H, d, J = 9.5Hz), 6.79-6.81 (1H, m), 6.87 (1H, br.s),
7.03-7.06 (2H, m), 7.07-7.11 (2H, m), 7.18-7.21 (2H, m), 7.39-7.44 (1H, m), 7.75 (1H,
dd, J = 6.8, 1.9Hz), 9.08 (1H, br.s)
3.22 (3H, s), 4.46 (2H, d, J = 5.3Hz), 4.51 (2H, s), 5.07 (2H, s), 5.27 (2H, s), 6.22 (1H, td, J
73 = 1.4, 6.7Hz), 6.40 (1H, d, J = 8.5Hz), 7.15 - 7.29 (5H, m), 7.38 - 7.46 (1H, m), 7.54 - 7.64
(1H, m), 7.76 (1H, dd, J = 1.5, 6.8Hz), 8.20 (1H, s), 8.34 (1H, t, J = 5.4Hz)
306761NZDIV
Example
Chemical shift
Number
3.22 (3H, s), 4.54 (4H, m), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H, td, J = 1.4, 6.7Hz), 6.40
(1H, ddd, J = 0.7, 1.4, 9.1Hz), 7.20-7.30 (4H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 9.2Hz), 7.52-
7.59 (2H, m), 7.76 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 7.84-7.91 (1H, m), 8.26 (1H, s), 8.58
(1H, t, J = 5.7Hz)
3.21 (3H, s), 3.92 (3H, s), 4.47-4.55 (4H, m), 5.06 (2H, s), 5.27 (2H, s), 6.21 (1H, td, J =
6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 7.17-7.31 (5H, m), 7.40 (1H, ddd, J = 8.9, 6.6, 2.1Hz),
7.67 (1H, dd, J = 8.6, 1.5Hz), 7.75 (1H, dd, J = 6.8, 2.1Hz), 8.20 (1H, s), 8.40 (1H, t, J =
.2Hz)
3.20 (3H, s), 3.86 (3H, s), 4.49-4.56 (4H, m), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J =
1.4, 6.7Hz), 6.39 (1H, ddd, J = 0.7, 1.4, 9.2Hz), 7.07 (1H, d, J = 7.8Hz), 7.18 (1H, d, J =
8.4Hz), 7.22-7.29 (4H, m), 7.39-7.44 (1H, m), 7.55 (1H, t, J = 8.1Hz), 7.76 (1H, ddd, J =
0.7, 2.1, 6.8Hz), 8.27 (1H, s), 8.34 (1H, t, J = 5.8Hz)
3.20 (3H, s), 3.79 (3H, s), 4.53 (4H, m), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H, td, J = 1.4,
6.7Hz), 6.40 (1H, dt, J = 1.0, 9.1Hz), 6.96-7.05 (2H, m), 7.22-7.31 (4H, m), 7.41 (1H, ddd,
J = 2.1, 6.6, 8.9Hz), 7.66 (1H, d, J = 8.6Hz), 7.76 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.29 (1H,
s), 8.40 (1H, t, J = 5.8Hz)
3.16 (3H, s), 4.43-4.52 (4H, m), 5.05 (2H, s), 5.26 (2H, s), 6.21 (1H, td, J = 1.4, 6.7Hz),
80 6.39 (1H, dt, J = 1.0, 9.2Hz), 7.23 (4H, q, J = 8.3Hz), 7.31-7.62 (5H, m), 7.75 (1H, ddd, J =
0.7, 2.1, 6.8Hz), 8.22 (1H, s), 8.33 (1H, t, J = 5.4Hz)
3.18 (3H, s), 3.76 (3H, s), 4.51 (4H, m), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J = 1.4,
6.7Hz), 6.40 (1H, dt, J = 1.2, 9.0Hz), 6.88-6.98 (2H, m), 7.03-7.33 (5H, m), 7.41 (1H, ddd,
J = 2.1, 6.6, 8.9Hz), 7.51 (1H, d, J = 9.1Hz), 7.76 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.26 (1H,
s), 8.38 (1H, t, J = 5.8Hz)
3.12 (3H, s), 3.83 (3H, s), 4.43 (2H, s), 4.52-4.59 (2H, m), 5.05 (2H, s), 5.25 (2H, s), 6.21
83 (1H, td, J = 1.4, 6.7Hz), 6.39 (1H, dt, J = 1.0, 9.2Hz), 7.15-7.44 (8H, m), 7.75 (1H, ddd, J =
0.7, 2.1, 6.8Hz), 8.08 (1H, t, J = 4.9Hz), 8.22 (1H, s)
3.17 (3H, s), 4.44 (2H, s), 4.54 (2H, d, J = 5.2 Hz), 5.05 (2H, s), 5.25 (2H, s), 6.21 (1H, td, J
85 = 6.7, 1.4Hz), 6.39 (1H, d, J = 9. 2Hz), 7.14-7.32 (6H, m), 7.34-7.44 (2H, m), 7.60 (1H, s),
7.75 (1H, dd, J = 6.8, 2.1Hz), 8.07-8.18 (2H, m), 8.21 (1H, s)
3.21 (3H, s), 3.74 (3H, s), 4.50 (2H, s), 4.55 (2H, d, J = 5.9Hz), 5.06 (2H, s), 5.28 (2H, s),
6.22 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 6.82-6.91 (2H, m), 7.18-7.33 (5H,
m), 7.41 (1H, ddd, J = 8.9, 6.6, 2.1Hz), 7.49 (1H, d, J = 8.4Hz), 7.76 (1H, d, J = 6.8, 2.1Hz),
7.81 (1H, br. s), 8.25 (1H, s), 8.30 (1H, t, J = 6.0Hz)
306761NZDIV
Example
Chemical shift
Number
3.21 (3H, s), 4.50 (2H, s), 4.70 (2H, d, J = 5.9Hz), 5.06 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J
= 1.4, 6.7Hz), 6.39 (1H, dd, J = 1.3, 9.1 Hz), 7.21-7.28 (4H, m), 7.32-7.44 (3H, m), 7.51
(1H, td, J = 1.5, 7.5 Hz), 7.76 (1H, dd, J = 2.1, 6.8 Hz), 7.86 (1H, dd, J = 1.4, 7.8 Hz), 8.26
(1H, s), 8.34 (1H, t, J = 5.9 Hz), 13.08 (1H, br. s)
3.21 (3H, s), 4.45 (2H, d, J = 5.8Hz), 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J
90 = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.2Hz), 7.16-7.31 (7H, m), 7.24 (1H, t, J = 72Hz), 7.38-7.44
(1H, m), 7.77 (1H, dd, J = 6.8, 2.1Hz), 8.26 (1H, s), 8.45 (1H, t, J = 5.8Hz)
3.20 (3H, s), 4.40 (2H, d , J = 5.9Hz), 4.54 (2H, s), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J
= 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 7.02-7.10 (2H, m), 7.16 (1H, d, J = 7.7Hz), 7.20 (1H,
t, J = 72Hz), 7.21-7.29 (4H, m), 7.35-7.43 (2H, m), 7.76 (1H, dd, J = 6.8, 2.1 Hz), 8.24
(1H, s), 8.41 (1H, t, J = 5.9Hz)
3.18 (3H, s), 4.43 (2H, d, J = 5.3Hz), 4.47 (2H, s), 5.05 (2H, s), 5.25 (2H, s), 6.21 (1H, td, J
= 6.6, 1.4Hz), 6.39 (1H, d, J = 9.2Hz),7.07 (1H, d, J = 8.3Hz), 7.14 (1H, t, J = 8.5Hz), 7.20
(2H, d, J = 8.2Hz), 7.24 (1H, t, J = 72Hz), 7.25 (2H, d, J = 8.3Hz), 7.36-7.47 (2H, m), 7.75
(1H, dd, J = 6.8, 2.1Hz), 8.11 (1H, t, J = 5.1Hz), 8.20 (1H, s)
3.21 (3H, s), 4.40 (2H, d, J = 5.8Hz), 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J
= 1.4, 6.7Hz), 6.39 (1H, dt, J = 1.0, 9.1Hz), 7.15 (2H, dd, J = 4.9, 8.4Hz), 7.20-7.30 (5H,
m), 7.41 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.76 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.25 (1H, s),
8.40 (1H, t, J = 5.8Hz)
3.21 (3H, s), 3.75 (3H, s), 4.36 (2H, d, J = 5.9Hz), 4.55 (2H, s), 5.08 (2H, s), 5.30 (2H, s),
95 6.19-6.27 (1H, m), 6.40 (1H, dd, J = 0.6, 9.2Hz), 6.65-6.75 (3H, m), 7.22-7.31 (4H, m),
7.41 (1H, ddd, J = 2.1, 6.6, 9.0Hz), 7.73-7.81 (1H, m), 8.25 (1H, s), 8.39 (1H, t, J = 5.9Hz)
3.21 (3H, s), 3.84 (3H, s), 4.39 (2H, d, J = 5.7Hz), 4.53 (2H, s), 5.07 (2H, s), 5.28 (2H, s),
6.22 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 6.68 (1H, ddd, J = 9.0, 4.9, 3.1Hz),
7.02 (1H, ddd, J = 10.1, 6.8, 3.1Hz), 7.19-7.30 (4H, m), 7.41 (1H, ddd, J = 8.9, 6.6,
2.1Hz), 7.76 (1H, dd, J = 6.8, 2.1Hz), 8.25 (1H, s), 8.39 (1H, t, J = 5.8 Hz)
2.37 (3H, s), 3.15 (3H, s), 4.42 (2H, dd, J = 1.7, 5.1Hz), 4.48 (2H, s), 5.05 (2H, s), 5.25
(2H, s), 6.21 (1H, td, J = 1.4, 6.7Hz), 6.39 (1H, dt, J = 0.9, 9.2Hz), 7.02 (2H, dd, J = 8.0,
11.8Hz), 7.16-7.29 (5H, m), 7.40 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.74 (1H, ddd, J = 0.7,
2.1, 6.8Hz), 8.04 (1H, t, J = 5.2Hz), 8.22 (1H, s)
3.18 (3H, s), 3.84 (3H, s), 4.49 (4H, d, J = 4.9Hz), 5.06 (2H, s), 5.26 (2H, s), 6.21 (1H, dt, J
99 = 1.4, 6.7Hz), 6.39 (1H, ddd, J = 0.7, 1.4, 9.1Hz), 7.12-7.28 (6H, m), 7.40 (1H, ddd, J =
2.1, 6.6, 8.9Hz), 7.75 (1H, ddd, J = 0.7, 2.1, 6.7Hz), 8.14 (1H, t, J = 5.1Hz), 8.21 (1H, s)
306761NZDIV
Example
Chemical shift
Number
3.20 (3H, s), 4.38 (2H, d, J = 5.6Hz), 4.52 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.21 (1H, dt, J
= 6.6, 1.2Hz), 6.39 (1H, d, J = 9.1Hz), 6.73 (1H,dt, J = 6.4, 1.4Hz), 6.83 (1H, dt, J = 8.2,
1.7Hz), 6.91 (1H, t, J = 7.9Hz), 7.23 (2H, d, J = 8.3Hz), 7.26 (2H, d, J = 8.2Hz), 7.38-7.43
(1H, m), 7.75 (1H, dd, J = 6.8, 1.7Hz), 8.24 (1H, s), 8.28 (1H, t, J = 5.1Hz), 9.73 (1H, br. s)
4.35 (2H, d, J = 5.7Hz), 5.03 (2H, s), 5.07 (2H, s), 5.36 (2H, br. s), 6.22 (1H, dt, J = 6.6, 1.2
Hz), 6.39 (1H, d, J = 8.8Hz), 6.70 (1H, dt, J = 7.6, 1.4Hz), 6.82 (1H, dt, J = 8.3, 1.6Hz),
6.90 (1H, t, J = 7.8Hz), 7.20 (2H, d, J = 8.1Hz), 7.26 (2H, d, J = 8.1Hz),7.38-7.43 (1H, m),
7.75 (1H, dd, J = 7.0, 1.8Hz), 7.99 (1H, s), 8.20 (1H, t, J = 5.6Hz), 9.70 (1H, br. s)
3.20 (3H, s), 3.84 (3H, s), 4.50 (2H, s), 4.68 (2H, d, J = 5.8Hz), 5.06 (2H, s), 5.28 (2H, s),
6.22 (1H, dt, J = 1.4, 6.7Hz), 6.39 (1H, ddd, J = 0.6, 1.3, 9.1Hz), 7.22-7.28 (4H, m), 7.36-
7.43 (2H, m), 7.45 (1H, dd, J = 1.2, 7.9Hz), 7.56 (1H, dt, J = 1.5, 7.5Hz), 7.77 (1H, ddd, J
= 0.7, 2.1, 6.8Hz), 7.86 (1H, dd, J = 1.4, 7.8Hz), 8.26 (1H, s), 8.32 (1H, t, J = 5.9Hz)
1.16 (3H, t, J = 7.5Hz), 2.62 (2H, q, J = 7.6Hz), 3.20 (3H, s), 4.41 (2H, d, J = 5.7Hz), 4.52
(2H, s), 5.06 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.2Hz),
7.07 (1H, t, J = 7.5Hz), 7.13-7.30 (6H, m), 7.41 (1H, ddd, J = 8.9, 6.6, 2.1Hz), 7.77 (1H,
dd, J = 6.8, 2.1Hz), 8.26 (1H, s), 8.35 (1H, t, J = 5.8Hz)
3.19 (3H, s), 3.72 (3H, s), 4.35 (2H, d, J = 5.8Hz), 4.53 (2H, s), 5.06 (2H, s), 5.28 (2H, s),
6.22 (1H, dt, J = 1.4, 6.7Hz), 6.39 (1H, dt, J = 1.0, 9.1Hz), 6.78-6.83 (1H, m), 6.83-6.88
(2H, m), 7.18-7.30 (5H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.77 (1H, ddd, J = 0.7,
2.1, 6.7Hz), 8.25 (1H, s), 8.36 (1H, t, J = 5.9Hz)
3.20 (3H, s), 3.82 (3H, s), 4.41(2H, d, J = 5.7Hz), 4.52 (2H, s), 5.05 (2H, s), 5.29 (2H, s),
104 6.87-6.90 (1H, m), 7.04-7.10 (2H, m), 7.25(2H, d, J = 8.1Hz), 7.30-7.35 (3H, m), 7.76
(1H, dd, J = 4.3, 1.0Hz), 8.02 (1H, d, J = 1.2Hz), 8.26 (1H, s), 8.36 (1H, t, J = 5.7Hz)
2.10 (3H, d, J = 0.6Hz), 3.20 (3H, s), 3.81 (3H, s), 4.43 (2H, d, J = 5.3Hz), 4.49 (2H, s),
.01 (2H, s), 5.25 (2H, s), 6.07 (1H, dd, J = 6.9, 1.9Hz), 6.20 (1H, s), 7.01 (1H, td, J = 9.2,
1.7Hz), 7.09-7.15 (1H, m), 7.18-7.24 (4H, m), 7.61 (1H, d, J = 6.9Hz), 8.20 (1H, s), 8.23
(1H, t, J = 5.0Hz)
3.20 (3H, s), 3.81 (3H, s), 2.50 (2H, d, J = 3.6Hz), 4.49 (2H, s), 5.00 (2H, s), 5.26 (2H, s),
6.43 (1H, dd, J = 10.0, 5.4Hz), 7.01 (1H, td, J = 9.2, 1.7Hz), 7.09-7.15 (1H, m), 7.21 (2H,
d, J = 8.2Hz), 7.27 (2H, d, J = 8.2Hz), 7.53-7.58 (1H, m), 8.01 (1H, dd, J = 4.6, 3.4Hz),
8.21 (1H, s), 8.23 (1H, t, J = 5.2Hz)
306761NZDIV
Example
Chemical shift
Number
2.50 (3H, t, J = 1.8Hz), 3.20 (3H, s), 3.81 (3H, s), 3.98 (2H, q, J = 7.0Hz), 4.43 (2H, d, J =
.1Hz), 4.49 (2H, s), 4.98 (2H, s), 5.25 (2H, s), 5.77 (1H, d, J = 2.7Hz), 5.92 (1H, dd, J =
7.6, 2.9Hz), 7.01 (1H, td, J = 9.2, 1.7Hz), 7.09-7.15 (1H, m), 7.18-7.23 (4H, m), 7.61 (1H,
d, J = 7.6Hz), 8.20 (1H, s), 8.23 (1H, t, J = 5.1Hz)
2.26 (3H, s), 3.81 (3H, s), 4.41 (2H, d, J=6.3Hz), 5.07 (2H, s), 5.16 (2H, s), 6.22 (1H, ddd,
J = 6.6, 6.6, 1.4Hz), 6.40 (1H, d, J = 8.8Hz), 6.81-6.85 (1H, m), 7.00-7.07 (2H, m), 7.17
(2H, d, J = 8.2Hz), 7.27 (2H, d, J = 8.1Hz), 7.41 (1H, ddd, J = 8.9, 6.5, 2.0Hz), 7.64 (1H, s),
7.76 (1H, dd, J = 6.7, 2.0Hz), 8.31 (1H, t, J = 6.0Hz)
3.82 (3H, s), 4.44 (2H, d, J = 6.2Hz), 5.08 (2H, s), 5.40 (2H, s), 6.22 (1H, dt, J = 6.6,
1.4Hz), 6.40 (1H, d, J = 8.9Hz), 6.85 (1H, dt, J = 6.6, 1.8Hz), 7.01-7.08 (2H, s), 7.19 (2H,
d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.41 (1H, ddd, J = 8.8. 6.6, 2.1Hz), 7.75 (1H, dd, J =
6.6, 1.7Hz), 8.09 (1H, s), 8.68 (1H, br. s)
1.90-1.94 (4H, m), 3.31-3.37 (4H, m), 3.82 (3H, s), 4.39 (2H, d, J = 5.6Hz), 5.26(2H,s),
126 6.44 (1H, d, J = 8.6Hz), 6.85-6.90 (1H, m), 7.03-7.10 (2H, m), 7.50 (1H, dd, J =
8.8,2.4Hz), 8.14 (1H, d, J = 2.3Hz), 8.36 (1H, d, J = 0.6Hz), 8.74 (1H, t, J = 5.8Hz)
2.81 (3H, s), 2.98 (1H, dd, J = 12.0, 7.3Hz), 3.26 (1H, dd, J = 12.0, 2.6Hz), 3.35-3.45 (2H,
m), 4.26-4.28 (1H, m), 5.04 (2H, s), 5.07 (2H, s), 5.37 (2H, br. s), 6.22 (1H, td, J = 6.6,
139 1.3Hz), 6.40 (1H, d, J = 8.8Hz), 6.68 (1H, d, J = 8.7Hz), 6.73 (1H, d, J = 2.4Hz), 6.80 (1H,
dd, J=8.6, 2.4Hz), 7.21 (2H, d, J = 8.2Hz), 7.27 (2H, d, J = 8.1Hz), 7.39-7.43 (1H,m), 7.76
(1H, dd, J = 7.0, 1.9Hz), 7.99 (1H, s), 8.00 (1H, t, J = 5.7Hz)
2.96-3.02 (1H, m), 3.29-3.34 (1H, m), 3.34-3.43 (2H, m), 4.07-4.12 (1H, m), 5.04 (2H, s),
.07 (2H, s), 5.36 (2H, br. s), 5.93 (1H, br. s), 6.22 (1H, td, J = 6.7, 1.4Hz), 6.40 (1H, d, J =
140 9.9Hz), 6.55-6.58 (1H, m), 6.68-6.71 (2H, m), 7.21 (2H, d, J = 8.1Hz), 7.27 (2H, d, J =
8.2Hz), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 7.0, 2.0Hz), 7.98 (1H, t, J = 5.8Hz), 7.99 (1H,
Biological Methods
The ability of the compounds of formula (I) to inhibit plasma kallikrein may be determined using the
following biological assays:
Determination of the IC for plasma kallikrein
Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g.
Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209;
306761NZDIV
Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human plasma kallikrein (Protogen)
was incubated at 25 C with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations
of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring
the change in optical absorbance at 410nm and the IC value for the test compound was determined.
Data acquired from these assays are shown in Table 14.
Selected compounds were further screened for inhibitory activity against the related enzyme KLK1. The
ability of the compounds of formula (I) to inhibit KLK1 may be determined using the following biological
assay:
Determination of the IC for KLK1
KLK1 inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et
al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stürzebecher et al.,
Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLK1 (Callbiochem) was incubated at 25 C with
the fluorogenic substrate H-DVal-Leu-Arg-AFC and various concentrations of the test compound.
Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical
absorbance at 410nm and the IC value for the test compound was determined.
Data acquired from this assay are shown in Table 14.
Selected compounds were further screened for inhibitory activity against the related enzyme FXIa. The
ability of the compounds of formula (I) to inhibit FXIa may be determined using the following biological
assay:
Determination of the % inhibition for FXIa
FXIa inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et
al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stürzebecher et al.,
Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human FXIa (Enzyme Research Laboratories) was
incubated at 25 C with the fluorogenic substrate Z-Gly-Pro-Arg-AFC and 40 µM of the test compound.
306761NZDIV
Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical
absorbance at 410nm.
Data acquired from this assay are shown in Table 14
Table 14
Example % Inhibition @ 40 M
IC (human PKal) nM IC50 (human KLK1) nM
Number (human FXIa)
1 698 >10000
2 8.7 >10000
3 2580 >10000
4 136 >10000
364 >10000
6 2360 >10000
7 >10000 >10000
8 539 >10000
9 239 >10000
1270 >10000
11 456 >10000
12 746 >10000
13 439 >10000
14 514 >10000
306761NZDIV
Example % Inhibition @ 40 M
IC (human PKal) nM IC50 (human KLK1) nM
Number
(human FXIa)
219 >10000
16 263 >10000
17 865 >10000
18 373 >10000
19 1130 >10000
740 >10000
21 257 >10000
22 1350 >10000
23 1060 >10000
24 717 >10000
1840 >10000
26 1340 >10000
27 >10000 >10000
28 280 >10000
29 2190 >10000
915 >10000
31 392 >10000
32 7870 >10000
306761NZDIV
Example % Inhibition @ 40 M
IC (human PKal) nM IC50 (human KLK1) nM
Number
(human FXIa)
36 4170 >10000
37 392 >10000
39 7870 >10000
40 3700 >10000
41 3.3 >40000
42 831 >10000
45 144 >10000
46 2400 >10000
47 753 >10000
48 647 >10000
49 5450 >10000
50 1800 >10000
51 48.9 >40000
52 23.3 >40000
53 20.2 >10000
54 2.1 >40000
58 5780 >10000
59 73.4 >10000
306761NZDIV
Example % Inhibition @ 40 M
IC (human PKal) nM IC50 (human KLK1) nM
Number
(human FXIa)
62 572 >10000
63 342 >10000
64 35.2 >10000
65 43.3 >10000
66 4.6 >10000
67 393 >10000
68 81.1 >10000
69 16.8 >40000 0
70 26.7 >10000 6
71 300 >10000 0
72 6610 >10000
73 120 >10000
76 28.3 >40000
77 0.6 >40000
78 612 >10000
79 14.7 >40000
80 20.4 >40000
81 2.3 >40000
306761NZDIV
Example % Inhibition @ 40 M
IC (human PKal) nM IC50 (human KLK1) nM
Number
(human FXIa)
83 6.8 >40000
85 79.2 >40000 46
86 8.7 >40000
87 >10000 >10000
90 154 >40000
91 523 >10000
92 16.0 >10000
94 780 >10000
95 308 >40000
96 75.0 >40000
97 153 >10000
99 6.4 >10000
129 437 >40000 0
130 174 >40000 0
131 1510 >10000 0
132 135 >40000 0
133 90.2 >10000 1
104 691 >10000
306761NZDIV
Example % Inhibition @ 40 M
IC (human PKal) nM IC50 (human KLK1) nM
Number
(human FXIa)
106 140 >10000
108 5.5 >10000
109 2980 >10000
121 43.9 >10000
124 191 >10000
126 742 >10000
64.7 >40000 33
140 10.6 >40000 9
Pharmacokinetics
Pharmacokinetic studies of the compounds in Table 15 were performed to assess the pharmacokinetics
following a single oral dose in male Sprague-Dawley rats. Two rats were given a single po dose of 5
mL/kg of a nominal 2 mg/mL (10 mg/kg) composition of test compound in vehicle. Following dosing,
blood samples were collected over a period of 24 hours. Sample times were 5, 15 and 30 minutes then
1, 2, 4, 6, 8 and 12 hours. Following collection, blood samples were centrifuged and the plasma fraction
analysed for concentration of test compound by LCMS. Oral exposure data acquired from these studies
are shown below:
Table 15: Oral exposure data
Example
Vehicle Dose po (mg/kg) Cmax (ng/mL) Tmax (min)
Number
% DMSO / 10%
9.5 351 60
cremophor / 80% SWFI
306761NZDIV
Example
Vehicle Dose po (mg/kg) Cmax (ng/mL) Tmax (min)
Number
% DMSO / 10%
.5 1534 180
cremophor / 80% SWFI
% cremophor / 5%
ethanol / 90% phosphate 13.7 101 15
buffered saline
% DMSO / 10%
17.9 1472 45
cremophor / 80% SWFI
% DMSO / 10%
8.6 1031 15
cremophor / 80% SWFI
% DMSO / 10%
11.3 2892 60
cremophor / 80% SWFI
% DMSO / 10%
.5 397 30
cremophor / 80% SWFI
Claims (25)
1. A compound of formula (I), or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer, and racemic and scalemic mixtures thereof), or a pharmaceutically acceptable salt or 5 solvate thereof, wherein the compound of formula (I) is, X R5 Formula (I) wherein 10 B is phenyl substituted with 1 to 4 substituents selected from alkyl , alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF and CF ; 3, 3 or B is selected from benzothiophenyl, benzofuranyl and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein said 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl or said 5 or 6 15 membered heterocyclic ring is substituted with 1 to 3 substituents selected from alkyl , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF and CF ; W is C and X, Y and Z are independently selected from C, N, O and S, such that the ring containing W, X, Y and Z is a five membered aromatic heterocycle; R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, -NR8R9, CN, - NR8COR9 and CF ; wherein at least one of R5 and R6 is present and is not H; R7 is H; 25 A is selected from aryl and heteroaryl; wherein aryl is substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - b b b (CH ) -O-heteroaryl, aryl , -O-aryl , -(CH ) -aryl , -(CH ) -heteroaryl, -COOR10, -CONR10R11, -(CH ) - 2 0-3 2 1-3 2 1-3 2 0-3 NR10R11, OCF and CF ; and heteroaryl is substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF , halo, CN, aryl, -(CH ) -aryl, -(CH ) -NR10R11, heteroaryl , -COOR10, - 3 2 1-3 2 0-3 CONR10R11 and CF ; R8 and R9 are independently selected from H and alkyl; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C -C ) or a branched saturated 1 10 hydrocarbon of between 3 and 10 carbon atoms (C -C ); alkyl may optionally be substituted with 1 or 2 3 10 10 substituents independently selected from (C -C )alkoxy, OH, CN, CF , COOR10, CONR10R11, fluoro and 1 6 3 NR10R11; alkyl is a linear saturated hydrocarbon having up to 6 carbon atoms or a branched saturated hydrocarbon of between 3 and 6 carbon atoms (C ); alkyl may optionally be substituted with 1 or 2 15 substituents independently selected from (C -C )alkoxy, OH, CN, CF , COOR10, CONR10R11 and fluoro; 1 6 3 cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6 carbon atoms; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C -C ) or a branched O-linked 20 hydrocarbon of between 3 and 6 carbon atoms (C -C ); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from OH, CN, CF , CONR10R11, fluoro and NR10R11; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - b b b 25 (CH2)0O-heteroaryl, aryl , -O-aryl , -(CH2)1aryl , -(CH2)1heteroaryl, -COOR10, -CONR10R11, -(CH2)0 NR10R11, OCF and CF ; aryl is phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF and NR10R11; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2, 3 or 4 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF , halo, CN, aryl, -(CH ) -aryl, -(CH ) -NR10R11, heteroaryl , -COOR10, -CONR10R11 and CF ; 2 1-3 2 0-3 3 heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 5 or 3 ring members independently selected from N, NR8, S and O; wherein heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, aryl, - (CH ) -aryl, -COOR10, -CONR10R11, CF and NR10R11; 2 1-3 3 c c c R10 and R11 are independently selected from H, alkyl , aryl and heteroaryl or R10 and R11 together 10 with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl , alkoxy , OH, halo and CF alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C -C ) or a branched O-linked 15 hydrocarbon of between 3 and 6 carbon atoms (C -C ); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from OH, CN, CF , CONR19R20, fluoro and NR19R20; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C -C ); alkyl may optionally be substituted with 1 or 2 3 10 20 substituents independently selected from (C -C )alkoxy , OH, CN, CF , COOR19, CONR19R20, fluoro and 1 6 3 NR19R20; aryl is phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl , alkoxy , OH, halo, CN, -COOR19, -CONR19R20, CF and NR19R20; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR21, S and O; wherein heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl , alkoxy , OH, halo, CN, aryl , -(CH ) -aryl , -COOR19, -CONR19R20, CF and NR19R20; 2 1-3 3 R19 and R20 are independently selected from H, or R19 and R20 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, OH, halo and CF ; 5 R21 is selected from H and alkyl ; wherein the compound is not selected from: benzoic acid, 3-[[[[1-[(3-chlorophenyl)methyl]methyl-1H-pyrazolyl]carbonyl]amino]methyl]-; 10 benzoic acid, 4-[[([1-[(3-chlorophenyl)methyl]methyl-1H-pyrazolyl]carbonyl]amino]methyl]-; 2-furancarboxylic acid, 5-[[[[1- [(3-chlorophenyl)methyl]methyl-1H-pyrazol yl)carbonyl]amino]methyl]-; benzoic acid, 5-[[[[1- [(3-chlorophenyl)methyl]methyl-1H-pyrazolyl] carbonyl]amino]methyl] methoxy-; and 15 3-furancarboxylic acid, 5-[[[[1-[(3-chlorophenyl)methyl]methyl-1H-pyrazol yl]carbonyl]amino]methyl]methyl-; benzoic acid, 4-[[[[1-[(3-chlorophenyl)methyl]methyl-1H-pyrazolyl]carbonyl]amino]methyl] methoxy; and N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 20 yl)methyl]phenyl}methyl)pyrazolecarboxamide.
2. The compound according to claim 1 wherein B is selected from phenyl substituted with 1 to 4 substituents selected from alkyl , alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF and CF ; or B is selected from benzothiophenyl, benzofuranyl, and a 5 or 6 membered heterocyclic ring 25 containing one or two heteroatoms selected from N, O and S; wherein said 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl or said 5 or 6 membered heterocyclic ring is substituted with 1 to 3 substituents selected from alkyl , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF and CF ; wherein alkyl , alkoxy, R8 and R9 are as defined in claim 1; 30 or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
3. The compound according to claim 1 or 2, wherein: B is phenyl substituted with 1 to 4 substituents selected from alkyl , alkoxy, OH, halo, CN, heteroaryl, COO(alkyl), NHCOR8, CONR8R9, OCF and CF ; or 3, 3 5 wherein B is selected from benzothiophenyl, benzofuranyl and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein said 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl or said 5 or 6 membered heterocyclic ring is substituted with 1 to 3 substituents selected from alkyl , alkoxy, OH, oxo, halo, CN, heteroaryl, COO(alkyl), NHCOR8, CONR8R9, OCF and CF ; 10 or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
4. The compound according to claims 1 or 2 , wherein B is selected from phenyl, thiophenyl, benzothiophenyl and pyridyl, each substituted with 1 to 3 substituents selected from alkyl , alkoxy, halo, 15 CN, COOR8, CONR8R9, OCF and CF ; wherein alkyl , alkoxy, R8 and R9 are as defined in claim 1; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
5. The compound according to any one of claims 1 to 4, wherein B is selected from phenyl and 20 pyridyl, each substituted with 1 to 3 substituents selected from alkyl , alkoxy, CF and halo; wherein alkyl and alkoxy are as defined in claim 1; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof. 25
6. The compound according to claim 5, wherein B is pyridyl substituted with 1 to 3 substituents selected from alkyl , alkoxy, CF and halo; wherein alkyl and alkoxy are as defined in claim 1; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
7. The compound according to any one of claims 1 to 6, wherein W is C and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a five membered aromatic heterocycle; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
8. The compound according to any one of claims 1 to 7, wherein W is C, X is N and Y and Z are selected from C and N; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
9. The compound according to any one of claims 1 to 8, wherein R5 and R6 are independently absent or independently selected from H, CH OCH , cycloalkyl, -NR8R9, -NR8COR9, CN and CF ; wherein cycloalkyl, R8 and R9 are as defined in claim 1; and wherein at least one of R5 and R6 is present and is not H; 15 or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
10. The compound according to any one of claims 1 to 9, wherein R5 is CH OCH ; 20 or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
11. The compound according to any one of claims 1 to 10, wherein A is phenyl substituted with -(CH ) -heteroaryl or -(CH ) -NR10R11 and, optionally, 1 2 1-3 2 1-3 25 or 2 additional substituents independently selected from alkyl, halo and CF3; wherein alkyl, heteroaryl, R10 and R11 are as defined in claim 1; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof. 30
12. The compound according to any one of claims 1 to 10, wherein A is pyridyl substituted with heteroaryl or -NR10R11 and, optionally, 1 or 2 additional substituents independently selected from alkyl, halo and CF ; wherein alkyl, heteroaryl , R10 and R11 are as defined in claim 1; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and 5 scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
13. The compound according to claim 11 or 12, wherein R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered carbon containing heterocylic ring, optionally containing an addition N atom, which may 10 be saturated or unsaturated with 1 or 2 double bonds, and optionally mono- or di-substituted with substituents selected from oxo, methyl, Cl and F; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof. 15
14. The compound according to any one of claims 1 to 13, wherein A is selected from: , , , , , and ; or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof. 5
15. The compound according to claim 14, wherein A is selected from: or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
16. The compound according to claim 14, wherein A is selected from: or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic 15 mixture thereof), a pharmaceutically acceptable salt or solvate thereof.
17. The compound according to claim 1, wherein the compound is selected from: 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 2-fluoro methoxy-benzylamide; N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl) (trifluoromethyl)pyrazolecarboxamide; N-[(2-fluoromethoxyphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl) (trifluoromethyl)pyrazolecarboxamide; N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; N-[(4-chloro-2,6-difluorophenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl)- 3-(trifluoromethyl)pyrazolecarboxamide; N-{[3-chlorofluoro(trifluoromethyl)phenyl]methyl}({4-[(4-methylpyrazol yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; N-[(2-fluoromethylphenyl)methyl]({4-[(4-methylpyrazolyl)methyl]phenyl}methyl) (trifluoromethyl)pyrazolecarboxamide; N-[(5-chlorobenzothiophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-cyclopropyl-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-fluoro-3,6-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(dimethylamino)-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-fluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-(difluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-amino-N-{[2-fluoro(trifluoromethyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-acetamido-N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-chloro-2,6-difluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-chlorocyanophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(trifluoromethyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-(difluoromethyl)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-(difluoromethyl)methoxyphenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-(difluoromethyl)fluoromethoxyphenyl]methyl}(methoxymethyl)({4-[(2- oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-carbamoylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-carbamoylmethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[3-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-(difluoromethoxy)fluorophenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2,5-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-fluoromethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(6-chlorofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-amino-N-[(2-fluorohydroxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-ethylfluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2,6-difluoromethoxyphenyl)methyl](methoxymethyl)({4-[(4-methyloxopyridin- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(5-fluorooxopyridin yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide; N-[(2-fluoromethoxyphenyl)methyl]methyl({4-[(2-oxopyridin yl)methyl]phenyl}methyl)imidazolecarboxamide; N-[(2-fluoromethoxyphenyl)methyl]({4-[(2-oxopyridinyl)methyl]phenyl}methyl) (trifluoromethyl)imidazolecarboxamide; 3-amino-N-[(7-chloromethyl-2,3-dihydro-1,4-benzoxazinyl)methyl]({4-[(2-oxopyridin- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide and pharmaceutically acceptable salts and solvates thereof.
18. A pharmaceutical composition comprising (i) a compound, or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer and a racemic and scalemic mixture thereof), a 5 pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 17 and (ii) a pharmaceutically acceptable carrier, diluent or excipient.
19. A pharmaceutical composition comprising: (i) a pharmaceutically acceptable carrier, diluent or excipient, and (ii) a compound of formula (I), or a tautomer, stereoisomer (including an enantiomer, a diastereoisomer, and racemic and scalemic mixtures thereof), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (I) is, X R5 Formula (I) wherein B is phenyl substituted with 1 to 4 substituents selected from alkyl , alkoxy, OH, halo, CN, heteroaryl, 10 COOR8, NHCOR8, CONR8R9, OCF and CF ; 3, 3 or B is selected from benzothiophenyl, benzofuranyl and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein said 5 or 6 membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl or said 5 or 6 membered heterocyclic ring is substituted with 1 to 3 substituents selected from alkyl , alkoxy, OH, oxo, 15 halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF and CF ; W is C and X, Y and Z are independently selected from C, N, O and S, such that the ring containing W, X, Y and Z is a five membered aromatic heterocycle; 20 R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, -NR8R9, CN, - NR8COR9 and CF ; wherein at least one of R5 and R6 is present and is not H; R7 is H; A is selected from aryl and heteroaryl; wherein aryl is substituted with 1, 2 or 3 substituents 25 independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - b b b (CH ) -O-heteroaryl, aryl , -O-aryl , -(CH ) -aryl , -(CH ) -heteroaryl, -COOR10, -CONR10R11, -(CH ) - 2 0-3 2 1-3 2 1-3 2 0-3 NR10R11, OCF and CF ; and heteroaryl is substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF , halo, CN, aryl, -(CH ) -aryl, -(CH ) -NR10R11, heteroaryl , -COOR10, - 3 2 1-3 2 0-3 CONR10R11 and CF ; 5 R8 and R9 are independently selected from H and alkyl; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C -C ) or a branched saturated 1 10 hydrocarbon of between 3 and 10 carbon atoms (C -C ); alkyl may optionally be substituted with 1 or 2 3 10 substituents independently selected from (C -C )alkoxy, OH, CN, CF , COOR10, CONR10R11, fluoro and 1 6 3 10 NR10R11; alkyl is a linear saturated hydrocarbon having up to 6 carbon atoms or a branched saturated hydrocarbon of between 3 and 6 carbon atoms (C ); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C -C )alkoxy, OH, CN, CF , COOR10, CONR10R11 and fluoro; 1 6 3 cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6 carbon atoms; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C -C ); alkoxy may optionally be substituted with 1 or 2 20 substituents independently selected from OH, CN, CF , CONR10R11, fluoro and NR10R11; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - b b b (CH ) -O-heteroaryl, aryl , -O-aryl , -(CH ) -aryl , -(CH ) -heteroaryl, -COOR10, -CONR10R11, -(CH ) - 2 0-3 2 1-3 2 1-3 2 0-3 25 NR10R11, OCF3 and CF3; aryl is phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF and NR10R11; 30 heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2, 3 or 4 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF , halo, CN, aryl, -(CH ) -aryl, -(CH ) -NR10R11, heteroaryl , -COOR10, -CONR10R11 and CF ; 2 1-3 2 0-3 3 heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 5 or 3 ring members independently selected from N, NR8, S and O; wherein heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, aryl, - (CH ) -aryl, -COOR10, -CONR10R11, CF and NR10R11; 2 1-3 3 c c c R10 and R11 are independently selected from H, alkyl , aryl and heteroaryl or R10 and R11 together 10 with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl , alkoxy , OH, halo and CF alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C -C ) or a branched O-linked 15 hydrocarbon of between 3 and 6 carbon atoms (C -C ); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from OH, CN, CF , CONR19R20, fluoro and NR19R20; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C -C ); alkyl may optionally be substituted with 1 or 2 3 10 20 substituents independently selected from (C -C )alkoxy , OH, CN, CF , COOR19, CONR19R20, fluoro and 1 6 3 NR19R20; aryl is phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl , alkoxy , OH, halo, CN, -COOR19, -CONR19R20, CF and NR19R20; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR21, S and O; wherein heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl , alkoxy , OH, halo, CN, aryl , -(CH ) -aryl , -COOR19, -CONR19R20, CF and NR19R20; 2 1-3 3 R19 and R20 are independently selected from H, or R19 and R20 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, OH, halo and CF ; 5 R21 is selected from H and alkyl ; wherein the compound is not: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 10 yl)methyl]phenyl}methyl)pyrazolecarboxamide.
20. The use of a compound as claimed in any one of claims 1 to 17 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.
21. The use of a composition as claimed in claim 18 or 19 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.
22. The use according to claim 20 or 21, wherein, the disease or condition in which plasma kallikrein 20 activity is implicated is selected from impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post operative surgery.
23. The use according to any one of claims 20-22, wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. 30
24. The use according to any one of claims 20 to 22, wherein the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema.
25. The use according to any one of claims 20 to 22, wherein the disease or condition in which plasma kallikrein activity is implicated is hereditary angioedema.
Applications Claiming Priority (3)
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GB1421083.5 | 2014-11-27 | ||
GBGB1421083.5A GB201421083D0 (en) | 2014-11-27 | 2014-11-27 | Enzyme inhibitors |
NZ731945A NZ731945A (en) | 2014-11-27 | 2015-11-26 | N-((het)arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors |
Publications (2)
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NZ770256A NZ770256A (en) | 2021-11-26 |
NZ770256B2 true NZ770256B2 (en) | 2022-03-01 |
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