Technical field
The present invention relates to therapeutically active compounds and pharma-
ceutically acceptable salts and esters thereof useful in the treatment of conditions
involving matriptase activity, particularly cancer.
Background of the invention
Cancer drug discovery has traditionally focused on targeting DNA synthesis and
cell division, resulting in drugs such as antimetabolites and DNA alkylating agents.
Although these drugs show efficacy, their lack of selectivity for tumor cells over normal
cells can lead to severe side effects. The recent recognition that certain genes are
associated with cancer has resulted in several rational and targeted drugs for cancer
therapy. However, many of the available targeted cancer treatments inhibit only a
specific aspect of cancer progression such as proliferation, angiogenesis or metastasis.
This limits their utility and necessitates their use in combination with traditional
chemotherapeutic agents. Examples of such targeted cancer drugs include erlotinib
(Tarceva®) and bevacizumab (Avastin ). Erlotinib inhibits cell proliferation, while
bevacizumab is an anti-angiogenesis drug. These drugs target kinases or proteins
involved in kinase signaling pathways. Recent findings indicate that matriptase, a
transmembrane serine protease, plays a role in triggering the formation of tumor cells.
Unlike kinases, the localization of matriptase on the cell surface makes it more
accessible to a potential inhibitor. Matriptase is over-expressed (up to several
hundredfold) in all phases of cancer in multiple cancer types and has also been shown to
play a role in invasion and metastasis. Therefore, a matriptase inhibitor could comprise a
potential first-in-class drug with a broad spectrum of anti-tumor activity including anti-
proliferative and anti-invasive activities.
Matriptase is a multi-domain 80-kDa type II transmembrane serine protease and
belongs to the S1 trypsin-like family. Matriptase is involved in matrix

remodeling/degradation, regulation of cell growth and survival, cell motility, cell
morphogenesis, and activation of other membrane bound proteins. It is also called the
membrane-type serine protease-1 (MT-SP1), the tumor-associated differentially
expressed gene-15 (TAGD-15), or epithin in mouse. Matriptase is overexpressed in a
vast array of human tumors of epithelial origin including prostate, ovarian, uterine,
colon, epithelial-type mesothelioma, cervical and head and neck squamous cell
carcinoma. Epidemiological studies have revealed that increased expression of
matriptase relative to HAI-1 correlates with the grade of the tumor and results in poor
prognosis in breast and ovarian cancer.
The role of matriptase has been well established in pathways involved in cancer
even though the exact function of human matriptase has not been elucidated. Matriptase
enhances tumor cell proliferation through phosphatidylinositol 3-Kinase signaling and
invasion through the HGF/cMet and uPAR activation. Glycosylation of matriptase by
UDP-GlcNAc alpha-mannoside betal -6-N-acetylglucosaminyltransferase (GnT-V)
plays a key role in metastasis by increasing the stability of degradation-resistant active
form of the enzyme. Furthermore, matriptase activates other proteases such as receptor-
bound urokinase-type plasminogen activator (uPA). Overexpression of uPA or its
receptor (uPAR) is a feature of malignancy and plays a critical role in angiogenesis,
tumor invasion and metastasis. Down-regulation of matriptase inhibits tumor invasion
through suppression of uPAR activation.
Several other "trypsin like serine proteases" such as uPA, trypsin, plasmin,
hepsin and kallikrein play a critical role in cancer affecting various pathways leading to
angiogenesis, invasion and metastasis. Urokinase-type plasminogen activator (uPA)
plays a major role in extracellular proteolytic events associated with tumor cell growth,
migration and angiogenesis. Many cancer cells secrete pro-uPA and its receptor uPAR.
Binding of pro-uPA to uPAR leads to its activation, with subsequent generation of
plasmin by the uPA-catalyzed hydrolysis of extracellular plasminogen. The increased
production of plasmin leads to degradation of extracellular matrix both by plasmin itself
and by other proteases that are activated by plasmin. The surface location of bound uPA
provides directionality to the degradation of matrix, thereby assisting the directional

migration of cancer cells. uPA in complex with uPAR also affects other biological
processes including signaling pathways that influence cell proliferation. Hepsin is
another type II transmembrane serine protease (TTSP)l expressed on the surface of
epithelial cells. It has been implicated in ovarian cancer and prostate cancer, where
several gene expression studies have identified it as one of the most highly induced
genes. Hepsin over-expression was associated with basement membrane disruption and
was shown to be connected the HGF/c-Met pathway and uPA pathway connecting
hepsin to the pathways leading to basement membrane disruption and tumor
progression.
Therefore, inhibitors of matriptase and other related serine proteases could be of
significant therapeutic value because of the following reasons:
- potential to be used as a 'mono-therapy' due to wide expression and activity of
matriptase and other proteases in both early and late stages of cancer
- superior safety profile due to localization of matriptase, uPA and hepsin at the
cell membrane which avoids the need of cellular entry of the drug
- superior efficacy profile due to tumor-specific expression
- potential for reducing morbidity due to a larger therapeutic window that results
from fewer therapy-related side effects typically associated with cytotoxic agents
Matriptase inhibitors have been described earlier e.g. in Enyedy, I. et al., J. Med.
Chem., 2001, 44, 1349-1355; and in international patent publications WO 01/97794,
WO 2004/058688, WO 2004/101507, WO 2008/085608, WO 2008/107176, WO
2008/097673, WO 2008097676 and WO 2008/107176. Other benzamidine compounds
have been described earlier e.g. in Phillips, G. et al., J. Med. Chem., 1999,42, 1749-
1756; Phillips, G. et al., J. Med. Chem., 1998, 41, 3557-3562; and EP 0 813 525.
Summary of the invention
It has been found that compounds of formula (I) are serine protease inhibitors. In
particular, it has been found that the compounds of formula (I) are potent and selective

matriptase inhibitors. The compounds of the invention are able to inhibit invasion and
metastasis of various tumor cells and inhibit tumor growth. Compounds of the invention
provide also good safety, and are therefore particularly useful in the treatment of cancer.
The compounds of the present invention have a structure represented by
formula (I)

wherein
P1 and P2 are, independently a bond or C1-3 alkyl;
A is CH or N;
B is CH or N;
Ri is hydrogen, -NHSO2R6, -CO-NR7R8, -CO-NR4-ZR9R13 or a group of
formula

wherein the ring portion in formula (II) is a 5 -12 membered saturated, partially
saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain
1-3 further heteroatoms selected from N, O, S or combinations thereof;
R3 is -C(NR17)NH2, or in case A is CH, R3 can also be amino C1-7 alkyl;
R10, R14 and R15 are independently hydrogen, halogen, halogen C1-7 alkyl, or
-C(NR17)NH2;
Q is hydrogen or halogen, with a proviso that R1 and Q are not simultaneously
hydrogen;
R4 is hydrogen or C1-7 alkyl;
R6 is ZR9R13;

Z is a 5 -12 membered saturated, partially saturated or aromatic ring which may
be monocyclic or bicyclic, and which may contain 1-3 heteroatoms selected from N, O,
S or combinations thereof;
R9 and R]3 are, independently, hydrogen, halogen, carboxy, carboxy Ci.7 alkyl,
C1-7 alkoxycarbonyl, RANH2 or -CORBNH2;
RA and RB is a bond or C1-7 alkyl;
R7 and R8 are, independently, hydrogen, amino C1-7 alkyl, carboxy C1-7 alkyl, or
in case A is CH, R7 and Rg, independently, can also be C1-7 alkyl,
with a proviso that R7 and Rg are not simultaneously hydrogen;
R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-7 alkyl, C1-7 alkoxycarbonyl C1-7
alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, RDC(NR)7)NH2, or a group of formula
(III)
y = 0-2; RD is a bond or C1-7 alkyl; G is CH or N;
Rn is hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7 alkoxycarbonyl,
aminocarbonyl, halogen C1-7 alkoxy, -C(NRn)NH2, -NHCOR°NH2, RJNHCOORU;
RG is C1-7 alkyl; RJ is a bond or C1-7 alkyl; Ru is hydrogen or C1-7 alkyl;
R12 and R16 are, independently, hydrogen, halogen or C1-7 alkyl;
R17 is hydrogen, -OH, -O(CO)OR18 or -(CO)OR18;
R18 is C1-7 alkyl;
or a pharmaceutically acceptable salt or ester thereof.
In one class of preferred compounds are compounds of formula (I), wherein R1 is
a group of formula (II). In another class of preferred compounds are compounds of
formula (I), wherein the ring portion of formula (II) is a 6 or 10 membered saturated,
partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which
may contain one further heteroatom N. Examples of particularly preferred compounds
are those, wherein the ring portion of formula (II) is piperidinyl, piperazinyl, nonahydro-
quinolinyl or 3,4-dihydro-lH-quinolinyl. In another class of preferred compounds are
compounds of formula (I), wherein R1 is -CO-NR4-ZR9R13. Z is suitably a 6 or 10

membered saturated, partially saturated or aromatic ring, which may be monocyclic or
bicyclic, and which may contain 1 or 2 N atoms. Examples of particularly preferred
compounds are those, wherein Z is cyclohexyl, piperidinyl, phenyl, naphthyl or
quinolinyl. In a subclass of preferred compounds are compounds, wherein Z is
cyclohexyl, R4 is hydrogen, R9 is RANH2 and R13 is hydrogen.
In another class of preferred compounds are compounds of formula (I), wherein
A is N and B is CH. In still another class of preferred compounds are compounds of
formula (I), wherein A is CH and B is CH. Particularly preferred are compounds of
formula (I), wherein R3 is -C(NR17)NH2 and R10, R14 and R15 are hydrogen. Examples of
particularly preferred compounds are those wherein R2 is a group of formula (III)
wherein G is CH, y is 0-1, R11 is -C(NR17)NH2 or amino C1-7 alkyl, R12 and Ri6 are
hydrogen. In still another class of preferred compounds are compounds of formula (I),
wherein P1 and P2 is a bond. In still another class of preferred compounds are
compounds of formula (I), wherein P1 is a bond and P2 is -CH2-.
The present invention also provides a pharmaceutical composition comprising a
compound of formula (I) together with a pharmaceutically acceptable carrier.
The present invention provides further a method for the treatment of a matriptase
dependent condition, comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of formula (I).
The present invention provides further a method for the treatment of cancer,
comprising administering to a subject in need thereof a therapeutically effective amount
of a compound of formula (I).
Detailed description of the invention
The compounds of the invention can be prepared according to the following
Schemes. It should be noted that any appropriate leaving groups, e.g. N-protecting
groups, such as t-butoxycarbonyl (t-BOC) group, can be used in well known manner
during the syntheses in order to improve the selectivity of the reaction steps.

Compounds of formula (I), wherein R, is -NHSO2R6, R3 is -C(NR17)NH2, R2 is a
group of formula (III) and R11 is -C(NR17)NH2 can be prepared according to the Scheme
1 or Scheme 2 by sulfonylating the amino group of the compound of formula (IV) with
suitable sulfonylchloride CI-SO2R6 using a base such as sodium hydride, TEA, DIPEA
or combinations thereof along with solvents such DMF, THF and the like at
temperatures ranging from about 0 °C to 80 °C. The reaction affords the sulfonamide of
formula (V).

Compound of formula (V) is converted to the corresponding imidate (VI') or
hydroxyamidine (VI) derivative as explained below.
Using the method of Scheme 1, the nitrile group of the compound (V) is reacted
with hydroxylamine hydrochloride with a suitable base such as TEA or DIPEA in
solvent such as DMF, THF and the like at temperatures ranging from about 20 °C to 100
°C to afford the hydroxyamidine compound (VI). This compound is either first
acetylated using acetic anhydride in solvents such as acetic acid at RT and then reduced
using a reducing agent such as Zn, Pd/C and the like in solvents such as methanol,

ethanol or acetic acid at temperatures ranging from about 20 °C to 50 °C to afford the
corresponding amidine compound (VIII). Alternatively the hydroxyamidine (VI) is
directly reduced with a reducing agent such as Pd/C in solvents such as methanol or
acetic acid at a temperature ranging from about 40 °C to 70 °C to afford the
corresponding amidine compound (VIII).
Subsequent to the above step, deprotection of the product from any protecting
groups such as t-BOC, where applicable, is carried out with appropriate reagents such as
HC1 - TFA or the like to afford the required final compounds.
Using the method of Scheme 2, the nitrile group of the compound of formula (V)
is allowed to react with alcoholic HC1 for approximately 15 to 48 h at a temperature
ranging from about 0 °C to about RT to afford the corresponding imidate ester (VI').
This compound is then subjected to reaction with alcoholic ammonia to get the
corresponding amidine compound (VIII).
Compounds of formula (I), wherein Ri is -CO-NR7R8, and R2 is a group of
formula (III) and R11 is -C(NR17)NH2, can be prepared according to the Scheme 3 by
coupling the carboxylic group of compound (IX) with amine HNR7R8. The reaction is
carried out in the presence of suitable coupling reagents, such as PyBOP, EDC.HC1 or
HOBt and the like, and a base such as DIPEA, TEA and the like in a solvent of such as
THF, DMF and the like under inert atmosphere at a temperature ranging from about 0
°C to 40 °C. The reaction affords the desired amide compound of formula (X). Starting
from compound (X) and following the last steps of Scheme 1 or 2 affords the final
product.

Compounds of formula (I), wherein R1 is a group of formula (II), and R2 is a
group of formula (III) and R11 is -C(NR17)NH2, can be prepared according to the
Scheme 5 such as to obtain first a compound of formula (XII) and following then the
last steps of Scheme 1 or 2 to obtain the final product.
R
R
Compounds of formula (I), wherein R1 is a group of formula (II), R2 is a group of
formula (III), and R9 or R13 is -C0RBNH2 group linked to a nitrogen atom of the ring
portion of formula (II), can be prepared according to the Scheme 6 such as to obtain first
a compound of formula (XV) by a acid coupling reaction and following then the last
steps of Scheme 1 or 2 to obtain the final product. L is an acid labile protection group
such as a t-BOC group.


Similarly, compounds of formula (I), wherein R1 is -CO-NR4-ZR9R13, R2 is a
group of formula (III), and R9 or R13 is -COR NH2 group linked to a nitrogen atom of
the ring portion Z, may also be prepared by reacting compound of formula (IX) with a
compound of formula HNR4-Z-L, wherein L is an acid labile protection group, such as a
t-BOC group, attached to the nitrogen atom of the ring portion Z. After deprotection, the

atnino moiety of the Z ring is coupled with HOOCRBNH2 by acid coupling reaction to
obtain first a compound of formula (XVI)

and following then the last steps of Scheme 1 or 2 to obtain the final product.
Compounds of formula (I), wherein R1 is a group of formula (II), R2 is a group of
formula (III), and R9 or R13 is carboxy C1-7 alkyl or RANH2 group linked to a nitrogen
atom of the ring portion of formula (II), may be prepared according to the Scheme 7
such as to obtain first a compound of formula (XVII) by an alkylhalide reaction and
following then the last steps of Scheme 1 or 2 to obtain the final product.


Similarly, compounds of formula (I), wherein R1 is -CO-NR4-ZR9R13, R2 is a
group of formula (III), and R9 or R]3 is carboxy C1-7 alkyl or RANH2 group linked to a
nitrogen atom of the ring portion Z, can be prepared by coupling the amino moiety of
the Z ring with a suitable alkylhalide, e.g. XRANH2, wherein X is halogen, to obtain a
compound of formula (XVIII)

and following then the last steps of Scheme 1 or 2 to obtain the final product.
Compounds of formula (I), wherein R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy
C1-7 alkyl, C1-7alkoxycarbonyl C1-7 alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, or
RDC(NR17)NH2, may be prepared starting from a compound of formula (XIX),

wherein R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-7 alkyl, C^alkoxycarbonyl C1-7
alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, or RDC(NR17)NH2, and Y is
-NH2, or -COOH, and following the general procedures of any of Schemes 1 to 7 to
obtain the final product.
Compounds of formula (I), wherein R2 is a group of formula (III) and R11 is
hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7 alkoxycarbonyl, halogen C1-7
alkoxy, -NHCORGNH2 or RJNHCOORU may be prepared starting from a compound of
formula (XX),


wherein T is hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7
alkoxycarbonyl, halogen C1-7 alkoxy, -NHCORGNH2 or RJNHCOORU, and Y is
-NH2, or -COOH, and following the general procedures of any of Schemes 1 to 7 to
obtain the final product.
Compounds of formula (I), wherein R3 is amino C1-7 alkyl or both R3 and R11 are
amino C1-7 alkyl, can be prepared by treating the nitrile compound of formula (V), (X),
(XI), (XII), (XV), (XVI), (XVII), (XVIII) or (XX) with Raney nickel and
NH3-methanol on hydrogen gas pressure.
Intermediate compounds of formula (IV) can be prepared according to Scheme 8
in a reaction between halide and alcohol. A halide (or alcohol) of formula (XXI),
wherein Mi and M2 is halogen or a hydroxyl group, is treated with an alcohol (or halide)
of formula (XXII), wherein Li is halogen or a hydroxyl group, in the presence of a base
such as potassium carbonate, sodium hydride, cesium carbonate and the like in suitable
solvent, such as DMF, THF and the like, at temperatures ranging from about 0 °C to 45
°C to obtain a halide (or alcohol) compound of formula (XXIII).
The halide (or alcohol) compound of formula (XXIII) is reacted with an alcohol
(or halide) compound of formula (XXIV), wherein Ti is halogen or a hydroxyl group, in
the presence of a base and suitable solvent at temperatures ranging from about 40 °C to
85 °C to obtain the nitro compound of formula (XXV). Reduction of the nitro group can
be carried out using a reducing agent such as zinc or palladium/carbon under hydrogen
pressure along with solvents such as acetic acid/ methanol/ ethanol at temperatures
ranging from about 0 °C to 80 °C.


Intermediate compound (IX) can be prepared in a similar manner using a reaction
between halide and alcohol according to Scheme 9, wherein M1, M2, L1 and T1 mean
halogen or a hydroxyl group. Hydrolysis of ester group of the compound of formula
(XXVIII) can be carried out using a base such as lithium hydroxide, sodium hydroxide
and the like in solvent such as THF-water mixture at temperatures ranging from about 0
°C to 25 °C.


Intermediate compounds of formula (XIX) can be prepared using a reaction
between halide and alcohol according to Scheme 10, wherein M2 and Li mean halogen
or a hydroxyl group, Yi means -NO2, -NH2, -COOEt or -COOH group, R2 is C1-7 alkyl,
amino C1-7 alkyl, carboxy C1-7 alkyl, C1-7 alkoxycarbonyl C1-7 alkyl, C1-7 alkylamino,
carboxy C1-7 alkylamino, RDC(NR17)NH2, and Y means -NH2 or -COOH group.


Compounds of formula (I) wherein R10, R14 and/or R15 is halogen, halogen C1-7
alkyl or -C(NR17)NH2 can be prepared according to the above Schemes starting from
compound (XXII) that contain 1 to 3 further nitrile, halogen and/or halogen C1-7 alkyl
substituents in the ring portion.
Pharmaceutically acceptable salts, e.g. acid addition salts with both organic and
inorganic acids are well known in the field of pharmaceuticals. Non-limiting examples
of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates,
formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
Pharmaceutically acceptable esters, when applicable, may be prepared by known
methods using pharmaceutically acceptable acids that are conventional in the field of
Pharmaceuticals and that retain the pharmacological properties of the free form. Non-
limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g.
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-buty\ esters. Phosphate
esters and carbonate esters, are also within the scope of the invention.

The terms employed herein have the following meanings:
The term "halo" or "halogen", as employed herein as such or as part of another
group, refers to chlorine, bromine, fluorine or iodine.
The term "C1-7 alkyl", as employed herein as such or as part of another group,
refers to a straight, branched or cyclized, saturated or unsaturated, chain radical having 1
to 7 carbon atoms. Representative examples of C1-7 alkyl include, but are not limited to,
methyl, ethyl, ethenyl, «-propyl, isopropyl, propenyl, «-butyl, isobutyl, sec-butyl, tert-
butyl, /?-pentyl, isopentyl, neopentyl, w-hexyl, cyclopentyl, cyclohexyl and the like. "C1-3
alkyl" is an embodiment of "C1-7 alkyl" having 1 to 3 carbon atoms.
The term "C2-7 alkenyl", as employed herein as such or as part of another group,
refers to a straight, branched or cyclized chain radical having 2 to 7 carbon atoms, and
containing one or several double bonds.
The term "hydroxy", as employed herein as such or as part of another group,
refers to an -OH group.The term "cyano", as employed herein as such or as part of
another group, refers to a -CN group. The term "amino", as employed herein as such or
as part of another group, refers to a-NH2 group. The term "carboxy", as employed
herein as such or as part of another group, refers to -COOH group. The term "carbonyl",
as employed herein as such or as part of another group, refers to a carbon atom double-
bonded to an oxygen atom (C=O).
The term "C1-7 alkoxy", as employed herein as such or as part of another group,
refers to C1-7 alkyl, as defined herein, appended to the parent molecular moiety through
an oxygen atom. Representative examples of C1-7 alkoxy include, but are not limited to
methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-bxAoxy, and the like.
The term "hydroxyl C1-7 alkyl", as employed herein, refers to at least one
hydroxy group, as defined herein, appended to the parent molecular moiety through a
C1-7 alkyl group, as defined herein. Representative examples of hydroxyl Cj-7 alkyl

include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-
hydroxypropyl, 1 -hydroxypropyl, 1-methyl-1-hydroxyethyl, 1-methyl-1-hydroxypropyl,
and the like.
The term "halo C1-7 alkyl", as employed herein, refers to at least one halogen, as
defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as
defined herein. Representative examples of halo C1-7 alkyl include, but are not limited
to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and the
like.
The term "cyano C1-7 alkyl", as employed herein, refers to a cyano group, as
defined herein, appended to the parent molecular moiety through a C1-7 alkyl group, as
defined herein. Representative examples of cyano C1-7 alkyl include, but are not limited
to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl, and the like.
The term "carboxy C1-7 alkyl", as employed herein as such or as part of another
group, refers to a carboxy group, as defined herein, appended to the parent molecular
moiety through a C1-7 alkyl group, as defined herein.
The term "halogen CR7 alkoxy", as employed herein, refers to at least one
halogen, as defined herein, appended to the parent molecular moiety through a C1-7
alkoxy group, as defined herein.
The term "C1-7 alkoxycarbonyl", as employed herein as such or as part of another
group, refers to a C1-7 alkoxy group, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein.
The term "aminocarbonyl", as employed herein as such or as part of another
group, refers to an amino group, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein.

The term "amino C1-7 alkyl", as employed herein, refers to at least one amino
group, as defined herein, appended to the parent molecular moiety through a C1-7 alkyl
group, as defined herein. Representative examples of amino C1-7 alkyl include, but are
not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-
aminopropyl, 2-aminopropyl, 4-aminobutyl, 1-methyl-1-aminoethyl, and the like.
The term "C1-7 alkylamino", as employed herein as such or as part of another
group, refers to at least one C1-7 alkyl group, as defined herein, appended to the parent
molecular moiety through an amino group, as defined herein. Representative examples
of C1-7 alkylamino include, but are not limited to methylamino, ethylamino,
propylamino, butylamino, dimethylamino, diethylamino, -N-ethyl-N-methylamino, and
the like.
The term "carboxy C1-7 alkylamino", as employed herein as such or as part of
another group, refers to at least one carboxy group, as defined herein, appended to the
parent molecular moiety through an C1-7 alkylamino group, as defined herein
The term "C1-7 alkoxy C1-7 alkyl", as employed herein, refers to at least one C1-7
alkoxy group, as defined herein, appended to the parent molecular moiety through an
C1-7 alkyl group, as defined herein.
The term "C1-7 alkoxycarbonyl C1-7 alkyl", as employed herein, refers to at least
one C1-7 alkoxycarbonyl group, as defined herein, appended to the parent molecular
moiety through an C1-7 alkyl group, as defined herein.
The term "substituted" as used herein in connection with various residues refers
to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C1-7 alkyl, halo
C1-7 alkyl, hydroxy, amino, C1-7 alkoxy, C2-7 acyl C1-7 alkylamino, amino C1-7 alkyl,
nitro, cyano, or thiol substituents.
The "substituted" groups may contain 1 to 3, preferably 1 or 2, most preferably 1
of the above mentioned substituents.

The definition of formula (I) above is inclusive of all the possible stereoisomers
of the compounds, including geometric isomers, e.g. Zand E isomers (cis and trans
isomers), and optical isomers, e.g. diastereomers and enantiomers, and all prodrugesters,
e.g. phosphate esters and carbonate esters. Furthermore, the invention includes in its
scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The
individual isomers may be obtained using the corresponding isomeric forms of the
starting material or they may be separated after the preparation of the end compound
according to conventional separation methods. For the separation of optical isomers, e.g.
enantiomers, from the mixture thereof the conventional resolution methods, e.g.
fractional crystallisation, may be used.
Compounds of the invention may be administered to a patient in therapeutically
effective amounts which range usually from about 0.1 to about 1000 mg per day
depending on the age, weight, ethnic group, condition of the patient, condition to be
treated, administration route and the protease inhibitor used. The compounds of the
invention can be formulated into dosage forms using the principles known in the art.
The compound can be given to a patient as such or in combination with suitable
pharmaceutical excipients in the form of tablets, granules, capsules, suppositories,
emulsions, suspensions or solutions. Choosing suitable ingredients for the composition
is a routine for those of ordinary skill in the art. Suitable carriers, solvents, gel forming
ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting
compounds and other ingredients normally used in this field of technology may be also
used. The compositions containing the active compound can be given enterally or
parenterally, the oral route being the preferred way. The contents of the active
compound in the composition is from about 0.5 to 100 %, preferably from about 0.5 to
about 20 %, per weight of the total composition.
The present invention will be explained in more detail by the following
experiments and examples. The experiments and examples are meant only for
illustrating purposes and do not limit the scope of the invention defined in claims.

EXPERIMENTS
1. Inhibition of matriptase and other proteases
Methods
Purified recombinant matriptase was used in a fluorescence-based screening
assay using Gln-Ala-Arg peptide as a substrate. In this assay the cleavage of AMC from
Boc-Gln-Ala-Arg-7- amido-4 methylcoumarin hydrochloride (Boc-Gln-Ala-Arg-AMC)
(Sigma, USA) was monitored by measuring the increase in fluorescence intensity of
AMC released upon proteolytic cleavage at 480 nm (X.ex= 360 nm). Similarly,
enzymatic assays in fluorimetric or colorimetric format for uPA, Factor Xa, thrombin,
plasmin and trypsin (Sigma, USA) were established using substrates pyroGlu-Gly-Arg-
pNA.HCl, Boc-Gln-Ala-Arg-AMC, CH3OCO-D-CHA-Gly-Arg-PNA.AcoH, Pyro Glu-
Phe-Lys~pNA.HCl and Boc-Gln-Ala-Arg-AMC, respectively.
Results
Enzymatic activity and selectivity of selected compounds of the invention on
different proteases is presented in Table 1. The compounds of the invention were found
to be potent and selective matriptase inhibitors.
TABLE 1. Inhibition of matriptase and other proteases



2. Cytotoxicity and inhibition of migration and invasion
Methods
Cytotoxicity of the compounds was tested in cell lines or primary cells using
Calcein AM assay. This assay measures cell viability by quantitation of cleaved
fluorescent product of a cell permeable substrate that is retained in the cytoplasm of
cells with uncompromised cytoplasmic membrane integrity. The cells were seeded into
96-well plate and allowed to adhere for a day followed by addition of compound at
several different concentrations. After four days of incubation with the compound,
media was removed from the cells followed by addition of PBS and addition of Calcein
AM reagent at 1 uM final concentration. The cells were then allowed to incubate at 37
°C for half an hour followed by reading on the fiuorimeter. Percent viability was
calculated based on fluorescence value obtained at 485/520 nm with cut off at 495 nm.
In the cytotoxicty assays, none of the compounds tested showed any effect up to 10 uM
when tested on the prostate cancer cell lines DU145 and LnCap.

Migration assays were performed to determine the effect of matriptase inhibitors
on cell motility. Cells were seeded with 10 μM test compound into transwell chambers
and allowed to migrate for 24 hours using a combination of 10 % FBS and 5 μg/ml
fibronectin as chemoattractant.
Cell invasion assays were done for quantitating the degree to which invasive
cells penetrate a barrier essentially as in migration assay but with the use of matrigel
consisting of basement membrane components in the transwell inserts and incubating
for 48 hours. The barrier used was matrigel. This was followed by fixing and staining of
the transwell insert with 0.5 % crystal violet in 25 % methanol in order to visualize cells
migrated.
Soft agar colony formation assays were performed to measure the long-term
survival and anchorage-independent growth capacity of tumor cells. DU145 cells were
seeded in 0.7 % nutrient agar with the test compound on an underlay of 1.4 % nutrient
agar in a six well plate. On the day following cell seeding, liquid cell culture medium
containing the compound was added to the well to prevent the agar from drying out and
was changed regularly till the completion of the experiment. The cells were allowed to
form colonies for a period of about three weeks following which the colonies were
stained with 0.005 % solution of crystal violet in 25 % methanol. The colonies were
counted under a dissecting microscope.
Results
Effects of selected compounds on cytotoxicity, migration and invasion of DU145
cells are presented in Table 2.

In order to determine the in vivo efficacy, xenograft models were established by
injecting 5 x 106 DU145 cells with matrigel or 5 x 106 PC3 cells without matrigel
subcutaneously. Once the rumors reached palpable size (-80 mm3), compound of
Example 27 was administered in a vehicle comprising of 2 % ethanol, 10 % hydroxyl
cyclodextrin in 0.9 % saline. The compound of Example 27 was dosed subcutaneously
to animals with DU145 tumors at 1.5, 5 and 15mg/kg for 15 days. In the PC3 xenograft
study, compound of Example 27 was administered at 0.5, 1.5, 5.0 and 15.0 mg/kg daily.
Results
In DU145 xenograft study the compound of Example 27 caused a significant
reduction in tumor volume as shown in Table 4.
TABLE 4. Tumor growth inhibition in DU145 model upon treatment with the
compound of Example 27 (for 15 days)

In the PC3 xenograft study, the compound of Example 27 caused significant and
dose-dependent inhibition of tumor growth as shown in Table 5.

TABLE 5. Tumor growth inhibition in PC3 model upon treatment with the
compound of Example 27 (for 21 days)

4. Maximum tolerated dose (MTD)
An MTD study was performed for the compound of Example 27. The objective
of the study was to establish the maximum dose that does not induce drug related
lethality and/or body weight loss of more than 20 % of baseline weight during the study
period of 14 days. The compound was administered at 1, 3, 10 and 30 mg/kg once daily
in male athymic mice via subcutaneous route in 5 mice each. Dosing of AUOR-05-0149
at the tested doses did not show any mortality. Body weight reduction was less than 2 %
and no gross changes in clinical signs were seen indicating doses up to 30 mg/kg are
well tolerated.
The preparation of the compounds of the invention is illustrated by the following
Examples.
EXAMPLES.
LCMS data has been recorded in +ve mode unless otherwise mentioned.
Example 1.
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
a) 2,6-Bis (4-cyano phenoxy)-3-nitro pyridine

Potassium carbonate (2.09 g, 15.1 mmol) was added to a stirred solution of 2,6-
Dichloro-3-nitro pyridine (1.0 g, 5.3 mmol), dissolved in 10 ml of DMF, at a
temperature of 5 °C. The flask was stirred for 10 min at the same temperature.
4-cyano phenol (1.26 g, 10.6 mmol), dissolved in 5 ml of DM,F was added dropwise to
the reaction mixture over a period of 10 min and the flask was heated to 80°C for 10-12
hrs. The reaction mixture was poured into ice-cold water and the product was extracted
with 250 ml of ethyl acetate. Ethyl acetate layer was washed with water and brine
solution. The organic layer was dried over anhydrous sodium sulphate and concentrated
under reduced pressure to afford 1.35 g of the required 2,6-Bis (4-cyano phenoxy)-3-
nitro pyridine which was used in the next step without further purification. 1H NMR
(DMSO-d6): 8 7.06 (1H, d), 7.32 (4H, dd), 7.82 (4H, t), 8.74 (1H, d).
b) 3-Amino-2,6-bis (4-cyano phenoxy) pyridine
10 % Pd/ carbon (0.24 g) was added under hydrogen atmosphere (balloon pressure)
to a stirred solution of 2,6-Bis (4-Cyano phenoxy)-3-nitro pyridine (1.20 g, 3.35 mmol)
in 20 ml of methanol: ethyl acetate (1:1) at ambient temperature and the reaction
mixture was stirred for lhr. The reaction mixture was filtered through celite, washed
with 20 ml of ethyl acetate and concentrated under reduced pressure. Water was added
to the residual mixture and it was extracted with ethyl acetate. Ethyl acetate layer was
washed with water followed by brine. The organic layer was dried over sodium sulphate
to afford 0.95 g of the title product which was used for the next step without further
purification. !H NMR (DMSO-d6): 5 5.32 (2H, brs), 6.82 (1H, d), 7.15 (1H, d), 7.22
(2H, d), 7.34 (2H, d), 7.80 (4H, m).
c) 2,6-Bis-(4-cyano-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
4-Fluoro benzene sulfonyl chloride (0.15 g, 0.77 mmol), dissolved in 2 ml of
tetrahydrofuran (THF), was added to a stirred solution of 3-amino-2,6-bis (4-cyano
phenoxy) pyridine (0.25 g, 0.77 mmol), triethylamine (0.155 g, 1.54 mmol) and N,N-
diisopropylethylamine (0.1 g, 0.77 mmol), in 10 ml of THF, in an inert atmosphere and

stirred at RT for 12hrs. The reaction mixture was concentrated and dissolved in 100 ml
of ethyl acetate, washed with 1 N HC1 followed by saturated brine solution and dried
over anhydrous sodium sulphate. The organic phase was concentrated and the crude
product was purified by column chromatography to afford 0.3 g of the required
compound. 'H NMR (DMSO-d6): 5 6.94 (1H, d), 7.12 (2H, m), 7.25 (1H, d), 7.35 (4H,
d), 7.56 (4H, m), 7.80 (4H, m), 8.04 (4H, m).
d) 2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)-
pyridine
2,6-Bis-(4-cyano-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine 0.3 g (0.61
mmol) was added to 70 ml of ethanol (saturated with HC1 gas at -25°C) and the reaction
mixture was kept in a tight vessel at room temperature overnight. The reaction mixture
was concentrated under reduced pressure to afford 0.46 g of the crude product which
was taken for the next step without purification. Percentage purity: 51.1 %, (M+l) =
578.1+1.
e) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
0.46 g (0.79 mmol) of 2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-3-(4-fluoro-
benzene-sulphonamido)-pyridine was added to 70ml of ammoniated ethanol (ethanol
saturated with NH3 gas at -50 °C). The reaction mixture was kept in tight vessel (sealed
tube) at room temperature for 48 hrs. The reaction mixture was cooled in dry ice and
concentrated under reduced pressure to afford a crude product which was purified by
reverse-phase preparative HPLC to afford 0.15 g of the required product. Percentage
purityrHPLC 98.16 %; LCMS 95.66 %. *H NMR (DMSO-d6): 8 6.9 (1H, d), 7.0 (2H, d),
7.3 (4H, m), 7.8 (6H, m), 9.25 (7H, m), 10.3 (1H, s).
Example 2.
2,6-Bis (4-carbamimidoyl phenoxy)-3-(2-naphthyl sulphonamido)-pyridine
Intermediates (a) and (b) are the same as in Example 1.

c) 2,6-Bis-(4-cyano-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine
2-Naphthyl sulfonyl chloride (0.17 g, 0.76 mmol) was added to a stirred solution of
3-amino-2,6-bis (4-cyano phenoxy) pyridine (0.25 g, 0.76 mmol) along with other
reagents as mentioned in Example l(c) to afford 0.27 g of the required product. 'H
NMR (DMSO-d6): 5 5.38 (1H, brs), 6.82 (1H, d), 7.12 (1H, d), 7.22 (2H, d), 7.35 (2H,
dd), 7.44 (1H, d), 7.80 (7H, m), 7.95 (2H, m), 8.15 (2H, d), 8.56 (1H, s).
d) 2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphonamido)-
pyridine
AW-Diisopropylethylamine (DIPEA) 0.36 ml (2.08 mmol) followed by 144 mg
(2.08 mmol) of hydroxylamine hydrochloride was added to a stirred solution of 2,6-bis-
(4-cyano-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine 0.27 g (0.52 mmol) in 10 ml
of ethanol and the flask was heated at 100°C for 8 hrs. The reaction mixture was
concentrated under reduced pressure to afford 0.35 g (57.5 %) of the product which was
used for the next step without further purification. M+= 584.1+1 (actual mass: 584.1).
e) 2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphon-
amido)-pyridine
Acetic anhydride (0.12 ml, 1.25 mmol) was added dropwise to a solution of 2,6-bis-
(4-(N-hydroxycarbamimidoyl)-phenoxy)-3 -(2-naphthyl-sulphonamido)-pyridine (0.3 5 g,
0.59 mmol) in 5 ml of acetic acid at room temperature. The reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was concentrated under reduced
pressure to afford 0.3 g (51.0 %) of the crude product which was used for the next step
without further purification. M+= LCMS (+ve mode) 668.1+1.
f) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine

10 % Pd/C (0.1 g) was added under an atmosphere of nitrogen gas to 2,6-bis-(4-(N-
acetylhydroxycarbamimidoyl)-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
0.3 g (0.44 mmol) dissolved in 50 ml methanol. 30 mg of 10 % Pd/C was added under
nitrogen atmosphere and the reaction mixture was stirred under hydrogen pressure
(balloon) at room temperature for 3 hours. The reaction mixture was passed through
celite, washed with methanol and concentrated under reduced pressure. The concentrate
was purified using reverse-phase preparative HPLC column to afford 0.06 g. of the
required product. Percentage purity: HPLC 85.01 %; LCMS 82.7 3%. !H NMR
(DMSO-d6): 5 6.75 (2H, d), 6.9 (1H, d), 7.3 (2H, d), 7.5 (2H, d), 7.65 (2H, m), 7.8 (3H,
d), 8.0 (4H, m), 8.35 (1H, s), 9.03 (4H, d), 9.2 (4H, s), 10.2 (1H, s).
Example 3.
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(8-quinoline-sulphonamido)-pyridine
Intermediates (a) and (b) are the same as in Example 1.
c) 2,6-Bis-(4-cyano phenoxy)-3-(8-quinoline-sulphonamido)-pyridine
8-Quinoline sulfonyl chloride (0.172 g, 0.76 mmol) was added to a stirred solution
of 3-amino-2,6-bis (4-cyano phenoxy) pyridine (0.25 g, 0.76 mmol). Using other
reagents and reaction conditions as mentioned in Example l(c) afforded 0.4 g of the
required product. JH NMR (DMSO-d6): 8 6.92 (1H, d), 7.11 (1H, d), 7.18 (2H, d), 7.25
(1H, d), 7.51 (2H, d), 7.56 (1H, dd), 7.66 (1H, t), 7.74 (2H, d), 7.80 (2H, m), 7.98 (1H,
d), 8.20 (2H, m), 8.3 8(1 H, d).
d) 2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulphonamido)-
pyridine
2,6-Bis-(4-cyano phenoxy)-3-(8-quinoline-sulphonamido)-pyridine 0.4 g (0.77
mmol), DIPEA 0.53 ml (3.08 mmol) and 214 mg (3.08 mmol) of hydroxylamine
hydrochloride were used to synthesize 2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-

3-(8-quinoline-sulphonamido)-pyridine using the procedure of Example 2(d) to afford
0.4 g of the required product. Percentage purity: 94.4 %, (M+l) = 585.1+1.
e) 2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-
sulphonamido)-pyridine
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulphonamido)-
pyridine 0.4g (0.68 mmol) was acetylated with 0.14g (1.36 mmol) of acetic anhydride
using the procedure of Example 2(e) to afford 0.4 g.of the required product. Percentage
purity: 38.6 %, (M+l) = 669.1+1.
f) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(8-quinoline-sulphonamido)-pyridine
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-
sulphonamido)-pyridine 0.4g (0.59 mmol) was reduced using the procedure of Example
2(f) to afford 0.2 g of required product. Percentage purity: HPLC 95.88 %; LCMS 97.3
%. lK NMR (DMSO-d6): 5 6.5 (2H, d), 6.85 (1H, d), 7.25 (2H, d), 7.55 (3H, m), 7.7
(1H, m), 7.8 (2H, d), 8.0 (1H, d), 8.25 (2H, t), 8.4 (1H, d), 8.98 (1H, d), 9.1 (4H, d), 9.2
(4H, d), 9.65 (1H, brs).
Example 4.
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(3,5-difluoro-benzene-sulphonamido)-
pyridine
Intermediates (a) and (b) are the same as in Example 1.
c) N-[2,6-Bis-(4-cyano-phenoxy)-pyridin-3-yl]-3,5-difluoro-benzenesulfonamide
3,5-difiuorobenzene sulfonyl chloride (0.5 g, 2.35 mmol) was added to a stirred
solution of 3-amino-2,6-bis (4-cyano phenoxy) pyridine (0.77 g, 2.35 mmol) using the
reagents and reaction conditions described in Example l(c) to afford 0.9 g of the
required product. 1H NMR (DMSO-d6): 5 6.82 (1H, d), 6.95 (1H, d), 7.11 (2H, d), 7.24
(3H, m), 7.34 (2H, d), 7.80 (7H, m).

d) 2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene-
sulphonamido)-pyridine
N-[2,6-Bis-(4-cyano-phenoxy)-pyridin-3-yl]-3,5-difluoro-benzenesulfonamide 0.9 g
(1.78 mmol), DIPEA 1.24 ml (7.12 mmol) and 0.494 g (7.12 mmol) of hydroxylamine
hydrochloride were used as described in Example 2(d) to afford 0.8 g of the required
product. Percentage purity: 62.1 %, (M+l) = 570.0+1.
e) 2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene-
sulphonamido)-pyridine
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene-sulphon-
amido)-pyridine, 0.8 g (1.40 mmol), was acetylated with 0.29 g (3.1 mmol) of acetic
anhydride using the procedure of Example 2(e) to afford 0.8 g of the required product.
Percentage purity: 47.3 %. (M+l) = 654.1+1.
f) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(3,5-difluoro-benzene-sulphonamido)-
pyridine
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene-
sulphonamido)-pyridine, 0.8 g (1.22 mmol), was reduced using the procedure of
Example 2(f) to afford 0.2 g of required product. Percentage purity: HPLC 88.35 %;
LCMS 93.37 %. 1H NMR (DMSO-d6): 8 6.6 (3H, m), 6.9 (1H, d), 7.05 (2H, d), 7.35
(2H, d), 7.5 (3H, m), 7.8 (2H, m), 7.9 (1H, d), 9.1 (3H, s), 9.25 (3H, s), 10.5 (1H, s).
Example 5.
2-(l - {2,6-Bis-[4-carbamimidoyl-phenoxy]-pyridine-3-carbonyl} -piperidin-4-yl)-
ethylamine
a) 2,6-Bis (4-Cyano phenoxy)-nicotinic acid ethyl ester

Potassium carbonate 1.58 g (11.5 mmol) was added to a stirred solution of 2,6-
dichloro-nicotinic acid ethyl ester 1.0 g (4.6 mmol) in 5 ml of DMF and stirred for 10
min. 4-Hydroxy-benzonitrile 1.36 g (11.5 mmol), dissolved in 5 ml of DMF, was added
dropwise to the stirred DMF solution and the flask was stirred at 80 °C for 4 hrs. The
reaction mixture was poured into ice-cold water and the result was partitioned using
ethyl acetate. The organic phase was washed with 1 M of Na2CO3 and saturated brine
solution, dried over sodium sulphate and concentrated. The oily residue was purified by
column chromatography using hexane-ethyl acetate (10 : 2) to afford 1.6 g of the
required product. Percentage purity: 84.8 %, (M+l) =385.1.
'H NMR (DMSO-d6): 5 1.36 (3H, t), 4.22 (2H, q), 6.78 (1H, d), 7.06 (4H, d), 7.58 (4H,
d), 8.21 (1H, d).
b) 2,6-Bis (4-cyano phenoxy)-nicotinic acid
0.2 g (8.4 mmol) of lithium hydroxide was added to a stirred solution of 2,6-bis (4-
cyano phenoxy)-nicotinic acid ethyl ester, 1.6 g (4.15 mmol), in a mixture of 5 ml of
water and 2.5 ml of THF (2:1) at 5 °C and the contents were stirred for 3 hrs at RT. The
reaction mixture was washed with diethylether. 6 N HC1 was added to aqueous layer
with stirring until the solution attained a pH of 2.The white precipitate obtained was
collected, washed with water and dried under reduced pressure to afford 1.1 g of the
required product. Percentage purity (LCMS): 83.2 %, (M+l) = 357.0+1. 1H NMR
(DMSO-d6): 5 6.98 (1H, d), 7.26 (4H, d), 7.80 (4H, d), 13.22 (1H, brs).
c) (2-{1 -[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-piperidin-4-yl} -ethyl)-
carbamic acid tert-butyl ester
A solution of 2,6-Bis (4-cyano phenoxy)-nicotinic acid, 0.335 g (0.94 mmol), in 5
ml of DMF was zidded dropwise to the stirred suspension of 0.489 g (0.94 mmol) of
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) in 5 ml
of DMF and followed by N,N.-diisopropylethylamine 0.242 g (1.88 mmol) while the
temperature was maintained below 5 °C during the addition. The mixture was stirred for
10 min and a solution of (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.214 g,

0.94 mmol) in 2 ml of DMF was added. The mixture was stirred overnight at RT. The
solvent was concentrated under reduced pressure and the residue was dissolved in a
mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2 - 3 with
6 N HC1 and the phases were separated. The aqueous phase was extracted with ethyl
acetate. The combined organic phase was washed with 10 % solution of potassium
hydrogen sulphate followed by saturated sodium bicarbonate solutiona and saturated
brine solution, and dried over sodium sulphate and concentrated. The crude oily residue
was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.4
g of the required product. Percentage purity: 36.3 %, (M+l) = 567.2. ]H NMR (DMSO-
d6): 5 1.35 (3H, m), 1.38 (9H, s), 1.65 (2H, m), 2.71 (2H, m), 2.95 (4H, m), 3.75 (2H,
m), 6.80 (1H, t), 6.95 (1H, d), 7.32 (4H, d), 7.68 (1H, m), 7.85 (4H, d).
d) 2-(l-{2,6-Bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin-
4-yl)-ethylamine
Using (2-{l-[2,6-bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-piperidin-4-yl}-
ethyl)-carbamic acid tert-butyl ester (0.4 g, 0.7 mmol) and following the procedure of
Example l(d) afforded 0.4 g of the required product. Percentage purity (LCMS): 30.7
%. (M+l) = 559.2.
e) 2-(l-{2,6-Bis-[4-carbamimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin-4-yl)-
ethylamine
Using (2-( 1 -{2,6-bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-
piperidin-4-yl)-ethylamine (0.4 g, 0.71 mmol) and following the procedure of Example
l(e) 0.05 g of the required product was obtained. Percentage purity: HPLC 93.52 %.
LCMS 96.46 %. 1H NMR (DMSO-d6): 5 1.5 (2H, m), 1.65 (2H, m,), 1.85 (2H, m), 2.8
(3H, m), 3.1 (1H, m), 3.7 (2H, m), 4.5 (1H, d), 6.9 (1H, d), 7.2 (1H, s), 7.4 (4H, t), 7.9
(5H, brs), 8.05 (1H, brs), 9.3 (6H, s).
Example 6.
N-(4-Ammo-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-nicotinamide

Intermediates (a) and (b) are the same as in Example 5.
c) (4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}-cyclohexyl)-
carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-cyano phenoxy)-nicotinic acid
0.335 g (0.94 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g,
0.94 mmol) were used to afford 0.35 g of the required product. Percentage purity
(LCMS): 86.8 %, (M+l) = 553.6 (with BOC). lU NMR (DMSO-d6): 5 1.25 (4H, m),
1.38 (9H, s), 1.82 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 6.74 (1H, d), 6.95 (1H, d,), 7.28
(4H, dd), 7.82 (4H, dd), 8.08 (1H, d), 8.21 (1H, d).
d) 4-({2,6-Bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-amino)-
cyclohexylamine
(4- {[2,6-Bis- (4-cyano-phenoxy)pyridine-3 -carbonyl] amino} -cyclohexyl)carbamic
acid tert-butyl ester (0.35 g, 0.63 mmol) was used and the procedure of Example l(d)
was followed to afford 0.3 g of the required product. Percentage purity (LCMS): 40.2 %,
(M+l) = 545.2.
e) N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-nicotinamide
4-( {2,6-Bis-| 4-ethoxycarbonimidoyl-phenoxy] -pyridine-3 -carbonyl} -amino)-
cyclohexylamine (0.3 g, 0.55 mmol) was used the procedure of Example l(e) was
followed to afford 0.05 g of the required product. Percentage purity: HPLC 97.07 %.
LCMS 81.64 %. 'HNMR(DMSO-d6): 5 1.4 (4H, m), 1.95 (4H, m), 3.0 (1H, m), 3.7
(1H, m), 6.9 (1H, d), 7.0 (2H, d,), 7.3 (4H, m), 7.8 (6H, m), 9.25 (7H, m), 10.3 (1H, s).
Example 7.
3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-amino }-propyl-
amine

Intermediates (a) and (b) are the same as in Example 5.
c) (3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propyl)-carbamic
acid tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-Cyano phenoxy)-nicotinic acid
0.335 g (0.94 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (0.163 g, 0.94
mmol) were used to afford 0.3 g of the required product. Percentage purity (LCMS):
78.7 %,(M+1) = 513.5+1.
d) 3- {[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-pyridine-3-carbonyl]-amino} -
propylamine
(3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propyl)-carbamic
acid tert-butyl ester (0.3 g, 0.58 mmol) was used following the procedure of Example
l(d) to afford 0.3 g of the required product. Percentage purity (LCMS): 38.6 %, (M+l)
=505.2.
e) 3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-amino}-
propylamine
3-{[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-pyridine-3-carbonyl]-amino}-
propylamine (0.3 g, 0.59 mmol) was used following the procedure of Example l(e) to
afford 0.12 g of the required product. Percentage purity: HPLC: 92.98 %. LCMS: 97.61
%. :H NMR (DMSO-d6): 5 1.8 (2H, m), 2.85 (2H, m), 3.45 (2H, m), 6.9 (1H, d), 7.0
(1H, s), 7.2 (1H, d), 7.3 (4H, m), 7.85 (6H, d), 8.3 (1H, d), 8.55 (1H, brs), 9.3 (7H, brs).
Example 8.
3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}propionic
acid
Intermediates (a) and (b) are the same as in Example 5.

c) 3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionicacid ethyl
ester
Following the procedure of Example 5(c) 2,6-bis (4-Cyano phenoxy)-nicotinic acid
0.5 g (1.42 mmol) and 3-amino-propionic acid ethyl ester (0.166 g, 1.42 mmol) were
used to afford 0.5 g of the required product. Percentage purity (LCMS): 30.7 %, (M +1)
= 456.1.
d) 3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic acid
3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic acid ethyl
ester (0.5 g, 1.09 mmol) was deesterified using the procedure of Example 5(b) to afford
0.35 g of the required product. Percentage purity (LCMS): 71.6 %, (M+l)= 428.4.
e) 3-{[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl]amino} -
propionic acid
3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic acid (0.35
g, 0.81 mmol) was used and the procedure of Example l(d) was followed to afford 0.3 g
of the required product. Percentage purity (LCMS): 38.6 %, (M+l) = 520.1 +2.
f) 3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]amino}propionic
acid
3 - {[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3 -carbonyl] amino} -
propionic acid (0.3 g, 0.57 mmol) was used and the procedure of Example l(e) was
followed to afford 0.15 g of the required product. Percentage purity: HPLC: 95.73 %.
LCMS: 97.10 %. 1HNMR (DMSO-d6): 5 2.3 (1H, m), 3.5 (1H, m), 6.9 (1H, d), 7.04
(1H, s), 7.22 (1H, s), 7.4 (3H, m), 7.88 (2H, d), 8.36 (1H, d), 8.52 (1H, m), 9.3 (4H, d).
Example 9.

3-{4-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-piperazin-l-yl}-
3 -oxo-propylamine
Intermediates (a) and (b) are the same as in Example 5.
c) 4-[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]-piperazine-1 -carboxylic acid
tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-cyano phenoxy)-nicotinic acid
1.25 g (3.5 mmol) and piperazine-1 -carboxylic acid tert-butyl ester (0.65 g, 3.5 mmol)
were used to afford 1.2 g of the required product. Percentage purity (LCMS): 95.6 %,
(M+l) =525.2 (with BOC). ]H NMR (DMSO-d6): 8 1.40 (9H, s), 3.30 (2H, m), 3.42
(4H, m), 3.61 (2H, m), 6.98 (1H, d), 7.35 (4H, m), 7.82 (4H, dd), 8.02 (2H, d).
d) 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine
4-[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]-piperazine-l-carboxylic acid
tert-butyl ester 1.2 g (2.28 mmol) was dissolved in 5 ml of DCM at 5°C under inert
atmosphere. 0.7 ml of TFA was added over a 10 minute period, while the temperature
was maintained at 5 °C. Stirring was continued for lhr at RT and reaction progress was
monitored by TLC. The reaction mixture was concentrated under reduced pressure and
the residual crude product was purified by column chromatography using chloroform:
ethylacetate (8 : 2) as eluant to afford 0.9 g of the required product. Percentage purity
(LCMS): 88.2 %, (M+l): 425.1. !H NMR (DMSO-d6): 5 3.15 (2H, m), 3.22 (2H, m),
3.64 (2H, m), 3.85 (2H, m), 7.00 (1H, d), 7.34 (4H, t), 7.82 (4H, t), 8.08 (1H, d), 9.02
(lH,brs).
e) (3-{4-[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]piperazin-1 -yl} -3-oxo
propyl)carbamic acid tert-butyl ester
A solution of 3-tert-butoxycarbonylamino-propionic acid, 0.177 g (0.94 mmol), in
3 ml of DMF was added dropwise to a stirred suspension of 0.72 g (3.76 mmol) of 1-

ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and
hydroxybenzotriazole (HOBT) 0.508 g (3.76 mmol) in 5 ml of DMF at RT. That was
followed by the addition of A^A'-diisopropylethylamine (DIPEA) 0.242 g (1.88 mmol)
while the temperature was maintained below 5 °C . The mixture was stirred for 10 min
and a solution of 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine (0.4 g,
0.94 mmol) in DMF (10 ml) was added followed by stirring overnight at RT. The
reaction mixture was concentrated under reduced pressure and partitioned between
water (150 ml) and ethyl acetate (150 ml) after the pH was adjusted to 2 - 3 with 6N
HC1. The organic phase was washed with 1 M Na2CO3 and saturated brine solution,
dried over sodium sulphate and concentrated. The crude oily residue was purified by
column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.45 g of the
required product. Percentage purity (LCMS): 10.3 %. (M+l) = 596.2 (with BOC).
f) 3-(4-{2,6-bis-(4-ethoxy-carbonimidoylphenoxy)pyridine-3-carbonyl}-piperazin-
l-yl)-3-oxo propylamine
(3 - { 4- [2,6-bis-(4-cyano-phenoxy)pyridine-3 -carbonyl]piperazin-1 -yl} -3 -oxo
propyl)carbamic acid tert-butyl ester (0.45 g, 0.75 mmol) was used and the procedure of
Example l(d) was followed to afford 0.3 g of the required product. Percentage purity
(LCMS): 32.8 %, (M+l) = 496.1.
g) 3- {4-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-piperazin-1 -yl} -
3 -oxo-propylamine
3-(4-{2,6-bis-(4-ethoxy-carbonimidoylphenoxy)pyridine-3-carbonyl}-piperazin-l-
yl)-3-oxo propylamine (0.3 g, 0.60 mmol) was used and the procedure of Example l(e)
was followed to afford 0.12g of the required product. Percentage purity: HPLC 73.56 %;
LCMS 97.21 %. 'H NMR (DMSO-d6): 5 1.8 (2H, m), 2.8 (2H, m), 3.4 (3H, m), 6.9 (1H,
d), 7.04 (1H, s), 7.20 (1H, s), 7.4 (5H, m), 7.88 (7H, m), 8.32 (1H, d), 8.54 (1H, brs),
9.34 (6H, s).
Example 10.

3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}-
piperidinyl)-3-oxo propylamine
Intermediates (a) and (b) are the same as in Example 5.
c) 4-{[2,6-Bis-(4-cyano-phenoxy)pyridme-3-carbonyl]amino}piperidine-l-
carboxylic acid tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-cyano phenoxy)-nicotinic acid
1.5 g (4.20 mmol) and 4-amino-piperidine-l-carboxylic acid tert-butyl ester (0.84 g,
4.20 mmol) were used to afford 1.7 g of the required product. Percentage purity
(LCMS): 74.6 %, (M+l) = 539.2 (with BOC).
d) 2,6-Bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide
Following the procedure of Example 9(d) 4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-
3-carbonyl]amino}piperidine-l-carboxylic acid tert-butyl ester (1.7 g, 3.15 mmol) were
used to afford 1.3 g of the required product. Percentage purity (LCMS): 97.9 %, (M+l)
= 439.1+1.
e) [3-(4-{[2,6-bis-(4-cyanophenoxy)pyridine-3-carbonyl]amino}piperidine-l-yl)-3-
oxo propyl] carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.177 g, 0.91 mmol) and 2,6-bis-(4-
cyano phenoxy)-N-piperidine-4-yl nicotinamide (0.4 g, 0.91 mmol) and other reagents
as described in Example 9(e) were used to afford 0.45 g of the required product.
Percentage purity (LCMS): 82.8 %, (M+l) = 610.1+1.
f) {3-[4-({2.,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-pyridine-3-carbonyl}-
amino)-piperidin-l-yl]-3-oxo propyl}-carbamic acid tert-butyl ester

[3-(4-{[2,6-bis-(4-cyanophenoxy)pyridine-3-carbonyl]amino}piperidine-l-yl)-3-
oxo propyl] carbamic acid tert-butyl ester (0.45 g, 0.73 mmol), hydroxylamine
hydrochloride (0.202 g, 2.92 mmol) and DIPEA (0.377 g, 2.92 mmol) were used
and the procedure of Example 2(d) was followed to afford 0.4 g of the required product.
Percentage purity (LCMS): 68.6 %, (M+l) = 676.3.
g) {3-[4-({2,6-bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-pyridine-3-
carbonyl}amino)-piperidin-l-yl]-3-oxo propyl}-carbamic acid tert-butyl ester
{ 3- [4-( {2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-pyridine-3 -carbonyl} -
amino)-piperidin-l-yl]-3-oxo propyl}-carbamic acid tert-butyl ester 0.4 g (0.59 mmol)
was acetylated with 0.123 g (1.2 mmol) of acetic anhydride. The procedure of Example
2(e) was followed to afford 0.45 g of the required product. Percentage purity (LCMS):
40.0 %, (M+l) = 660.2+1 (de-boc).
h) [3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}-
piperidinyl)-3-oxo propyl] carbamic acid tert-butyl ester
{3 - [4-( {2,6-bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-pyridine-3 -
carbonyl}amino)-piperidin-l-yl]-3-oxo propyl}-carbamic acid tert-butyl ester 0.45 g
(0.59 mmol) was reduced by using the procedure of Example 2(f) to afford 0.2 g of the
required product. Percentage purity (LCMS): 58.5 %. (M+l) = 644.3+1.
i) 3 -(4- {[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3 -carbonyl] -amino} -
piperidinyl)-3-oxo propylamine
The -Boc group was removed from [3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)-
pyridine-3-carbonyl]-amino}-piperidinyl)-3-oxopropyl]carbamic acid tert-butyl ester
0.2 g (0.31 mmol) using the procedure of Example 9(d) to afford 0.055 g of the
required product. Percentage purity (LCMS): HPLC 95.77 %, LCMS 88.95 %. 'H
NMR (DMSO-de): 5 1.4 (3H, m), 1.9 (2H, m), 2.6 (1H, m), 3.0 (2H, m), 3.2 (1H, m),

3.7 (2H, d), 4.2 (2H, d), 6.9 (1H, d), 7.05 (1H, s), 7.2 (1H, s), 7.4 (3H, m), 7.9 (5H, s),
8.3 (2H, dd), 9.35 (6H, d).
Example 11.
N-[l-(3-amino-propyl)piperidin-4-yl]-2,6-bis-(4-carbamimidoyl-phenoxy)-
nicotinamide
Intermediates (a) to (d) are the same as in Example 10.
e) [3-(4-{[2.,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidine-l-yl)
propyl] carbamic acid tert-butyl ester
0.117 g (0.85 mmol) of K2CO3 and A^-diisopropylethylamine 0.072 g (0.56 mmol)
followed by 0.201 g (0.85 mmol) of (3-bromo-propyl)-carbamic acid tert-butyl ester,
dissolved in 5 ml of DMF, were added to a stirred solution of 0.373 g (0.85 mmol) of
2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide, dissolved in 5 ml of DMF
over a period of 15 minutes at 20 °C. Reaction mixture was allowed to attain RT and
heated to 45 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure
to remove the solvent. The residue was partitioned between water (150 ml) and ethyl
acetate (150 ml). The organic phase was washed with 1 M Na2CC>3 and saturated brine
solution, and dried over sodium sulphate. The solution was concentrated and the oily
residue was purified by column chromatography using hexane-ethyl acetate (10 : 2) to
afford 0.45 g of the required product. Percentage purity (LCMS): 72.5 %, (M+l) =
596.2+1.
f) 3-(4-[{2,6-bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl}amino]-
piperidin-1-yl) propylamine
[3 -(4- {[2,6-bis-(4-cyano-phenoxy)pyridine-3 -carbonyl]amino}piperidine-1 -yl)
propyl] carbamic acid tert-butyl ester (0.45 g, 0.75 mmol) was used and the procedure of
Example l(d) was followed to afford 0.3 g of the required product. Percentage purity
(LCMS): 55.6 %, (M+l) = 496.2+1.

g) N-[l-(3-amino-propyl)piperidin-4-yl]-2,6-bis-(4-carbamimidoyl-phenoxy)-
nicotinamide
3-(4-[{2,6-bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl}amino]-
piperidin-1-yl) propylamine (0.3 g, 0.60 mmol) was used by following the procedure of
Example l(e) to afford 0.12 g of the required product. Percentage purity: HPLC: 92.11
%. LCMS: 90.51 %. !H NMR (DMSO-d6): 5 1.8 (2H, m), 2.0 (5H, m), 2.9 (2H, m),
3.15 (4H, m), 4.0 (2H, m), 6.9 (1H, d), 7.35 (3H, d), 7.85 (3H, m), 8.0 (3H, brs), 8.2
(1H, d), 8.5 (1H, d), 9.3 (7H, d), 10.1 (1H, brs).
Example 12.
(2-{l-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidin-4-
yl}-ethylamine
a) 2,6-bis (4-Cyano phenoxy)-isonicotinic acid ethyl ester
Potassium carbonate 3.17 g (23.0 mmol) was added to 2,6-dichloro-isonicotinic
acid ethyl ester 1.0 g (4.6 mmol), dissolved in 5 ml of DMF, and stirred for 10 min. This
was followed by the dropwise addition of 4-hydroxy-benzonitirle 1.64 g (13.8 mmol),
dissolved in 5 ml of DMF, followed by stirring at 100 °C for 3 hrs. The reaction mixture
was poured into ice-cold water and extracted with ethyl acetate. The organic phase was
washed with 1 1VI Na2CC>3 and saturated brine solution, dried over sodium sulphate and
concentrated. The crude oily residue was purified by column chromatography using
hexane-ethyl acetate (10: 2) to afford 0.4 g of the required product. Percentage purity
(LCMS): 87.4 %. (M+l) = 385.1+1. JHNMR (DMSO-d*): 5 1.42 (3H, t), 4.44 (2H, q),
7.16 (4H, d), 7.27 (2H, d), 7.64 (4H, d).
b) 2,6-bis (4-Cyano phenoxy)-isonicotinic acid

0.4 g (1.03 rnmol) of 2,6-bis (4-Cyano phenoxy)-isonicotinic acid ethyl ester was
hydrolysed by using the procedure of Example 5(b) to afford 0.3 g of the required
product. 'H NMR (DMSO-d6): 5 7.22 (2H, s), 7.38 (4H, d), 7.82 (4H, d).
c) (2- {1 -[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]piperidine-4-yl}ethyl)-
carbamic acid tert-butyl esters
2,6-bis (4-Cyano phenoxy)-isonicotinic acid (0.3 g, 0.84 mmol) and (2-piperidin-4-
yl-ethyl)-carbamic acid tert-butyl ester (0.191g, 0.84 mmol) were coupled using the
procedure of Example 5(c) to afford 0.4 g.of the required product. Percentage purity
(LCMS): 79.0 %, (M+l) = 567.2 (with-BOC). 'HNMR (DMSO-do): 5 1.15 (2H, m),
1.38 (9H, s), 1.62 (2H, m), 1.75 (1H, m), 2.74 (1H, m), 2.88 (3H, m), 3.55 (1H, m), 4.42
(1H, m), 6.80 (1H, m), 6.89 (2H, s), 7.35 (4H, d), 7.84 (4H, d).
d) (2- {1 - [2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl] -
piperidine-4-yl}ethyl)carbamic acid tert-butyl esters
(2-{l-[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]piperidine-4-yl}ethyl)-
carbamic acid tert-butyl esters (0.4 g, 0.70 mmol), hydroxylamine hydrochloride (0.194
g, 2.8 mmol) and DIPEA (0.36 g, 2.8 mmol) were used and the procedure of Example
2(d) was followed to afford 0.3g of the required product. Percentage purity (LCMS):
59.2%, (M+l) = 633.3+1.
e) (2-{1 -[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-
carbonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters
(2-{1 - [2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl]-
piperidine-4-yl}ethyl)carbamic acid tert-butyl esters 0.3 g (0.473 mmol) was acetylated
with 0.095 g (0.95 mmol) of acetic anhydride using the procedure of Example 2(e) to
afford 0.3 g of the required product. Percentage purity (LCMS): 56.2 %, (M+l) =
717.3+1.

f) (2- {1 -[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidine-4-
yl}ethyl)carbamic acid tert-butyl esters
(2- {1 -[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-
carbonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters 0.3 g (0.41 mmol) was
reduced using the procedure of Example 2(f) to afford 0.17 g of required product.
Percentage purity (LCMS): 59.3 %, (M+l) = 601.3.
g) 2-{1 -[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidine-4-
yl}ethylamine
The -Boc group was removed from (2-{l-[2,6-Bis-(4-carbamimidoyl-phenoxy)-
pyridine-4-carbonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters 0.17 g (0.31
mmol) using the procedure of Example 9(d) to afford 50 mg of the required product.
Percentage purity: HPLC: 95.99 %. LCMS: 98.52 %. 'H NMR (DMSO-d6): 5 1.1 (2H,
m), 1.5 (2H, m), 1.6 (2H, m), 1.75 (1H, m), 2.7 (1H, m), 2.85 (2H, m), 3.05 (1H, m),
3.55 (1H, m), 4.4 (1H, m), 6.9 (1H, s), 7.4 (4H, d), 7.75 (3H, brs), 7.85 (4H, d), 9.3 (8H,
s).
Example 13.
N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-isonicotinamide
Intermediates (a) and (b) are the same as in Example 12.
c) (4-{[2,6-Bis-(4-cyano-phenoxy)-pyridme-4-carbonyl]amino}-cyclohexyl)-
carbamic acid tert-butyl esters
2,6-bis (4-Cyano phenoxy)-isonicotinic acid (0.428 g, 1.2 mmol) and (4-amino-
cyclohexyl)-carbamic acid tert-butyl ester (0.282 g, 1.32 mmol) were coupled using the
procedure of Example 5(c) to afford 0.51 g of the required product. Percentage purity
(LCMS -ve mode): (M-l) = 553.2. lH NMR (DMSO-d6): 5 1.25 (4H, m), 1.40 (9H, s),

1.84 (4H, m), 2.74 (1H, s), 2.80 (1H, m), 3.22 (2H, m), 3.72 (1H, m), 6.78 (1H, d), 7.28
(1H, s), 7.35 (3H, d), 7.85 (4H, d), 7.95 (1H, s), 8.60 (1H, brs).
d) (4-{[2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl]-
amino}cyclohexyl)carbamic acid tert-butyl esters
(4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-cyclohexyl)-carbamic
acid tert-butyl esters (0.276 g, 0.70 mmol), hydroxylamine hydrochloride (0.208 g, 3.0
mmol) and DIPEA (0.387 g, 3.0 mmol) were used and the procedure of Example 2(d)
was followed to afford 0.7g of the required product. Percentage purity (LCMS): 47.3 %,
(M+l) = 619.2.
e) (4- {[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-
carbonyl]-amino}cyclohexyl)carbamic acid tert-butyl esters
(4-{[2,6-Bis~(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl]-
amino}cyclohexyl)carbamic acid tert-butyl esters 0.6 g (0.96 mmol) was acetylated with
0.2 g (2.0 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 0.65
g of the required product. Percentage purity (LCMS): 59.4 %, (M+l) = 703.2+1.
f) (4-{[2,6-Bis (4-carbamimidoyI-phenoxy)-pyridine-4-carbonyl]amino} cyclo-
hexyl)-carbamic acid tert-butyl esters
(4- {[2,6-Bis~(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl] -
amino}cyclohexyl)carbamic acid tert-butyl esters 0.65 g (0.92 mmol) was reduced by
using the procedure of Example 2(f) to afford 0.56 g of required product. Percentage
purity (LCMS): 60.2 %, (M+l) = 587.2+1.
g) N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-isonicotinamide
The -Boc group was removed from (4-{[2,6-bis(4-carbamimidoyl-phenoxy)-
pyridine-4-carbonyl]amino} cyclohexyl)-carbamic acid tert-butyl esters 0.55 g (0.93

mmol) using the procedure of Example 9(d) to afford 0.26 mg of the required product.
Percentage purity: HPLC: 94.36 %. LCMS: 96.21 %. JH NMR (DMSO-d6): 8 1.4 (3H,
m), 2.0 (4H, m), 3.0 (2H, m), 3.75 (1H, m), 7.26 (2H, s), 7.4 (3H, d), 7.86 (3H, d), 8.0
(3H, brs), 8.72 (1H, m), 9.30 (6H, d).
Example 14.
N-(4-aminocyclohexyl)-2,6-bis[4-(N-hydroxy-carbamimidoyl)-phenoxy]-
isonicotinamide
Intermediates (a) to (d) are the same as in Example 13.
e) N-(4-aminocyclohexyl)-2,6-bis[4-(N-hydroxycarbamimidoyl)phenoxy]-
isonicotinamide
The -Boc group was removed from (4-{[2,6-Bis-(4-(N-hydroxy-carbamimidoyi)-
phenoxy)-pyridine-4-carbonyl]-amino}cyclohexyl)carbamic acid tert-butyl esters 0.25 g
(0.41 mmol) using the procedure of Example 9(d) to afford 0.115 g of the required
product. The crude product was purified by reverse-phase preparative HPLC to afford
0.115 g of the required product. Percentage purity: HPLC: 97.73 %. LCMS: 94.78 %. 1H
NMR (DMSO-d6): 5 1.4 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.75 (1H, m), 7.20 (2H, s),
7.36 (4H, d), 7.76 (4H, d), 7.9 (3H, brs), 8.5 (2H, m), 8.68 (1H, d). 11.0 (2H, s)
Example 15.
N-[l -(4-amino butyryl) piperidin-4-yl]-2,6-bis[4-carbamimidoylphenoxy]-
isonicotinamide
Intermediates (a) and (b) are the same as in Example 12.
c) 4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-piperidine-l-
carboxylic acid tert-butyl ester

2,6-bis (4-Cyano phenoxy)-isonicotinic acid (0.220 g, 0.61 mmol) and 4-amino-
piperidine-1-carboxylic acid tert-butyl ester (0.142 g, 0.71 mmol) were coupled using
the procedure of Example 5(c) to afford 0.295 g of the required product. Percentage
purity (LCMS): 59.4 %, (M+l) = 439.2+1 (with BOC). 1H NMR (DMSO-d6): 5 1.40
(9H, s), 1.81 (4H, m), 2.86 (4H, m), 3.82 (1H, m), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H,
d), 8.64 (1H, d).
d) 2,6-Bis (4-cyano phenoxy)-N-piperidin-4-yl-isonicotinamide
The -Boc group was removed from 4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-
carbonyljamino} -piperidine-1-carboxylic acid tert-butyl ester 0.29 g (0.53 mmol) using
the procedure of Example 9(d) to afford 0.2 g of the required product. Percentage purity
(LCMS): 88.3 %, (M+l) = 439.2+1. !H NMR (DMSO-d6): 5 1.62 (2H, m), 2.00 (3H,
m), 3.02 (2H, m), 4.05 (2H, m), 7.30 (6H, m), 7.85 (4H, d), 8.32 (2H, brs), 8.88 (1H, d).
e) [3-(4-{[2,6-Bis(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}piperidin-l-yl)-
propyl]carbamic acid tert-butyl ester
2,6-Bis (4-cyano phenoxy)-N-piperidin-4-yl-isonicotinamide 0.16 g (0.364 mmol),
(3-bromo-propyl)-carbamic acid tert-butyl ester 0.12 g (0.50 mmol) and potassium
carbonate 0.175 g (1.26 mmol) were used and the procedure of Example ll(e) was
followed to afford 0.175 g of the required product. Percentage purity (LCMS): 80.4 %,
(M+l) = 596.2+1. 1H NMR (DMSO-d6): 5 1.40 (9H, s), 1.88 (9H, m), 2.95 (4H, m),
3.85 (2H, m), 6.86 (2H, brs), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.15 (2H, brs),
9.02 (1H, brs).
f) [3-(4-{ [2,6-Bis(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl]-
amino}-piperidin-1 -yl)-propyl]carbamic acid tert-butyl ester
[3-(4-{[2,6-Bis(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}piperidin-l-yl)-
propyljcarbamic acid tert-butyl ester (0.17 g, 0.28 mmol), hydroxylamine hydrochloride
(87.5 mg, 1.26 mmol) and DIPEA (162.8 mg, 1.26 mmol) were used and the procedure

Example 2(d) was followed to afford 0.13 g of the required product. Percentage purity
(LCMS): 42.4 %, (M+l) = 662.3+1.
g) [3-(4-{[2.16-Bis(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-
carbonyl]amino}-piperidin-l-yl)-propyl]carbamic acid tert-butyl ester
[3-(4-{[2,6-Bis(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl]-
amino}-piperidin-l-yl)-propyl]carbamic acid tert-butyl ester 0.13 g (0.19 mrnol) was
acetylated using 45 mg (0.4 mmol) of acetic anhydride following the procedure of
Example 2(e) to afford 0.12 g of the required product. Percentage purity (LCMS): 66.9
%5 (M+l) = 746.3+1.
h) [3-(4-{[2,6-Bis(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]amino}-
piperidin-l-yl)propyl]carbamic acid tert-butyl ester
[3 -(4- {[2,6-Bis(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-
carbonyl]amino}-piperidin-l-yl)-propyl]carbamic acid tert-butyl ester 0.13 g (0.17
mmol) was reduced using the procedure of Example 2(f) to afford 0.115 g of the
required product. Percentage purity (LCMS): 81.1 %, (M+l) = 630.3+1.
i) N-[l-(4-amino butyryl) piperidin-4-yl]-2,6-bis-[4-carbamimidoyl
phenoxyj-isonicotinamide
The -Boc group was removed from [3-(4-{[2,6-bis(4-carbamimidoyl-phenoxy)-
pyridine-4-carbonyl]amino}-piperidin-l-yl)propyl]carbamic acid tert-butyl ester 0.115 g
(0.18 mmol) using the procedure of Example 9(d) to afford 28 mg of the required
product. Percentage purity:HPLC: 97.58 %. LCMS: 96.9 %. lH NMR (DMSO-d6): 8 1.8
(2H, m), 2.0 (5H, m), 2.9 (2H, m), 3.15 (4H, m), 3.55 (1H, m), 4.1 (1H, m), 7.3 (2H, s),
7.4 (4H, d), 7.85 (6H, m), 8.9 (1H, d), 9.3 (6H, s), 10.05 (1H, brs).
Example 16.

4- {4-[4-(2-aminoethyl)piperidine-1 -carbonyl] -6-isopropoxypyridine-2-y loxy} -
benzamidine
a) 2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester
2,6-Dihydroxyisonicatonic acid (2.0 g, 12.9 mmol) was dissolved in 20 ml of
propane-2-ol at 0 °C. 2 ml of concentrated sulfuric acid was added to the stirred solution
of dihydroxy acid at 0 °C over a period of 10 min and then the contents of the flask were
refluxed overnight at 100 °C. The solvent was removed under reduced pressure and the
crude residual mixture was dissolved in 250 ml of ethylacetate and washed with water.
The organic phase was dried over anhydrous sodium sulphate, concentrated under
reduced pressure and subjected to column chromatography, using chloroform :
ethylacetate (8 : 2) as eluant to afford 0.5 g of required product. !H NMR (CDC13): 8 1.2
(6H, d), 1.35 (6H, d), 4.8 (1H, m), 5.25 (1H, m), 6.85 (1H, s), 6.95 (1H, s), 10.52 (1H,
brs).
b) 2-(4-Cyano-phenoxy)-6-isopropoxy-isonicotinic acid isopropyl ester
2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester (0.5 g, 2.09 mmol) and
0.577 g (4.18 mmol) potassium carbonate was dissolved in 5 ml of dry DMF. 0.25 g
(2.09 mmol) of 4-fluorobenzonitrile, dissolved in 5 ml of DMF, was added to the stirred
solution of hydroxynicotinate over a period of 15 min and then the contents of the
reaction flask were stirred overnight at 100 °C. Reaction mixture was concentrated and
the residue was dissolved in 100 ml of ethylacetate and washed with water. Ethyl acetate
layer was dried over anhydrous sodium sulphate and concentrated under reduced
pressure to afford 0.3 g of required product which was used for the next step without
further purification. 1H NMR (CDC13): 5 1.2 (6H, d), 1.35 (6H, d), 4.8 (1H, m), 5.25
(1H, m), 7.2 (3H, m), 7.7 (3H, m).
c) 2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid

2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid isopropyl ester (0.3 g, 0.88
mmol) was deesterified using the procedure of Example 5(b) to afford 0.20 g of the
required product. Percentage purity (LCMS): 96.71 %. !H NMR (DMSO-d6): 5 1.2 (6H,
d), 4.8 (1H, m), 6.85 (1H, s), 6.9 (1H, s), 7.4 (2H, d), 7.98 (2H, m), 14.0 (1H, brs).
d) (2- {1 -[2-(4-cyano-phenoxy)-6-isopropoxy-pyridine-4-carbonyl]piperidin-4-
yl}ethyl)-carbamic acid tert-butyl ester
2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid (0.20 g, 0.67 mmol) and (2-
piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.16 g, 0.7 mmol) were coupled
using the procedure of Example 5(c) to afford 0.12 g of the required product. 1H NMR
(DMSO-d6): 5 1.12 (2H, m), 1.15 (6H, d), 1.4 (9H, s), 1.6 (2H, m), 1.75 (1H, m), 2.7
(1H, m), 2.98 (3H, m), 3.5 (1H, m), 4.45 (1H, m), 4.8 (1H, m), 6.48 (1H, s), 6.58 (1H,
s), 6.8 (1H, brs), 7.38 (2H, d), 7.9 (2H, d).
e) 4- {4-[4-(2-Amino-ethyl)-piperidine-1 -carbonyl] -6-isopropoxy-pyridin-2-yloxy} -
benzimidic acid ethyl ester
(2- {1 -[2-(4-cyano-phenoxy)-6-isopropoxy-pyridine-4-carbonyl]piperidin-4-
yl}ethyl)-carbamic acid tert-butyl ester (0.12 g, 0.23 mmol) was used and the procedure
of Example l(d) was followed to afford 0.11 g of the required product. Percentage
purity (LCMS): 51.13%.
f) 4-{4-[4-(2-amino-ethyl)piperidine-l-carbonyl]-6-isopropoxy-pyridine-2-yloxy}-
benzamidine
4-{4-[4-(2-Amino-ethyl)-piperidine-l-carbonyl]-6-isopropoxy-pyridin-2-yloxy}-
benzimidic acid ethyl ester (0.11 g, 0.24 mmol) was used and the procedure of Example
l(e) was followed to afford 50 mg.of the required product. Percentage purity: HPLC:
99.46 %. LCMS: 97.7 %. 1H NMR (DMSO-d6): 5 1.15 (6H, s), 1.5 (2H, m), 1.6 (2H,
m), 1.75 (1H, m), 2.7 (1H, m), 2.85 (2H, m), 3.0 (1H, m), 3.2 (2H, s), 4.45 (1H, m), 4.85

(1H, m), 6.5 (1H, s), 6.6 (1H, s), 7.4 (2H, d), 7.75 (3H, brs), 7.9 (2H, d), 9.25 (2H, m),
9.35 (2H, s).
Example 17.
4-[5-[4-(2-aminoethyl)-piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-
pyridine-2 -yloxy] benzamidine
a) 2-Chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester
96.7 mg (0.7 mmol) of potassium carbonate was added to a stirred solution of 2,6-
dichloro nicotinic acid ethyl ester 0.15 g (0.7 mmol) in 10 ml of 7V,iV-dimethyl-
formamide (DMF) cooled to 5 °C .This was followed by dropwise addition (over a
period of 10 minutes) of 4-cyano phenol 80 mg (0.68 mmol) dissolved in 2 ml DMF.
The reaction mixture was allowed to stir at RT for 2 hrs, concentrated under reduced
pressure and the residue was dissolved in 100 ml of ethylacetate. The organic layer was
washed with water and dried over anhydrous sodium sulphate and concentrated under
reduced pressure. The crude product was purified by column chromatography using
hexane: ethylacetate (8:2) as eluants to afford 0.13 g of the required product. lH NMR
(DMSO-d6): 5 1.3 (3H, t), 4.3 (2H, q), 7.26 (1H, s), 7.38 (1H, s), 7.48 (2H, d), 7.96 (2H,
d).
b) 6-(4-cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester
Potassium carbonate (60 mg, 0.43 mmol) was added to a stirred and cooled (0 °C)
solution of 2-chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester 0.13 g (0.43 mmol) in
10 ml DMF and stirred for 10 min at the same temperature. This was followed by the
addition of 76.5 mg (0.43 mmol) of 4-trifluoromethoxy phenol, dissolved in 2 ml of
DMF, over a period of 10 minutes. After the addition was completed, the contents were
allowed to stir at RT. This was followed by heating for 3 hrs at 80 °C. The reaction
mixture was concentrated under reduced pressure, poured into ice-cold water and
dissolved in 50 ml of ethyl acetate. Organic layer was then washed with brine solution
followed by water and the crude product was purified by column chromatography using

hexane: ethyl acetate (8:2) to afford 0.18 g of the required product. Percentage purity:
LCMS (-ve mode): 20.12 %.
c) 6-(4-Cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid
6-(4-cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester
(0.18 g, 0.40 mmol) was deesterified by using the procedure of Example 5(b) to afford
0.15 g of the required product. Percentage purity:LCMS (-ve mode): 41.96 %.
d) (2-{l-[6-(4-cyano phenoxy)-2-(4-trifluoromethoxy phenoxy)pyridine-3-
carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
6-(4-Cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid (0.15 g, 0.36
mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.082 g, 0.36 mmol)
were coupled using the procedure of Example 5(c) to afford 0.15 g of the required
product. Percentage purity (LCMS): 43.23 %.
e) 4-[5-[4-(2-Aminoethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-
phenoxy)pyridine-2-yloxy]benzimidic acid ethyl ester
(2-{ l-[6-(4-cyano phenoxy)-2-(4-trifluoromethoxy phenoxy)pyridine-3-carbonyl]-
piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (0.15 g, 0.24 mmol) was used and the
procedure of Example l(d) was followed to afford 0.20 g of the required product.
LCMS (+ve mode): 35.2 %.
f) 4-[5-[4-(2-aminoethyl)-piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-
pyridine-2-yloxy]benzamidine
4-[5-[4-(2-Ajninoethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-
pyridine-2-yloxy]benzimidic acid ethyl ester (0.20 g, 0.34 mmol) was used and the
procedure of Example l(e) was followed to afford 0.1 g of the required product.
Percentage purity:HPLC: 89.68 %. LCMS: 74.9 %. 'HNMR (DMSO-d6): 8 1.05 (1H,

m), 1.25 (1H, m), 1.65 (5H, m), 2.8 (4H, m), 3.2 (1H, m), 4.5 (1H, m), 6.85 (1H, d),
7.25 (2H, s), 7.35 (4H, m), 7.85 (4H, m), 7.9 (1H, m), 9.2 (2H, s), 9.3 (2H, s).
Example 18.
4-[5-[4-(2-amino-ethyl)piperidine-l-carbonyl]-6-(4-fluoro-phenoxy)pyridine-2-
yloxy] -benzamidine
Intermediate (a) is the same as in Example 17.
b) 6-(4-Cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid ethyl ester
2-Chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester (0.25 g, 0.81 mmol) and 4-
fluorophenol (0.09 g, 0.81 mmol) were coupled using the procedure of Example 17(b) to
afford 0.23 g of the required product. Percentage purity (LCMS): 61.86 %.
c) 6-(4-cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid
6-(4-Cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid ethyl ester (0.23 g, 0.60
mmol) was deesterified using the procedure of Example 5(b) to afford 0.2 g of the
required product. Percentage purity: LCMS (-ve mode): 57.29 %.
d) (2-{l-[6-(4-cyano phenoxy)-2-(4-fluoro phenoxy )pyridine-3-carbonyl]piperidin-
4-yl}ethyl)carbarnic acid tert-butyl ester
6-(4-cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid (0.2 g, 0.57 mmol) and (2-
piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.13 g, 0.57 mmol) were coupled
using the procedure of Example 5(c) to afford 0.25 g of the required product. Percentage
purity:LCMS (-ve mode): 67.5 %.
e) 4-[5-[4-(2-Amino-ethyl)-piperidine-l-carbonyl]-6-(4-fluoro-phenoxy)-pyridin-2-
yloxy]-benzimidic acid ethyl ester

(2-{ 1 -[6-(4-cyanophenoxy)-2-(4-fluorophenoxy)pyridine-3-carbonyl] piperidin-4-
yl}ethyl)carbamic acid tert-butyl ester (0.25 g, 0.44 mmol) was used and the procedure
of Example l(d) was followed to afford 0.28 g of the required product. Percentage
purity (LCMS): 51.02%.
f) 4-[5-[4-(2-amino ethyl)piperidine-l-carbonyl]-6-(4-fluoro phenoxy)pyridine-2-
yloxy]benzamidine
4-[5-[4-(2-Amino-ethyl)-piperidine-l-carbonyl]-6-(4-fluoro-phenoxy)-pyridin-2-
yloxy]-benzimidic acid ethyl ester (0.28 g, 0.55 mmol) was used and the procedure of
Example l(e) was followed to afford 0.12 g of the required product. Percentage
purity:HPLC: 95.03 %. LCMS: 90.18 %. !H NMR (DMSO-d6): 6 1.05 (2H, m), 1.25
(1H, s), 1.5 (2H, m), 1.65 (2H, m), 1.75 (1H, m), 2.8 (2H, m), 3.05 (3H, m), 3.65 (1H,
d), 4.5 (1H, d), 6.8 (1H, s), 7.18 (2H, d), 7.36 (2H, d), 7.68 (2H, brs), 7.82 (1H, d), 7.94
(1H, m), 8.98 (1H, s), 9.30 (1H, s).
Example 19.
4-[3-[4-(2-aminoethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy
phenoxy)pyridin-2-yloxy]benzamidine
a) 2-Chloro-6-(4-trifluoromethoxy phenoxy)nicotinic acid ethyl ester
2,6-dichloronicotinic acid ethyl ester (0.22 g, 0.1 mmol) and 4-trifluoromethoxy-
phenol (0.178 g, 0.1 mmol) were coupled using the procedure of Example 17(a) to
afford 0.3 g of the required product. Percentage purity (LCMS): 64.0 %.
b) 2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester
2-Chloro-6-(4-trifluoromethoxy phenoxy)nicotinic acid ethyl ester (0.3 g, 0.83
mmol) and 4-cyanophenol (98.8 mg, 0.83 mmol) were coupled using the procedure of
Example 17(b) to afford 0.23 g of the required product. Percentage purity (LCMS):
82.35 %.

c) 2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid
2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester
(0.23 g, 0.51 mmol) was deesterified using the procedure of Example 5(b) to afford 0.2
g of the required product. Percentage purity: LCMS (-ve mode): 66.14 %.
d) (2- {1 - [2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)pyridine-3 -carbonyl]
piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid (0.2 g, 0.48
mmol) and (2-Piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.11 g, 0.48 mmol)
were coupled using the procedure of Example 5(c) to afford 0.21 g of the required
product. Percentage purity (LCMS): 68.11 %.
e) 4-[3-[4-(2-Amino-ethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-
pyridine-2-yloxy |benzimidic acid ethyl ester
(2-{l-[2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)pyridine-3-carbonyl]
piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (0.2 g, 0.319 mmol) was used and the
procedure of Example l(d) was followed to afford 0.25 g of the required product.
Percentage purity (LCMS): 52.44 %.
f) 4-[3-[4-(2-Amino-ethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-
pyridine-2-yloxy Jbenzamidine
4-[3-[4-(2-Amino-ethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-
pyridine-2-yloxy]benzimidic acid ethyl ester (0.25 g, 0.43 mmol) was used and the
procedure of Example l(e) was followed to afford 0.050 g of the required product.
Percentage purity: HPLC: 94.13 %; LCMS: 91.76 %. !H NMR (DMSO-d6): 8 1.5 (2H,
m), 1.65 (2H, m), 1.75 (1H, m), 2.3 (1H, m), 2.8 (4H, m), 3.1 (2H, m), 3.65 (1H, d), 4.5

(1H, d), 6.88 (1H, s), 7.26 (2H, m), 7.36 (3H, m), 7.82 (2H, d), 7.94 (2H, brs), 9.14 (2H,
s), 9.34 (2H, s).
Example 20.
4-[5-[4-(2-amino-ethyl)piperidine-l-carbonyl]-3-fluoro-6-(3-trifluoromethoxy
phenoxy)-pyridine-2-yloxy]benzamidine
a) 2-chloro-6-(4-cyano phenoxy)-5-fluoro nicotinic acid ethyl ester
2,6-Dichloro-5-fluoro-nicotinic acid ethyl ester (3.5 g, 15.0 mmol) and 4-cyano-
phenol (1.78 g, 15.0 mmol) were coupled using the procedure of Example 17(a) to
afford 2.4 g of the required product. 1H NMR (DMSO-d6): 5 1.35 (3H, t), 4.4 (2H, q),
7.58 (2H, d), 8.0 (2H, d), 8.4 (1H, d).
b) 6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy)nicotinic acid
ethyl ester
2-chloro-6-(4-cyano phenoxy)-5-fluoro nicotinic acid ethyl ester (2.4 g, 7.49 mmol)
and 3-trifluoromethoxyphenol (1.33 g, 7.49 mmol) were coupled using the procedure of
Example 17(b) to afford 1.8 g of the required product. lH NMR (DMSO-d6): 8 1.35
(3H, t), 4.4 (2H, q), 7.22 (2H, d), 7.3 (3H, d), 7.34 (1H, m), 7.54 (2H, d), 8.38 (1H, d).
c) 6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy) nicotinic acid
6-(4-cyano phenoxy)-5-fiuoro-2-(3-trifluorornethoxy phenoxy)nicotinic acid ethyl
ester (1.8 g, 2.79 mmol) was deesterified using the procedure of Example 5(b) to afford
1.3 g of the required product. 1H NMR (DMSO-d6): 6 7.22 (2H, d), 7.3 (4H, m), 7.74
(2H, d), 8.34 (1H, d), 13.2 (1H, brs).
d) (2-{l-[6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy)pyridine-3-
carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester

6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy) nicotinic acid (1.3 g,
2.99 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.684 g, 3.0
mmol) were coupled using the procedure of Example 5(c) to afford 1.1 g of the required
product. 'H NMR (DMSO-d6): 5 1.2 (2H, m), 1.4 (9H, d), 1.5 (2H, m), 1.6 (2H, m), 2.2
(1H, m), 2.35 (1H, m), 3.0 (3H, m), 3.7 (1H, m), 4.45 (1H, m), 6.78 (1H, m), 7.18 (1H,
m), 7.26 (2H, m), 7.32 (1H, s), 7.46 (1H, m), 7.76 (1H, m), 7.86 (1H, s), 8.1 (1H, m).
e) 4-[5-[4-(2-Amino ethyl)piperidine-1 -carbonyl] -3 -fluoro-6-(3 -trifluoromethoxy
phenoxy)pyridine-2-yloxy]benzimidic acid ethyl ester
(2-{ 1 -[6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy) pyridine-3-
carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (1.1 g, 1.70 mmol) was used
and the procedure of Example l(d) was followed to afford 1.0 g of the required product.
Percentage purity (LCMS): 11.21 %.
f) 4- [5 - [4-(2-Aminoethyl)piperidine-1 -carbonyl-3 -fluoro-6-(3 -trifluoromethoxy
phenoxy)pyridine-2-yloxy]benzamidine
4-[3-[4-(2-Amino-ethyl)piperidine-l-carbonyl]-6-(3-trifluoromethoxy-phenoxy)-
pyridine-2-yloxy|benzimidic acid ethyl ester (1.0 g, 1.69 mmol) was used and the
procedure of Example l(e) was followed to afford 0.250 g of the required product.
Percentage purity: HPLC: 98.16 %. LCMS: 90.93 %. 1H NMR (DMSO-d6): 5 1.5 (3H,
m), 1.6 (2H, m), 1.75 (2H, m), 2.0 (1H, m), 2.8 (4H, m), 4.5 (1H, m), 7.1 (2H, m), 7.25
(2H, m), 7.45 (2H, d), 8.0 (3H, m), 8.1 (2H, m), 9.20 (2H, s), 9.35 (2H, s).
Example 21.
2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-2-naphthalenesulfonamide
a) 1,5-Bis-(4-cyano-phenoxy)-2-nitrobenzene
4-cyanophenol 4.5g (23.0 mmol), dissolved in 5 ml of DMF, was added to a stirred
suspension of sodium hydride 0.92g (23.0 mmol) in 5 ml of DMF cooled to 5 °C. The

reaction flask was stirred for 10 min at the same temperature and this was followed by
dropwise addition (over 15 min) of 2,4-dichloronitrobenzene 2.0 g (10.5 mmol)
dissolved in 5 ml of DMF. The reaction mixture was stirred for 6 h at 70 °C. The
reaction mass was poured into ice-cold water and extracted with 200 ml of ethylacetate.
The organic phase was washed with 1 M Na2CO3 and saturated brine solution. The
solution was dried over sodium sulphate and concentrated to afford an oily residue,
which was purified by column chromatography using chlorofrom-ethyl acetate (10:2)
to afford 2.5 g of the required product. 1H NMR (DMSO-d6): 6 6.79 (1H, d), 6.93 (1H,
d), 7.06 (2H, d), 7.18 (2H, d), 7.75 (4H, d), 8.16 (1H, d).
b) 1,5-Bis-(4-cyano-phenoxy)-2-aminobenzene
Zinc dust, 0.4 g (5.3 mmol) was added portionwise to a reaction flask containing a
stirred mixture (10 min) of l,5-bis-(4-cyano-phenoxy)-2-nitrobenzene 1.5 g (4.2 mmol)
and 0.085 g (0.08 mmol) of ammonium chloride dissolved in 25 ml of methanol. The
reaction mixture was allowed to stir for 1 h at room temperature. Reaction mixture was
filtered through celite and the filtrate was concentrated to afford a brown viscous residue
which was partitioned between ethyl acetate and water. The organic layer was dried over
anhydrous sodium sulfate and concentrated to afford an oily residue, which was purified
by column chromatography using chloroform-ethyl acetate (10 : 1) to afford 1.3 g of the
required product.
1H NMR (DMSO-d*): 5 5.10 (2H, brs), 6.85 (3H, m), 7.06 (4H, m), 7.80 (4H, m).
c) Naphthalene-2-sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl]-amide
l,5-Bis-(4-cyano-phenoxy)-2-aminobenzene 0.175 g (0.54 mmol), 2-naphthalene-
sulfonyl chloride 0.148 g (0.65 mmol) and iV.iV-diisopropylethylamine (DIPEA) 0.85 g
(0.65 mmol) were dissolved in 5 ml of dry toluene and refluxed for 8 h. The reaction
mixture was concentrated under reduced pressure and the residue was partitioned
between water and ethyl acetate after the pH was adjusted to 2 with 6 N HC1. The
organic phase was washed with 1 M Na2CC>3 (5 x 100 ml) and saturated brine solution.
The solution was dried over sodium sulphate and concentrated to afford an oily residue,

which was purified by column chromatography using hexane-ethyl acetate (10 : 2) to
afford 0.190 g of the required product. 1H NMR (DMSO-d6): 5 6.45 (3H, m), 7.16 (5H,
m), 7.42 (6H, m), 7.75 (2H, dd), 8.10 (2H, d), 8.35 (1H, s).
> d) Naphthalene-2-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl]-
amide
Using naphthalene-2-sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl]-amide (0.19
g, 0.36 mmol) and following the procedure of Example l(d) afforded 0.13 g of the
i required product. Percentage purity (LCMS): 69.6 %, (M+l) = (609.1+1).
e) Naphthalene-2-sulfonic acid [2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
Using naphthalene-2-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-
phenyl]-amide (0.13 g, 0.21 mmol) and following the procedure of Example l(e) 0.033
g of the required product was obtained. Percentage purity: HPLC: 96.91 %; LCMS:
96.74 %. 1H NMR (DMSO-de): 6 6.5 (1H, s), 6.7 (3H, m), 6.95 (2H, m), 7.2 (3H, m),
7.3 (1H, s) 7.45 (1H, m), 7.55 (2H, d), 7.7 (2H, m), 7.75 (1H, m), 7.85 (2H, d), 7.95
(2H, m), 8.1 (1H, m), 8.3 (1H, s), 9.0 (3H, m), 9.15 (2H, s), 9.25 (2H.s).
Example 22.
4-Fluorobenzene-sulfonic acid [2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]-
amide
Intermediates (a) and (b) are the same as in Example 21.
c)N-[2,4-Bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzenesulfonamide
4-Fluorobenzene sulfonyl chloride (0.126 g, 0.65 mmol) was added to a stirred
solution of l,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along with
other reagents as mentioned in Example 20(c) to afford 0.18 g of the required product.

]H NMR (DMSO-d6): 8 6.86 (1H, brs), 6.95 (3H, m), 7.26 (2H, d), 7.34 (1H, d), 7.54
(3H, t), 7.82 (2H, d), 7.95 (2H, d), 7.95 (2H, m).
d) 4-Fluorobenzene-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-
phenyl]-amide
Using N-[2,4-bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzene sulfonamide (0.18
g, 0.37 mmol) and following the procedure of Example l(d) afforded 0.16 g of the
required product. Percentage purity (LCMS): 62.0 %, (M+l) = (577.1+1).
e) 4-Fluorobenzene-sulfonic acid [2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]-
amide
Using 4-fiuorobenzene-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-
phenyl]-amide (0.16 g, 0.27 mmol) and following the procedure of Example l(e) 0.033
g.of the required product was obtained. Percentage purity: HPLC: 96.54 %, LCMS: 95.4
%. 1H NMR (DMSO-de): 5 6.5 (1H, s), 6.75 (1H, s), 6.95 (3H, m), 7.2 (2H, d), 7.3 (2H,
d) 7.4 (1H, d), 7.75 (3H, m), 7.85 (2H, d), 8.6 (1H, s), 8.95 (3H, brs), 9.25 (3H, brs),
10.2 (1H, brs).
Example 23.
2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-l-naphthalenesulfonamide
Intermediates (a) and (b) are the same as in Example 21.
c) Naphthalene- 1-sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl]-amide
1-Naphthalene sulfonyl chloride (0.148 g, 0.65 mmol) was added to a stirred
solution of l,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along with
other reagents as mentioned in Example 20(c) to afford 0.19 g of the required product.
1H NMR (DMSO-de): 8 6.45 (3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 7.85
(3H,m).

d) 2,4-Bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl-1 -naphthalenesulfonamide
Using naphthalene-1-sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl]-amide (0.19
g, 0.36 mmol) and following the procedure of Example l(d) afforded 0.16 g of the
required product. Percentage purity (LCMS): 55.3 %, (M+l) = (609.19+1H).
e) 2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-1 -naphthalenesulfonamide
Using 2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl-1 -naphthalene sulfonamide
(0.16 g, 0.26 mmol) and following the procedure of Example l(e) 0.035 g.of the
required product was obtained. Percentage purity:HPLC 94.73 %; LCMS 96.0 %. !H
NMR (DMSO-d6): 5 6.55 (1H, s), 7.1 (2H, d), 7.3 (2H, m), 7.4 (2H, d), 7.75 (4H, m),
7.9 (4H, m), 8.2 (1H, d), 8.4 (1H, d), 8.5 (2H, brs), 9.1 (4H, d), 9.3 (4H, s).
Example 24.
N-(4-Amino-cyclohexyl)-3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzamide
a) 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid ethyl ester
Potassium carbonate 2.1g (15.2 mmol) dissolved in DMF solution was added to
3,5-dihydroxy-benzoic acid ethyl ester 1.5 g (8.2 mmol) dissolved in 15 ml of DMF.
This was followed by dropwise addition of 6-chloro-nicotinonitrile 2.1g (15.2 mmol)
dissolved in 5 ml of DMF. After complete addition, the reaction mixture was stirred at
60 °C for 8-10 h. The reaction mixture was quenched with ice cold water and extracted
with ethyl acetate. The organic layer was washed with water followed by brine, dried
over anhydrous sodium sulphate and concentrated to afford a crude solid which was
purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 2.5 g
of the required product. 'H NMR (DMSO-de): 5 1.30 (3H, t), 4.32 (2H, q), 7.35 (2H, d),
7.52 (1H, t), 7.68 (2H, d), 8.39 (2H, d), 8.69 (2H, s).
b) 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid

2.3 g (5.9 mmol) of 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid ethyl ester was
hydrolysed by using the procedure of Example 5(b) to afford 1.8 g.of the required
product. 'H NMR (DMSO-d6): 8 7.34 (2H, d), 7.48 (1H, t), 7.61 (2H, d), 8.38 (2H, dd),
8.70 (2H,d), 13.5 (lH,brs).
c) {4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester
Following the procedure of Example 5(c) 3,5-bis-(5-cyano-pyridin-2-yloxy)-
benzoic acid 0.35 g (0.97 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl
ester (0.2 g, 0.97 mmol) were used to afford 0.4 g of the required product. 1H NMR
(DMSO-d6): 5 1.47 (9H, s), 1.72 (5H, m), 1.82 (3H, m), 3.20 (1H, m), 3.72 (1H, m),
6.74 (1H, m), 7.18 (1H, d), 7.32 (1H, s), 7.50 (1H, brs), 7.59 (1H, s), 8.08 (1H, brs),
8.30 (2H, dd), 8.39 (1H, dd), 8.67 (2H, d).
d) N-(4-Amino-cyclohexyl)-3,5-bis-(5-ethoxycarbonimidoyl-pyridin-2-yloxy)-
benzamide
Using {4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (0.13 g, 0.23 mmol) and following the procedure of Example l(d)
afforded 0.12 g of the required product. Percentage purity (LCMS): 74.6 %, (M+l) =
546.2.
e) N-(4-Amino-cyclohexyl)-3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzamide
Using N-(4-amino-cyclohexyl)-3,5-bis-(5-ethoxycarbonimidoyl-pyridin-2-yloxy)-
benzamide (0.12 g, 0.21 mmol) and following the procedure of Example l(e) 0.044 g.of
the required product was obtained. Percentage purity: HPLC 98.4 %, LCMS 96.7 %. lH
NMR (DMSO-d6): 5 1.8-2.0 (5H, m), 3.0 (2H, m), 3.7 (3H, m), 7.32 (2H, d), 7.40 (1H,
s), 7.62 (2H, d), 7.88 (3H, brs), 8.30 (2H, dd), 8.42 (1H, m), 8.62 (2H, d), 9.24 (4H, s),
9.42 (3H, s).

Example 25.
4-amino-l-{4-[3,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-l-
yl}-butan-l-one
Intermediates (a) and (b) are the same as in Example 24.
c) 4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine-l-carboxylic acid tert-
butyl ester
Following the procedure of Example 5(c) 3,5-bis-(5-cyano-pyridin-2-yloxy)-
benzoic acid 0.6 g (1.67 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.31 g,
1.67 mmol) were used to afford 0.55 g of the required product. 1H NMR (DMSO-d6): 5
1.42 (9H, s), 3.45 (6H, m), 3.56 (2H, m), 7.20 (2H, d), 7.27 (1H, t), 7.32 (2H, d), 8.37
(2H, dd), 8.70 (2H, d).
d) 4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine
Using 4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine-l-carboxylic acid
tert-butyl ester (0.5 g, 0.94 mmol) and following the procedure of Example 9(d)
afforded 0.4 g of the required product. ]H NMR (DMSO-d6): 8 3.20 (4H, m), 3.46 (4H,
m), 5.42 (1H, brs), 7.18 (2H, d), 7.25 (1H, t), 7.31 (2H, d), 8.41 (2H, dd), 8.75 (2H, d).
e) 4-{4-[3,5»Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazin-1 -yl} -4-oxo-butyl)-
carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-
benzoyl]-piperazine 0.4 g (0.93 mmol) and 4-tert-butoxycarbonylamino-butyric acid
(0.19 g, 0.93 mmol) were used to afford 0.35 g of the required product. 1H NMR
(DMSO-d6): 8 1.39 (9H, s), 1.60 (2H, q), 2.32 (3H, m), 2.94 (2H, q), 3.50 (7H, m), 6.80
(1H, brs), 7.15 (1H, d), 7.28 (1H, t), 7.32 (2H, d), 8.37 (2H, dd), 8.72 (2H, d).

f) [4-(4-{3,5-Bis-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yloxy]-benzoyl}-
piperazin-l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester
4- { 4- [3,5 -Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazin-1 -yl} -4-oxo-butyl)-
carbamic acid tert-butyl ester 0.35 g (0.57 mmol), DIPEA 0.3 g (2.28 mmol) and 0.158
g (2.28 mmol) of hydroxylamine hydrochloride were used as described in Example 2(d)
to afford 0.25 g of the required product. Percentage purity (LCMS): 86.1 %, (M+l) =
677.2 (with BOC). lU NMR (DMSO-d6): 5 1.40 (9H, s), 1.62 (2H, q), 2.33 (2H, m),
2.92 (3H, m), 3.18 (1H, m), 3.50 (4H, m), 3.62 (2H, m), 6.16 (3H, brs), 6.82 (2H, t),
7.08 (2H, s), 7.18 (3H, d), 8.14 (2H, dd), 8.48 (2H, s), 9.85 (2H, brs).
g) [4-(4-{3,5-Bis-[5-(N-(acetylhydroxy)-carbamimidoyl)-pyridin-2-yloxy]-
benzoyl}-piperazin-l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester
[4-(4-{3,5-Bis-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yloxy]-benzoyl}-piperazin-
l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester 0.25 g (0.37 mmol) was acetylated with
0.08 g (0.8 mmol) of acetic anhydride using the procedure of Example 2(e) to afford
0.25 g of the required product. Percentage purity (LCMS): 86.1 %, (M+l) = 761.2 (with
BOC). ]H NMR (DMSO-de): 8 1.36 (9H, s), 1.62 (2H, m), 2.14 (6H, s), 2.33 (3H, m),
2.93 (3H, m), 3.55 (6H, brs), 6.82 (1H, brs), 6.95 (4H, brs), 7.18 (5H, m), 8.18 (2H, dd),
8.50 (2H, s).
h) (4-{4-[3,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-l-yl}-4-
oxo-butyl)-carbamic acid tert-butyl ester
[4_(4_ { 3,5-Bis- [5-(N-(acetylhydroxy)-carbamimidoyl)-pyridin-2-yloxy] -benzoyl} -
piperazin-l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester 0.25 g (0.32 mmol) was
reduced using the procedure of Example 2(f) to afford 0.12 g of the required product.
Percentage purity (LCMS): 68.7 %, (M+l) = 645.3+1.
i) 4-{4-[3,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-l-yl}-4-
oxo-butanylamine

Using (4-{4~[3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-l-yl}-
4-oxo-butyl)-carbamic acid tert-butyl ester (0.12 g, 0.18 mmol) and following the
procedure of Example 9(d) afforded 0.05 g of the required product. Percentage purity:
HPLC 87.7%, LCMS 86.4%. ]H NMR (DMSO-d6): 6 1.2 (2H, m), 1.75 (2H, m), 2.8
(2H, m), 3.2 (8H, m), 4.2 (2H, brs), 7.22 (3H, m), 7.36 (2H, m), 7.80 (3H, brs), 8.30
(2H, m), 8.66 (2H, s), 9.22 (3H, s), 9.44 (3H, s).
Example 26.
1 -[(4-Amino-ethyl)-piperidine-1 -carbonyl]-3,5-bis-(4-carbamimidoyl-phenoxy)-
benzene
a) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid ethyl ester
Potassium carbonate 0.61 lg (4.4 mmol) was added to a stirred solution of 3,5-
dihydroxy-benzoic acid ethyl ester 0.5 g (1.7 mmol) dissolved in 15 ml of DMF and
stirred for 10 min. This was followed by dropwise addition of 4-fluorobenzonitrile 0.82g
(6.8 mmol), dissolved in 5 ml of DMF, and the contents of the flask were stirred at 80
°C for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl
acetate. The organic phase was washed with Na2CO3 and saturated brine solution, dried
over sodium sulphate and concentrated to afford an oily residue which was purified by
column chromatography using hexane-ethyl acetate (10: 2) to afford 0.4g of the required
product. The yield was 0.6 g. lH NMR (DMSO-d6): 5 1.30 (3H, t), 4.30 (2H, q), 7.25
(2H, d), 7.32 (1H, t), 7.46 (2H, d), 7.90 (2H, d).
b) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid
3,5-Bis-(4-cyano-phenoxy)-benzoic acid ethyl ester 0.6 g (1.56 mmol) was
hydrolysed by using the procedure of Example 5(b) to afford 0.45 g of required product.
lU NMR (DMSO-d6): 8 7.27 (3H, d), 7.40 (2H, d), 7.92 (2H, d), 13.5 (1H, brs).

c) l-[(4-Boc-Amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-(4-cyano-phenoxy)-
benzene
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.45 g (1.26 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.287 g,
1.26 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): 5
1.05 (2H, m), 1.30 (2H, m), 1.40 (9H, s), 1.45 (4H, m), 2.60 (1H, m), 2.94 (3H, m), 3.54
(1H, m), 4.38 (1H, m), 6.78 (1H, t), 6.75 (2H, d), 7.04 (1H, t), 7.25 (4H, d), 7.88 (2H,
d).
d) l-[(4-Boc-Amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-[4-(N-hydroxy-
carbamimidoyl)-phenoxy] -benzene
Following the procedure of Example 2(d) l-[(4-boc-amino-ethyl)-piperidine-l-
carbonyl]-3,5-bis-(4-cyano-phenoxy)-benzene 0.4 g (0.7 mmol) and other reagents were
used to afford 0.35 g of the required product. Percentage purity (LCMS): 69.2 %, (M+l)
= 632.2+1.
e) 1 -[(4-Boc-Amino-ethyl)-piperidine-l -carbonyl]-3,5-bis-[4-(N-acetyl-
hydroxycarbamimidoyl)-phenoxy]-benzene
Following the procedure of Example 2(e) l-[(4-boc-amino-ethyl)-piperidine-l-
carbonyl]-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzene 0.35 g (0.55 mmol)
was used to afford 0.3 g of the required product. Percentage purity (LCMS): 51.0 %,
(M+l) = 716.3 (with BOC).
f) l-[(4-Boc-Amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-(4-carbamimidoyl-
phenoxy)-benzene
1 -[(4-Boc-amino-ethyl)-piperidine-1 -carbonyl]-3,5-bis-[4-(N-acetylhydroxy-
carbamimidoyl)-phenoxy]-benzene 0.3 g (0.41 mmol) was reduced using the procedure

of Example 2(f) to afford 0.2 g of required product. Percentage purity (LCMS): 74.0 %,
(M+l)= 600.3+1.
g) 1 -[(4-Amino-ethyl)-piperidine-1 -carbonyl]-3,5-bis-(4-carbamimidoyl-phenoxy)-
benzene
Using l-[(4-boc-Ammo-ethyl)-piperidine-l -carbonyl]-3,5-bis-(4- carbamimidoyl-
phenoxy)-benzene (0.2 g, 0.33 mmol) and following the procedure of Example 9(d)
afforded 0.06 g of the required product. Percentage purity: HPLC; 97.85 %; LCMS;
94.26 %. !H NMR (DMSO-d6): 8 1.05 (2H, m), 1.4-1.8 (5H, m), 2.8 (3H, m), 3.0 (1H,
m), 3.4 (1H, m), 4.4 (1H, m), 6.95 (3H, brs), 7.3 (3H, d), 7.9 (6H, d), 9.1-9.6 (7H, d).
Example 27.
N-(4-Amino-cyclohexyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-benzamide
Intermediates (a) and (b) are the same as in Example 26.
c) {4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-
butyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.45 g (1.26 mmol) and (4-arnino-cyclohexyl)-carbamic acid tert-butyl ester (0.27 g,
1.26 mmol) were used to afford 0.52 g of the required product. !H NMR (DMSO-d6): 8
1.31 (4H, m), 1.45 (9H, s), 1.80 (4H, m), 3.22 (1H, m), 3.68 (1H, m), 6.78 (1H, d, J=7.8
Hz), 7.24 (2H, d, J=9.6 Hz), 7.51 (2H, d, J=2.1 Hz), 7.89 (2H, d, J=8.7 Hz), 8.35 (1H, d,
J=7.5 Hz).
d) (4-{3,5-Bis-[4-(N-hydroxyearbamimidoyl)-phenoxy]-benzoylamino}-
cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3,5-bis-(4-cyano-phenoxy)-
benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester 0.5 g (9 mmol) and other

reagents were used to afford 0.4 g of the required product. Percentage purity (LCMS):
68.0 %, (M+l) = 618.2+1. 'H NMR (DMSO-d6): 5 1.31 (4H, m), 1.45 (9H, s), 1.80 (4H,
m), 3.22 (1H, m), 3.68 (1H, m), 6.78 (1H, d, J=7.8 Hz), 7.24 (2H, d, J=9.6 Hz), 7.42
(2H, d, J=2.1 Hz), 7.75 (2H, d, J=8.7 Hz), 7.92 (4H, brs), 8.35 (1H, d, J=7.5 Hz), 11.05
(2H, brs).
e) (4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-
cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure as in Example 2(e) (4-{3,5-bis-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester 0.4
g (0.64 mmol) was used to afford 0.45 g of the required product. Percentage purity
(LCMS): 89.0 %, (M+l) = 702.3+1. 'HNMR (DMSO-d6): 8 1.28 (4H, m), 1.45 (9H, s),
1.75 (4H, m), 2.62 (6H, s), 3.31 (1H, m), 3.78 (1H, m), 6.81 (1H, d, J=7.8 Hz), 7.04
(2H, d, J=9.2 Hz), 7.31 (2H, d, J=1.9 Hz), 7.58 (2H, d, J=8.6 Hz), 8.30 (5H, brs).
f) {4-[3,5-Bis-(4-carbamimidoyl phenoxy)benzoylamino]cyclohexyl}carbamic acid
tert-butyl ester
(4- { 3,5 -Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino} -
cyclohexyl)-carbamic acid tert-butyl ester 0.45 g (0.64 mmol) was reduced using the
procedure of Example 2(f) to afford 0.3 g of required product. Percentage purity
(LCMS): 74.0 %, (M+l) = 586.2+1.
g) N-(4-Amino-cyclohexyl)-3,5 -bis-(4-carbamimidoyl-phenoxy)-benzamide
Using {4-[3,5-bis-(4-carbamimidoyl phenoxy) benzoylamino]cyclohexyl} carbamic
acid tert-butyl ester (0.3 g, 0.51 mmol) and following the procedure of Example 9(d)
afforded 0.06 g of the required product. Percentage purity: HPLC; 87.7 %, LCMS; 94.5
%. !H NMR (DMSO-d6): 8 1.44 (4H, m), 1.82 (4H, m), 3.05 (2H, m), 7.15 (1H, m),
7.35 (2H, d, J=9.4 Hz), 7.50 (2H, d, J=2.0 Hz), 7.88 (2H, d, J=8.6 Hz), 8.45 (1H, m),
9.11 (4H, brs), 9.25 (4H, brs).

Example 28.
4- {3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino} -
cyclohexylamine
Intermediates (a) to (d) are the same as in Example 27.
e) 4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino} -
cyclohexylamine
Using (4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino }-
cyclohexyl)-carbamic acid tert-butyl ester (0.3 g, 0.48 mmol) and following the
procedure of Example 9(d) afforded 0.06 g of the required product. Percentage purity:
HPLC 96.2 %; LCMS; 97.2 %. !H NMR (DMSO-de): 5 1.38 (4H, m), 1.92 (4H, m),
3.02 (2H, m), 3.71 (2H, m), 7.04 (2H, brs), 7.23 (4H, d), 7.44 (2H, s), 7.78 (5H, d), 7.92
(3H, brs), 8.44 (2H, brs), 11.05 (2H, brs).
Example 29.
3-{4-[3,5-Bis-(4- carbamimidoyl -phenoxy)-benzoyl]-piperazin-l-yl}-
propylamine
Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine-l-carboxylic acid tert-butyl
ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.45 g (1.26 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 1.26 mmol)
were used to afford 0.5 g of the required product. JH NMR (DMSO-d6): 5 1.40 (9H,
sm), 3.35 (6H, m), 3.55 (2H, m) 7.02 (2H, d), 7.08 (1H, t), 7.26 (2H, d), 7.88 (2H, d).
d) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine

Following the procedure of Example 9(d) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-
piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 0.95 mmol) was used to afford 0.35
g of the required product. ]H NMR (DMSO-d6): 8 3.15 (4H, m), 3.45 (4H, m), 7.06 (2H,
d), 7.11 (1H, t), 7.26 (4H, d), 7.90 (4H, d), 8.25 (2H, brs).
e) (3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-propyl)-carbamic
acid tert-butyl ester
Following the procedure of Example 1 l(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-
piperazine 0.35 g (0.82 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester
(0.195 g, 0.82 mmol) were used to afford 0.35 g of the required product. 1H NMR
(DMSO-d6): 5 1.39 (9H, s), 1.52 (2H, m), 2.35 (8H, m), 2.95 (2H, m), 3.56 (2H, brs),
6.79 (1H, m), 6.90 (2H, d), 7.04 (1H, t), 7.25 (4H, d), 7.88 (4H, d).
f) 3-(4-{3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl}-piperazin-l-yl)-
propylamine
Using (3-{4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-propyl)-carbamic
acid tert-butyl ester (0.35 g, 0.60 mmol) and following the procedure of Example l(d)
afforded 0.15 g of the required product. Percentage purity (LCMS): 56.0 %, (M+l) =
573.3.
g) 3-(4-{3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-piperazin-l-yl)-
propylamine
Using 3 -(4- {3,5 -Bis- [4-(ethoxycarbonimidoyl)-phenoxy] -benzoyl} -piperazin-1 -yl)-
propylamine (0.15 g, 0.26 mmol) and following the procedure of Example l(e) afforded
0.035 g of the required product. Percentage purity: HPLC; 90.82 %, LCMS; 91.76 %. !H
NMR (DMSO-d6): 5 1.9 (3H, m), 2.85 (3H, m), 2.8-3.2 (6H, m), 4.4 (2H, m), 7.05 (3H,
brs), 7.30 (4H, d), 7.90 (6H, d), 9.1 (3H, brs), 9.30 (4H, s).

/o
Example 30.
3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-l-yl}-3-oxo-
propylamine
Intermediates (a) and (b) are the same as in Example 26.
Intermediates (c) and (d) are the same as in Example 29.
e) (3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-3-oxo-propyl)-
carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09 mmol) and 4-[3,5-bis-(4-
cyano-phenoxy)-benzoyl]-piperazine (0.5 g, 1.09 mmol) and other reagents as described
in Example 9(e) were used to afford 0.5 g.of the required product.
'H NMR (DMSO-d6): 5 1.38 (9H, s), 2.45 (2H, m), 3.14 (2H, m), 3.52 (8H, m), 6.71
(1H, brs), 7.01 (2H, s), 7.08 (1H, t), 7.28 (4H, d), 7.89 (4H, d).
f) 3-{4-[3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-l-yl}-3-
oxo-propylamine
Using (3 - {4- [3,5 -bis-(4-cyano-phenoxy)-benzoyl] -piperazin-1 -yl} -3 -oxo-propyl)-
carbamic acid tert-butyl ester (0.5 g, 0.83 mmol) and following the procedure of
Example l(d) afforded 0.25 g of the required product. Percentage purity (LCMS): 33.3
%,(M+1) = 587.2+1.
g) 3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-l-yl}-3-oxo-
propylamine
Using 3-{4-[3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-l-yl}-
3-oxo-propylamine (0.25 g, 0.42 mmol) and following the procedure of Example l(e)
afforded 0.06 g of the required product. Percentage purity: HPLC; 98.99 %; LCMS;
91.36 %. 'H NMR (DMSO-d6): 8 2.1 (3H, m), 2.70 (1H, m), 3.0 (1H, m), 3.15 (3H,

brs), 3.75 (3H, m), 7.0 (3H, m), 7.30 (4H, d), 7.8 (2H, m), 7.9 (4H, d), 9.1 (2H, brs),
9.30 (5H,s), 9.45 (lH,m).
Example 31.
2-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-l-yl}-ethylamine
Intermediates (a) and (b) are the same as in Example 26.
Intermediates (c) and (d) are the same as in Example 29.
e) (2-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-1 -yl}-ethyl)-carbamic acid
tert-butyl ester
Following the procedure of Example 1 l(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-
piperazine 0.35 g (0.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.183
g, 0.82 mmol) were used to afford 0.4 g of the required product. lH NMR (DMSO-d6): 8
1.39 (9H, s), 2.28 (6H, m), 3.04 (2H, m), 3.54 (2H, m), 6.65 (1H, brs), 6.98 (2H, d),
7.05 (1H, t), 7.25 (4H, d), 7.88 (4H, d).
f) 2-{4-[3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-l-yl}-
ethylamine
Using (2- {4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl] -piperazin-1 -yl} -ethyl)-carbamic
acid tert-butyl ester (0.4 g, 0.70 mmol) and following the procedure of Example l(d)
afforded 0.2 g of the required product. Percentage purity (LCMS): 79.3 %, (M+l) =
559.2+1.
g) 2-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-l-yl}-ethylamine
Using 2-{4-[3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-l-yl}-
ethylamine (0.2 g, 0.35 mmol) and following the procedure of Example l(e) afforded
0.04 g of the required product. Percentage purity: HPLC: 87.99 %; LCMS: 96.56 %. JH

NMR (DMSO-de): 6 1.1 (3H, t), 3.1 (8H, m), 7.0 (3H, s), 7.30 (4H, d), 7.9 (4H, d), 8.2
(2H, brs), 9.30 (8H, s).
Example 32.
N-[l-(3-Amino-propyl)-piperidin-4-yl]-3,5-bis-(4-carbamimidoyl-phenoxy)-
benzamide
Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-l-carboxylic acid tert-
butyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.45 g (1.26 mmol) and 4-amino-piperidine-l-carboxylic acid tert-butyl ester (0.252 g,
1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): 8
1.40 (9H, s), 1.75 (2H, m), 2.82 (2H, m), 3.18 (2H, d), 3.92 (3H, m), 7.25 (5H, m), 7.54
(2H, d), 7.88 (4H, d), 38 (1H, brs).
d) 3,5-Bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide
Using 4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-l-carboxylic acid
tert-butyl ester (0.5 g, 0.92 mmol) and following the procedure of Example 9(d)
afforded 0.35 g of the required product. 1H NMR (DMSO-d6): 5 1.60 (2H, m), 1.95 (2H,
m), 3.05 (2H, m), 3.34 (2H, m), 4.08 (1H, brs), 7.24 (5H, d), 7.57 (2H, s), 7.90 (4H, d),
8.60 (1H, brs), 8.74 (1H, brs).
e) (3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidin-l-yl}-propyl)-
carbamic acid tert-butyl ester
Following procedure of Example 1 l(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-
yl-benzamide 0.35 g (0.79 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester
(0.188 g, 0.79 mmol) were used to afford 0.4 g of the required product. !H NMR

(DMSO-d6): 5 1.38 (9H, s), 1.52 (4H, m), 1.75 (2H, m), 1.90 (2H, m), 2.28 (2H, m),
2.82 (1H, m), 2.92 (2H, m), 3.74 (1H, brs), 3.68 (1H, m), 6.79 (1H, brs), 7.18 (1H, t),
7.26 (4H, d), 7.52 (2H, s), 7.88 (4H, d), 8.38 (1H, d).
f) 3-(4-{3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoylamino}-piperidin-l-
yl)-propylamine
Using (3-{4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-piperidin-1 -yl}-propyl)-
carbamic acid tert-butyl ester (0.4 g, 0.67 mmol) and following the procedure of
Example l(d) afforded 0.2 g of the required product. Percentage purity (LCMS): 99.0%
(M+l) = 587.3+1.
g) 3 - {4-[3,5 -Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-piperidin-1 -yl} -
propylamine
Using 3-(4-{3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoylamino}-piperidin-
l-yl)-propylamine (0.2 g, 0.34 mmol) and following the procedure of Example l(e)
afforded 0.04 g of the required product. Percentage purity: HPLC 95.27 %; LCMS 95.15
%. 'H NMR (DMSO-d6): 8 1.80 (2H, m), 2.0 (4H, m), 2.85 (2H, m), 3.1 (4H, m), 3.5
(2H, d), 4.0 (1H, m), 7.15 (1H, s), 7.30 (4H, d), 7.5 (2H, s), 7.9 (7H, d), 8.65 (1H, d),
9.25 (8H,d), 10.1 (lH,brs).
Example 33.
N-(4-Amino-cyclohexyl)-3,5-bis-(4-aminomethyl-phenoxy)-benzamide
Intermediates (a), (b) and (c) are the same as in Example 26.
d) {4-[3,5-Bis-(4-aminomethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester
0.05g of Raney nickel was added to 0.3g (0.54 mmol) of {4-[3,5-bis-(4-cyano-
phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester stirred with 50 ml

of 10 % NH3-methanol. The reaction mixture was stirred overnight on hydrogen gas
pressure (50 psi) at 50 °C. The reaction mixture was filtered through celite and
concentrated to afford 0.25 g of the required product which was used for the next step
without further purification. Percentage purity (LCMS): 70.8 %, (M+l) = 560.2+1
e) N-(4-Amino-cyclohexyl)-3,5-bis-(4-aminomethyl-phenoxy)-benzamide
Using {4-[3,5-bis-(4-aminomethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (0.25 g, 0.44 mmol) and following the procedure of Example 9(d)
afforded 0.03 g of the required product. Percentage purity: HPLC 98.8 %; LCMS 96.0
%. JH NMR (DMSO-d6): 8 1.37 (4H, m), 1.88 (4H, m), 2.96 (1H, m), 3.70 (1H, m),
4.02 (4H, s), 6.76 (1H, s),7.14 (4H, d), 7.25 (2H, s), 7.51 (4H, d), 7.82 (3H, brs), 8.18
(5H,brs), 8.42(lH,brs).
Example 34.
4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazine-l-carboxylicacid
ethyl ester
Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine-l-carboxylic acid ethyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.45 g (1.26 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.234 g, 1.26
mmol) were used to afford 0.5 g of the required product. !H NMR (DMSO-d6): 5 1.18
(3H, t), 3.52 (8H, m), 4.15 (2H, q), 7.00 (2H, s), 7.07 (1H, s), 7.28 (2H, d), 7.88 (2H, d).
d) 4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperazine-l-
carboxylic acid ethyl ester
Following the procedure of Example 2(d) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-
piperazine-1-carboxylic acid ethyl ester 0.5 g (1.0 mmol) and other reagents were used

to afford 0.4 g of the required product. Percentage purity (LCMS): 51.8 %, (M+l) =
562.2+1.
e) 4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperazine-
1-carboxylic acid ethyl ester
Following the procedure of Example 2(e) 4-{3,5-bis-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoyl}-piperazine-1-carboxylic acid ethyl ester 0.4 g (0.71
mmol) was used to afford 0.4 g of the required product. Percentage purity (LCMS): 67.6
%, (M+l) = 646.2+1.
f) 4-{3,5-Bis-[4-carbamimidoyl-phenoxy]-benzoyl} -piperazine-1 -carboxylic acid
ethyl ester
4-{3,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl} -piperazine-1 -
carboxylic acid ethyl ester 0.4 g (0.61 mmol) was reduced by using the procedure of
Example 2(f) to afford 0.15 g of required product. Percentage purity: HPLC: 94.1 %;
LCMS: 92.83 %. 1H NMR (DMSO-d6): 5 1.2 (3H, t), 3.4 (8H, m), 4.05 (2H, q), 6.95
(2H, s), 7.35 (4H, d), 7.9 (4H, d), 9.06 (3H, brs), 9.3 (4H, s).
Example 35.
l-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-quinoline
Intermediates (a) and (b) are the same as in Example 26.
c) 1 -[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-quinoline
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.45 g (1.26 mmol) and decahydro-quinoline (0.175 g, 1.26 mmol) were used to afford
0.5 g of the required product. JH NMR (DMSO-d6): 8 1.40 (6H, m), 1.62 (5H, m), 1.82
(1H, m), 3.10 (1H, m), 3.20 (1H, m), 3.91 (1H, m), 4.12 (1H, m), 6.88 (1H, s), 6.95 (1H,
s), 7.02 (1H, t), 7.28 (2H, d), 7.88 (2H, d).

d) l-[3,5-Bis-((N-hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-quinoline
Following the procedure of Example 2(d) l-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-
nonahydro-quinoline 0.5 g (1.04 mmol) and other reagents were used to afford 0.52 g of
the required product. Percentage purity (LCMS): 41.7 %, (M+l) = 543.2+1.
e) l-[3,5-Bis-((N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-
quinoline
Following the procedure of Example 2(e) l-[3,5-bis-((N-hydroxycarbamirnidoyl)-
phenoxy)-benzoyl]-nonahydro-quinoline 0.5 g (0.91 mmol) was used to afford 0.45 g of
the required product. Percentage purity (LCMS): 63.0 %, (M+l) = 627.2+1.
f) l-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-quinoline
l-[3,5-Bis-((N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-
quinoline, 0.45 g (0.71 mmol) was reduced using the procedure of Example 2(f) to
afford 0.2 g of required product. Percentage purity: HPLC 95.37 %; LCMS 93.43 %. 'H
NMR(DMSO-d6): 5 1.7 (11H, m), 1.85 (1H, m), 3.20 (2H, m), 3.9 (1H, m), 4.05 (1H,
m), 6.84 (1H, brs), 6.9 (1H, brs), 7.0 (1H, s), 7.54 (4H, d), 7.88 (4H, d), 9.12 (4H, s),
9.28 (4H, s).
Example 36.
3,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diisobutyl-benzamide
Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N,N-diisobutyl-benzamide
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.8 g (2.24 mmol) and diisobutyl-amine (0.29 g, 2.24 mmol) were used to afford 0.74 g

of the required product. lU NMR (DMSO-d6): 5 0.72 (6H, d), 0.88 (6H, d), 1.82 (1H,
m), 2.00 (1H, m), 3.06 (2H, d), 3.24 (2H, d), 6.98 (2H, d), 7.04 (1H, t), 7.22 (4H, d),
7.89 (4H, d).
d) 3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-N,N-diisobutyl-benzamide
Using 3,5-bis-(4-cyano-phenoxy)-N,N-diisobutyl-benzamide (0.74 g, 1.58 mmol)
and following the procedure of Example l(d) afforded 0.8 g of the required product.
Percentage purity (LCMS): 52.8 %, (M+l) = 559.3+1.
e) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diisobutyl-benzamide
Using 3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-N,N-diisobutyl-benzamide (0.8
g, 0.1.42 mmol) and following the procedure of Example l(e) afforded 0.36 g of the
required product. Percentage purity: HPLC; 97.51 %; LCMS; 97.48 %. 1H NMR
(DMSO-d6): 5 0.7 (6H, s), 0.80 (6H, s), 1.8 (1H, m), 2.0 (1H, m), 3.1 (2H, d), 3.2 (2H,
d), 6.9 (2H, d), 7.0 (1H, s), 7.3 (4H, d), 7.88 (4H, d), 9.12 (4H, s), 9.28 (4H, s).
Example 37.
2-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-isoquinoline
Intermediates (a) and (b) are the same as in Example 26.
c) 2-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-isoquinoline
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
1.2 g (3.36 mmol) and decahydro-isoquinoline (0.467 g, 3.36 mmol) were used to afford
1.25 g of the required product. lH NMR (DMSO-d6): 6 1.30 (5H, m), 1.62 (5H, m), 1.85
(1H, m), 3.05 (1H, m), 3.18 (1H, m), 3.51 (1H, m), 3.90 (1H, m), 4.12 (1H, m), 6.86
(1H, s), 6.95 (1H, s), 7.04 (1H, t), 7.26 (2H, d), 7.86 (2H, d).

d) 2-[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-
isoquinoline
Following the procedure of Example 2(d) 2-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-
nonahydro-isoquinoline 1.25 g (2.61 mmol) and other reagents were used to afford 1.3 g
of the required product.Percentage purity (LCMS): 80.0 %, (M+l) = 543.2+1.
e) l-[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-
isoquinoline
Following the procedure of Example 2(e) 2-[3,5-bis-(4-(N-hydroxycarbamimidoyl)-
phenoxy)-benzoyl]-nonahydro-isoquinoline 1.3 g (2.39 mmol) was acetylated to afford
1.2 g of the required product. Percentage purity (LCMS): 70.0 %, (M+l) - 627.2+1.
f) 2-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-isoquinoline
2-[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-
isoquinoline, 1.2 g (1.91 mmol) was reduced using the procedure of Example 2(f) to
afford 0.4 g of required product. Percentage purity: HPLC 95.37 %, LCMS 93.43 %. !H
NMR (DMSO-de): 5 1.7 (11H, m), 1.85 (1H, m), 3.20 (2H, m), 3.9 (1H, m), 4.05 (1H,
m), 6.84 (1H, brs), 6.9 (1H, brs), 7.0 (1H, s), 7.54 (4H, d), 7.88 (4H, d), 9.12 (4H, s),
9.28 (4H, s).
Example 38.
3,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diethyl-benzamide
Intermediates (a) and (b) are same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N,N-diethyl-benzamide
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
1.2 g (3.36 mmol) and diethyl-amine (0.245 g, 3.36 mmol) were used to afford 1.0 g of

the required product. 'H NMR (DMSO-d6): 5 1.15 (6H, m), 3.22 (2H, m), 3.40 (2H, m),
6.94 (2H, d), 7.05 (1H, t), 7.25 (2H, d), 7.88 (2H, d).
d) N,N-Diethyl-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzamide
Following the procedure of Example 2(d) N,N-diethyl-3,5-bis-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzamide 1.0 g (2.43 mmol) and other reagents were used to
afford 1.1 g of the required product. Percentage purity (LCMS): 80.0 %, (M+l) =
477.2+1.
e) N,N-Diethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzamide
Following the procedure of Example 2(e) N,N-diethyl-3,5-bis-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzamide 1.1 g (2.3 mmol) was acetylated to afford 1.0 g of
the required product. Percentage purity (LCMS): 77.0 %, (M+l) = 561.2+1.
f) 3,5-Bis-(4-carbonimidoyl-phenoxy)-N,N-diethyl-benzamide
N,N-Diethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzamide, 1.0
g (1.78 mmol) was reduced using the procedure of Example 2(f) to afford 0.35 g of
required product. Percentage purity:HPLC 95.41 %, LCMS 93.34 %. !H NMR (DMSO-
d6): 5 1.02 (6H, s), 3.2 (2H, m), 3.4 (2H, m), 6.9 (2H, d), 7.0 (1H, s), 7.3 (4H, d), 7.88
(4H, d), 9.24 (3H, s), 9.30 (3H, s).
Example 39.
N-(3-Amino-propyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-N-cyclopropyl-
benzamide
Intermediates (a) and (b) are the same as in Example 26.
c) (3-{[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-cyclopropyl-amino}-propyl)-carbamic
acid tert-butyl ester

Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
1.2 g (3.36 mmol.) and (3-cyclopropylamino-propyl)-carbamic acid tert-butyl ester (0.72
g, 3.36 mmol) were used to afford 1.5 g of the required product. 1H NMR (DMSO-d6): 5
0.48 (1H, m), 0.65 (2H, m), 1.38 (9H, s), 1.42 (2H, m), 1.68 (2H, m), 2.95 (2H, m), 3.22
(2H, m), 6.80 (1H, brs), 6.95 (1H, s), 7.08 (2H, m), 7.25 (4H, m), 7.88 (4H, m).
d) [3-({3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-
amino)-propyl]-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) (3-{[3,5-bis-(4-cyano-phenoxy)-benzoyl]-
cyclopropyl-amino}-propyl)-carbamic acid tert-butyl ester 1.5 g (2.71 mmol) and other
reagents were used to afford 1.3 g of the required product. Percentage purity (LCMS):
42.8.0 %, (M+l) = 618.2 (with BOC).
e) [3-({3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-
cyclopropyl-amino)-propyl]-carbamic acid tert-butyl ester
Following the procedure of Example 2(e) [3-({3,5-bis-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-amino)-propyl]-carbamic acid tert-
butyl ester 1.3 g (2.1 mmol) was acetylated to afford 1.25 g of the required product.
Percentage purity (LCMS): 83.0 %, (M+l) = 702.3.
f) [3-({3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-amino)-
propylj-carbamic acid tert-butyl ester
[3-({3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-
amino)-propyl]-carbamic acid tert-butyl ester, 1.25 g (1.77 mmol) was reduced using the
procedure of Example 2(f) to afford 0.85 g of the required product. Percentage purity
(LCMS): 72.0 %, (M+l) = 486.3+1 (de-Boc mass; -100).

g) 3,5-Bis-(4-carbamimidoyl-phenoxy)-cyclohexa-l,5-dienecarboxylic acid (3-
amino-propyl)-cyclopropyl-amide
Using [3-({3,5-bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-amino)-
propylj-carbamic acid tert-butyl ester (0.85 g, 1.44 mmol) and following the procedure
of Example 9(d) afforded 0.2 g of the required product. Percentage purity: HPLC 96.18
%; LCMS 94.22 %. lH NMR (DMSO-d6): 5 0.50 (2H, m), 0.65 (2H, m), 1.88 (2H, m),
2.85 (3H, m), 3.49 (2H, m), 7.02 (1H, t), 7.14 (2H, s), 7.25 (4H, d), 7.80 (2H, brs),
7.88 (4H, d), 9.22 (3H, s), 9.28 (3H, s).
Example 40.
[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-3,4-dihydro-lH-quinoline
Intermediates (a) and (b) are the same as in Example 26.
c) [3,5-Bis-(4-cyano-phenoxy)-benzoyl]-3,4-dihydro-lH-quinoline
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
1.2 g (3.36 mmol) and 1,2,3,4-tetrahydro-quinoline (0.44 g, 3.36 mmol) were used to
afford 1.3 g of the required product. 1H NMR (DMSO-d6): 5 1.92 (2H, t), 2.54 (2H, m),
3.75 (2H, t), 6.92 (2H, d), 7.08 (7H, m), 7.82 (4H, d).
d) [3,5 -Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl] -3,4-Dihydro-1H-
quinoline
Following the procedure of Example 2(d) [3,5-bis-(4-cyano-phenoxy)-benzoyl]-3,4-
dihydro-lH-quinoline 1.3 g (2.75mmol) and other reagents were used to afford 1.25 g of
the required product. Percentage purity (LCMS): 66.1 %, (M+l) = 537.2.2+1.
e) [3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-Dihydro-
lH-quinoline

Following the procedure of Example 2(e) [3,5-bis-[4-(N-hydroxycarbamimidoyl)-
phenoxy]-benzoyl]-3,4-Dihydro-lH-quinoline 1.25 g (2.32 mmol) was acetylated to
afford 1.2 g of the required product. Percentage purity (LCMS): 65.5 %, (M+l) =
621.2+1.
f) [3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-3,4-Dihydro-lH-quinoline
[3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-dihydro-lH-
quinoline, 1.2 g (1.93 mmol) was reduced using the procedure of Example 2(f) to afford
0.75 g of required product. Percentage purity: HPLC 99.56 %; LCMS 96.29 %. lU
NMR (DMSO-ds): 5 1.92 (2H, q), 2.74 (2H, t), 3.75 (2H, t), 6.85 (1H, brs), 6.90 (2H, d),
6.98 (1H, t), 7.15 (7H, m), 7.84 (4H, d), 9.14 (4H, s), 9.26 (4H, s).
Example 41.
[3,4-Dihydro-1 H-isoquinoline-2-carbonyl]-3,5 -Bis-(4-carbamimidoyl-phenoxy)-
benzene
Intermediates (a) and (b) are the same as in Example 26.
c) [3,4-Dihydro-1 H-isoquinoline-2-carbonyl]-3,5-Bis-(4-cyano-phenoxy)-benzene
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.8 g (2.24 mmol) and 1,2,3,4-tetrahydro-isoquinoline (0.3 g, 2.26 mmol) were used to
afford 0.9 g of the required product. 1H NMR (DMSO-d6): 6 2.82 (2H, m), 3.58 (1H,
m), 3.80 (1H, m), 4.08 (1H, m), 4.74 (1H, m), 7.10 (3H, m), 7.20 (4H, m), 7.28 (4H, d),
7.90 (2H, d).
d) [3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-Bis-(4-(N-hydroxy-
carbamimidoyl)-phenoxy)-benzene
Following the procedure of Example 2(d) [3,4-dihydro-lH-isoquinoline-2-
carbonyl]-3,5-Bis-(4-cyano-phenoxy)-benzene 0.9 g (1.9 mmol) and other reagents were

used to afford 0.85 g of the required product. Percentage purity (LCMS): 38.9 %, (M+l)
= 537.0+1.
e) [3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-Bis-(4-(N-acetylhydroxy-
carbamimidoyl)-phenoxy)-benzene
Following the procedure of Example 2(e) [3,4-dihydro-lH-isoquinoline-2-
carbonyl]-3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-benzene 0.85 g (1.58 mmol)
was acetylated to afford 0.8 g of the required product. Percentage purity (LCMS): 58.1
%, (M+l) = 621.2+1.
f) [3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-Bis-(4-carbamimidoyl-phenoxy)-
benzene
[3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-bis-(4-(N-acetylhydroxy-
carbamimidoyl)-phenoxy)-benzene, 0.8 g (1.28 mmol) was reduced using the procedure
of Example 2(f) to afford 0.15 g of required product. Percentage purity: HPLC 93.50 %;
LCMS 94.20 %. 'HNMR (DMSO-d6): 5 2.80 (2H, m), 3.60 (1H, m), 3.80 (1H, m), 4.67
(2H, m), 6.98 (2H, m), 7.05 (1H, s), 7.18 (4H, m), 7.35 (4H, d), 7.90 (4H, d), 9.10 (4H,
brs), 9.28 (3H, brs).
Example 42.
N-(4-Amino cyclohexyl)-3-(3-carbamimidoyl benzyloxy)-5-(4-carbamimidoyl
phenoxy) benzamide
a) 3-(4-Cyano phenoxy)-5-hydroxy benzoic acid ethyl ester
Potassium carbonate 6.7g(48.5mmol) followed by 4-fluoro benzonitrile 3.3 g
(27.2mmol) in 10ml DMF was added to a solution of 3,5-dihydroxy benzoic acid ethyl
ester 5 g (27.4mmol) in 20 ml of DMF at 20°C. The reaction mixture was allowed to
attain RT and was then heated to 45 °C for 10 h. The reaction mixture was quenched
with ice cold water and extracted with ethyl acetate. The organic layer was washed with

water followed by brine, dried over anhydrous sodium sulphate and concentrated. The
crude compound was purified by column chromatography using hexane-ethyl acetate
(10 : 2) to afford 1.15 g of the required product. lU NMR (DMSO-d6): 6 1.3 (3H, t), 4.3
(2H, q), 6.76 (1H, s), 7.02 (1H, s), 7.36 (2H, d), 7.24 (1H, s), 7.88 (2H, d), 10.3 (1H, s).
b) 3-(3-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester
Potassium carbonate K2CO3 0.44 g (3.18mmol) followed by 3-cyano benzylbromide
0.31 g (1.58 mmol) in 2 ml of DMF were added to a solution of 3-(4-cyano phenoxy)-5-
hydroxy benzoic acid ethyl ester 0.45 g (1.58mmol) in 7 ml of DMF at 20°C. The
reaction mixture was allowed to attain RT and stirred overnight. The reaction mixture
was quenched with ice cold water, extracted with ethyl acetate. The organic layer was
washed with water followed by brine, dried over anhydrous sodium sulphate and
concentrated to afford 0.51 g of a thick oily liquid. 1H NMR (CDC13): 5 1.3 (3H, t), 4.3
(2H, q), 5.25 (2H, s), 6.88 (1H, s), 7.02 (2H, d), 7.34 (1H, s), 7.5 (2H, m), 7.66 (4H, m),
7.78 (1H, s).
c) 3-(3-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid
1.6 g (4.01 mmol) of 3-(3-cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid
ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.2 g of the
required product. fH NMR (DMSO-d6): 5 5.25 (2H, s), 7.16 (4H, m), 7.44 (1H, s), 7.64
(1H, m), 7.9 (5H, m), 13.4 (1H, brs).
d) {4-[3-(3-Cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino]cyclohexyl}-
carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(3-cyano benzyloxy)-5-(4-cyano
phenoxy) benzoic acid 0.46 g (1.24 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-
butyl ester (0.265 g, 1.24 mmol) were used to afford 0.52 g of the required product. lH
NMR (DMSO-d6): 5 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m),

5.25 (2H, s), 6.74 (1H, d), 7.02 (1H, s), 7.32 (2H, d), 7.22 (1H, s), 7.44 (1H, s), 7.64
(1H, m), 7.84 (4H, m), 7.95 (1H, s), 8.3 (1H, d).
e) 4- [3 -(3 -ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-
phenoxy)benzoylamino]cyclohexylamine
Using {4-[3-(3-cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino] cyclohexyl}-
carbamic acid tert-butyl ester (0.5 g, 0.88 mmol) and following the procedure of
Example l(d) afforded 0.3 g of the required product. Percentage purity (LCMS): 64.2
%, (M+l) = 558.2+1.
f) N-(4-Amino cyclohexyl)-3-(3-carbamimidoyl benzyloxy)-5-(4-carbamimidoyl-
phenoxy) benzamide
Using 4-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl
phenoxy)benzoyl amino]cyclohexylamine (0.3 g, 0.53 mmol) and following the
procedure as in Example l(e) afforded 0.16 g of the required product. Percentage purity:
HPLC 96.67 %; LCMS 99.51 %. ]H NMR (DMSO-dfi): 8 1.4 (4H, m), 1.9 (4H, m), 3.0
(1H, m), 3.70 (1H, m), 5.30 (2H, s), 7.0 (1H, s), 7.2 (3H, d), 7.45 (1H, s), 7.70 (1H, m),
7.8-8.0 (7H, m), 8.4 (1H, d), 9.25 (4H, d), 9.4 (4H, d).
Example 43.
N-(4-Aminocyclohexyl)-3-(4-carbamimidoylbenzyloxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester
Using 0.66 g (2.3 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester
and 4-cyanobenzylbromide (0.45 g, 2.3 mmol) and following the procedure of Example

42(b) afforded 0.72 g of the required product. lR NMR (DMSO-d6): 5 1.3 (3H, t), 4.3
(2H, q), 5.35 (2H, s), 7.16 (4H, m), 7.44 (1H, s), 7.66 (2H, s), 7.88 (4H, d).
c) 3-(4-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid
0.72 g (1.8 inmol) of 3-(4-cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid
ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 0.55 g of the
required product. 'H NMR (DMSO-d6): 6 5.25 (2H, s), 7.10 (1H, m), 7.18 (3H, m), 7.42
(1H, s), 7.66 (2H, s), 7.88 (4H, d).
d) {4-[3-(4-Cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino]cyclohexyl}
carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-cyano benzyloxy)-5-(4-cyano
phenoxy) benzoic acid 0.55 g (1.48 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-
butyl ester (0.316 g, 1.48 mmol) were used to afford 0.75 g of the required product. 1H
NMR (DMSO-d()): 5 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m),
5.3 (2H, s), 6.74 (1H, d), 7.02 (1H, s), 7.1 (2H, s), 7.22 (1H, s), 7.44 (1H, s), 7.66 (2H,
d), 7.88 (4H,m), 8.28(1 H, d).
e) 4-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-phenoxy)-
benzoyl aminojcyclohexylamine
Using {4-[3-(4-cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino]-
cyclohexyl}carbamic acid tert-butyl ester (0.75 g, 1.32 mmol) and following the
procedure of Example l(d) afforded 0.35 g of the required product. Percentage purity
(LCMS): 33.7 %, (M+l) - 558.2+1.
f) N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-
phenoxy) benzamide

Using 4-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-
phenoxy)-benzoylamino]cyclohexylamine (0.35 g, 0.62 mmol) and following the
procedure of Example l(e) afforded 0.12 g of the required product. Percentage purity:
HPLC: 91.03 %; LCMS: 96.32 %. 1H NMR (DMSO-d6): 8 1.4 (4H, m), 1.9 (4H, m), 3.0
(1H, m), 3.70 (1H, m), 5.30 (2H, s), 7.0 (1H, s), 7.2 (3H, d), 7.45 (1H, s), 7.70 (2H, d),
7.9 (6H, m), 8.4 (1H, m), 9.3 (7H, t).
Example 44.
N-(4-Amino-cyclohexyl)-3-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-
hydroxycarbamimidoyl)-phenoxy]-benzamide
Intermediates (a) to (d) are the same as in Example 43.
e) (4- {3 - [4-(N-Hydroxycarbamimidoyl)-benzyloxy] -5 - [4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-cyano benzyloxy)-5-(4-cyano
phenoxy)benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester 0.65 g (1.14 mmol)
and other reagents were used to afford 0.52 g of the required product.
Percentage purity (LCMS): 48.2 %, (M+l) = 632.3+1.
f) N-(4-Amino-cyclohexyl)-3-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-
hydroxycarbamimidoyl)-phenoxy]-benzamide
Using (4-{3-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
(0.5 g, 0.8 mmol) and following the procedure of Example 9(d) afforded 0.28 g of the
required product. Percentage purity: HPLC 96.4 %; LCMS 96.7 %. 1H NMR (DMSO-
d6): 5 1.48 (4H, m), 1.98 (4H, m), 3.04 (1H, m), 3.76 (1H, m), 5.42 (2H, s), 7.05 (1H, s),
7.24 (3H, m), 7.48 (2H, m), 7.70 (2H, d), 7.81 (4H, d), 7.91 (3H, brs), 8.42 (1H, d), 8.72
(2H,brs), 11.04 (2H,brs).

Example 45.
N-(4-Aminocyclohexyl)-3-(4-aminomethylbenzyloxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(4-(tert~Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy)
benzoic acid ethyl ester
Using 0.85 g (3.0 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester
and (4-bromomethyl-benzyl)-carbarnic acid tert-butyl ester (0.9 g, 3.0 mmol) and
following the procedure of Example 42(b) afforded 1.32 g of the required product. 1H
NMR (CDC13): 6 1.3 (3H, t), 1.4 (9H, s), 4.15 (2H, d), 4.3 (2H, q), 5.25 (2H, s), 7.18
(4H, m), 7.26 (2H, d), 7.4 (4H, m), 7.88 (2H, d).
c) 3-(4-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy)
benzoic acid
1.3 g (2.58 mmol) of 3-(4-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-
cyano phenoxy) benzoic acid ethyl ester was hydrolysed using the procedure of Example
5(b) to afford 1.1 g.of the required product. 'HNMR (DMSO-d6): 8 1.4 (9H, s), 4.15
(2H, d), 5.2 (2H, s), 7.08 (1H, m), 7.16 (3H, m), 7.26 (2H, d), 7.88 (2H, d), 13.2 (1H,
brs)
d) {4-[3-(4-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano
phenoxy)benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-(tert-butoxycarbonyl aminomethyl)
benzyloxy)-5-(4-cyano phenoxy) benzoic acid 1.1 g (2.31 mmol) and (4-amino-
cyclohexyl)-carbamic acid tert-butyl ester (0.494 g, 2.31 mmol) were used to afford 1.24
g of the required product. 1H NMR (DMSO-d6): 5 1.2 (4H, m), 1.4 (18H, s), 1.8 (4H,

m), 3.2 (1H, m), 3.7 (1H, m), 4.1 (2H, d), 5.15 (2H, s), 6.74 (1H, d), 6.88 (1H, s), 7.12
(2H, d), 7.18 (1H, s), 7.26 (2H, d), 7.4 (4H, d), 7.86 (2H, d), 8.26 (1H, d).
e) 4-[3-(4-Amino cyclohexylcarbamoyl)-5-(4-aminomethyl benzyloxy)
phenoxy]benzimidic acid ethyl ester
Using {4-[3~(4-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano
phenoxy)benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester (1.2 g, 1.78 mmol)
and following the procedure of Example l(d) afforded 0.5 g of the required product.
Percentage purity (LCMS): 52.0 %, (M+l) = 516.2 + 1.
f) N-(4-Aminocyclohexyl)-3 -(4-aminomethylbenzyloxy)-5 -(4-carbamimidoyl-
phenoxy) benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-aminomethyl benzyloxy)
phenoxy]benzimidic acid ethyl ester (0.5 g, 0.96 mmol) and following the procedure of
Example l(e) afforded 0.15 g of the required product. Percentage purity: HPLC 96.46
%; LCMS 98.41 %. !H NMR (DMSO-d6): 5 1.4 (4H, m), 1.85 (2H, m), 1.95 (2H, m),
3.0 (1H, m), 4.1 (3H, s), 5.20 (2H, s), 7.0 (1H, s), 7.2 (3H, m), 7.5 (5H, m), 7.85 (4H,
m), 8.25 (2H, brs), 8.4 (1H, d), 9.2 (4H, s).
Example 46.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) to (d) are the same as in Example 45.
e) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoylammo}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-(tert-butoxycarbonylamino-
methyl)benzyloxy)-5-(4-cyanophenoxy)benzoylamino] cyclohexyl}carbamic acid tert-

butyl ester 0.6 g (0.89 mmol) and other reagents were used to afford 0.55 g of the
required product. Percentage purity (LCMS): 38.9 %, (M+l) = 703.3+1.
g) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy] -benzamide
Using (4-{3-[4-(tert-butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
(0.55 g, 0.78 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the
required product. Percentage purity:HPLC 96.9 %; LCMS 92.4 %. 1H NMR (DMSO-
d6): 5 1.40 (4H, m), 1.90 (4H, m), 3.00 (1H, m), 3.71 (1H, m), 4.15 (2H, s), 5.18 (2H, s),
6.98 (1H, s), 7.16 (3H, m), 7.40 (1H, s), 7.50 (4H, m), 7.76 (2H, d), 7.90 (3H, brs), 8.30
(4H, brs), 8.65 (1H, brs), 11.25 (1H, brs).
Example 47.
N-(4-Aminocyclohexyl)-3-(3-aminomethylbenzyloxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(3-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy)
benzoic acid ethyl ester
Using 1.4 g (4.94 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester
and (3-bromomethyl-benzyl)-carbamic acid tert-butyl ester (1.48 g, 4.94 mmol) and
following the procedure of Example 42(b) afforded 1.9 g of the required product. !H
NMR (DMSO-d6): 5 1.3 (3H, t), 1.4 (9H, s), 4.15 (2H, d), 4.35 (2H, q), 5.25 (2H, s),
7.18 (5H, m), 7.32 (3H, m), 7.44 (2H, s), 7.88 (2H, d).
c) 3-(3-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy)
benzoic acid

1.9 g (3.78 mmol) of 3-(3-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-
cyano phenoxy) benzoic acid ethyl ester was hydrolysed using the procedure of Example
5(b) to afford 1.35 g of the required product. [H NMR (DMSO-d6): 5 1.4 (9H, s), 4.05
(2H, s), 5.2 (2H, s), 7.1 (5H, m), 7.3 (5H, m), 7.9 (2H, m), 13.2 (1H, brs)
d) {4-[3-(3-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyano phenoxy)-
benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(3-(tert-butoxycarbonyl aminomethyl)
benzyloxy)-5-(4-cyano phenoxy) benzoic acid 0.65 g (1.36 mmol) and (4-amino-
cyclohexyl)-carbamic acid tert-butyl ester (0.29 g, 1.36 mmol) were used to afford 0.7 g
of the required product. 'H NMR (DMSO-dg): 5 1.2 (4H, m), 1.4 (18H, s), 1.8 (4H, m),
3.2 (1H, m), 3.7 (1H, m), 4.1 (2H, d), 5.15 (2H, s), 6.74 (1H, d), 6.9 (1H, s), 7.10 (2H,
d), 7.2 (2H, m), 7.35 (3H, m), 7.45 (2H, m), 7.86 (2H, d), 8.26 (1H, d).
e) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(3-aminomethyl benzyloxy)
phenoxy]benzimidic acid ethyl ester
Using {4-[3-(3-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano
phenoxy)benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester (0.7 g, 1.04 mmol)
and following the procedure of Example l(d) afforded 0.3 g of the required product.
Percentage purity (LCMS): 98.0 %, (M+l) = 703.3+1.
f) N-(4-Amino cyclohexyl)-3-(3-aminomethyl benzyloxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(3-aminomethyl benzyloxy)
phenoxy]benzimidic acid ethyl ester (0.3 g, 0.58 mmol) and following the procedure of
Example l(e) afforded 0.12 g of the required product. Percentage purity: HPLC 97.76
%; LCMS 92.64 %. lH NMR (DMSO-d6): 5 1.35 (4H, m), 1.9 (4H, m), 3.0 (2H, m), 4.1
(2H, d), 5.20 (2H, s), 7.0 (1H, s), 7.2 (3H, m), 7.45 (3H, m), 7.55 (1H, s), 7.85 (4H, m),
8.2 (2H, brs), 8.35 (1H, d), 9.0 (2H, s), 9.25 (2H, s).

Example 48.
N-(4-Amino-cyclohexyl)-3-(3-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzamide
Intermediates (a) to (d) are the same as in Example 47.
e) (4-{3-[3-(tert-Butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(3-(tert-butoxycarbonylamino-
methyl)benzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl} carbamic acid tert-
butyl ester 0.65 g (0.97 mmol) and other reagents were used to afford 0.6 g of the
required product. Percentage purity (LCMS): 38.9 %, (M+l) = 503.3+1 (de-Boc; 2 x
100).
f) N-(4-Amino-cyclohexyl)-3-(3-aminomethyl-benzyloxy)-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzamide
Using (4-{3-[3-(tert-butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
(0.6 g, 0.85 mmol) and following the procedure of Example 9(d) afforded 0.2 g of the
required product. Percentage purity: HPLC 98.8 %; LCMS 94.1 %. 2H NMR (DMSO-
d6): 5 1.4 (4H, m), 1.82 (4H, m), 3.03 (1H, m), 3.65 (1H, m), 4.10 (3H, brs), 5.18 (2H,
s), 6.98 (1H, s), 7.18 (3H, d), 7.4 (1H, s), 7.46 (3H, m), 7.55 (1H, s), 7.76 (2H, d), 7.88
(3H, brs), 8.25 (3H, brs), 8.38 (1H, d), 11.10 (1H, brs).
Example 49.
N-(4-Amino cyclohexyl)-3-(3-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy)
benzamide
Intermediate (a) is the same as in Example 42.

b) 3-(4-Cyano phenoxy)-5-hydroxy benzoic acid
1.2 g (4.23 inmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester was
hydrolysed using the procedure of Example 5(b) to afford 0.95 g of the required product.
'H NMR (DMSO-d6): 5 6.75 (1H, s), 7.0 (1H, s), 7.15 (2H, d), 7.25 (1H, s), 7.85 (2H,
d), 10.2 (1H, s), 13.2 (1H, brs).
c) {4-[3-(4-Cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid
tert-butyl ester
Following trie procedure of Example 5(c) 3-(4-cyano phenoxy)-5-hydroxy benzoic
acid 0.9 g (3.52 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g,
3.52 mmol) were used to afford 0.6 g of the required product. 'H NMR (DMSO-d6): 5
1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.15 (1H, m), 3.7 (1H, m), 6.62 (1H, s), 6.76
(1H, d), 7.04 (1H, s), 7.16 (3H, m), 7.86 (2H, m), 8.2 (1H, d), 10.0 (1H, s).
d) {4-[3-(3-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]-cyclohexyl} -
carbamic acid tert-butyl ester
Using 0.6 g (1.32 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]
cyclohexyl}carbamic acid tert-butyl ester and l-bromo-3-bromomethyl-benzene (0.33 g,
1.32 mmol) and following the procedure of Example 42(b) afforded 0.7 g of the
required product. 'H NMR (DMSO-d6): 5 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2
(1H, m), 3.7 (1H, m), 5.2 (2H, s), 6.76 (1H, d), 7.0 (1H, s), 7.12 (2H, d), 7.2 (1H, s),
7.44 (3H, m), 7.56 (1H, d), 7.68 (1H, s), 7.84 (2H, d), 8.3 (1H, d).
e) 4-[3-(4-amino-cyclohexyl-carbamoyl)-5-(3-bromobenzyloxy)phenoxy]-
benzimidic acid ethyl ester
Using {4-[3-(3-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]-
cyclohexyl}-carbamic acid tert-butyl ester (0.7 g, 1.12 mmol) and following the

procedure of Example l(d) afforded 0.35 g of the required product. Percentage purity
(LCMS): 59.0 %, (M+l) = 503.3+1.
f) N-(4-Amino cyclohexyl)-3-(3-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy)
benzamide
Using 4-[3-(4-amino-cyclohexyl-carbamoyl)-5-(3-bromobenzyloxy) phenoxy]-
benzimidic acid ethyl ester (0.35 g, 0.61 mmol) and following the procedure of Example
l(e) afforded 0.15 g of the required product. Percentage purity: HPLC 98.8 %; LCMS
96.6 %. 'H NMR (DMSO-d6): 8 1.40 (4H, m), 1.92 (4H, m), 3.02 (1H, m), 3.71 (1H,
m), 5.20 (2H, s), 7.02 (1H, s), 7.14 (1H, s), 7.21 (2H, d), 7.42 (3H, m), 7.58 (1H, d),
7.68 (1H, s), 7.88 (4H, d), 8.35 (1H, d), 9.12 (2H, brs), 9.26 (2H, brs).
Example 50.
N-(4-Amino-cyclohexyl)-3-(3-bromo-benzyloxy)-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) to (d) are the same as in Example 49.
e) (4-{3-(3-Bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-
benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(3-bromo-benzyloxy)-5-(4-cyano-
phenoxy)benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester 0.58 g (0.93 mmol)
and other reagents were used to afford 0.6 g of the required product.
Percentage purity (LCMS): 48.2 %, (M+l) = 653.2+1.
f) N-(4-Amino-cyclohexyl)-3-(3-bromo-benzyloxy)-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy] -benzamide
Using (4-{3-(3-bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-
benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 0.91 mmol) and

following the procedure of Example 9(d) afforded 0.35 g of the required product.
Percentage purity: HPLC 98.4 %; LCMS 97.2 %. ]H NMR (DMSO-d6): 5 1.40 (4H, m),
1.90 (4H, m), 3.00 (1H, m), 3.70 (1H, m), 5.18 (2H, s), 6.98 (1H, m), 7.11 (1H, s), 7.18
(2H, d), 7.42 (3H, m), 7.52 (1H, d), 7.68 (1H, s), 7.78 (2H, d), 7.90 (3H, brs), 8.36 (1H,
d), 8.85 (lH,brs), 11.15 (lH,brs).
Example 51.
N-(4-Amino cyclohexyl)-3-(4-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy)
benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]cyclohexyl}-
carbamic acid tert-butyl ester
Using 1.3 g (2.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]
cyclohexyl}carbamic acid tert-butyl ester and l-bromo-4-bromomethyl-benzene (0.72 g,
2.88 mmol) and following the procedure of Example 42(b) afforded 1.5 g of the
required product. 1H NMR (DMSO-d6): 5 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2
(1H, m), 3.7 (1H, m), 5.2 (2H, s), 6.78 (1H, d), 6.88 (1H, s), 7.12 (2H, d), 7.2 (1H, s),
7.4 (3H, s), 7.6 (2H, d), 7.86 (2H, d), 8.28 (1H, d).
e) 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromobenzyloxy)phenoxy]-
benzimidic acid ethyl ester
Using {4-[3-(4-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]
cyclohexyl}-carbamic acid tert-butyl ester (0.85 g, 1.36 mmol) and following the
procedure of Example l(d) afforded 0.7 g of the required product. Percentage purity
(LCMS): 68.08 %, (M+l) = 565.1+1.
f) N-(4-Amino cyclohexyl)-3-(4-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy)
benzamide

Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromo benzyloxy) phenoxy]-
benzimidic acid ethyl ester (0.7 g, 1.23 mmol) and following the procedure of Example
l(e) afforded 0.32 g of the required product. Percentage purity: HPLC 98.39 %; LCMS
99.72 %. 'HNMR (DMSO-de): 5 1.40 (4H, m), 1.85(2H, m), 1.95 (2H, m), 3.0 (1H, m),
3.70 (1H5 m), 5.20 (2H, s), 7.0 (1H, s), 7.2 (3H, s), 7.45 (3H, d), 7.6 (2H, d), 7.9 (5H,
m), 8.36 (1H, d), 9.26 (4H, d).
Example 52.
N-(4- Amino-cyclohexyl)-3 -(4-bromo-benzyloxy)-5 - [4-(N-hydroxy-
carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) to (d) are the same as in Example 51.
e) (4- { 3 -(4-Bromo-benzyloxy)-5 -[4-(N-hydroxycarbamimidoyl)-phenoxy]-
benzoylamino}"Cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-bromo-benzyloxy)-5-(4-cyano-
phenoxy)benzoylamino]cyclohexyl}-carbamic acid tert-butyl ester 0.6 g (0.96 mmol)
and other reagents were used to afford 0.45 g of the required product.
Percentage purity (LCMS): 38.9 %, (M+l) = 652.2+1.
f) N-(4-Amino-cyclohexyl)-3-(4-bromo-benzyloxy)-5-[4-(N-hydroxy-
carbamimidoyl)-phenoxy] -benzamide
Using (4-{3-(4-bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]-
benzoylamino} -cyclohexyl)-carbamic acid tert-butyl ester (0.45 g, 0.68 mmol) and
following the procedure of Example 9(d) afforded 0.21 g of the required product.
Percentage purity: HPLC 97.9 %; LCMS 98.5 %. 'H NMR (DMSO-d6): 5 1.40 (4H, m),
1.92 (4H, m), 3.00 (1H, m), 3.70 (1H, m), 5.18 (2H, s), 6.96 (1H, m), 7.18 (3H, m), 7.42
(3H, d), 7.61 (2H, d), 7.76 (2H, d), 7.90 (3H, brs), 8.36 (1H, d), 8.85 (2H, brs), 11.14
(1H, brs).

Example 53.
N-(4-Amino cyclohexyl)-3-(6-bromopyridine-3-ylmethoxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4- [3 -(6~bromopyridine-3 -ylmethoxy)-5-(4-cyanophenoxy)benzoylamino] -
cyclohexyljcarbamic acid tert-butyl ester
Using 1.4 g (3.1 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-
cyclohexyl}-carbamic acid tert-butyl ester and 2-bromo-5-bromomethyl-pyridine (0.77
g, 3.1 mmol) and following the procedure of Example 42(b) afforded 1.5 g of the
required product. 'H NMR (DMSO-d6): 5 1.20 (4H, m), 1.40 (9H, s), 1.80 (4H, m), 3.2
(1H, m), 3.70 (1H, m), 5.25 (2H, s), 6.75 (1H, d), 7.0 (1H, s), 7.15 (2H, d), 7.22 (1H, s),
7.45 (1H, s), 7.7 (1H, d), 7.85 (3H, m), 8.3 (1H, d), 8.5 (1H, s).
e) 4- [3 -(4-aminocyclohexylcarbamoyl)-5-(6-bromopyridine-3 -ylmethoxy)
phenoxy] benzimidic acid ethyl ester
Using {4-[3-(6-bromopyridine-3-ylmethoxy)-5-(4-cyanophenoxy)benzoyl amino]-
cyclohexyl}carbamic acid tert-butyl ester (0.9 g, 1.44 mmol) and following the
procedure of Example l(d) afforded 0.54 g of the required product. Percentage purity
(LCMS): 68.08 % (M+l) = 566.1+1.
f) N-(4-Amino cyclohexyl)-3-(6-bromo pyridine-3-ylmethoxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromo benzyloxy) phenoxy]-
benzimidic acid ethyl ester (0.54 g, 0.95 mmol) and following the procedure of Example
l(e) afforded 0.14 g of the required product. Percentage purity: HPLC 95.76 %; LCMS
99.15 %. ]H NMR (DMSO-d6): 5 1.40 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.70 (1H, m),

5.2 (2H, s), 7.0 (1H, s), 7.2 (3H, m), 7.4 (1H, s), 7.7 (1H, d), 7.9 (5H, m), 8.4 (1H, d),
8.5 (1H, d), 9.2 (2H, s), 9.3 (2H, s).
Example 54.
N-(4-Aminocyclohexyl)-3-(6-aminopyridin-3-ylmethoxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {5-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-
phenoxy)-phenoxymethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester
Using 1.2 g (2.65 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-
cyclohexyl}-carbamic acid tert-butyl ester and (5-bromomethyl-pyridin-2-yl)-carbamic
acid tert-butyl ester (0.76 g, 2.65 mmol) and following the procedure of Example 42(b)
afforded 1.42 g of the required product. 'H NMR (DMSO-d6): 5 1.25 (4H, m), 1.4 (27H,
s), 1.8 (4H, m), 3.20 (1H, m), 3.75 (1H, m), 5.25 (2H,s), 6.75 (1H, d), 7.05 (1H, s), 7.15
(2H, d), 7.2 (1H, s), 7.45 (2H, m), 7.85 (2H, d), 7.95 (1H, d), 8.25 (1H, d), 8.5 (1H, s).
e) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(6-amino-pyridin-3-ylmethoxy)-
phenoxy]-benzimidic acid ethyl ester
Using {5-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-
phenoxy)-phenoxymethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (1.4 g, 2.12
mmol) and following the procedure of Example l(d) afforded 0.64 g of the required
product. Percentage purity (LCMS): 83.8 %, (M+l) = 566.1+1.
f) N-(4-Amino cyclohexyl)-3-(6- amino pyridine-3-ylmethoxy)-5-(4-
carbamimidoyl phenoxy) benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(6-amino-pyridin-3-ylmethoxy)-
phenoxy]-benzimidic acid ethyl ester (0.64 g, 1.27 mmol) and following the procedure

of Example l(e) afforded 0.14 g of the required product. Percentage purity: HPLC 96.58
%; LCMS 94.17 %. 1HNMRCDMSO-d6): 6 1.4 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.7
(1H, m), 5.05 (2H, s), 7.0 (2H, m), 7.2 (2H, d), 7.4 (1H, s), 7.86 (5H, m), 8.0 (1H, d),
8.1 (2H, s), 8.36 (1H, d), 9.08 (2H, s), 9.26 (2H,s).
Example 55.
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy-
methyl]-benzoic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 49.
d) 4-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)-
phenoxy methyl]benzoic acid ethyl ester
Using 1.2 g (2.65 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-
cyclohexyl}-carbamic acid tert-butyl ester and 4-bromomethyl-benzoic acid ethyl ester
(0.644 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 1.32 g of
the required product. Percentage purity (LCMS): 84.4 %, (M+l) = 613.2+1.
e) 4-[3-(4- Amino cyclohexyl carbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)
phenoxymethyl] benzoic acid ethyl ester
Using 4-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano-
phenoxy)-phenoxy methyl]benzoic acid ethyl ester (1.32 g, 2.12 mmol) and following
the procedure of Example l(d) afforded 0.54 g of the required product. Percentage
purity (LCMS): 68.7 %, (M+l) = 559.2+1.
f) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy) phenoxy-
methyl]-benzoic acid ethyl ester
Using 4-[3-(4- amino cyclohexyl carbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)
phenoxymethyl jbenzoic acid ethyl ester (0.54 g, 0.96 mmol) and following the

procedure of Example l(e) afforded 0.23 g of the required product. Percentage purity:
HPLC 97.37 %; LCMS 97.15%. 'HNMR (DMSO-d6): 8 1.35 (3H, t), 1.4 (4H, m), 1.95
(4H, m), 3.0 (1H, m), 3.7 (1H, m), 4.35 (2H, q), 5.3 (2H, s) 7.0 (1H, s), 7.2 (3H, m),
7.42 (1H, s), 7.60 (2H, d), 7.82 (4H, m), 8.0 (2H, d), 8.38 (1H, d), 9.08 (2H, s), 9.26
(2H, s).
Example 56.
4-{3-[4-(2-aminoethyl)piperidine-l-carbonyl]-5-phenethyloxyphenoxy}-
benzamidine
Intermediate (a) is the same as in Example 42.
b) 3-(4- Cyano phenoxy)-5-phenethyloxy benzoic acid ethyl ester
Using 1.0 g (3.53 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester
and (2-bromo-ethyl)-benzene (0.65 g, 3.53 mmol) and following the procedure of
Example 42(b) afforded 0.95 g of the required product. 1H NMR (CDC13): 8 1.35 (3H,
t), 3.1 (2H, t), 4.2 (2H, t), 4.35 (2H, q), 6.78 (1H, t), 7.0 (2H, s), 7.22 (1H, m) 7.32 (5H,
m), 7.42 (1H, m), 7.62 (2H, s).
c) 3-(4- Cyano phenoxy)-5-phenethyloxy benzoic acid
0.95 g (2.45 mmol) of 3-(4- cyano phenoxy)-5-phenethyloxy benzoic acid ethyl
ester was hydrolysed using the procedure of Example 5(b) to afford 0.6 g.of the required
product. 1H NMR (DMSO-d6): 8 3.02 (2H, t), 4.26 (2H, t), 7.0 (1H, t), 7.18 (3H, m),
7.24 (1H, m) 7.32 (5H, m), 7.88 (2H, s), 13.4 (1H, brs).
d) (2- {1 -[3 -(4-cyanophenoxy)-5-phenethyloxybenzoyl]piperidin-4-yl}ethyl)-
carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4- cyano phenoxy)-5-phenethyloxy
benzoic acid 0.6 g (1.66 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl

ester (0.378 g, 1.66 mmol) were used to afford 0.55 g of the required product. 'H NMR
(DMSO-d6): 5 1.05 (3H, m), 1.4 (9H, s), 1.55 (2H, m), 1.7 (1H, m), 2.1 (5H, s), 3.0 (5H,
m), 4.2 (2H, t), 4.4 (1H, m), 6.62 (1H, s), 6.78 (2H, s), 7.14 (2H, d), 7.24 (1H, m), 7.3
(4H, d), 7.88 (2H, d).
e) 4-{3-[4-(2-aminoethyl)piperidine-l-carbonyl]-5-phenethyloxyphenoxy}-
benzimidic acid ethyl ester
Using (2- {1 -[3-(4-cyanophenoxy)-5-phenethyloxybenzoyl]piperidin-4-yl}ethyl)-
carbamic acid tert-butyl ester (0.55 g, 0.96 mmol) and following the procedure of
Example l(d) afforded 0.28 g of the required product. Percentage purity (LCMS): 56.4
%,(M+1) = 515.2+1
f) 4-{3-[4-(2-aminoethyl)piperidine-1 -carbonyl]-5-phenethyloxyphenoxy} -
benzamidine
Using 4-{3-[4-(2-aminoethyl)piperidine-l-carbonyl]-5-phenethyloxy phenoxy}-
benzimidic acid ethyl ester (0.28 g, 0.54 mmol) and following the procedure of Example
l(e) afforded 0.06 g of the required product. Percentage purity: HPLC 87.23 %; LCMS
76.08 %. ]HNMR (DMSO-d6): 5 1.10 (3H, t), 1.50 (2H, m), 1.60 (2H, m), 1.75 (1H,
m), 2.70 (1H, m), 2.85 (2H, m), 3.05 (3H, m), 3.6 (1H, m), 4.25 (2H, t), 4.45 (1H, m),
6.6 (s), 6.8 (2H, m), 7.25 (2H, m), 7.35 (3H, s), 7.7 (2H, brs), 7.9 (2H, s), 9.05 (2H, s),
9.25 (2H, s).
Example 57.
2-{l-[3-(3-Carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)-benzoyl]-
piperidin-4-yl} -ethylamine
Intermediates (a) - (c) are the same as in Example 42.
d) (2-{l-[3-(3-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin-4-yl}ethyl)-
carbamic acid tert-butyl ester

Following the procedure of Example 5(c) 3-(3-cyano-benzyloxy)-5-(4-cyano-
phenoxy)-benzoic acid 0.75 g (2.02 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid
tert-butyl ester (0.46 g, 2.02 mmol) were used to afford 0.7 g of the required product.
Percentage purity (LCMS): 62.3 %, (M+l) = 480.2+1 (de-Boc mass, -100).
e) 2-{ 1 -[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-
phenoxy)benzoyl]piperidin-4-yl} ethylamine
Using (2-{ 1 -[3-(3-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl] piperidin-4-
yl}ethyl)-carbamic acid tert-butyl ester (0.7 g, 1.2 mmol) and following the procedure of
Example l(d) afforded 0.43 g of the required product. Percentage purity (LCMS): 49.2
%, (M+l) = 572.3+1.
f) 2-{l-[3-(3-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)-benzoyl]-
piperidin-4-yl} ethylamine
Using 2-{ l-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy carbonimidoyl-
phenoxy)benzoyl]piperidin-4-yl}ethylamine (0.43 g, 0.54 mmol) and following the
procedure of Example l(e) afforded 0.16 g of the required product. Percentage purity:
HPLC 98.59 %; LCMS 98.49 %. ]HNMR (DMSO-ds): 8 1.10 (2H, m), 1.50 (2H, m),
1.60 (2H, m), 1.75 (1H, m), 2.80 (3H, m), 3.0 (2H, m), 4.45 (1H, m), 5.2 (2H, s), 6.65
(1H, s), 6.9 (2H, s), 7.25 (2H, s), 7.65 (1H, m), 7.7 - 7.85 (5H, m), 7.9 (3H, s), 9.1 (2H,
s), 9.25 (3H, d), 9.4 (2H, s).
Example 58.
2-{l-[3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)benzoyl]-
piperidin-4-yl} ethylamine
Intermediates (a) - (c) are the same as in Example 43.

d) (2- {1 -[3 -(4-cyanobenzyloxy)-5 -(4-cyanophenoxy)benzoyl]piperidin-4-yl} ethyl)-
carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-cyano-benzyloxy)-5-(4-cyano-
phenoxy)-benzoic acid 0.8 g (2.16 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid
tert-butyl ester (0.49 g, 2.16 mmol) were used to afford 0.92 g of the required product.
'HNMR (DMSO-d6): 5 1.10 (2H, m), 1.30 (2H, m), 1.4 (9H, s), 1.50 (2H, m), 1.75 (1H,
m), 2.70 (1H, m), 2.8 (3H, m), 3.5 (1H, m), 4.4 (1H, m), 5.2 (2H, s), 6.65 (1H, s), 6.78
(1H, m), 6.88 (2H, m), 7.16 (2H, s), 7.64 (2H, d), 7.88 (4H, m).
e) 2-{l-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-
phenoxy)benzoyl]piperidin-4-yl} ethylamine
Using (2-{ 1 -[3-(4-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin -4-
yl}ethyl)-carbamic acid tert-butyl ester (0.92 g, 1.58 mmol) and following the procedure
of Example l(d) afforded 0.54 g of the required product. Percentage purity (LCMS):
30.4%, (M+l) = 572.3+1.
f) 2-{l-[3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)benzoyl]-
piperidin-4-yl} ethylamine
Using 2-{ l-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy carbonimidoyl-
phenoxy)benzoyl]piperidin-4-yl}ethylamine (0.54 g, 0.94 mmol) and following the
procedure of Example l(e) afforded 0.32 g of the required product. Percentage purity:
HPLC 98.97 %; LCMS 93.02 %. !H NMR (DMSO-d6): 5 1.10 (2H, m), 1.50 (2H, m),
1.60 (2H, m), 1.75 (1H, m), 2.85 (4H, m), 3.0 (1H, m), 4.45 (1H, m), 5.3 (2H, s), 6.65
(1H, s), 6.9 (2H, s), 7.2 (2H, d), 7.7 (2H, d), 7.8 (2H, brs), 7.9 (4H, t), 9.3 (6H, t).
Example 59.
4-[3-(4-aminomethyl benzyloxy)-5-(4-carbamimidoyl phenoxy)benzoyl]-
piperazine-1-carboxylic acid ethyl ester

Intermediate (a) is the same as in Example 42.
Intermediates (b) and (c) are the same as in Example 45.
d) 4- [3 - [4-(tert-butoxycarbonylaminomethyl)benzyloxy] -5 -(4-cyanophenoxy)-
benzoyl] piperazine-1-carboxylic acid ethyl ester
Following the procedure of Example 5(c) 3-(4-(tert-butoxycarbonyl aminomethyl)
benzyloxy)-5-(4-cyano phenoxy) benzoic acid 0.85 g (1.79 mmol) and piperazine-1-
carboxylic acid ethyl ester (0.283 g, 1.79 mmol) were used to afford 0.91 g of the
required product 1H NMR (DMSO-d6): 5 1.20 (3H, t), 1.40 (9H, s), 3.3 (2H, m), 3.6
(6H, m), 4.05 (2H, q), 4.15 (2H, d), 5.1 (2H, s), 6.7 (1H, s), 6.9 (2H, s), 7.18 (2H, d),
7.26 (2H, d), 7.4 (3H, d), 7.86 (2H, d), 7.86 (2H, s).
e) 4-[3-(4-aminomethyl benzyloxy)-5-(4-ethoxy carbonimidoyl phenoxy)
benzoyl]piperazine-l-carboxylic acid ethyl ester
Using 4-[3-|4-(tert-butoxycarbonylaminomethyl)benzyloxy]-5-(4-cyanophenoxy)-
benzoyl] piperazine-1-carboxylic acid ethyl ester (0.91 g, 1.48 mmol) and following the
procedure of Example l(d) afforded 0.34 g of the required product. Percentage purity
(LCMS): 73.3 %, (M+l) = 560.2+1.
f) 4-[3-(4-Aminomethylbenzyloxy)-5-(4-carbamimidoylphenoxy)benzoyl]-
piperazine-1-carboxylic acid ethyl ester
Using 4-[3-(4-aminomethyl benzyloxy)-5-(4-ethoxy carbonimidoyl phenoxy)-
benzoyl]piperazine-l-carboxylic acid ethyl ester (0.34 g, 0.6 mmol) and following the
procedure of Example l(e) afforded 0.15 g of the required product. Percentage purity:
HPLC 93.79 %; LCMS 95.27 %. ]H NMR (DMSO-d6): 5 1.2 (3H, t), 3.4 (2H, m), 3.6
(2H, m), 3.75 (6H, m), 4.1 (2H, q), 5.2 (2H, s), 6.66 (1H, s), 6.9 (2H, s), 7.22 (2H, d),
7.5 (3H, s), 7.88 (2H, d), 8.2 (2H, brs), 9.06 (2H, s), 9.25 (2H, s).

Example 60.
4-[3-(4-Carbamimidoylphenoxy)-5-(4-ethoxycarbonylbenzyloxy)-benzoyl]-
piperazine-1-carboxylic acid ethyl ester
Intermediates (a) and (b) are the same as in Example 49.
c) 4-[3-(4-Cyano phenoxy)-5-hydroxy benzoyl]piperazine-l-carboxylic acid ethyl
ester
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-hydroxy benzoic
acid 0.9 g (3.52 mmol) and piperazine-1-carboxylic acid ethyl ester (0.556 g, 3.52
mmol) were used to afford 0.52 g of the required product. Percentage purity (LCMS):
90.2%, (M+l) = 395.1+1.
d) 4-[3-(4-Cyanophenoxy)-5-(4-ethoxycarbonyl-benzyloxy)-benzoyl]piperazine-l-
carboxylic acid ethyl ester
Using 0.52 g (1.31 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]-
piperazine-1-carboxylic acid ethyl ester and 4-bromomethyl-benzoic acid ethyl ester
(0.318 g, 1.31 mmol) and following the procedure of Example 42(b) affored 0.61 g of
the required product. Percentage purity (LCMS): 60.0 % (M+l) = 557.2+1.
e) 4-[3-(4-E;thoxycarbonimidoyl phenoxy)-5-(4-ethoxycarbonyl benzyloxy)-
benzoyl]piperazine-l-carboxylic acid ethyl ester
Using 4-[3-(4-cyanophenoxy)-5-(4-ethoxycarbonyl-benzyloxy)-benzoyl]piperazine-
1-carboxylic acid ethyl ester (0.6 g, 1.07 mmol) and following the procedure of Example
l(d) afforded 0.32 g of the required product. Percentage purity (LCMS): 42.2 %, (M+l)
= 603.2+1.
f) 4-[3-(4-Carbamimidoylphenoxy)-5-(4-ethoxycarbonylbenzyloxy)-benzoyl]-
piperazine-1-carboxylic acid ethyl ester

Using 4-[3-(4-ethoxycarbonimidoyl phenoxy)-5-(4-ethoxycarbonyl benzyloxy)-
benzoyl]piperazine-l-carboxylic acid ethyl ester (0.32 g, 0.53 mmol) and following the
procedure of Example l(e) afforded 0.15 g of the required product. Percentage purity:
HPLC 94.77 %; LCMS 99.8 %. 1H NMR (DMSO-d6): 5 1.2 (3H, t), 1.35 (3H, t), 3.3
(2H, m), 3.4 (2H, m), 3.6 (4H, m), 4.1 (2H, q), 4.4 (2H, q), 5.3 (2H, s), 6.7 (1H, s), 6.9
(2H, d), 7.25 (2H, d), 7.6 (2H, d), 7.85 (2H, d), 8.0 (2H, d), 9.0 (2H, s), 9.25 (2H, s).
Example 61.
4-[3-(4-Bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzoyl]piperazine-l-
carboxylic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 60.
d) 4-[3-(4-Bromo benzyloxy)-5-(4-cyano phenoxy)benzoyl]piperazine-l-carboxylic
acid ethyl ester
Using 0.75 g (1.89 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]-
piperazine-1-carboxylic acid ethyl ester and l-bromo-4-bromomethyl-benzene (0.472 g,
1.89 mmol) and following the procedure of Example 42(b) afforded 0.85 g of the
required product. Percentage purity (LCMS): 75.2 %, (M+l) = 563.1+1.
e) 4- [3 -(4-Bromobenzyloxy)-5 -(4-ethoxycarbonimidoylphenoxy)benzoyl] -
piperazine-1-carboxylic acid ethyl ester
Using 4-[3-(4-bromobenzyloxy)-5-(4-cyano phenoxy)benzoyl]piperazine-1 -
carboxylic acid ethyl ester (0.85 g, 1.5 mmol) and following the procedure of Example
l(d) afforded 0.37 g of the required product. Percentage purity (LCMS): 43.1 %, (M+l)
= 609.1+1.

f) 4-[3-(4-Bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzoyljpiperazine-1-
carboxylic acid ethyl ester
Using 4-[3-(4-bromobenzyloxy)-5-(4-ethoxycarbonimidoylphenoxy)benzoyl]-
piperazine-1-carboxylic acid ethyl ester (0.37 g, 0.6 mmol) and following the procedure
of Example l(e) afforded 0.15 g of the required product. Percentage purity: HPLC 98.96
%; LCMS 91.78 %. lH NMR (DMSO-d6): 8 1.2 (3H, t), 3.35 (6H, m), 3.6 (2H, m), 3.6
(4H, m), 4.1 (2H, q), 5.2 (2H, s), 6.68 (1H, s), 6.7 (2H, m), 7.24 (2H, d), 7.4 (2H, d),
7.6 (2H, d), 7.86 (2H, d), 8.9 (2H, s), 9.25 (2H, s).
Example 62.
3-(3-Amino benzyloxy)-N-(4-amino cyclohexyl)-5-(4-carbamimidoyl phenoxy)
benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyano phenoxy)-5-(3-nitro benzyloxy) benzoic acid ethyl ester
Using 1.2 g (4.23 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester
and l-bromomethyl-3-nitro-benzene (0.913 g, 4.23 mmol) and following the procedure
of Example 42(b) afforded 1.43 g of the required product. :H NMR (DMSO-d6): 8 1.3
(3H, t), 4.3 (2H, q), 5.4 (2H, s), 7.2 (4H, m), 7.45 (1H, s), 7.72 (1H, t), 7.9 (3H, m), 8.25
(lH,d),8.35(lH,s).
c) 3-(4-Cyano phenoxy)-5-(3-nitro benzyloxy) benzoic acid
1.43 g (3.41 mmol) of 3-(4-cyano phenoxy)-5-(3-nitro benzyloxy) benzoic acid
ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.1 g of the
required product. !H NMR (DMSO-d6): 8 5.4 (2H, s), 7.16 (4H, d), 7.45 (1H, s), 7.5
(1H, t), 7.9 (3H, d), 8.22 (1H, d), 8.34 (1H, s), 13.4 (1H, brs)

d) {4-[3-(4-cyanophenoxy)-5-(3-nitrobenzyloxy)benzoylamino]cyclohexyl}-
carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-(3-nitro
benzyloxy) benzoic acid 1.1 g (2.81 mmol) and (4-amino-cyclohexyl)-carbamic acid
tert-butyl ester (0.6 g, 2.81 mmol) were used to afford 1.2 g of the required product. 'H
NMR (DMSO-d6): 5 1.2 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m),
5.35 (2H, s), 6.78 (1H, d), 7.04 (1H, s), 7.12 (2H, d), 7.22 (1H, s), 7.46 (1H, s), 7.72
(1H, t), 7.9 (3H, d), 8.2 (1H, d), 8.34 (2H, m).
e) {4-[3-(3-amino benzyloxy)-5-(4-cyano phenoxy)benzoylamino]cyclohexyl}
carbamic acid tert-butyl ester
1.2 g (2.04 mmol) of {4-[3-(4- cyano phenoxy)-5-(3-nitro benzyloxy)benzoyl
aminojcyclohexyl}carbamic acid tert-butyl ester, dissolved in 10 ml of THF, 0.455 g
(8.16 mmol) of iron powder and 0.436 g (8.16 mmol) of NH4CI solution (5 ml water)
were mixed. The resulting reaction mixture was refluxed overnight. After completion of
reaction, the reaction mixture was filtered through celite, and the filtrate was
concentrated under reduced pressure. 100 ml water was added to the concentrated
mixture and the mixture was extracted with 100 ml of ethyl acetate. The organic layer
was washed with water followed by saturated brine, dried over anhydrous sodium
sulphate and concentrated to afford crude compound which was purified by column
chromatography using hexane-ethylacetate (10 : 2) to afford 0.75 g of the required
product. !H NMR (DMSO-d6): 5 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7
(1H, m), 5.0 (2H, s), 5.15 (2H, s), 6.5 (2H, m), 6.62 (1H, s), 6.78 (1H, d), 6.94 (1H, s),
7.0 (1H, t), 7.12 (3H, m), 7.4 (1H, s), 7.82 (2H, d), 8.26 (1H, d).
f) 4-[3-(3-amino benzyloxy)-5-(4- aminocyclohexyl carbamoyl) phenoxy]
benzimidic acid ethyl ester
Using {4-[3-(3-aminobenzyloxy)-5-(4-cyano phenoxy)benzoylamino]
cyclohexyl}carbamic acid tert-butyl ester (0.65 g, 1.16 mmol) and following the

procedure of Example l(d) afforded 0.23 g of the required product. Percentage purity
(LCMS): 98.0 %, (M+l) = 502.2+1.
g) 3-(3-Arninobenzyloxy)-N-(4-aminocyclohexyl)-5-(4-carbamimidoylphenoxy)
benzamide
Using 4-[3-(3-amino benzyloxy)-5-(4- aminocyclohexyl carbamoyl) phenoxy]
benzimidic acid ethyl ester (0.23 g, 0.45 mmol) and following the procedure of Example
l(e) afforded 0.04 g of the required product. Percentage purity: HPLC 97.77 %; LCMS
94.67 %. lH NMR (DMSO-ds): 5 1.40 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.7 (1H, m),
5.10 (2H, s), 6.85 (3H, m), 6.95 (1H, s), 7.20 (4H, m), 7.40 (1H, s), 7.85 (5H, s), 8.35
(1H, d), 9.1 (2H, brs), 9.25 (2H, s).
Example 63.
N-(4-Amino cyclohexyl)-3-[3-(3-amino propionylamino)benzyloxy]-5-(4-
carbamimidoyl phenoxy) benzamide
Intermediates (a) - (e) are the same as in Example 62.
f) {4-[3-[3-(3-tert-butoxycarbonylaminopropionylamino)benzyloxy]-5-(4-cyano
phenoxy)-benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09 mmol) and {4-[3-(3-
amino benzyloxy)-5-(4-cyano phenoxy)benzoylamino]cyclohexyl} carbamic acid tert-
butyl ester (0.6 g, 1.09 mmol) and other reagents as described in Example 9(e) were
used to afford 0.45 g.of the required product. !H NMR (DMSO-d6): 5 1.25 (4H, m), 1.4
(18H, s), 1.8 (4H, m), 2.45 (2H, m), 3.1 (3H, m), 3.7 (2H, m), 5.15 (2H, s), 6.74 (1H, d),
6.88 (1H, m), 6.98 1H, s), 7.12 (3H, d), 7.2 (1H, s), 7.3 (1H, t), 7.42 (1H, s), 7.54 (1H,
d), 7.72 (1H, s), 7.86 (2H, d), 8.26 (1H, d).
g) 4-{3-(4-Amino cyclohexyl carbamoyl)-5-[3-(3-amino propionylamino)
benzyloxy]phenoxy}benzimidic acid ethyl ester

Using {4-[3-[3-(3-tert-butoxycarbonylaminopropionylammo)benzyloxy]-5-(4-cyano
phenoxy)-benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester (0.45 g, 0.61 mmol)
and following the procedure of Example l(d) afforded 0.15 g of the required product.
Percentage purity (LCMS): 51.2 %, (M+l) = 573.3+1.
h) N-(4-Aminocyclohexyl)-3-[3-(3-aminopropionylamino)benzyloxy]-5-(4-
carbamimidoyl phenoxy) benzamide
Using 4-{3-(4-amino cyclohexyl carbamoyl)-5-[3-(3-amino propionylamino)-
benzyloxy]phenoxy}benzimidic acid ethyl ester (0.15 g, 0.26 mmol) and following the
procedure of Example l(e) afforded 0.03 g of the required product. Percentage purity:
HPLC 91.6 %; LCMS 92.3 %. 'H NMR (DMSO-d6): 5 1.40 (4H, m), 1.92 (4H5 m), 2.72
(2H, t), 3.0 (1H, m), 3.10 (2H, q), 3.72 (1H, m), 5.14 (2H, s), 6.98 (1H, s), 7.14 (1H, s),
7.20 (2H, d), 7.35 (1H, t), 7.40 (1H, s), 7.72 (1H, s), 7.81 (3H, brs), 7.88 (6H, d), 8.35
(1H, d), 9.14 (2H, brs), 9.25 (2H, s), 10.24 (1H, brs).
Example 64.
N-(4- Aminocyclohexyl)-3 -(4-carbamimidoylphenoxy)-5 -(3 -carbamimidoyl-
propoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-cyanophenoxy)-5-(3-cyanopropoxy)benzoylamino]cyclohexyl}-
carbamic acid tert-butyl ester
Using 0.75 g (1.66 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]
cyclohexyl}carbamic acid tert-butyl ester and 4-bromo-butyronitrile (0.245 g, 1.66
mmol) and following the procedure of Example 42(b) afforded 0.82 g of the required
product. 1H NMR (DMSO-d6): 5 1.20 (3H, m), 1.4 (9H, s), 1.8 (4H, m), 2.05 (3H, m),
2.65 (2H, m), 3.2 (1H, m), 3.7 (1H, m), 4.1 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14
(2H, d), 7.2 (1H, s), 7.34 (1H, s), 7.86 (2H, d), 8.28 (1H, d)

e) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(3-ethoxycarbornmidoylpropoxy)
phenoxyjbenzimidic acid ethyl ester
Using {4-[3-(4-cyanophenoxy)-5-(3-cyano propoxy)benzoylamino] cyclohexyl}-
carbamic acid tert-butyl ester (0.82 g, 1.58 mmol) and following the procedure of
Example l(d) afforded 0.43 g of the required product. Percentage purity (LCMS): 62.1
%,(M+1) = 510.2+1.
f) N-(4-Aminocyclohexyl)-3-(4-carbamimidoylphenoxy)-5-(3-carbamimidoyl
propoxy)benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(3-ethoxycarbonimidoylpropoxy)-
phenoxyjbenzimidic acid ethyl ester (0.43 g, 0.84 mmol) and following the procedure of
Example l(e) afforded 0.14 g of the required product. Percentage purity: HPLC 98.11
%; LCMS 99.32 %. 'H NMR (DMSO-d6): 5 1.40 (4H, m), 1.9 (4H, m), 2.1 (2H, m), 2.6
(2H, m), 3.0 (2H, m), 4.1 (2H, m), 6.90 (1H, s), 7.20 (3H, m), 7.35(1H, s), 7.85 (5H, s),
8.35 (1H, d), 8.7 (2H, brs), 8.95 (2H, s), 9.1 (2H, brs), 9.25 (2H, s).
Example 65.
N-(4-Aminocyclohexyl)-3-(4-carbamimidoylbutoxy)-5-(4-carbamimidoyl-
phenoxy)-benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-cyanobutoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbamic
acid tert-butyl ester
Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]
cyclohexyl}carbamic acid tert-butyl ester and 5-bromo-pentanenitrile (0.304 g, 1.88
mmol) and following the procedure of Example 42(b) afforded 1.0 g of the required
product. 'HNMR (DMSO-d6): 8 1.25 (3H, m), 1.4 (9H, s), 1 8 (7H, m), 2.6 (3H, m), 3.2

(1H, m), 3.7 (1H, m), 4.2 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14 (3H, m), 7.34 (1H, s):
7.88 (2H, d), 8.28 (1H, d).
e) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-butoxy)-
phenoxyj-benzimidic acid ethyl ester
Using {4-[3-(4-cyanobutoxy)-5-(4-cyanophenoxy)benzoylamino] cyclohexyl}-
carbamic acid tert-butyl ester (1.0 g, 1.87 mmol) and following the procedure of
Example l(d) afforded 0.52 g of the required product. Percentage purity (LCMS): 64.4
%, (M+l) = 524.3+1
f) N-(4-Aminocyclohexyl)-3-(4-carbamimidoylbutoxy)-5-(4-carbamimidoyl
phenoxy)benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-butoxy)-
phenoxyj-benzimidic acid ethyl ester (0.52 g, 0.99 mmol) and following the procedure
of Example l(e) afforded 0.23 g of the required product. Percentage purity: HPLC 97.4
%; LCMS 92.3 %. 'H NMR (DMSO-d6): 8 1.41 (4H, m), 1.72 (4H, m), 1.85 (2H, m),
1.95 (2H, m), 2.44 (2H, t), 3.00 (1H, m), 3.82 (1H, m), 4.08 (2H, m), 6.89 (1H, s), 7.12
(1H, s), 7.20 (2H, d), 7.32 (1H, s), 7.86 (4H, d), 8.34 (1H, d), 8.68 (2H, brs), 8.92 (2H,
brs), 9.14 (2H, brs), 9.26 (2H, brs).
Example 66.
N-(4-Aminocyclohexyl)-3-(5-carbamimidoylpentyloxy)-5-(4-carbamimidoyl-
phenoxy)-benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(5-cyanopentyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-
carbamic acid tert-butyl ester

Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]
cyclohexyljcarbamic acid tert-butyl ester and 6-bromo-hexanenitrile (0.33 g, 1.88
mmol) and following the procedure of Example 42(b) afforded 1.15 g of the required
product. 'H NMR (DMSO-d6): 8 1.25 (3H, m), 1.4 (9H, s), 1.6 (4H, m), 1.8 (6H, m), 3.2
(1H, m), 3.7 (1H, m), 4.05 (2H, m), 6.75 (1H, d), 6.90 (1H, s), 7.14 (3H, m), 7.34 (1H,
s), 7.88 (2H, d), 8.28 (1H, d).
e) 443-(4-Amino-cyclohexylcarbamoyl)-5-(5-ethoxycarbommidoyl-pentyloxy)-
phenoxy]-benzimidic acid ethyl ester
Using {4-[3-(5-cyanopentyloxy)-5-(4-cyanophenoxy)benzoylamino] cyclohexyl}-
carbamic acid tert-butyl ester (1.15 g, 2.1 mmol) and following the procedure of
Example l(d) afforded 0.61 g of the required product. Percentage purity (LCMS): 70.5
%,(M+1) = 538.3+1.
f) N-(4-Amino cyclohexyl)-3-(5-carbamirnidoyl pentyloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(5-ethoxycarbonimidoyl-pentyloxy)-
phenoxy]-benzimidic acid ethyl ester (0.61 g, 1.13 mmol) and following the procedure
of Example l(e) afforded 0.25 g of the required product. Percentage purity: HPLC 98.2
%; LCMS 90.6 %. 1H NMR (DMSO-d6): 5 1.42 (4H, m), 1.72 (4H, m), 1.86 (2H, m),
1.98 (2H, m), 2.42 (2H, t), 3.00 (1H, m), 3.72 (1H, m), 4.06 (2H, t), 6.89 (1H, s), 7.12
(1H, s), 7.20 (2H, d), 7.32 (1H, s), 7.88 (4H, d), 8.32 (1H, d), 8.68 (2H, brs), 8.90 (2H5
brs), 9.14 (2H, brs), 9.26 (2H, brs).
Example 67.
5-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-
pentanoic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 49.

d) 5-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)
phenoxy]pentanoic acid ethyl ester
Using 0.63 g (1.39 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]
cyclohexyl}carbamic acid tert-butyl ester and 5-bromo-pentanoic acid ethyl ester (0.29
g, 1.39 mmol) and following the procedure of Example 42(b) afforded 0.71 g of the
required product. !H NMR (DMSO-d6): 8 1.2 (4H, m), 1.25 (2H, m), 1.4 (9H, s), 1.75
(9H, m), 2.35 (2H, m) 3.2 (1H, m), 3.7 (1H, m), 4.05 (4H, m), 6.75 (1H, d), 6.9 (1H, s),
7.15 (3H, d), 7.35 (1H, s), 7.85 (2H, d), 8.25 (1H, d).
e) 5-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)
phenoxyjpentanoic acid ethyl ester
Using 5-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano-
phenoxy)phenoxy]pentanoic acid ethyl ester (0.71 g, 1.22 mmol) and following the
procedure of Example l(d) afforded 0.36 g of the required product. Percentage purity
(LCMS): 90.9 %, (M+l) = 525.2+1.
f) 5-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-
pentanoic acid ethyl ester
Using 5-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)
phenoxyjpentanoic acid ethyl ester (0.36 g, 0.68 mmol) and following the procedure of
Example l(e) afforded 0.18 g of the required product. Percentage purity: HPLC 96.9 %;
LCMS 95.1 %. 1H NMR (DMSO-de): 5 1.18 (3H, t), 1.40 (4H, m), 1.72 (4H, m), 1.92
(4H, m), 2.38 (2H, t), 3.02 (1H, m), 3.72 (1H, m), 4.05 (4H, m), 6.88 (1H, s), 7.12 (1H,
s), 7.21 (2H, d), 7.30 (1H, s), 7.88 (4H, d), 8.34 (1H, d), 9.14 (2H, brs), 9.26 (2H, brs).
Example 68.
6-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-
hexanoic acid ethyl ester

Intermediate (a) - (c) are the same as in Example 49.
d) 6- [3 -(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)-
phenoxyjhexanoic acid ethyl ester
Using 0.84 g (1.86 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]
cyclohexyl}carbamic acid tert-butyl ester and 6-bromo-hexaanoic acid ethyl ester (0.41
g, 1.86 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the
required product. ]H NMR (DMSO-d6): 8 1.15 (3H, t), 1.25 (2H, m), 1.4 (9H, s), 1.45
(3H, m), 1.6 (2H, m) 1.7 (2H, m), 1.8 (4H, m), 2.3 (2H, t), 3.2 (1H, m), 3.7 (1H, m),
4.05 (4H, m), 6.72 (1H, d), 6.88 (1H, s), 7.12 (3H, m), 7.3 (1H, s), 7.84 (2H, d), 8.24
(1H, d).
e) 6-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)
phenoxy] hexanoic acid ethyl ester
Using 6-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano-
phenoxy)-phenoxy]hexanoic acid ethyl ester (0.95 g, 1.6 mmol) and following the
procedure of Example l(d) afforded 0.45 g of the required product. Percentage purity
(LCMS): 90.08 %, (M+l) = 539.3+1.
f) 6-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]-
hexanoic acid ethyl ester
Using 6-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)
phenoxy]hexanoic acid ethyl ester (0.45 g, 0.83 mmol) and following the procedure of
Example l(e) afforded 0.17 g of the required product. Percentage purity: HPLC 95.7 %;
LCMS 95.0 %. 'HNMR (DMSO-d6): 5 1.18 (3H, t), 1.42 (6H, m), 1.60 (2H, m), 1.74
(2H, m), 1.78 (2H, brs), 1.98 (2H, brs), 2.32 (2H, t), 3.02 (1H, m), 3.70 (1H, m), 4.06
(4H, m), 6.90 (1H, s), 7.12 (1H, s), 7.22 (2H, d), 7.32 (1H, s), 7.88 (4H, d), 8.35 (1H, d),
9.14 (2H, brs), 9.28 (2H, brs).

Example 69.
N-(4-Arnino cyclohexyl)-3-(4-carbamimidoyl-2-chloro phenoxy)-5-(4-
carbamimidoyl phenoxy)benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(2-Chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid ethyl ester
To 1.2 g (4.23 mmol) of 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester,
dissolved in 10 ml of DMF, potassium carbonate 1.17g (8.46 mmol) was added and
stirred for 30 minutes at RT. 1.31 g (8.46 mmol) of 3-chloro-4-fluoro-benzonitrile,
dissolved in 5 ml of DMF, was added dropwise to the reaction mixture during 15 min
and final contents were stirred at 80 °C overnight. The reaction mixture was
concentrated, residue was dissolved in 200 ml of ethyl acetate and partitioned with
water. The organic layer was washed with brine followed by of water. Organic layer was
dried over anhydrous sodium sulphate and concentrated under reduced pressure. The
crude product was subjected to column chromatography, using silica-gel and eluted with
hexane : ethyl acetate (8 :2) to afford 1.4 g of pure product. JH NMR (DMSO-d6): 8 1.3
(3H, t), 4.3 (2H, q), 7.2-7.36 (4H, m), 7.44 (2H, dd), 7.88 (3H, m), 8.26 (1H, d).
c) 3-(2-Chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid
3-(2-Chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid ethyl ester, 1.4 g
(3.34 mmol), was hydrolysed using the procedure of Example 5(b) to afford 1.05 g of
required product. !H NMR (DMSO-de): 8 7.2-7.42 (6H, m), 7.88 (3H, m) 8.26 (1H, s),
13.8(lH,brs).
d) {4-[3-(2-Chloro-4-cyanophenoxy)-5-(4-cyano phenoxy)benzoylamino]
cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(2-chloro-4-cyano phenoxy)-5-(4-cyano
phenoxy)benzoic acid 1.0 g (2.55 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-

butyl ester (0.54 g, 2.55 mmol) were used to afford 1.2 g of the required product. LH
NMR (DMSO-d6): 5 1.24 (4H, m), 1.38 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.68 (1H, m),
6.76 (1H, d), 7.22 (4H, m), 7.5 (2H, s), 7.88 (3H, m), 8.26 (1H, d), 8.38 (1H, d).
e) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)-
phenoxy]-3-chloro benzimidic acid ethyl ester
Using {4-[3-(2-chloro-4-cyanophenoxy)-5-(4-cyano phenoxy)benzoyl amino]-
cyclohexyl}carbamic acid tert-butyl ester (1.2 g, 2.04 mmol) and following the
procedure of Example l(d) afforded 0.64 g of the required product. Percentage purity
(LCMS): 44.3 %, (M+l) = 539.3+1.
f) N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-2-chlorophenoxy)-5-(4-
carbamimidoyl phenoxy)benzamide
Using 4- [3 -(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)-
phenoxy]-3-chloro benzimidic acid ethyl ester (0.64 g, 1.1 mmol) and following the
procedure of Example l(e) afforded 0.16 g of the required product. Percentage purity:
HPLC 99.16 %, LCMS 92.13 %. lH NMR (DMSO-d6): 5 1.4 (4H, m), 1.9 (4H, m), 3.0
(1H, s), 3.7 (1H, m) 7.16 (1H, s), 7.32 (3H, m), 7.48 (2H, s), 7.82 (1H, dd), 7.9 (4H, m),
8.14 (1H, d), 8.46 (1H, d), 9.2 (2H, s), 9.3 (2H, s), 9.38 (3H, s).
Example 70.
4-[3-[4-(2-Aminoethyl)piperidine-l-carbonyl]-5-(3-aminopropoxy)phenoxy]
benzamidine
Intermediate (a) is the same as in Example 42.
b) 3-(3-tert-Butoxycarbonylamino propoxy)-5-(4-cyano phenoxy)benzoic acid ethyl
ester

Following the procedure of Example 69(b) 3-(4-cyano-phenoxy)-5-hydroxy-benzoic
acid ethyl ester 0.9 g (3.17 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester
(1.5 g, 6.34 mmol) were used to afford 0.95 g of the required product. !H NMR
(DMSO-d6): 5 2.05 (4H, m), 3.35 (2H, m), 3.90 (3H, s), 4.08 (2H, t), 4.72 (1H, brs),
6.78 (1H, t), 7.02 (2H, d), 7.28 (1H, s), 7.41 (1H, s), 7.62 (2H, d), 8.05 (1H, brs).
c) 3-(3- tert-Butoxycarbonylamino propoxy)-5-(4-cyano phenoxy)benzoic acid
3-(3-tert-Butoxycarbonylamino propoxy)-5-(4-cyano phenoxy)benzoic acid ethyl
ester, 0.95 g (2.15 mmol) was hydrolysed by using the procedure of Example 5(b) to
afford 0.7 g of required product. !H NMR (DMSO-d6): 5 1.85 (2H, t), 3.12 (2H, m),
4.02 (2H, t), 6.85 (1H, s), 6.95 (1H, s), 7.15 (3H, m), 7.32 (1H, s), 7.85 (2H, d), 13.22
(lH,brs).
d) {3-[3-[4-(2-tert-Butoxycarbonylaminoethyl)piperidine-1 -carbonyl]-5-(4-cyano
phenoxy)phenoxy]propyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(3- tert-butoxycarbonylamino propoxy)-
5.(4_Cyan0 phenoxy)benzoic acid 0.7 g (1.69 mmol) and (4-amino-cyclohexyl)-carbamic
acid tert-butyl ester (0.38 g, 1.69 mmol) were used to afford 0.72 g of the required
product. Percentage purity (LCMS): 47.0 %, (M+l) = 422.3+1 (de bisboc mass -200).
e) 4-[3-[4-(2-amino ethyl)piperidine-l-carbonyl]-5-(3-amino propoxy)phenoxy]
benzimidic acid ethyl ester
Using {3-[3-[4-(2-tert-butoxycarbonylaminoethyl)piperidine-l-carbonyl]-5-(4-
cyano phenoxy)phenoxy]propyl}carbamic acid tert-butyl ester (0.72 g, 1.15 mmol) and
following the procedure of Example l(d) afforded 0.25 g of the required product.
Percentage purity (LCMS): 63.9 %, (M+l) = 468.2+1.
f) 4-[3-[4-(2-Amino ethyl)piperidine-l-carbonyl]-5-(3-amino propoxy)phenoxy]
benzamidine

Using 4-[3-[4-(2-amino ethyl)piperidine-l-carbonyl]-5-(3-amino propoxy)
phenoxyjbenzimidic acid ethyl ester (0.25 g, 0.53 mmol) and following the procedure of
Example l(e) afforded 0.065 g of the required product. Percentage purity: HPLC 97.13
%; LCMS 89.6 %. !H NMR (DMSO-d6): 8 1.10 (2H, m), 1.50 (2H, m), 1.60-1.80 (3H,
m), 2.0 (2H, m), 2.70 (1H, m), 2.8 (2H, m), 3.0 (3H, m), 4.1 (2H, t), 4.5 (1H, s), 6.60
(1H, s), 6.8 (2H, s), 7.20 (2H, d), 7.80 (3H, brs), 7.9 (4H, d), 9.3 (3H, s).
Example 71.
N-(4-Aminocyclohexyl)-3-(6-aminopyridine-3-yloxy)-5-(4-carbamimidoyl-
phenoxy)-benzamide
Intermediatse (a) - (c) are the same as in Example 49.
d) {4-[3-(4-Cyanophenoxy)-5-(6-nitropyridine-3-yloxy)benzoylamino]-cyclo-
hexyl}carbamic acid tert-butyl ester
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-
benzoylarnino]cyclohexyl}carbamic acid tert-butyl ester 1.2 g (2.65 mmol) and 5-
chloro-2-nitro-pyridine (0.84 g, 5.31 mmol) were used to afford 1.2 g of the required
product. 1H NMR (DMSO-d6): 5 1.28 (3H, m), 1.4 (10H, s), 1.8 (5H, m), 3.20 (1H, m),
3.7 (1H, m), 6.75 (1H, d), 7.25 (2H, d), 7.35 (1H, d), 7.5 (2H, s), 7.8 (1H, dd), 7.9 (2H,
d), 8.35 (2H, d), 8.5 (1H, s).
e) {4-[3-(6-Aminopyridine-3-yloxy)-5-(4-cyanophenoxy)benzoylamino]-
cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 62(e) {4-[3-(4-cyanophenoxy)-5-(6-nitro-
pyridine-3-yloxy)benzoylamino]-cyclohexyl}carbamic acid tert-butyl ester 1.2 g (2.09
mmol) was used to afford 0.45 g of the required product. 1H NMR (DMSO-d6): 5 1.28
(4H, m), 1.4 (10H, s), 1.8 (4H, m), 3.20 (1H, m), 3.7 (1H, m), 5.9 (2H, s), 6.5 (1H, d),
6.75 (1H, d), 6.85 (2H, s), 7.15 (3H, d), 7.3 (3H, m), 7.85 (3H, d), 8.3 (1H, m).

t) 4-[3-(4-Amino cyclohexylcarbamoyl)-5-(6-amino pyridine-3-yloxy)
phenoxyjbenzimidic acid ethyl ester
Using {4-[3-(6-aminopyridine-3-yloxy)-5-(4-cyanophenoxy)benzoylamino]-
cyclohexyl}carbamic acid tert-butyl ester (0.45 g, 0.82 mmol) and following the
procedure of Example l(d) afforded 0.21 g of the required product. Percentage purity
(LCMS): 93.0 %, (M+l) = 489.2+1.
g) N-(4-Amino cyclohexyl)-3-(6-amino pyridine-3-yloxy)-5-(4-carbamimidoyl
phenoxy)benzamide
Using 4-[3-(4-amino cyclohexylcarbamoyl)-5-(6-amino pyridine-3-yloxy)-
phenoxyjbenzimidic acid ethyl ester (0.21 g, 0.42 mmol) and following the procedure of
Example l(e) afforded 0.065 g of the required product. Percentage purity: HPLC 95.3
%; LCMS 90.3 %. 'H NMR (DMSO-d6): 8 1.39 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.70
(1H, m), 6.88 (1H, d), 7.02 (1H, s), 7.24 (2H, d), 7.36 (2H, d), 7.72 (1H, d), 7.86 (5H,
d), 7.96 (1H, s), 8.42 (1H, d), 9.23 (4H, d).
Example 72. N-(4-Aminocyclohexyl)-3-(4-aminophenoxy)-5-(4-
carbamimidoylphenoxy)-benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-Cyanophenoxy)-5-(4-nitro phenoxy)benzoylamino]cyclohexyl} -
carbamic acid tert-butyl ester
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-
benzoylamino]cyclohexyl} carbamic acid tert-butyl ester 1.1 g (2.43 mmol) and 1-
chloro-4-nitro-benzene (0.765 g, 4.86 mmol) were used to afford 0.94 g of the required
product. ^NMR (DMSO-d6): 5 1.2 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7
(1H, m), 6.7 (1H, d), 7.25 (5H, m), 7.55 (2H, m), 7.8 (2H, d), 8.3 (2H, d), 8.4 (1H, d).

e) {4-[3-(4-Aminophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-
carbamic acid tert-butyl ester
Following the procedure of Example 62(e) {4-[3-(4-cyanophenoxy)-5-(4-nitro
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.94 g (1.64 mmol)
was used to afford 0.39 g of the required product. 'H NMR (DMSO-d6): 6 1.2 (4H, m),
1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.1 (2H, s), 6.6 (2H, d), 6.76 (2H,
m), 6.82 (2H, d), 7.14 (2H, d), 7.26 (2H, s), 7.86 (2H, d), 8.28 (1H, d).
f) 4- [3 -(4-Aminocyclohexylcarbamoyl)-5-(4-aminophenoxy)phenoxy]-benzimidic
acid ethyl ester
Using {4-[3-(4-aminophenoxy)-5-(4-cyanophenoxy)benzoylamino] cyclohexyl}-
carbamic acid tert-butyl ester (0.39 g, 0.71 mmol) and following the procedure of
Example l(d) afforded 0.16 g of the required product. Percentage purity (LCMS): 80.0
%,(M+1) = 488.2+1
g) N-(4-Aminocyclohexyl)-3-(4-aminophenoxy)-5-(4-carbamimidoylphenoxy)-
benzamide
Using 4-[3 -(4-aminocyclohexylcarbamoyl)-5 -(4-aminophenoxy) phenoxy] -
benzimidic acid ethyl ester (0.16 g, 0.32 mmol) and following the procedure of Example
l(e) afforded 0.05 g of the required product. Percentage purity: HPLC 97.05 %; LCMS
96.25 %. >H NMR (DMSO-d6): 5 1.40 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.70 (1H, m),
6.85 (1H, s), 7.0 (4H, s), 7.3 (4H, d), 7.85 (5H, d), 8.4 (1H, d), 9.2 (2H, s), 9.3 (2H, d).
Example 73.
N-(4-Aminocyclohexyl)-3-[4-(3-aminopropionylamino)phenoxy]-5-(4-
carbamimidoyl phenoxy)benzamide
Intermediates (a) - (e) are the same as in Example 72.

f) {4-[3-[4-(3-tert-Butoxycarbonyl amino propionylamino)phenoxy]-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.31 g, 1.63 mmol) and {4-[3-(4-
aminophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbamic acid tert-butyl
ester (0.884 g, 1.63 mmol) and other reagents as described in Example 9(e) were used to
afford 0.75 g.of the required product. 'H NMR (DMSO-d6): 8 1.25 (4H, m), 1.4 (18H,
s), 1.8 (4H, m), 2.4 (2H, m), 3.2 (3H, m), 3.7 (1H, m), 6.72 (1H, d), 6.88 (2H, m), 7.06
(2H, d), 7.16 (2H, d), 7.32 (2H, s), 7.64 (2H, d), 7.86 (2H, d), 8.3 (1H, d).
g) 4-{3-(4-Amino cyclohexylcarbamoyl)-5-[4-(3-amino propionylamino) phenoxy]
phenoxy}benzimidic acid ethyl ester
Using {4-[3-[4-(3-tert-butoxycarbonyl amino propionylamino)phenoxy]-5-(4-cyano
phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester (0.75 g, 1.05 mmol)
and following the procedure of Example l(d) afforded 0.34 g of the required product.
Percentage purity (LCMS): 85.9 %, (M+l) = 559.2+1.
h) N-(4-Aminocyclohexyl)-3-[4-(3-aminopropionylamino)phenoxy]-5-(4-
carbamimidoyl phenoxy)benzamide
Using 4-{3-(4-aminocyclohexylcarbamoyl)-5-[4-(3-amino propionyl amino)
phenoxy] phenoxy}benzimidic acid ethyl ester (0.34 g, 0.60 mmol) and following the
procedure of Example l(e) afforded 0.14 g of the required product. Percentage purity:
HPLC 96.79 %; LCMS 92.82 %. lH NMR (DMSO-d6): 5 1.35 (4H, m), 1.9 (4H, m), 2.7
(2H, t), 2.95 (2H, m), 3.1 (2H, m), 6.9 (1H, s), 7.1 (2H, d), 7.3 (4H, d), 7.65 (2H, d),
7.85 (8H, m), 8.4 (1H, d), 9.1 (2H, s), 9.25 (2H, s), 10.35 (lH,s).
Example 74.
N-(4-Aminocyclohexyl)-3 -(4-carbamimidoyl-3 -methylphenoxy)-5 -(4-
carbamimidoyl phenoxy)benzamide

Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-Cyano-3-methyl phenoxy)-5-(4-cyano phenoxy)benzoylamino]
cyclohexyl}carbamic acid tert-butylester
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-
benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.85 g (1.88 mmol) and 4-
fluoro-2-methyl-benzonitrile (0.508 g, 3.76 mmol) were used to afford 0.76 g of the
required product. 'HNMR (DMSO-d6): 8 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 2.45
(3H, s), 3.15 (1H, m), 3.7 (1H, m), 6.72 (1H, d), 7.02 (1H, d), 7.2 (4H, m), 7.5 (2H, s),
7.8 (1H, d), 7.88 (2H, d), 8.34 (1H, d).
e) (4-{3-[4-(N-Hydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-hydroxy-
carbamimidoyl)phenoxy]benzoylamino}cyclohexyl) carbamic acid tert-butylester
Following the procedure of Example 2(d) {4-[3-(4-cyano-3 -methyl phenoxy)-5-(4-
cyano phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butylester 0.76 g (1.34
mmol) and other aproperiate reagents were used to afford 0.64 g of the required product.
Percentage purity (LCMS): 44.5 %, (M+l) = 632.3+1.
f) (4-{3-[4-(N-Acetylhydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-hydroxy-
carbamimidoyl)phenoxy]benzoylamino}cyclohexyl) carbamic acid tert-butylester
Following the procedure of Example 2(e) (4-{3-[4-(N-hydroxycarbamimidoyl)-3-
methylphenoxy]-5-[4-(N-hydroxy-carbamimidoyl)phenoxy] benzoylamino}cyclohexyl)
carbamic acid tert-butylester 0.64 g (1.01 mmol) was used to afford 0.52 g of the
required product. Percentage purity (LCMS): 49.7 %, (M+l) = 716.3.
g) {4-[3-(4-Carbamimidoyl-3-methylphenoxy)-5-(4-carbamimidoylphenoxy)-
benzoylamino]cyclohexyl} carbamic acid tert-butylester

(4-{3-[4-(N-Acetylhydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-acetyl-
hydroxy-carbamimidoyl)phenoxy]benzoylamino}cyclohexyl) carbamic acid tert-
butylester 0.52 g (0.72 mmol) was reduced using the procedure of Example 2(f) to
afford 0.25 g of required product. Percentage purity (LCMS): 44.5 %, (M+l) = 600.3+1.
h) N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-3-methylphenoxy)-5-(4-
carbamimidoyl phenoxy)benzamide
Using {4-[3-(4-carbamimidoyl-3-methylphenoxy)-5-(4-carbamimidoylphenoxy)-
benzoylamino]cyclohexyl} carbamic acid tert-butylester (0.25 g, 0.41 mmol) and
following the procedure of Example 9(d) afforded 0.05 g of the required product.
Percentage purity: HPLC 97.87 %; LCMS 97.27 %. JH NMR (DMSO-d6): 8 1.4 (4H,
m), 1.85 (2H, m), 1.95 (2H, m), 2.4 (3H, s), 3.0 (1H, s), 3.7 (1H, m) 7.0 (1H, s), 7.1
(1H, d), 7.18 (1H, s), 7.28 (2H, d), 7.46 (2H, s), 7.54 (1H, s), 7.88 (5H, m), 8.44 (1H, d),
9.14 (2H,s), 9.28 (6H,s).
Example 75.
N-(4-Amino cyclohexyl)-3,5-bis-(4-carbamimidoyl benzyloxy)benzamide
a) 3,5-Bis (4-cyano phenoxy)benzoic acid ethyl ester
To a solution of 3,5-dihydroxy benzoic acid ethyl ester 1.2 g (6.58 mmol), dissolved
in 10 ml DMF, was added K2CO3 3.63 g (26.32mmol) followed by 4-bromomethyl-
benzonitrile 5.16 g (26.32mmol) in 5 ml of DMF at 20 °C. The reaction mixture was
allowed to attain RT and then heated to 35 °C for 8 h. The solvent was removed under
reduced pressure and the residue was dissolved in 200 ml of ethyl acetate. The organic
layer was washed with brine and water. Organic phase was dried over anhydrous sodium
sulphate and solvent was removed under reduced pressure. The crude product was
subjected to column chromatography and eluted using hexane : ethyl acetate (8:2) to
afford 2.1 g of purified product. 'H NMR (DMSO-de): 1.3 (3H, t), 4.3 (2H, q), 5.3 (4H,
s), 7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).

b) 3,5-Bis (4-cyano phenoxy)benzoic acid
2.1 g (5.46 inmol) of 3,5-bis (4-cyano phenoxy)benzoic acid ethyl ester was
hydrolysed using the procedure of Example 5(b) to afford 1.65 g.of the required product.
1H NMR (DMSO-d6): 5.2 (4H, s), 6.8 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
c) {4-[3,5-Bis (4-cyano benzyloxy)benzoylamino]cyclohexyl}carbamic acid tert-
butyl ester
3,5-Bis (4-cyano phenoxy)benzoic acid (0.75 g, 2.1 mmol) and (4-amino-cyclo-
hexyl)-carbamic acid tert-butyl ester (0.45 g, 2.1 mmol) and other reagents as described
in Example 9(e) were used to afford 0.82 g.of the required product. 1H NMR (DMSO-
ds): 5 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.70 (2H, m), 5.25 (4H, s), 6.72 (1H, m),
6.84 (1H, s), 7.12 (2H, s), 7.64 (4H, d), 7.86 (4H, d), 8.18 (1H, m).
d) N-(4-Aminocyclohexyl)-3,5-bis-(4-ethoxycarbonimidoyl benzyloxy)benzamide
Using {4-[3,5-Bis(4-cyanobenzyloxy)benzoylamino]cyclohexyl} carbamic acid tert-
butyl ester (0.82 g, 1.41 mmol) and following the procedure of Example l(d) afforded
0.32 g of the required product. Percentage purity (LCMS): 49.4 %, (M+l) = 572.3+1.
e) N-(4-Amino cyclohexyl)-3,5-bis-(4-carbamimidoyl benzyloxy)benzamide
Using N-(4-aminocyclohexyl)-3,5-bis-(4-ethoxycarbonimidoyl benzyloxy)-
benzamide (0.32 g, 0.55 mmol) and following the procedure of Example l(e) afforded
0.07 g of the required product. Percentage purity: HPLC 98.01 %; LCMS 99.73 %. ]H
NMR (DMSO-d6): 5 1.4 (4H, m), 1.8 (2H, m), 2.0 (2H, m), 3.0 (1H, m), 3.70 (1H, m),
5.3 (4H, s), 6.9 (1H, s), 7.15 (2H, d), 7.7 (4H, d), 7.85 (4H, s), 7.9 (3H, m), 8.3 (1H, m),
9.3 (8H, s).

Example 76.
2-{l-[3,5-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-
ethylamine
Interaiediates (a) and (b) are the same as in Example 75.
c) (2-{l-[3,5-Bis-(4-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic acid
tert-butyl ester
3,5-Bis (4-cyano phenoxy)benzoic acid (0.64 g, 1.79 mmol) and (2-piperidin-4-yl-
ethyl)-carbamic acid tert-butyl ester (0.408 g, 1.79 mmol) and other reagents as
described hi Example 9(e) were used to afford 0.72 g.of the required product.
Percentage purity (LCMS): 88.39 %. 1H NMR (DMSO-d6): 8 1.3 (2H, m), 1.35 (9H, m),
1.5 (3H, m), 1.7 (1H, m), 2.98 (2H, m), 3.45 (2H, m), 5.25 (4H, s), 6.58 (2H, s), 6.76
(2H, m), 7.65 (4H, d), 7.88 (4H, d).
d) 2-{l-[3,5-Bis-(4-ethoxycarbonimidoylbenzyloxy)benzoyl]piperidine-4-yl}-
ethylamine
Using (2-{l-[3,5-bis-(4-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic
acid tert-butyl ester (0.72 g, 1.21 mmol) and following the procedure of Example l(d)
afforded 0.34 g of the required product. Percentage purity (LCMS): 49.9 %, (M+l) =
586.3+1.
e) 2-{1 -[3,5-Bis-(4-ethoxycarbamimidoylbenzyloxy)benzoyl]piperidine-4-yl} -
ethylamine
Using 2-{ l-|3,5-bis-(4-ethoxycarbonimidoylbenzyloxy)benzoyl] piperidine-4-yl}-
ethylamine (0.34 g, 0.58 mmol) and following the procedure of Example l(e) afforded
0.17 g of the required product. Percentage purity:HPLC 96.25 %; LCMS 97.96 %. 'H
NMR (DMSO-d6): 8 1.05 (2H, m), 1.50-1.8 (5H, m), 2.8 (4H, m), 3.5 (1H, m), 4.4 (1H,
m), 5.25 (4H, s), 6.60 (2H, s), 6.8 (1H, brs), 7.65 (4H, d), 7.85 (6H, d), 9.4 (7H, s).

Example 77.
N-(4-Amino cyclohexyl)-3,5-bis-(3-carbamimidoyl benzyloxy)benzamide
a) 3,5-Bis (3-cyano phenoxy)benzoic acid ethyl ester
3,5-Dihydroxy benzoic acid ethyl ester (1.45 g, 7.95 mmol) and 3-bromomethyl-
benzonitrile (6.23 g, 31.8 mmol) and other reagents as described in Example 75(a) were
used to afford 2.3 g.of the required product. 1H NMR (DMSO-dg): 1.15 (3H, t), 4.15
(2H, q), 5.3 (4H, s), 7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
b) 3,5-Bis (3-cyano phenoxy)benzoic acid
2.3 g (5.98 mmol) of 3,5-bis (3-cyano phenoxy)benzoic acid ethyl ester was
hydrolysed using the procedure of Example 5(b) to afford 1.85 g.of the required product.
!H NMR (DMSO-d6): 6.86 (1H, s), 7.2 (2H, d), 7.62 (2H, s), 7.82 (4H, m), 7.94 (2H, s).
c) {4-[3,5-Bis (3-cyano benzyloxy)benzoylamino]cyclohexyl}carbamic acid tert-
butyl ester
3,5-Bis (3-cyano phenoxy)benzoic acid (1.2 g, 3.36 mmol) and (4-amino-cyclo-
hexyl)-carbamic acid tert-butyl ester (0.72 g, 3.36 mmol) and other reagents as described
in Example 9(e) were used to afford 1.33 g.of the required product.
'H NMR (DMSO-d6): 5 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.20 (1H, m), 3.70 (1H,
m), 5.25 (4H, s), 6.74 (1H, m), 6.86 (1H, s), 7.16 (2H, s), 7.64 (2H, t), 7.82 (4H, t), 7.94
(2H, s), 8.22 (1H, d)
d) 4-[3,5-Bis (3-ethoxycarbonimidoyl benzyloxy)benzoylamino]cyclohexylamine
Using {4-[3,5-bis(3-cyano benzyloxy)benzoylamino]cyclohexyl}carbamic acid tert-
butyl ester (1.33 g, 2.3 mmol) and following the procedure of Example l(d) afforded
0.91 g of the required product. Percentage purity (LCMS): 14.8 %, (M+l) = 572.3+1.

e) N-(4-Amino cyclohexyl)-3,5-bis-(3-carbamimidoyl benzyloxy)benzamide
Using 4-[3,5-Bis (3-ethoxycarbonimidoyl benzyloxy)benzoylamino] cyclo-
i hexylamine (0.91 g, 1.58 mmol) and following the procedure of Example l(e) afforded
0.16 g of the required product. Percentage purity: HPLC 98.81 %; LCMS 97.40 %. 'H
NMR (DMSO-d6): 5 1.4 (4H, m), 1.9 (4H, m), 3.0 (1H, m), 3.70 (1H, m), 5.25 (4H, s),
6.9 (1H, s), 7.15 (2H, d), 7.7 (2H, t), 7.80 (4H, t), 7.9 (5H, s), 8.3 (1H, m), 9.4 (8H, s).
| Example 78.
2-{l-[3,5-Bis-(3 -carbamimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl} -ethyl-
amine
Intermediates (a) and (b) are the same as in Example 77.
c) (2-{l-[3,5-Bis-(3-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic acid
tert-butyl ester
3,5-Bis (3-cyano phenoxy)benzoic acid (0.6 g, 1.68 mmol) and (2-piperidin-4-yl-
ethyl)-carbamic acid tert-butyl ester (0.383 g, 1.68 mmol) and other reagents as
described in Example 9(e) were used to afford 0.65 g.of the required product.
'H NMR (DMSO-d6): 5 1.25 (2H, m), 1.4 (9H, s), 1.5 (3H, m), 1.7 (2H, m), 2.7 (2H,
m), 2.9 (3H, m), 4.4 (1H, m), 5.25 (4H, s), 6.6 (2H, s), 6.80 (2H, brs), 7.62 (2H, t), 7.82
(4H, m), 7.94 (2H, s).
d) 2-{l-[3,5-Bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-
ethylamine
Using (2-{ 1 -[3,5-bis-(3-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic
acid tert-butyl ester (0.65 g, 1.09 mmol) and following the procedure of Example l(d)
afforded 0.43 g of the required product. Percentage purity (LCMS): 36.1 %, (M+l) =
586.3+1.

e) 2-{l-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-
ethylamine
Using 2-{l-[3,5-bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-
ethylamine (0.43 g, 0.73 mmol) and following the procedure of Example l(e) afforded
0.081 g of the required product. Percentage purity: HPLC 97.84 %; LCMS 98.96 %. !H
NMR (DMSO-d6): 5 1.0 (2H, m), 1.50-1.6 (4H, m), 1.75 (1H, m), 2.7 (1H, m), 2.8-3.0
(4H, m), 4.45 (1H, m), 5.4 (4H, s), 6.6 (2H, s), 6.8 (1H, brs), 7.65 (2H, m), 7.75 (6H,
brs), 7.9 (2H, s), 9.45 (8H, s).
Example 79.
N-(4-Amino cyclohexyl)-2,4-bis-(4-carbamimidoyl benzyloxy)benzamide
a) [4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester
2,4-Dihydroxy benzoic acid (1.6 g, 10.38 mmol) and (4-amino-cyclohexyl)-
carbamic acid tert-butyl ester (2.22 g, 10.38 mmol) and other reagents as described in
Example 9(e) were used to afford 0.95 g of the required product. ]H NMR (DMSO-de):
8 1.20 (4H, m), 1.4 (9H, m), 2.1 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 6.2 (2H, d), 6.74
(1H, s), 7.7 (1H, s), 8.26 (1H, s), 10.0 (1H, brs), 13.0 (1H, brs).
b) {4-[2,4-Bis-(4-cyano benzyloxy) benzoylamino]cyclohexyl}carbamic acid tert-
butyl ester
[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.95 g,
2.71 mmol) and 4-bromomethyl-benzonitrile (2.12 g, 10.84 mmol) and other reagents as
described in Example 75(a) were used to afford 1.2 g of the required product. 'H NMR
(DMSO-d6): 6 1.20 (5H, m), 1.4 (9H, m), 1.75 (4H, m), 3.6 (1H, m), 5.3 (4H, s), 6.7
(1H, s), 6.85 (1H, s), 7.35 (2H, d), 7.5 (1H, s), 7.75 (4H, d), 7.9 (4H, s).
c) 4-[2,4-Bis-(4-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine

{2-[l-(2, 4-Dihydroxy benzoyl)piperidin-4-yl]ethyl}carbamic acid tert-butyl ester
(1.13 g, 3.1 mmol) and 4-bromomethyl-benzonitrile (2.43 g, 12.4 mmol) and other
reagents as described in Example 75(a) were used to afford 1.3 g of the required
product.1H NMR (DMSO-d6): 5 1.35 (8H, s), 2.1 (4H, s), 2.9 (3H, m), 4.55 (4H, d),
5.25 (3H, s), 5.5 (2H, t), 6.8 (1H, m), 7.3 (1H, d), 7.4 (1H, d), 7.5 (4H, d), 7.66 (1H, d),
7.8 (3H, m), 7.86 (2H, m).
c) 2-{l-[254-Bis-(4-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-
ethylamine
Using (2-{l-[2,4-bis-(4-cyano-benzyloxy)benzoyl]piperidin-4-yl}ethyl) carbamic
acid tert-butyl ester (1.3 g, 2.18 mmol) and following the procedure of Example l(d)
afforded 0.52 g of the required product Percentage purity (LCMS): 71.2 %, (M+l) =
586.3+1.
d) 2- {1 -[2,4-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl} -ethyl-
amine
Using 2-{ 1 -[2,4-bis-(4-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl} -
ethylamine (0.52 g, 0.88 mmol) and following the procedure of Example l(e) afforded
0.19 g of the required product. Percentage purity: HPLC 90.96 %; LCMS 98.53 %. JH
NMR (DMSO-d6): 8 1.0 (1H, m), 1.30 (1H, m), 1.5 (3H, m), 1.7 (1H, m), 2.7 (4H, m),
2.9 (1H, m), 3.4 (1H, m), 4.5 (1H, m), 5.30 (4H, d), 6.65 (1H, d), 6.8 (1H, s), 7.15 (1H,
m), 7.7 (7H, m), 7.85 (4H, d) 9.2 (4H, s), 9.35 (4H, s).
Example 81.
N-(4-Amino cyclohexyl)-2.4-bis (3-carbamimidoyl benzyloxy)benzamide
Intermediate (a) is the same as in Example 79(a).
b) {4-[2,4-Bis-(3-cyano benzyloxy) benzoylamino]cyclohexyl}carbamic acid tert-
butyl ester

[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.85 g,
2.42 mmol) and 3-bromomethyl-benzonitrile (1.89 g, 9.68 mmol) and other reagents as
described in Example 75(a) were used to afford 0.75 g of the required product. 1H NMR
(DMSO-d6): 5 1.4 (9H, s), 1.75 (4H, m), 3.15 (1H, m), 3.65 (2H, m), 4.55 (1H, m), 5.25
(4H, s), 6.72 (2H, m), 6.9 (1H, s), 7.7 (6H, m), 7.85 (4H, m), 7.94 (1H, s), 8.04 (1H, s).
c) 4-[2,4-Bis-(3-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine
Using {4-[2,4-bis-(3-cyanobenzyloxy) benzoylamino]cyclohexyl} carbamic acid
tert-butyl ester (0.75 g, 1.29 mmol) and following the procedure of Example l(d)
afforded 0.32 g of the required product. Percentage purity (LCMS): 90.7 %, (M+l) =
572.3+1.
d) 4- [2,4-Bis-(3 -carbamimidoyl-benzyloxy)benzoylamino] -cyclohexyl-amine
Using 4-[2,4-bis-(3-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-
amine (0.32 g, 0.55 mmol) and following the procedure of Example l(e) afforded 0.08 g
of the required product. Percentage purity: HPLC 95.22 %; LCMS 93.7 %. 'H NMR
(DMSO-ck): 5 1.2 (2H, m), 1.40 (2H, m), 1.9 (4H, m), 2.95 (1H, m), 3.7 (1H, m), 5.35
(4H, d), 6.75 (1H, d), 6.9 (1H, s), 7.7 (5H, m), 7.85 (7H, m), 9.1-9.4 (8H, s).
Example 82.
2- {1 - [2,4-Bis-(3 -carbamimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl} -
ethylamine
Intermediate (a) is the same as in Example 80(a).
b) (2-{l-[2,4-Bis(3-cyano benzyloxy)benzoyl]piperidin-4-yl}ethyl)carbamic acid
tert-butyl ester

{2-[l-(2, 4-Dihydroxy benzoyl)piperidin-4-yl]ethyl}carbamic acid tert-butyl ester
(1.05 g, 2.88 mniol) and 3-bromomethyl-benzonitrile (2.25 g, 11.5 mmol) and other
reagents as described in Example 75 (a) were used to afford 1.15 g of the required
product. !H NMR (DMSO-do): 5 1.4 (9H, s), 2.1 (2H, d), 2.6 (1H, m), 2.95 (4H, m),
3.45 (1H, m), 4.5 (2H, m), 5.2 (4H, s), 6.7 (2H, d), 6.84 (1H, d), 7.14 (1H, dd), 7.52
(1H, m), 7.62 (3H, d), 7.7 (2H, d), 7.8 (5H, m), 7.95 (1H, s).
c) 2-{1 -[2,4-Bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-
ethylamine
Using (2-{ l-[2,4-Bis(3-cyanobenzyloxy)benzoyl]piperidin-4-yl}ethyl) carbamic
acid tert-butyl ester (1.15 g, 1.93 mmol) and following the procedure of Example l(d)
afforded 0.41 g of the required product. Percentage purity (LCMS): 62.5 %, (M+l) =
586.3+1.
d) 2- {1 - [2,4-Bis-(3-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl} -ethyl-
amine
Using 2- {1 -[2,4-bis-(3 -ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl} -
ethylamine (0.41 g, 0.69 mmol) and following the procedure of Example l(e) afforded
0.16 g of the required product. Percentage purity: HPLC 91.53 %; LCMS 95.59 %. 1H
NMR (DMSO-d6): 5 0.9 (2H, m), 1.25 (2H, m), 1.5 (3H, m), 1.75 (1H, m), 2.8 (3H, m),
2.9 (1H, m), 3.4 (2H, m), 4.5 (1H, m), 5.25 (3H, d), 6.55 (1H, s), 6.7 (1H, d), 6.9 (1H,
d), 7.3 (1H, m), 7.8 (8H, m) 7.9 (1H, s), 9.25 (3H, d), 9.4 (3H, s).
Example 83.
4-[3-(4-Aminomethyl phenoxy)-5-(4-carbamimidoyl phenoxy)benzoyl]-l-
carboxylic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 62.

g) 4-[3-(4-Aminomethyl phenoxy)-5-(4-ethoxycarbonimidoyl phenoxy)benzoyl]
piperazine-1-carboxylic acid ethyl ester
Using 4-[3-[4-(tert-butoxycarbonylaminomethyl)-phenoxy]-5-(4-cyano-phenoxy)-
benzoyl] piperazine-1-carboxylic acid ethyl ester (0.38 g, 0.63 mmol) and following the
procedure of Example l(d) afforded 0.17 g of the required product. Percentage purity
(LCMS): 81.7 %, (M+l) = 546.2+1.
h) 4-[3-(4-Aminomethylphenoxy)-5-(4-carbamimidoyl phenoxy)benzoyl]-
piperazine-1-carboxylic acid ethyl ester
Using 4-[3-(4-aminomethyl phenoxy)-5-(4-ethoxycarbonimidoyl phenoxy)-
benzoyl]piperazine-l-carboxylic acid ethyl ester (0.17 g, 0.31 mmol) and following the
procedure of Example l(e) afforded 0.07 g of the required product. Percentage purity:
HPLC 97.62 %; LCMS 94.31 %. !H NMR (DMSO-d6): 5 1.2 (3H, t), 3.35 (2H, m), 3.55
(2H, m), 3.9 (6H, m), 4.1 (2H, q), 6.8 (1H, s), 6.85 (2H, m), 7.20 (2H, d), 7.3 (2H, d),
7.5 (2H, d), 7.9 (2H, d), 8.2 (3H, brs), 9.1 (2H, s), 9.3 (2H, s).
Example 84.
N-(4-Amino cyclohexyl)-3-(4-aminomethyl phenoxy)-5-(4-carbamimidoyl
phenoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-[4-Aminomethylphenoxy]-5-hydroxybenzoylamino]cyclohexyl} carbamic
acid tert-butyl ester
Using {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic
acid tert-butyl ester (2.0 g, 4.43 mmol) and following the procedure of Example 83(d)
afforded 1.5 g of the required product. JH NMR (DMSO-dg): 8 1.2 (4H, m), 1.4 (9H, s),
1.8 (4H, m), 3.2 (1H, m), 3.7 (3H, m), 6.48 (1H, s), 6.78 (1H, d), 6.9 (1H, s), 7.0 (2H,
m), 7.38 (lH,m), 8.18 (1H, d).

e) {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-
cyclohexyl} carbamic acid tert-butyl ester
Using 1.5 g (3.29 mmol) of {4-[3-[4-aminomethylphenoxy]-5-hydroxybenzoyl-
amino]cyclohexyl} carbamic acid tert-butyl ester and boc-anhydride (0.787 g, 3.61
mmol) and following the procedure of Example 83(e) afforded 1.4 g of the required
product. JH NMR (DMSO-d6): 5 1.2 (3H5 m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (2H, m), 3.7
(1H, m), 4.15 (2H, d), 6.45 (1H, s), 6.7 (1H, d), 6.9 (1H, s), 7.0 (3H, d), 7.25 (2H, d),
7.4 (1H, brs), 8.15 (1H, d), 9.8 (1H, s).
f) {4-[3-[4-(tert-Butoxycarbonylamino methyl)phenoxy]-5-(4-cyano phenoxy)
benzoylamino]cyclohexyl} carbamic acid tert-butyl ester
Using 1.4 g (2.51 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-
hydroxybenzoylamino]-cyclohexyl} carbamic acid tert-butyl ester and 4-fluoro-
benzonitrile (0.76 g, 6.27 mmol) and following the procedure of Example 42(b)
afforded 1.53 g of the required product. !H NMR (DMSO-d6): 5 1.3 (4H, m), 1.4 (18H,
s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 4.15 (2H, d), 6.72 (1H, d), 7.20 (1H, s), 7.06
(2H, d), 7.18 (2H, d), 7.28 (2H, d), 7.38 (3H, d), 7.86 (2H, s), 8.3 (1H, d).
g) 4- [3 -(4-Amino-cyclohexylcarbamoyl)-5-(4-aminomethyl-phenoxy)-phenoxy] -
benzimidic acid ethyl ester
Using {4-[3-[4-(tert-butoxycarbonylamino methyl)phenoxy]-5-(4-cyano phenoxy)
benzoylamino]cyclohexyl}carbamic acid tert-butyl ester (1.53 g, 2.32 mmol) and
following the procedure of Example l(d) afforded 1.15 g of the required product.
Percentage purity (LCMS): 33.53 %, (M+l) = 502.2+1.
h) N-(4-Aminocyclohexyl)-3-(4-aminomethylphenoxy)-5-(4-carbamimidoyl
phenoxy) benzamide

Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-aminomethyl-phenoxy)-phenoxy]-
benzimidic acid ethyl ester (1.15 g, 2.28 mmol) and following the procedure of Example
l(e) afforded 0.75 g of the required product. Percentage purity: HPLC 96.64 %; LCMS
96.88 %. 1H NMR (DMSO-de): 6 1.45 (4H, t), 1.90 (4H, m), 3.0 (1H, m), 3.7 (1H, m),
4.05 (2H, d), 6.9 (1H, s), 7.18 (2H, d), 7.26 (2H, d), 7.38 (2H, s), 7.52 (2H, d), 7.88 (4H,
d), 8.22 (2H, brs), 8.42 (1H, d), 9.2 (2H, brs), 9.3 (2H, s).
Example 85.
(4-{3-(4-Amino-cyclohexylcarbamoyl)-5-[4-(N-hydroxycarbamimidoyl)-
phenoxy]-phenoxy}-benzyl)-carbamic acid ethyl ester
Intermediates (a) to (d) are the same as in Example 84.
e) (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}-
cyclohexyl)-carbamic acid tert-butyl ester
To 1.0 g (2.19 mmol) of {4-[3-(4-aminomethyl-phenoxy)-5-hydroxy-benzoyl-
amino]-cyclohexyl}-carbamic acid tert-butyl ester, dissolved in 5 ml of THF, 0.13 g
(5.47 mmol) of sodium hydride was added at 0 °C and the mixture was stirred for 15
min at same temperature. 0.26 g (2.40 mmol) of ethylchloroformate, dissolved in 2 ml
of THF, was added dropwise to the stirred solution during 10 min and then the reaction
mixture was stirred at RT for 6 h. After raction completion, solvent was removed under
reduced pressure and the obtained residue was dissolved in 200 ml of ethyl acetate.
Organic layer was washed with (3 x 100 ml) of brine followed by water (2 x 100 ml).
Organic phase was dried over anhydrous sodium sulphate and concentrated under
reduced pressure to afford 0.56 g of required product which was used for the next step
witout further purification. Percentage purity (LCMS): 59.7 %, (M+l) = 527.2+1.
f) (4-{3-(4-Cyano-phenoxy)-5-[4-(ethoxycarbonylamino-methyl)-phenoxy]-
benzoylarnino}-cyclohexyl)-carbamic acid tert-butyl ester

Using 0.56 g (1.06 mmol) of (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-
hydroxy-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester and 4-fluoro-
benzonitrile (0.32 g, 2.65 mmol) and following the procedure of Example 42(b)
afforded 0.61 g of the required product. Percentage purity (LCMS): 45.2 %, (M+l) =
628.3+1.
g) (4- {3 -[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) (4-{3-(4-cyano-phenoxy)-5-[4-(ethoxy-
carbonylamino-methyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl
ester 0.61 g (0.97 mmol) and other reagents were used to afford 0.68 g of the required
product. Percentage purity (LCMS): 38.9 %, (M+l) = 661.3+1.
h) (4-{3-(4-Amino-cyclohexylcarbamoyl)-5-[4-(N-hydroxycarbamimidoyl)-
phenoxy]-phenoxy}-benzyl)-carbamic acid ethyl ester
Using (4-{3-[4-(ethoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy
carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
(0.68 g, 1.02 mmol) and following the procedure of Example 9(d) afforded 0.28 g of the
required product. Percentage purity: HPLC 97.5 %; LCMS 96.6 %. 1H NMR (DMSO-
d6): 8 1.24 (3H, t), 1.38 (4H, m), 1.92 (4H, m), 3.0 (1H, m), 3.8 (1H, m), 4.00 (2H, q),
4.20 (2H, d), 6.88 (1H, s), 7.06 (2H, d), 7.22 (2H, d), 7.32 (4H, m), 7.65 (2H, m), 7.78
(5H, m), 8.18 (1H, d), 11.0 (1H, brs).
Example 86.
4-[3-(4-Aminomethylphenoxy)-5-(octahydroquinoline-l-carbonyl)-phenoxy]-
benzmidine
Intermediates (a) and (b) are the same as in Example 49.
c) 4-[3-Hydroxy-5-(octahydroquinoline-l-carbonyl)phenoxy]benzonitrile

3-(4-Cyano-phenoxy)-5-hydroxy-benzoic acid (1.5 g, 5.87 mmol) and decahydro-
quinoline (0.89 g, 6.45 mmol) and other reagents as described in Example 9(e) were
used to afford 1.6 g of the required product. 1H NMR (DMSO-d6): 8 1.35 (6H, m), 1.80
(7H, m), 3.0 (1H, m), 3.6 (1H, m), 4.5 (1H, m), 6.44 (1H, s), 6.54 (2H, m), 7.16 (2H, d)
7.88 (2H, d), 10.1 (lH,brs).
d) [3-(4-amino methyl phenoxy)-5-hydroxy phenyl]-(octahydro quinolin-1-
yl)methanone
Using 4-[3-hydroxy-5-(octahydro quinoline-l-carbonyl)phenoxy] benzonitrile (1.6
g, 4.27 mmol) and following the procedure of Example 83(d) afforded 1.2 g of the
required product. Percentage purity (LCMS): 94.5 %, (M+l) = 661.3+1.
e) {4-[3-hydroxy-5-(octahydroquinoline-l-carbonyl)phenoxy]benzyl}carbamic
acid tert-butyl ester
Using 1.2 g (3.17 mmol) of [3-(4-amino methyl phenoxy)-5-hydroxy phenyl]-
(octahydro quinolin-l-yl)methanone and boc-anhydride (0.76 g, 3.48 mmol) and
following the procedure of Example 83 (e) afforded 1.34 g of the required product.
]H NMR (DMSO-d6): 5 1.30 (8H, m), 1.40 (9H, s), 1.55 (2H, m), 1.75 (4H, m), 3.0 (1H:
m), 3.55(1H, m), 4.1 (2H, d), 6.24 (1H, s), 6.42 (2H, s), 7.0 (2H, d), 7.26 (2H, d), 7.4
(1H, t), 9.8 (1H, s).
f) {4-[3-(4-Cyanophenoxy)-5-(octahydroquinoline-l-carbonyl)phenoxy]benzyl}-
carbamic acid tert-butyl ester
Using 1.34 g (2.79 mmol) of {4-[3-hydroxy-5-(octahydroquinoline-l-carbonyl)
phenoxy]benzyl}carbamic acid tert-butyl ester and 4-fluorobenzonitrile (0.84 g, 6.97
mmol) and following the procedure of Example 42(b) afforded 1.6 g of the required
product. !H NMR (DMSO-d6): 5 1.30 (8H, m), 1.40 (9H, s), 1.8 (8H, m), 4.1 (2H, d),

6.68 (1H, s), 6.82 (2H, s), 7.08 (2H, d), 7.22 (2H, d), 7.28 (2H, d), 7.4 (1H, t), 7.88 (2H,
d).
g) {4-[3-[4-(N-Hydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-1 -
carbonyl)-phenoxy]benzyl} carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-cyanophenoxy)-5-(octahydro-
quinoline-l-carbonyl)phenoxy]benzyl}-carbamic acid tert-butyl ester 1.6 g (2.76 mmol)
and other reagents were used to afford 1.43 g of the required product.
Percentage purity (LCMS): 54.6 %, (M+l) = 612.3+1.
h) {4- [3-[4-(N-acetylhydroxycarbamimidoyl)phenoxy]-5-(octahydro quinoline-1 -
carbonyl)phenoxy]benzyl} carbamic acid tert-butyl ester
{4- [3 - [4-(N-Hydroxycarbamimidoyl)phenoxy] -5 -(octahydroquinoline-1 -carbonyl)-
phenoxy]benzyl} carbamic acid tert-butyl ester, 1.4 g (2.28 mmol) was acetylated with
0.26 g (2.5 mmol) of acetic anhydride using the procedure of Example 2(e) to afford
1.04 g of the required product. Percentage purity (LCMS): 36.1 %, (M+l) = 654.3+1.
i) 4-[3-(4-Aminomethylphenoxy)-5-(octahydroquinoline-l-carbonyl)phenoxy]
benzmidine
1.0 g (1.52 mmol) of {4-[3-[4-(N-acetylhydroxycarbamimidoyl)phenoxy]-5-
(octahydro quinoline-l-carbonyl)phenoxy]benzyl} carbamic acid tert-butyl ester was
reduced using the procedure of Example 2(f) to afford 0.43 g of required product.
Percentage purity: HPLC 83.4 %; LCMS 96.26 %. !H NMR (DMSO-d6): 5 1.3 (5H, m),
1.55 (2H, m), 1.75 (5H, m), 2.7 (1H, m), 3.05 (1H, m), 4.0 (2H, d), 4.25 (1H, m), 4.45
(1H, m), 6.75 (4H, m), 7.2 (2H, d), 7.3 (2H, d), 7.55 (2H, d), 7.9 (2H, d), 8.4 (3H, brs),
9.1(2H,s),9.4(2H,s)

Example 87.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2,6-
difluoro-phenoxy)-benzamide
Intermediates (a) and (e) are the same as in Example 84.
f) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2,6-difluoro-
phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using 0.5 g (0.89 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-
hydroxybenzoylamino]-cyclohexyl} carbamic acid tert-butyl ester and 3,4,5-trifluoro-
benzonitrile (0.34 g, 2.22 mmol) and following the procedure of Example 42(b)
afforded 0.4 g of the required product. 1H NMR (DMSO-d6): 5 1.25 (4H, m), 1.38 (18H,
d), 1.78 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.74 (1H, d), 6.90 (1H, s),
7.02 (2H, d), 7.20 (2H, d), 7.28 (2H, d), 7.40 (1H, m), 8.08 (2H, d), 8.32 (1H, d).
g) (4- {3 - [4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5- [2,6-difluoro-4-(N-
hydroxycarbamimidoyl)-phenoxy]-benzoylamino} -cyclohexyl)-carbamic acid tert-butyl
ester
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2,6-
difluoro-phenoxy)-benzoylamino]-cyclohexyl} -carbamic acid tert-butyl ester (0.4 g,
0.57 mmol) and following the procedure of Example 2(d) afforded 0.45 g of the
required product. Percentage purity (LCMS): 83.53 %, (M+l) = 525.2+1 (de-bis BOC
product mass).
h) (4- {3 - [4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5- [2,6-difluoro-4-(N-
acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-
butyl ester
Using (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(N-
hydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl

ester (0.45 g, 0.62 mmol) and following the procedure of Example 2(e) afforded 0.5 g of
the required product. Percentage purity (LCMS): 81.00 %, (M+l) = 667.2+1 (de-BOC
product mass).
i) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-2,6-
difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(N-
acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino} -cyclohexyl)-carbamic acid tert-
butyl ester 0.5 g (0.65 mmol) was reduced using the procedure of Example 2(f) to afford
0.3 g of required product. Percentage purity (LCMS): 85.0 %, (M+l) = 709.3+1.
j) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2,6-
difluoro-phenoxy)-benzamide
Using {4- [3- [4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-
2,6-difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.3 g,
0.42 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the
required product. Percentage purity: HPLC; 97.83 %, LCMS; 92.22 %. 1H NMR
(DMSO-d6): 5 1.44 (4H, m), 1.88 (4H, m), 3.02 (1H, m), 3.48 (1H, m), 4.05 (2H, d),
6.92 (1H, s), 7.14 (2H, d), 7.25 (2H, d), 7.50 (2H, d), 7.90 (5H, m), 8.25 (3H, brs), 8.44
(1H, d), 9.52 (4H, d).
Example 88.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2-
trifluoromethyl-phenoxy)-benzamide
Intermediates (a) and (e) are the same as in Example 84.
g) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2-
trifluoromethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester

Using 0.46 g (0.82 mmol) of {4-[3-[4-tert-butoxycarbonylaminomethylphenoxy]-5-
hydroxybenzoylamino]-cyclohexyl} carbamic acid tert-butyl ester and 4-fluoro-3-tri-
fluoromethylbenzonitrile (0.313 g, 1.65 mmol) and following the procedure of Example
42(b) afforded 0.3 g of the required product. JH NMR (DMSO-d6): 5 1.25 (4H, m), 1.38
(18H, d), 1.8 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.75 (1H, d), 7.02 (1H,
s), 7.08 (2H, d), 7.20 (1H, d), 7.28 (2H, d), 7.41 (3H, m), 8.1 (1H, m), 8.38 (2H, m).
h) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethyl-4-
(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino} -cyclohexyl)-carbamic acid tert-
butyl ester
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2-tri-
fluoromethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.3
g, 0.41 mmol) and following the procedure of Example 2(d) afforded 0.3 g of the
required product. Percentage purity (LCMS): 75.8 %, (M+l) = 557.2+1 (de-bis BOC
product mass).
i) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethyl-4-
(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid
tert-butyl ester
Using (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy] -5- [2-trifluoromethyl-
4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino} -cyclohexyl)-carbamic acid tert-
butyl ester (0.3 g, 0.39 mmol) and following the procedure of Example 2(e) afforded
0.35 g of the required product. Percentage purity (LCMS): 59.00 %, (M+l) = 699.2+1
(de-BOC product mass).
j) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-2-
trifluoromethyl-phenoxy)-benzoylamino]-cyclohexyl} -carbamic acid tert-butyl ester
(4-{3.[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethyl-4-(N-
acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino} -cyclohexyl)-carbamic acid tert-

butyl ester 0.35 g (0.47 mmol) was reduced using the procedure of Example 2(f) to
afford 0.2 g of required product. Percentage purity (LCMS): 70.0 %, (M+l) = 741.3+1.
k) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2-
trifluoromethyl-phenoxy)-benzamide
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-
2,6-difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.3 g,
0.42 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the
required product. Percentage purity: HPLC; 99.55 %, LCMS; 96.52 %. 1H NMR
(DMSO-de): 5 1.44 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 3.0 (1H, m), 3.6 (1H, m), 4.05
(2H, d), 7.08 (1H, s), 7.22 (2H, d), 7.30 (1H, d), 7.42 (2H, d), 7.52 (2H, d), 7.88 (3H,
brs), 8.08 (1H, d), 8.22 (2H, brs), 8.28 (1H, s), 8.48 (1H, d), 9.45 (4H, d).
Example 89.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-2,6-difluoro-phenoxy)-5-(4-
carbamimidoyl-phenoxy)-benzamide
a) 3-(4-Cyano-2,6-difluoro-phenoxy)-5-hydroxy-benzoic acid ethyl ester
Using 1.5 g (9.55 mmol) of 3,4,5-trifluoro-benzonitrile and 3,5-dihydroxy-benzoic
acid ethyl ester (1.73 g, 9.55 mmol) and following the procedure of Example 42(a)
afforded 1.2 g of the required product. lH NMR (DMSO-d6): 8 1.28 (3H, t), 4.27 (2H,
q), 6.67 (1H, t), 6.92 (1H, s), 7.18 (1H, s), 8.08 (2H, d), 10.20 (1H, brs).
b) 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-hydroxy-
benzoic acid ethyl ester
0.9 g (2.82 mmol) of 3-(4-cyano-2,6-difluoro-phenoxy)-5-hydroxy-benzoic acid
ethyl ester was dissolved in 50 ml of methanol and 1.23 g (5.64 mmol) of di-tert-butyl
dicarbonate was slowly added at 0 °C. Nickel chloride (60.0 mg, 0.28 mmol) and
sodium borohydride (0.75 g, 19.74 mmol) were added at 0 °C at 10 minutes interval

each. After complete addition the reaction mixture was stirred at RT for 30 minutes.
Then 0.3 g (3.22 mmol) of diethylenetriamine was added during 15 minutes and finally
reaction mixture was stirred for 2 hrs at RT. Reaction progress was monitored by TLC.
The reaction mixture was concentrated under reduced pressure and partitioned between
water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with 2 x 100
ml solution of saturated sodium bicarbonate solution and then with 2 x 100 ml of
saturated brine solution, dried over sodium sulphate and concentrated. The crude residue
was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.5
g of the required product. 1H NMR (DMSO-d6): 8 1.25 (3H, t), 1.40 (9H, s), 4.18 (2H,
d), 4.28 (2H, q) 6.60 (1H, s), 6.84 (1H, s), 7.10 (1H, s), 7.18 (2H, d), 7.54 (1H, t), 10.2
(1H, brs).
c) 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-
phenoxy)-benzoic acid ethyl ester
Using 0.5 g (1.18 mmol) of 3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-
phenoxy]-5-hydroxy-benzoic acid ethyl ester and 4-fluorobenzonitrile (0.21 g, 1.77
mmol) and following the procedure of Example 42(b) afforded 0.3 g of the required
product. !H NMR (DMSO-d6): 5 1.25 (3H, t), 1.42 (9H, s), 4.2 (2H, d), 4.28 (2H, q),
7.22 (6H, m), 7.32 (1H, s), 7.54 (1H, t), 7.90 (2H, d).
d) 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-
phenoxy)-benzoic acid
1.1 g (2.09 mmol) of 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-
phenoxy]-5-(4-cyano-phenoxy)-benzoic acid ethyl ester was hydrolysed using the
procedure of Example 5(b) to afford 0.8 g of the required product. !H NMR (DMSO-
d6): 8 1.42 (9H, s), 4.22 (2H, d), 7.25 (7H, m), 7.52 (1H, m), 7.90 (2H, s), 12.4 (1H,
brs).
e) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-
phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester

3-[4-(tert-butoxycarbonylammo-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-
phenoxy)-benzoic acid (0.6 g, 1.2 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-
butyl ester (0.28 g, 1.3 mmol) and other reagents as described in Example 9(e) were
used to afford 0.4 g of the required product. lH NMR (DMSO-d6): 5 1.24 (4H, m), 1.42
(18H, s), 1.8 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.20 (2H, d), 6.74 (1H5 d), 7.0 (1H,
s), 7.16 (4H, m), 7.24 (1H, s), 7.38 (1H, s), 7.54 (1H, t), 7.88 (2H, d), 36 (1H, d).
f) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N-
hydroxycarbamimidoyl)-phenoxy]-benzoylamino} -cyclohexyl)-carbamic acid tert-butyl
ester
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-
cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.53 g, 0.76
mmol) and following the procedure of Example 2(d) afforded 0.6 g of the required
product. Percentage purity (LCMS): 74.23 %, (M+l) = 725.3+1.
g) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N-
acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino} -cyclohexyl)-carbamic acid tert-
butyl ester
Using (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N-
hydroxycarbamimidoyl)-phenoxy] -benzoylamino} -cyclohexyl)-carbamic acid tert-butyl
ester (0.6 g, 0.82 mmol) and following the procedure of Example 2(e) afforded 0.6 g of
the required product. Percentage purity (LCMS): 21.0 %, (M+l) = 667.2+1 (de-BOC
product mass).
h) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-
carbamimidoyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
(4-{3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N-
acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino} -cyclohexyl)-carbamic acid tert-

butyl ester 0.6 g (0.78 mmol) was reduced using the procedure of Example 2(f) to afford
0.35 g of required product. Percentage purity (LCMS): 75.0 %, (M+l) = 709.3+1.
i) N-(4-Amino-cyclohexyl)-3 -(4-aminomethyl-2,6-difluoro-phenoxy)-5 -(4-
carbamimidoyl-phenoxy)-benzamide
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-
carbamimidoyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
(0.35 g, 0.49 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the
required product. Percentage purity: HPLC; 98.72 %, LCMS; 96.32 %. JH NMR
(DMSO-de): 8 1.38 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 2.98 (1H, m), 3.65 (1H, m),
4.14 (2H, d), 6.98 (1H, t), 7.22 (3H, m), 7.38 (1H, s), 7.50 (2H, d), 7.90 (5H, m), 8.45
(3H, m), 9.30 (4H, d).
Example 90.
l-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperidine-4-carboxylic acid
Intermediates (a) and (b) are the same as in Example 26.
c) l-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid ethyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.6 g (1.68 mmol) and piperidine-4-carboxylic acid ethyl ester (0.31 g, 2.02 mmol) were
used to afford 0.54 g of the required product. JH NMR (DMSO-d6): 8 1.18 (3H, t), 1. 5
(2H, m), 1.82 (2H, m), 2.6 (1H, m), 2.90 (1H, m), 3.12 (1H, m), 3.52 (1H, m), 4.08 (2H,
q), 4.25 (1H, m), 6.96 (2H, d), 7.06 (1H, t), 7.26 (4H, d), 7.88 (4H, d).
d) 1 -[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid
0.48 g (0.96 mmol) of l-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-
carboxylic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to
afford 0.4 g of the required product. !H NMR (DMSO-de): 8 1.28 (2H, m), 1.5 (2H, m),

1.82 (2H, m), 3.10 (1H, m), 3.58 (1H, m), 4.24 (1H, m), 6.98 (1H, d), 7.16 (2H, m), 7.25
(4H, m), 7.88 (4H, m), 12.5 (1H, brs).
e) l-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidine-4-
carboxylic acid
Using l-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid (0.4 g,
0.85 mmol) and following the procedure of Example 2(d) afforded 0.4 g of the required
product. Percentage purity (LCMS): 95.0 %, (M+l) = 531.0+1.
f) l-{3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-piperidine-4-carboxylicacid
1 - { 3,5 -Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoyl} -piperidine-4-
carboxylic acid 0.4 g (0.74 mmol) was reduced using the procedure of Example 2(f) to
afford 0.1 g of required product. Percentage purity: HPLC; 95.33 %, LCMS; 98.43 %.
1H NMR (DMSO-d6): 5 1.48 (2H, m), 1.85 (2H, m), 2.92 (1H, m), 3.10 (1H, m), 3.58
(1H, m), 4.25 (2H, m), 6.92 (2H, d), 7.0 (1H, t), 7.32 (4H, d), 7.88 (4H, d), 9.12 (4H,
brs), 9.28 (4H, brs).
Example 91.
4- {1 - [3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl] -piperidin-4-yl} -butyric acid
Intermediates (a) and (b) are the same as in Example 26.
c) 4-{l-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidin-4-yl}-butyric acid ethyl
ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
1.2 g (3.37 mmol) and 4-piperidin-4-yl-butyric acid ethyl ester (0.68 g, 3.7 mmol) were
used to afford 0.9 g of the required product. [H NMR (DMSO-d6): 5 1.20 (4H, m), 1. 52
(5H, m), 1.70 (1H, m), 2.3 (2H, t), 2.68 (1H, m), 3.6 (3H, s), 4.4 (2H, q), 4.25 (1H, m),
6.95 (2H, d), 7.04 (1H, t), 7.25 (4H, d), 7.88 (4H, d).

d) 4-(l-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-
butyric acid ethyl ester
Using 4-{l-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidm-4-yl}-butyric acid ethyl
ester (1.0 g, 1.91 mmol) and following the procedure of Example 2(d) afforded 1.1 g of
the required product. Percentage purity (LCMS): 28.2 %, (M+l) = 589.2+1.
e) 4-(l-{3,5~Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl}-
piperidin-4-yl)-butyric acid ethyl ester
Using 4-(l-{3,5-bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoyl} -piperidin-4-
yl)-butyric acid ethyl ester (1.0 g, 1.65 mmol) and following the procedure of Example
2(e) afforded 0.6 g of the required product. Percentage purity (LCMS): 38.0 %, (M+l) =
673.2+1.
f) 4-( 1 -{3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-butyric
acid ethyl ester
4-(l-{3,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl} -piperidin-4-
yl)-butyric acid ethyl ester 0.6 g (0.87 mmol) was reduced using the procedure of
Example 2(f) to afford 0.14 g of required product. Percentage purity: HPLC; 90.04 %,
LCMS; 81.94 %. 'HNMR (DMSO-d6): 8 1.20 (2H, m), 1. 52 (4H, m), 1.70 (1H, m),
2.30 (2H, t), 2.7 (2H, m), 3.0 (1H, m), 3.6 (3H, s), 4.4 (2H, m), 6.9 (2H, s), 7.0 (1H, s),
7.32 (4H, d), 7.88 (4H, d), 9.25 (8H, brs).
Example 92.
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]-
benzoic acid
Intermediates (a) - (c) are the same as in Example 49.

d) {4-[3-(4-Cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoylamino]-cyclohexyl}-
carbamic acid tert-butyl ester
Using 3.0 g (6.6 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-
cyclohexyl}-carbamic acid tert-butyl ester and 4-fluorobenzaldehyde (1.66 g, 13.3
mmol) and following the procedure of Example 42(b) afforded 2.2 g of the required
product. lU NMR (DMSO-d6): 5 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m),
3.68 (1H, m), 6.75 (1H, d), 7.25 (4H, m), 7.50 (2H, s), 7.82 (2H, d), 7.95 (2H, d), 8.38
(lH,d),9.94(lH,s).
e) 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
phenoxyj-benzoic acid
0.5 g (0.9 mmol) of {4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoyl-
amino]-cyclohexyl}-carbamic acid tert-butyl ester was dissolved in 15 ml of THF and
0.43 g (2.7 mmol) of potassium permanganate, dissolved in 8 ml of water, was added to
THF solution at 10 °C during 10 minutes. The reaction mixture stirred over night at RT.
Reaction progress was monitored by TLC. Reaction mixture was filtered through celite
and washed with THF and thus obtained mother liquor was concentrated under vacuo.
Product was crystallized with ethyl acetate to afford 0.25 g of required product. !H
NMR (DMSO-de): 8 1.25 (4H, m), 1.36 (9H, s), 1.78 (4H, m), 3.18 (1H, m), 3.66 (1H,
m), 6.75 (1H, d), 6.94 (3H, m), 7.18 (2H, d), 7.36 (2H, s), 7.86 (4H, d), 8.38 (1H, d).
f) 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
phenoxy]-benzoic acid benzyl ester
0.6 g (1.05 mmol) of 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-
cyano-phenoxy)-phenoxy]-benzoic acid was dissolved in 5 ml of DMF. At 0 °C 50 mg
(0.35 mmol) of potassium carbonate followed by 45 mg (0.26 mmol) benzylbromide
were added and the reaction mixture was stirred for 4 hrs at RT. Reaction progress was
monitored by TLC. Upon completion of the reaction the contents were diluted with 50
ml of ice-water and extarted with 3 x 50 ml of ethyl acetate, dried over anhydrous

sodium sulphate and concentrated under vacuo. Thus obtained crude residue was
purified by column chromatography using 60-120 mesh silica-gel and eluted with
ethylacetate : hexane (1 : 9) to give 0.38 mg of the required product. !H NMR (DMSO-
d6): 5 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m), 3.66 (1H, m), 5.36 (2H, s),
6.76 (1H, d), 7.22 (5H, m), 7.46 (7H, m), 7.88 (2H, d), 8.05 (2H, d), 8.36 (1H, d).
g) 4-{3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-
hydroxycarbamimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester
Using 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-
phenoxy)-phenoxy]-benzoic acid benzyl ester (0.4 g, 0.61 mmol) and following the
procedure of Example 2(d) afforded 0.39 g of the required product. Percentage purity
(LCMS): 52.0 %, (M+l) = 694.3+1.
h) 4- { 3 -(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5 - [4-(N-
acetylhydroxycarbamimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester
Using 4-{3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-
hydroxycarbamimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester (0.39 g, 0.56
mmol) and following the procedure of Example 2(e) afforded 0.41 g of the required
product. Percentage purity (LCMS): 53.0 %, (M+l) = 680.5+1 (Boc-acid mass).
i) 4- [3 -(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5 -(4-carbamimidoyl-
phenoxy)-phenoxy]-benzoic acid
4_ {3 -(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5- [4-(N-acetylhydroxy-
carbamimidoyl)-phenoxy]-phenoxy}-benzoic acid benzyl ester 0.41 g (0.56 mmol) was
reduced using the procedure of Example 2(f) to afford 0.13 g of required product.
Percentage purity: (LCMS): 74.1 %, (M+l) = 587.1+1.
j) N-(4-Amino-cyclohexyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-benzamide

Using 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-carbam-
imidoyl-phenoxy)-phenoxy]-benzoic acid (0.13 g, 0.22 mmol) and following the
procedure of Example 9(d) afforded 35 mg of the required product. Percentage purity:
HPLC; 97.00 %, LCMS; 93.86 %. lH NMR (DMSO-d6): 8 1.40 (4H, m), 1.92 (4H, m),
3.02 (1H, m), 3.70 (1H, m), 7.02 (1H, s), 7.15 (2H, d), 7.35 (2H, d), 7.45 (2H, d), 7.76
(1H, brs), 7.88 (4H, dd), 8.40 (1H, d), 8.88 (2H, brs), 9.25 (2H, brs).
Example 93.
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]-
benzoic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 49.
d) 4- [3 -(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-
phenoxyj-benzoic acid ethyl ester
Using 2.0 g (4.4 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-
cyclohexyl}-carbamic acid tert-butyl ester and 4-fluoro-benzoic acid ethyl ester (1.2 g,
6.6 mmol) and following the procedure of Example 42(b) afforded 1.8 g of the required
product. 'H NMR (DMSO-d6): 5 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m),
3.68 (1H, m), 4.30 (2H, q), 6.75 (1H, d), 7.20 (5H, m), 7.48 (2H, d), 7.88 (2H, d), 8.00
(2H, d), 8.36 (1H, d).
e) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-phenoxy)-
phenoxyj-benzoic acid ethyl ester
Using 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-
phenoxy)-phenoxy]-benzoic acid ethyl ester (0.6 g, 1.0 mmol) and following the
procedure of Example l(d) afforded 0.55 g of the required product. Percentage purity
(LCMS): 96.0 %, (M+l) = 545.4+1.

f) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]-
benzoic acid
Using 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-phenoxy)-
phenoxyj-benzoic acid (0.45 g, 0.82 mmol) and following the procedure of Example
l(e) afforded 0.25g of the required product. Percentage purity: HPLC 97.88 %; LCMS
95.45 %. 1H NMR (DMSO-d6): 5 1.45 (4H, m), 1.95 (4H, m), 3.0 (2H, m), 3.4 (1H, m),
4.34 (2H, m), 7.1 (1H, s), 7.18 (2H, d), 7.3 (2H, d), 7.5 (2H, d) 7.9 (4H, m), 8.0 (2H, d),
8.4 (1H, m), 9.00 (2H, brs), 9.26 (2H, brs).
Example 94.
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl-
phenoxy)-benzamide
Intermediates (a) - (e) are the same as in Example 92.
f) {4-[3-(4-Carbamoyl-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclo-
hexyl}-carbamic acid tert-butyl ester
0.6 g (1.05 mmol) of 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-
cyano-phenoxy)-phenoxy]-benzoic acid was dissolved in 15 ml of THF. At -10 C 0.18
ml (1.57 mmol) of N-methylmorpholine was added. The reaction mixture was stirred for
15 minutes at 0 °C. 0.14 ml (1.36 mmol) of tert-butylchloroformate was added and the
reaction mixture was stirred for 1 hr at RT. Further 6.0 ml of 30 % of ammonia solution
was added during 10 minutes at 0 °C and reaction progress was monitored by TLC.
Upon completion of the reaction the contents were diluted with 50 ml ethyl acetate.
Organic layer was separated and washed with 3 x 50 ml saturated sodium bicarbonate
solution, dried over anhydrous sodium sulphate and concentrated under reduced
pressure to afford 0.4 g of required product. Percentage purity (LCMS): 60.0 %, (M+l)
= 570.2.

g) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamoyl-phenoxy)-phenoxy]-
benzimidic acid ethyl ester
Using {4-[3-(4-carbamoyl-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-
cyclohexyl}-carbamic acid tert-butyl ester (0.45 g, 0.79 mmol) and following the
procedure of Example l(d) afforded 0.48 g of the required product. Percentage purity
(LCMS): 77.0 %, (M+l) = 516.1+1.
h) N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl-
phenoxy)-benzamide
Using 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamoyl-phenoxy)-phenoxy]-
benzimidic acid ethyl ester (0.48 g, 0.93 mmol) and following the procedure of Example
l(e) afforded 0.055g of the required product. Percentage purity: HPLC 97.22 %; LCMS
93.33 %. 'H NMR (DMSO-d6): 5 1.45 (4H, m), 1.90 (4H, m), 3.0 (1H, m), 3.7 (1H, m),
7.0 (1H, s), 7.15 (2H, d) 7.32 (3H, d), 7.45 (2H, d), 7.88 (6H, m), 8.40 (1H, d), 8.88
(2H, brs), 9.25 (2H, brs).
Abbreviations:
DMF - A^N-dimethylformamide
THF - Tetrahydrofuran
TEA - Triethyl Amine
EDC - l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
HOBT- hydroxybenzotriazole
DIPEA - N, jV-diisopropylethylarnine
PyBop - Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
Na2CO3 - Sodium carbonate
RT - Room temperature

Claims
1. A compound of formula (I)

wherein
P1 and P2 are, independently a bond or C1-3 alkyl;
A is CH or N;
B is CH or N;
R1 is hydrogen, -NHSO2R6, -CO-NR7R8, -CO-NR4-ZR9R13 or a group of
formula

wherein the ring portion in formula (II) is a 5 -12 membered saturated, partially
saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain
1-3 further heteroatoms selected from N, O, S or combinations thereof;
R3 is -C(NR17)NH2, or in case A is CH, R3 can also be amino C1-7 alkyl;
R10, R14 and R15 are independently hydrogen, halogen, halogen C1-7 alkyl, or
-C(NR17)NH2;
Q is hydrogen or halogen, with a proviso that R1 and Q are not simultaneously
hydrogen;
R4 is hydrogen or C1-7 alkyl;
R6 is ZR9R13;

Z is a 5 -12 membered saturated, partially saturated or aromatic ring which may
be monocyclic or bicyclic, and which may contain 1-3 heteroatoms selected from N, O,
S or combinations thereof;
R9 and Ri3 are, independently, hydrogen, halogen, carboxy, carboxy C1-7 alkyl,
C1-7 alkoxycarbonyl, RANH2 or -CORBNH2;
RA and RB is a bond or C1-7 alkyl;
R7 and R8 are, independently, hydrogen, amino C1-7 alkyl, carboxy C1-7 alkyl, or
in case A is CH, R7 and R8, independently, can also be C1-7 alkyl,
with a proviso that R7 and R8 are not simultaneously hydrogen;
R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-7 alkyl, C1-7 alkoxycarbonyl C1-7
alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, RDC(NR17)NH2, or a group of formula
(III)

y = 0-2; RD is a bond or C1-7 alkyl; G is CH or N;
Rn is hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7 alkoxycarbonyl,
aminocarbonyl, halogen C1-7 alkoxy, -C(NR17)NH2, -NHCORgH2, RJNHCOORU;
RG is C1-7 alkyl; RJ is a bond or C1-7 alkyl; Ruis hydrogen or C1-7 alkyl;
R12 and R16 are, independently, hydrogen, halogen or C1-7 alkyl;
Rn is hydrogen, -OH, -O(CO)OR18 or -(CO)OR18;
R18 is C1-7 alkyl;
or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1, wherein R1 is a group of formula (II).
3. A compound according to claim 2, wherein the ring portion of formula (II) is a
6 or 10 membered saturated, partially saturated or aromatic ring, which may be
monocyclic or bicyclic, and which may contain one further heteroatom N.
4. A compound according to claim 3, wherein the ring portion of formula (II) is
piperidinyl, piperazinyl, nonahydro-quinolinyl or 3,4-dihydro-lH-quinolinyl.
5. A compound according to claim 1, wherein R1 is -CO-NR4-ZR9R13.

6. A compound according to claim 5, wherein Z is a 6 or 10 membered saturated,
partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which
may contain 1 or 2 N atoms.
7. A compound according to claim 6, wherein Z is cyclohexyl, piperidinyl,
phenyl, naphthyl or quinolinyl.
8. A compound according to claim 7, wherein Z is cyclohexyl, R4 is hydrogen,
R9 is RANH2 and R13 is hydrogen.
9. A compound according to any of claims 1 to 8, wherein A is N and B is CH.

10. A compound according to any of claims 1 to 8, wherein A is CH and B is
CH.
11. A compound according to any of claims 1 to 7, wherein R3 is
-C(NR17)NH2 and R10, R14 and R15 are hydrogen.
12. A compound according to any of claims 1 to 11, wherein R2 is a group of
formula (III) wherein G is CH, y is 0-1, R11 is -C(NR17)NH2 or amino C1-7 alkyl, R12 and
R16 are hydrogen.
13. A compound according to any of claims 1 to 12, wherein P] and P2 is a bond.
14. A compound according to any of claims 1 to 12, wherein P1 is a bond and P2
is -CH2-.
15. A pharmaceutical composition comprising a compound of formula (I)
together with a pharmaceutically acceptable carrier.
16. A method for the treatment of a matriptase dependent condition, comprising
administering to a subject in need thereof a therapeutically effective amount of a
compound of formula (I).
17. A method for the treatment of cancer, comprising administering to a subject
in need thereof a therapeutically effective amount of a compound of formula (I).

A compound of formula (I) wherein R1 to R15, P1, P2, A, B and Q are as defined in the claims and
pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as matriptase inhibitors and are useful in the treatment of matriptase dependent conditions, particularly cancer.