NICOTINAMIDE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC
USE THEREOF AS ANTICANCER DRUGS
The present invention relates to nicotinamide derivatives, to the compositions comprising
them and to their therapeutic application, in particular as anticancer drugs. The invention also
relates to the process for the preparation of these compounds and to some of the
intermediates.
[The prior art]
International Application WO 2005/051366 describes compounds of general formula (A):

in which Z represents a phenyl or indanyl group and not a pyridinyl group.
International Application WO 2007/016538 describes compounds of general formula (B):

in which Q can represent an R13-NR12-C(=O)- group, it being possible for R13 to be a 2-, 3- or
4-pyridinyl group, R4 and R5 representing a hydrogen atom or an alkyl, alkoxy, -OH, -CF3 or
-CN group. These compounds are used in the treatment of obesity.
[Description of the invention]
Definitions used
In the context of the present invention:
• halogen atom is understood to mean: a fluorine, chlorine, bromine or iodine atom;
• alkyl group is understood to mean: a saturated aliphatic hydrocarbon group comprising
from 1 to 6 carbon atoms (advantageously from 1 to 4 carbon atoms) obtained by
removing a hydrogen atom from an alkane. The alkyl group can be linear or branched.

Mention may be made, by way of examples, of the methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl, 2,2-dimethylpropyl or hexyl groups;
• alkoxy group is understood to mean: an -O-alkyl group, where the alkyl group is as
defined above;
• cycloalkyl group is understood to mean: a cyclic alkyl group comprising between 3 and 8
carbon atoms, all the carbon atoms being involved in the cyclic structure. Mention may be
made, by way of examples, of the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
groups;
• heterocycloalkyl group is understood to mean: a cycloalkyl group comprising at least one
heteroatom (O, S, N) involved in the ring and connected to the carbon atoms forming the
ring. Mention may be made, by way of examples, of the pyrrolidinyl, piperidinyl,
piperazinyl or N-(C1-C4 alkyl)piperazinyl, azepanyl, thiomorpholinyl, 1-oxothiomorpholinyl
or 1,1-dioxothiomorpholinyl groups.
According to a 1st aspect, a subject-matter of the present invention is a compound of
formula (I):

in which:
• Z and Z' represent N or CH;
• x is an integer having the value 1 or 2, representing the number of fluorine atom(s)
attached to the central phenyl nucleus;
• L represents a -CH=CH- or-(CH2)nNH- group in which the NH group is attached to the
C=O and n is an integer having the value 0,1 or 2;
• R1 represents a hydrogen atom or a (C1-C6)alkyl, (C3-C6)cycloalkyl or phenyl group;
• R1 represents a hydrogen atom or a (C1-C6)alkyl group;
• R2 represents:

- a (C3-C6)cycloaIkyl group;
- a (C1-C6)alkyl group, optionally substituted by:
o one or more hydroxyl or (C1-C4)alkoxy groups;
o an -NRaRb group in which Ra and Rb represent, independently of one another,
a hydrogen atom or a (C1-C6)alkyl group or form, together with the nitrogen atom to

which they are connected, a (C4-C6)heterocycloalkyl group optionally comprising,
in the ring, the-S(O)q- group with q= 0,1 or 2 or the -NH- or -N(C1-C4 alkyl)- group
and being optionally substituted by one or more substituent(s), which are identical
to or different from one another when there are several of them, chosen from an
-OH, (C1-C4)alkoxy or (C1-C4)alkyI group;
• R3 represents at least one substituent of the pyridine nucleus chosen from a hydrogen
atom, a fluorine atom, a (C1-C4)alkyl group or an -NRcRd group in which Rc and Rd
represent a hydrogen atom or a (C1-C4)alkyl group.
R1 represents a hydrogen atom, a (C1-C6)alkyl group, a (C3-C6)cycloalkyl group, for example
a cyclopropyl group, or a phenyl group. R'1 represents a hydrogen atom or a (C1-C6)alkyl
group. More particularly, R'1 represents a hydrogen atom. R1 and/or R'1 can be chosen from
those described in Table I.
R2 represents:
- a (C3-C6)cycloalkyl group, such as, for example, the cyclopropyl or cyclopentyl group;
- a (C1-C6)alkyl group, optionally substituted by:
o one or more -OH or (C1-C4)alkoxy, for example methoxy, group(s);
o an -NRaRb group in which Ra and Rb represent, independently of one another, a
hydrogen atom or a (C1-C6)alkyl group or form, together with the nitrogen atom to
which they are connected, a (C4-C6)heterocycloalkyl group optionally comprising, in
the ring, the -S(O)q- group with q= 0, 1 or 2 or the -NH- or -N(C1-C4 alkyl)- group.
Preferably, q= 1 or 2.
The heterocycloalkyl group formed by Ra and Rb can, for example, be the pyrrolidinyl
i
i
I
group.

The heterocycloalkyl group formed by Ra and Rb can optionally be substituted by one or more
substituent(s), identical to or different from one another when there are several of them,
chosen from: -OH; (C1-C4)alkoxy: for example methoxy; or (C1-C4)alkyl: for example methyl.

The pyridine nucleus can comprise from 1 to 4 R3 substituents chosen from a hydrogen
atom, a fluorine atom, a (C1-C4)alkyl group or an -NRcRd group in which Re and Rd represent
a hydrogen atom or a (C1-C4)alkyl group. R3 can be chosen from those described in Table I.
Preferably, R3 is in the 5 and/or 6 position on the pyridine nucleus. Preferably, the number of
R3 substituents is equal to 1 and/or R3 is in the 5 or 6 position on the pyridine nucleus, as is
represented below:

R3 is more preferably still in the 6 position. Preferably, R3 represents a hydrogen atom or
-NH2.
L represents a -CH=CH- or-(CH2)nNH- group in which the NH group is attached to the C=0
and n is an integer having the value 0, 1 or 2. Preferably, n is equal to 1. L can be one of
those described in Table I. Preference is also given, in the case where L represents the
-CH=CH- group, to the E isomers rather than the Z isomers.
Z and Z' represent N or CH. For example, Z and Z' can respectively represent N and CH, CH
and CH or N and N:


x is an integer having the value 1 or 2, representing the number of fluorine atom(s) attached
to the central phenyl nucleus. More particularly, x has the value 1.
The subgroup of formula (I1):

in which R1, R'1, R2, R3 and x are as defined above, is singled out.

in which R1 represents a (C1-C4)alkyl group, R2 represents a (C1-C6)alkyl group optionally
substituted by the -NRaRb group in which Ra and Rb form, together with the nitrogen atom to
which they are connected, the (C4-C6)heterocycloalkyl group optionally comprising, in the
ring, the -S(O)q- group with q= 0, 1 or 2 or the -NH- or -N(C1-C4 alkyi)- group and R3 and x
are as defined above, is singled out. More particularly, x has the value 1. More particularly
still, x has the value 1 and the fluorine atom is in the 3 position.
Mention may be made, among the compounds which are subject-matters of the invention, of
those in Table I.
The compounds of the invention, including the compounds given in the examples, can exist in
the form of bases or of addition salts with acids. Such addition salts also come within the
invention. These salts are advantageously prepared with pharmaceutically acceptable acids
but the salts of other acids, for example of use in the purification or isolation of the

compounds, also come within the invention. The compounds according to the invention can
also exist in the form of hydrates or solvates, namely in the form of combinations or
associations with one or more molecules of water or with a solvent. Such hydrates and
solvates also come within the invention.
The compounds can comprise one or more asymmetric carbon atoms. They can thus exist in
the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and
their mixtures, come within the invention.
According to the present invention, the N-oxides of the compounds comprising an amine or a
nitrogen atom also come within the invention.
According to a 2nd aspect, a subject-matter of the invention is the process for the
preparation of the compounds of the invention and some of the reaction intermediates.
Preparation of the compounds of formula (I) or (Y) for which L = -(CH2)nkNH-
These compounds can be prepared according to one of the following schemes 1-3.

A coupling of Suzuki type of P1 and P2 is carried out. Hal represents a halogen atom
(chlorine, bromine, iodine). The coupling is carried out in the presence of a palladium (in the
(O) or (II) oxidation state) complex in a basic medium. The complex can, for example, be
Pd(PPh3)4, PdCI2(PPh3)2, Pd(OAc)2, PdCI2(dppf) or bis[di(tert-butyl)(4-dimethylaminophenyl)-
phosphine]dichloropalladium(ll). The most frequently used complexes are palladium(O)
complexes. The base can, for example, be K2CO3, NaHCO3, Et3N, K3PO4, Ba(OH)2, NaOH,
KF, CsF, Cs2CO3, and the like. The coupling can be carried out in a mixture of an ethereal
solvent and of an alcohol, for example a dimethoxyethane (DME)/ethanol mixture; it can also
be a toluene/water mixture. The temperature is between 50 and 120°C. The reaction time
can, in some cases, be lengthy (see Ex.1.3.).

Further details on Suzuki coupling, on the operating conditions and on the palladium
complexes which can be used will be found in: N.Miyaura and A.Suzuki, Chem. Rev. 1995,
95, 2457-2483; A.Suzuki in "Metal-catalyzed cross-coupling reactions"; Diederich, F. and
Stang, P.J., Editors, Wiley-VCH; Weinhein, Germany, 1998, chap. 2, 49-97; Littke, A. and Fu,
G., Angew. Chem. Int. Ed., 1999, 38, 3387-3388 and Chemler, S. R. Angew.Chem.lnt.Ed.,
2001,40,4544-4568.
K and K' represent a hydrogen atom, an alkyl group or an aryl group which are optionally
connected to one another to form, together with the boron atom and the two oxygen atoms, a
5- to 7-membered ring optionally substituted by at least one (C1-C4)alkyl group or to which is
optionally fused, over two consecutive carbon atoms on the said ring, a phenyl group. For
example, use may be made of one of the following groups:

According to Scheme 2, a Suzuki coupling (see above) is carried out between P1 and P3, in
order to obtain P4, and then P4 is reacted with P5 in the presence of an agent which makes it
possible to introduce the "C=O" unit (for example phosgene, triphosgene or N,N'-
disuccinimidyl carbonate DSC). The reaction which makes it possible to introduce "C=O" is
preferably carried out in the presence of a base, such as, for example, triethylamine, and at a
temperature of between -5°C and ambient temperature. The solvent can be THF. See Ex.1.4.


According to Scheme 3, the compound of formula (I) is obtained by an amidation reaction
starting from P6 and the amine R2NH2 or a salt of this amine, for example hydrochloride (see
Ex.3.2). The amidation can advantageously be earned out in the presence of an acid activator
(also known as coupling agent), such as, for example, (benzotriazol-1-
yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33-6,
see also B.Castro and J.R. Dormoy, Tetrahedron Letters, 1975, 16, 1219). The reaction is
preferably carried out in the presence of a base (such as triethylamine) at ambient
temperature in a solvent, such as tetrahydrofuran (THF) or dimethylformamide (DMF).
P6 is, for its part, obtained by a coupling reaction of Suzuki type between P2 and the
compound P8 of formula:

P8 is obtained from the acid P7 by monosubstitution by an amine of formula R-iR'iNH. In the
case of an aliphatic amine, the reaction can be carried out at ambient temperature and in a
protic solvent, such as an alcohol or water, or in an aprotic solvent, such as THF. In the case
of an aniline, a strong base, such as, for example, LiHMDS (((CH3)3Si)2NLi), is added, and
the reaction is carried out under hot conditions. The monosubstitution is described on
pages 14 and 15 of FR 2917412, in the case where Z=N and Z'=CH, but can be applied to
other Z/Z' combinations. See also Ex.1.1.

Z=N, Z'=CH: P7 is a 2,6-dihalonicotinic acid, for example 2,6-dichloronicotinic acid, which
is commercially available (see Ex. 1.1);
Z=N, Z'=N: P7 is a 2,4-dihalopyrimidinecarboxylic acid, for example 2,4-
dichloropyrimidinecarboxylic acid, which is commercially available (CAS No. 37131-89-8);
Z=CH, Z'=CH: P7 is a 2,4-dihalobenzoic acid, for example 2,4-dichlorobenzoic acid, which
is commercially available (CAS No. 50-84-0).
In the case where Z and T both represent N and Hal represents a chlorine atom, Pa can also
be obtained from the commercial compound 2,4-dichloro-5-pyrimidinecarboxylic acid ethyl
ester:

Scheme 5, which uses an ester functional group subsequently converted to an acid
functional group, also applies to the case where Z=N and Z'=CH: see the conditions in
Chem.Pharm.Bull., 2000, 48(12), 1847-1853 (reactions of Tables 1 and 2).
Pi is obtained from the acid P8 by amidation using the amine R2NH2 or a salt of this amine,
for example the hydrochloride. The amidation can advantageously be carried out in the
presence of an acid activator (also known as coupling agent), such as, for example,
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (or BOP,
CAS No. 56602-33-6, see also Castro, B. and Dormoy, J.R., Tetrahedron Letters, 1975, 16,
1219). The reaction is preferably carried out in the presence of a base (such as triethylamine)
at ambient temperature in a solvent, such as tetrahydrofuran (THF) or dimethylformamide
(DMF). See Ex.1.2.
preparation of P%
The compounds P3 for which K and K' form the following group are commercially
available or can be prepared according to the coupling reaction between a fluorinated
bromoaniline and bis(pinacolato)diboron which is described in Scheme 2 on pages 150-151
of WO 2007/064931: 3-F (4-amino-3-fluorophenylboronic acid pinacol ester, CAS No.

819058-34-9, Boron Molecular Inc., PO Box 12592, Research Triangle Park, NC 27709); 2-F
(4-amino-2-fluorophenylboronic acid pinacol ester, CAS No. 819057-45-9, Boron Molecular,
described on page 185 of WO 2007/064931); 2-F, 5-F (CAS No. 939807-75-7, compound
described on page 184 of WO 2007/064931); 3-F, 5-F (CAS No. 939968-08-8, described on
page 182 of WO 2007/064931).
The compounds P3 for which K and K' represent a hydrogen atom can be prepared from the
fluorinated bromoaniline by the reactions described in Tetrahedron Letters, 2003, 44, 7719-
7722.
preparation of P?
The compounds P2 are obtained from the compounds P3 and P5 in the presence of an agent
which makes it possible to introduce the "C=O" unit, according to a reaction as described
above.
compounds R?NH?
The amines R2NH2 are commercial products or products already described in published
documents; for example:
• 1-(2-aminoethyl)piperidine: CAS No. 27578-60-5, described in Justus Liebigs Annalen der
Chemie, 1950, 566, 210-44, sold by ACROS;
• 1-piperidinepropanamine: CAS No. 3529-08-6, described in Bioorganic & Med. Chem. Lett.,
2006, 16(7), 1938-1940;
• 1-piperidinebutanamine: CAS No. 74247-30-6, described in Bioorganic & Med. Chem. Lett.,
2006, 16(7), 1938-1940;
• 1-(2-aminoethyl)-4-piperidinol: CAS No. 129999-60-6, described in J. Med. Chem., 2005,
48(21), 6690-6695, and on page 17 of WO 2005/061453 (ref. Ex. 10);
• 1-(2-aminoethyl)-3-piperidinol: CAS No. 847499-95-0, described in J. Med. Chem., 2005,
48(21), 6690-6695, and on page 16 of WO 2005/061453 (ref. Ex. 8);
• 2-(4-methoxy-1-piperidinyl)ethylamine: CAS No. 911300-69-1, described in J. Med. Chem.,
2007, 50(20), 4818-4831;
• pyrrolidineethanamine: CAS No. 7154-73-6, described in Anales de Quimica, 1974, 70(9-
10), 733-737, sold by International Laboratory Ltd, 1067 Sneath Ln, San Bruno, CA94066,
USA;
• 1-piperazineethanamine: CAS No. 140-31-8, described in EP 151232;

• azepan-1-ylethylamine: CAS No. 51388-00-2, described in Anales de Quimica, 1974, 70(9-
10), 733-737;
• 2-(1,1-dioxothiomorpholin-4-yl)ethylamine: CAS No. 89937-52-0, sold by Intern. Lab. Ltd;
• N-(2-aminoethyl)thiamorpholine 1-oxide: CAS No. 1017791-77-3, sold by Sinova Inc.,
3 Bethesda Metro Center, Suite 700, Bethesda, MD, 20814, USA.
A method for producing compounds in which R2 represents a (C1-C6)alkyl group substituted
by the -NRaRb group in which Ra and Rb form, together with the nitrogen atom to which they
are connected, the (C4-C6)heterocycloalkyl group optionally comprising, in the ring, the -
S(O)q- group with q= 0, 1 or 2 or the -NH- or -N(C1-C4 alkyl)- group is described in Scheme
6, which takes its inspiration from Scheme 3 of Bioorg. Med. Chem., 2007, 15, 365-373 or
from Scheme 2 of Bioorg. Med. Chem. Lett., 2008, 18,1378-1381:

Another method, described in Scheme 6', takes its inspiration from Figure 2 of Bioorg. Med.
Chem. Lett., 2006, 16,1938-1940:

compounds P*
Ps can be either commercially available or prepared according to the methods known to a
person skilled in the art. Use may be made, for example, of the hydrogenation of the cyano
compound in order to obtain P5 with n=1:

The hydrogenation conditions may be those described in Ex.19 and 20 of WO 00/46179 or in
Synlett., 2001, 10,1623-1625.

The compounds 3-picolylamine (CAS No. 3731-52-0), 3-(2-aminoethyl)pyridine (CAS No.
20173-24-4), 2-amino-5-aminomethylpyridine (CAS No. 156973-09-0), 2-methyl-5-
aminomethylpyridine (CAS No. 56622-54-9), 3-methyl-5-aminomethylpyridine (CAS
No. 771574-45-9), 2-(BOC-amino)-5-(aminomethyl)pyridine (CAS No. 187237-37-2) and 2,5-
diaminopyridine (CAS No. 4318-76-7) are commercial products. 2-Amino-5-
aminomethylpyridine can also be prepared according to EP 0607804. 5-Aminomethyl-2-
(dimethylamino)pyridine (CAS No. 354824-17-2) is commercially available or can be
prepared according to J. Agr. Food Chem., 2008, 56(1), 204-212. 2-Amino-3-methyl-5-
aminomethylpyridine (CAS No. 187163-76-4) can be obtained by catalytic hydrogenation of
the compound 6-amino-5-methylnicotinonitrile (CAS No. 183428-91-3), the amine functional
group being doubly protected by BOC. The catalytic hydrogenation of 6-methylamino-3-
pyridinecarbonitrile (CAS No. 261715-36-0) makes possible access to 2-methylamino-5-
aminomethylpyridine.
The preparation of 5-aminomethyl-2-(dimethylamino)pyridine (CAS No. 779324-37-7) and of
5-aminomethyl-2-(dimethylamino)pyridine (CAS No. 354824-17-2) in the hydrochloride form
is also described on page 106 of WO 2007/044449 (Ex. 207 and 208).
Preparation of the compounds of formula (I) in which L = -CH=CH-
These compounds are obtained by an amidation reaction between P4 and the acid Pi0 or the
acyl halide P'10 derived from P10. The amidation using P10 can advantageously be carried out
in the presence of an acid activator, such as, for example, BOP.

P10 can be either commercially available or prepared according to the methods known to a
person skilled in the art. For example, trans-3-(3-pyridyl)acrylic acid is sold by Sigma-Aldrich.
(6-Aminopyridin-3-yl)acrylic acid (CAS No. 234098-57-8; compound E: CAS No. 167837-43-
6) is described in J. Med. Chem., 2002, 45(15), 3246-3256 (see Scheme 4). P10 can be
prepared from a bromoaniline and acrylic acid according to the teaching of J. Med. Chem.,
2002, 45(15), 3246-3256. Use may also be made of a coupling using a bromoaniline and an
alkyl acrylate and then the ester functional group can be saponified to give the acid functional
group (see, in this connection, the method which makes it possible to prepare (6-

aminopyridin-3-yl)acrylic acid described in section [483] of US 2008269220 or [354] of
EP1726580).
P10 can also be prepared according to J. Org. Chem., 1998, 63, 8785-8789, from the
corresponding (3-formylpyridine or else according to J. Med. Chem., 1989, 32(3), 583-93 from
2-chloro-5-nitropyridine. The acyl halide P'10 is obtained by a reaction known to a person
skilled in the art from the acid P10 and an acylating agent, such as, for example, SOCI2 or
(COCI)2.
These compounds can also be prepared according to the following scheme 8:
Scheme 8

According to Scheme 8, P4 is reacted with acryloyl chloride in the presence of a base,
such as, for example, triethylamine, and at a temperature of between 0°C and ambient
temperature, in order to produce Pn. The solvent can be dichloromethane (DCM) (see
Ex. 4.1).
Pn is then reacted with P12 (Hal represents a halogen atom) in the presence of a
palladium complex, such as, for example, Pd(OAc)2, tri(ortho-tolyl)phosphine and a base,
such as, for example, diisopropylethylamine. The solvent can, for example, be
propionitrile. The temperature is between ambient temperature and the reflux
temperature of the solvent.

Protection of the primary or secondary amine functional group
It may be necessary to use, in at least one of the stages, a protective group (PG) in order to
protect one or more chemical functional group(s), in particular a primary or secondary amine
functional group. For example, when Ra and Rb both represent a hydrogen atom, the
amidation of Scheme 3 is carried out using, for R2NH2, the compound 2HN-(C1-C6)alkyl-NH-
PG, where PG advantageously represents BOC (tert-butoxycarbonyl). Likewise, when the
heterocycloalkyl group formed by Ra and Rb represents the piperazinyl group, the
-NH- functional group thereof can advantageously be protected using the following
compound R2NH2 where PG advantageously represents BOC.
Likewise, when R3 represents the -NH2 or -NHRC group, the amine functional group can
advantageously be protected by one or two PG group(s), preferably BOC or FMOC (9-
fluorenylmethyl carbamate). Use may be made, for example, of the following compound P5:

The chemical functional group(s) is/are subsequently obtained by a stage of deprotection
(final or intermediate), the conditions of which depend on the nature of the functional group(s)
protected and on the protective group used. Reference may be made to "Protective Groups in
Organic Synthesis" by T.Greene, Wiley, 4th ed., ISBN = 978-0-471-69754-1, in particular to
chap. 7 as regards the protective groups for the amine functional group. In the case of the
protection of the -NH2 or -NH- functional groups by BOC, the deprotection stage is carried
out in an acidic medium using, for example, HCI or trifluoroacetic acid (TFA). Thus, if
appropriate, the associated salt (hydrochloride or trifluoroacetate) is obtained.
Preparation of the salts
The salts are obtained during the deprotection stage described above or else by bringing the
acid into contact with the compound in its base form.

In the preceding Schemes, the starting compounds and the reactants, when their method of
preparation is not described, are commercially available or are described in the literature or
else can be prepared according to methods which are described therein or which are known
to a person skilled in the art. A person skilled in the art may also take his inspiration from the
operating conditions given in the examples which are described below.
Preparation of the N-oxides
The N-oxides of the compounds comprising an amine or a nitrogen atom are prepared
according to the methods known to a person skilled in the art by reaction of the amine with
organic peracids, such as peracetic acid, trifluoroperacetic acid, performic acid, perbenzoic
acid or the derivatives of perbenzoic acid, such as 3-chloroperbenzoic acid, at temperatures
of between 0°C and 90°C, preferably at temperatures of less than 50°C.
According to a 3rd aspect, the invention relates to a pharmaceutical composition comprising
a compound as defined above in combination with a pharmaceutically acceptable excipient.
The excipient is chosen from the normal excipients known to a person skilled in the art
according to the pharmaceutical form and the method of administration desired. The method
of administration can, for example, be orally or intravenously.
According to a 4th aspect, a subject-matter of the invention is a medicament which
comprises a compound as defined above and the use of a compound as defined above in the
manufacture of a medicament. It may be of use in treating a pathological condition, in
particular cancer. The medicament (and a compound according to the invention) can be
administered in combination with one (or more) anticancer drug(s). This treatment can be
administered simultaneously, separately or else sequentially. The treatment will be adjusted
by the practitioner according to the patient and the tumour to be treated.
According to a 5th aspect, the invention also relates to a method for the treatment of the
pathologies indicated above which comprises the administration, to a patient, of an effective
dose of a compound according to the invention or one of its salts, the salts being
pharmaceutically acceptable, or hydrates or solvates.
[Examples]
The following examples illustrate the preparation of some compounds in accordance with the
invention. The numbers of the compounds given in the examples refer to those given in the

table below, in which the chemical structures and the physical properties of a few compounds
according to the invention are illustrated.
In the examples, the following abbreviations are used:
AcOEt: ethyl acetate
MeOH: methanol
DIPEA: diisopropylethylamine
The compounds were analysed by coupled HPLC-UV-MS (liquid chromatography, ultraviolet
(UV) detection and mass detection). The device used is composed of an Agilent
chromatographic sequence equipped with an Agilent diode array detector and with a Waters
ZQ single quadrupole mass spectrometer or a Waters Quattro-Micro triple quadrupole mass
spectrometer.
The compounds were analysed by coupled HPLC-UV-MS (liquid chromatography, ultraviolet
(UV) detection and mass detection). The device used is composed of a chromatographic
sequence equipped with a diode array detector (Agilent HP1110 or Waters Acquity UPLC)
and with a quadrupole mass spectrometer (Waters ZQ, QM or SQD).
Mass spectrometry conditions
The liquid phase chromatography/mass spectrometer (LC/MS) spectra were recorded in
positive electrospray (ESI) mode, in order to observe the ions resulting from the protonation
of compounds analysed (MH+) or from the formation of adducts with other cations, such as
Na+, K+, and the like. The HPLC conditions are chosen from one of the following methods:


NMR conditions
The 1H NMR spectra are recorded on a Bruker Avance 250/Bruker Avance 400 or Bruker
Avance II 500 spectrometer. The central peak of the d6-DMSO (2.50 ppm) is used as internal
reference. The following abbreviations are used: s: singlet; d: doublet; dd: split doublet;
t: triplet; q: quartet; m: broad unresolved peak/multiplet; br.s: broad signal.
Example 1: 6-(4-r3-(6-aminopvridin-3-vimethvnureido1-3-fluorophenvl)-2-ethvlamino-N-
r2-(piperidin-1-vl)ethvnnicotinamide (compound No. 1 prepared according to Scheme
21

1.1. 6-Chloro-2-(ethylamino)nicotinic acid
26.1 g (0.136 mol) of 2,6-dichloronicotinic acid and 180 ml of 70% aqueous ethylamine
solution are mixed in a round-bottom flask. The mixture is stirred at ambient temperature (AT)
for 5 days. It is evaporated under reduced pressure (RP). The residue is taken up in 100 ml of
water. The solution is cooled with an ice bath and acidified to pH 3 with a 5N HCI solution.
The precipitate is filtered off, washed with cold water and dried under vacuum over P205 at
60°C. 24.93 g (91.4%) of white solid are obtained. M.p. = 157-159°C.
1.2. 6-Chloro-2-ethvlamino-N-r2-(piperidin-1-vl)ethvnnicotinamide
5.0 g (24.92 mmol) of 6-chloro-2-(ethylamino)nicotinic acid are dissolved in 300 ml of THF in
a round-bottom flask. 10.41 ml (74.77 mmol) of triethylamine, then 7.08 ml (49.84 mmol) of
1-(2-aminoethyl)piperidine and subsequently 11.02 g (24.92 mmol) of BOP are added. The
mixture is stirred at AT for 15 h. The solvent is evaporated and the residue is taken up in ethyl
acetate. The organic phase is washed with water and then with a saturated NaCI solution. It
is dried over Na2S04, filtered and evaporated. The residue is purified by flash
chromatography (1 to 10% DCM-MeOH gradient). 7.5 g are obtained (yd: 96.8%). LCMS: M+
310, rt (retention time)=1.01 min.

1.3.6-(4-Amino-3-fluorophenvl)-2-ethvlamino-N-r2-(piperidin-1 -vltethvUnicotinamide
5 g (16.1 mmol) of 6-chloro-2-ethylamino-N-[2-(piperidin-1-yl)ethyl]nicotinamide are
introduced into a 1 litre three-necked flask. 4-Amino-3-fluorophenylboronic acid pinacol ester
(1.1 eq., 4.2 g), 300 ml of 1,2-dimethoxyethane, 60 ml of ethanol and 120 ml of a saturated
NaHCO3 solution are added. Argon is bubbled in for 15 min and then palladiumtetrakis
Pd(PPh)4 (0.1 eq., 1.86 g) is added. The mixture is heated at reflux (~100°C) for 16 h. The
mixture is concentrated, the residue is taken up in DCM and the organic phase is washed
with H20, twice, and H20/NaCI, dried over sodium sulphate and concentrated. The product is
subjected to flash chromatography on a column of silica, 400 g, 99/1 to 90/10 DCM/methanol
gradient. 4.8 g (yd=78%) of 6-(4-amino-3-fluorophenyl)-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide are obtained. LCMS(TFA3): MH+ 386, rt=0.90 min.
1.4. 6-(4-r3-(6-Aminopvridin-3-vlmethvnureido1-3-fluorophenvl)-2-ethvlamino-N-r2-
(piperidin-1-vDethvnnicotinamide

3.5 g (9.1 mmol) of 6-(4-amino-3-fluorophenyl)-2-ethylamino-N-[2-(piperidin-1-yl)ethyl]-
nicotinamide are dissolved in 300 ml of anhydrous THF in a 1 litre round-bottom flask. DMAP
(1.2 eq., 1.33 g) and N,N'-disuccinimidyl carbonate ([74124-79-1], 1.2 eq., 2.8 g) are added.
The mixture is stirred at AT for 5 h. Triethylamine (3 eq., 3.8 ml) and 2-[di(boc)amino]-5-
(aminomethyl)pyridine (1.2 eq., 3.53 g) are then added and the mixture is stirred overnight at
AT. The mixture is concentrated. The residue is taken up in DCM and the organic phase is
washed with H20, twice, and H20/NaCI, dried and concentrated. The residue is subjected to
flash chromatography on silica, 95/5 to 79/20 DCM/MeOH gradient + 1% of 20% NH4OH.
After concentrating, the fraction thus obtained is taken up in 200 ml of DCM and then 35 ml
(50 eq.) of TFA are added under cold conditions. The mixture is stirred at AT until the
"di(boc)amino" product has disappeared. The mixture is concentrated and then the residue is
taken up in a 10% Na2CO3 solution. The organic phase is extracted with DCM and
concentrated. The residue is crystallized from ethyl acetate under hot conditions. The product
is filtered off, rinsed with AcOEt and dried in an oven. 3 g (yd=63%) of 6-{4-[3-(6-
aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide are obtained. LCMS(TFA3): MH+ 535, rt=0.79 min; 1H NMR (250 MHz,
d6-DMSO) 8 ppm 1.22 (t, 3 H), 1.29 - 1.68 (m, 6 H), 2.26 - 2.47 (m, 6 H), 3.28 -3.42 (m, 2 H),

3.43 - 3.62 (m, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 6.97 (t, 1 H), 7.16 (d, 1 H),
7.35 (dd, 1 H), 7.79 - 8.07 (m, 4 H), 8.28 (t, 1 H), 8.33 - 8.46 (m, 2 H), 8.49 (s, 1 H). M.p.
(melting point) = 175-177°C.
Example 2: 6^4-r3-f6-Aminopvridin-3-vlmethvl)ureido1-3-fluorophenvl)-2-ethylamino-N-
(2-hvdroxvethvl)nicotinamide (compound No. 8 prepared according to Scheme 1)
2.1.6-Chloro-2-(ethvlamino)-N-(2-hvdroxvethvl)nicotinamide

0.5 g (2.49 mmol) of 6-chloro-2-(ethylamino)nicotinic acid is dissolved in 30 ml of THF.
1.04 ml (0.76 mmol) of triethylamine, 0.304 g (4.98 mmol) of 2-hydroxyethylamine and 1.10 g
(2.49 mmol) of BOP are added. The mixture is stirred at AT for 70 h. The solvent is
evaporated and the residue is taken up in ethyl acetate; the organic phase is washed with
water and then with a saturated NaCI solution. It is dried over Na2S04, filtered and
evaporated. The residue is purified by flash chromatography (DCM/MeOH 1-5%). 600 mg
(yd=99%) are obtained. LCMS(TFA3): MH+ 244, rt=1.03 min.
2.2. Di(terf-butvni5-r((r2-fluoro-4-(4.4.5.5-tetramethvl-1.3.2-dioxaborolan-2-
v0phenvl1carbamovl)amino)methvllpvridin-2-vl)imidodicarbonate

5.0 g (21.09 mmol) of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and
3.09 g (25.31 mmol) of DMAP (4-dimethylaminopyridine) are dissolved in 500 ml of THF.
6.48 g (23.31 mmol) of DSC are added and the mixture is stirred at AT for 18 h. 8.81 ml
(63.27 mmol) of triethylamine and 8.18 g (23.31 mmol) of di(terf-butyl)
[5-(aminomethyl)pyridin-2-yl]imidodicarbonate are added. The mixture is stirred at AT for 5 h.
The solvent is evaporated and the residue is taken up in DCM. The organic phase is washed
with water and then with a saturated NaCI solution. It is dried over sodium sulphate, filtered
and evaporated. The residue is purified by flash chromatography. 12 g of product composed
of a 50/50 mixture of pinacolic ester and of boronic acid are obtained. LCMS(LS) MH+ 587,
rt=6.17 min, and MH+ 505, rt=4.97 min.

2.3. DMterf-butvn r5-(n(4-f6-(ethvlamino)-5-r(2-hvdroxvethvncarbamovnpvridin-2-vlV2-
fluorophenvncarbamovnamino)methvl)pyridin-2-vnimidodicarbonate

0.3 g (1.23 mmol) of compound obtained in stage 2.1, 0.794 g (1.35 mmol) of compound
obtained in stage 2.2, 15 ml of saturated NaHCO3 solution, 38 ml of DME and 7 ml of ethanol
are placed in a three-necked flask. The mixture is degassed with argon and then 0.142 g
(0.12 mmol) of Pd(PPh3)4 is added. The mixture is heated at reflux for 6 h. The solvents are
evaporated and the residue is taken up in DCM. The organic phase is washed with water and
then with a saturated NaCI solution. It is dried over Na2S04, filtered and evaporated. The
residue is purified by flash chromatography (DCM/MeOH 0-15%). 600 mg (yd=73%) are
obtained. LCMS(TFA3): MH+ 668, rt=1.44 min.
2.4. 6-{4-r3-(6-Aminopvridin-3-vlmethvl)ureido1-3-fluorophenvl)-2-ethvlamino-N-(2-
hvdroxvethvOnicotinamide

0.6 g (0.9 mmol) of the compound obtained in stage 2.3 is dissolved in 20 ml of DCM. The
solution is cooled with an ice bath and 2.08 ml (27 mmol) of TFA are added. The mixture is
stirred at AT for 18 h. The solvents are evaporated and the residue is taken up in an Na2CO3
solution. The product is filtered off, rinsed with water and dried in an oven over P2O5. 200 mg
(yd= 47.6%) are obtained. LCMS(TFA3): MH+ 468, rt=0.72 min; 1H NMR (250 MHz, d6-
DMSO) 8 ppm 1.22 (t, 3 H), 3.31 (s, 2 H), 3.43 - 3.62 (m, 4 H), 4.13 (d, 2 H), 4.71 (t, 1 H),
5.83 (s, 2 H), 6.44 (d, 1 H), 6.97 (t, 1 H), 7.16 (d, 1 H), 7.35 (dd, 1 H), 7.78 - 7.98 (m, 3 H),
8.01 (d, 1 H), 8.28 (t, 1 H), 8.34 - 8.47 (m, 2 H), 8.49 (d, 1 H).
Example 3: 6-(4-f3-(6-Aminopvridin-3-vlmethvl)ureido1-3-fluorophenyl)-N-r2-(azepan-1 -
vl)ethvll-2-(ethvlamino)nicotinamide (compound No. 15 prepared according to Scheme
31
3.1. 6-(44r((6-rBisfte/t-butoxvcarbonvnamino1pvridin-3-vl)methvncarbamovnaminoV3-
fluorophenyl)-2-(ethvlamino)nicotinicacid


1.2 g (5.98 mmol) of 6-chloro-2-(ethylamino)nicotinic acid, 3.86 g (6.58 mmol) of di(terf-butyl)
{5-[({[2-fluoro^-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl}amino)methyl]-
pyridin-2-yl}imidodicarbonate, 80 ml of DME, 15 ml of ethanol and 40 ml of saturated
NaHCO3 solution are placed in a three-necked flask. The mixture is degassed with argon and
then heated at reflux for 18 h. The solvents are evaporated and the residue is taken up in
water. The product is filtered off, rinsed with water and dried in an oven over P205. It is
purified by flash chromatography, DCM/MeOH 1-20%. 1.8 g of a mixture of mono- and
di(BOC) compounds are obtained. LCMS(LS) MH+ 525, rt=4.60 min, and MH+ 625, rt=5.59
min.
3.2. 6«{4-r3-(6-Aminopvridin-3-vlmethvl)ureidol-3-fluorophenvl>-N-r2-(azepan-1-vl)ethvn-
2-(ethylamino)nicotinamide

0.2 g (0.32 mmol) of the compound obtained in stage 3.1 is dissolved in 30 ml of THF.
0.115 g (0.64 mmol) of 2-(azepan-1-yl)ethanamine hydrochloride, 0.18 ml (0.13 mmol) of
triethylamine and 0.142 g (0.32 mmol) of BOP are added. The mixture is stirred at AT for
18 h. It is evaporated, the residue is taken up in DCM and the organic phase is washed with
water and then with a saturated NaCI solution. It is dried over Na2S04, filtered and
evaporated. The residue is purified by flash chromatography, DCM/MeOH 0-10%. 0.250 g of
a mono- and di(BOC) mixture is obtained. This product is dissolved in 15 ml of DCM, the
solution is cooled with an ice bath and 0.5 ml of TFA is added. The mixture is stirred at AT for
18 h. It is evaporated and the residue is taken up in an Na2CO3 solution. The precipitate is
filtered off, washed with water and dried in an oven over P205. 0.13 g (yd=74%) is obtained.
LCMS (TFA3) MH+ 549, rt=0.85 min; 1H NMR (400 MHz, d6-DMSO) 5D ppm 1.22 (t, 3 H),
1.56 (m, 8 H), 2.67 (m, 6 H), 3.32 (m, 2 H), 3.45 - 3.63 (m, 2 H), 4.13 (d, 2 H), 5.84 (s, 2 H),
6.43 (d, 1 H), 6.97 (t, 1 H), 7.15 (d, 1 H), 7.34 (d, 1 H), 7.83 -8.00 (m, 4 H), 8.27 (t, 1 H), 8.35
(t, 1 H), 8.41 (t, 1 H), 8.49 (s, 1 H).

Example 4: 6444(E)-3-(6-Aminopvridin-3-vl)acrvlovlamino1-3-fluorophenvl}-2-
ethylamino-N-r2-(piperidin-1-v0ethvnnicotinamide (compound No. 43 prepared
according to Scheme 8)
i
4.1. 6-(4-Acrvlovlamino-3-fluorophenvl)-2-ethvlamino-N-r2-(piperidin-1-vl)ethvn-
nicotinamide
0.385 g (1 mmol) of the compound obtained in stage 1.3 is dissolved in 20 ml of DCM.
0.28 ml (2 mmol) of triethylamine and 0.111 g (1.1 mmol) of DMAP are added, followed by
0.2 ml (2.2 mmol) of acryloyl chloride. The mixture is stirred at ambient temperature for 18 h.
The solvents are evaporated and the residue is taken up in DCM. The organic phase is
washed with an Na2CO3 solution and then with a saturated NaCI solution. It is dried over
sodium sulphate and filtered and then the filtrate is evaporated. The residue is purified by
flash chromatography (95/5/0.2 DCM/CH3OH/20% NH4OH). 0.195 g (44.4%) is obtained.
LCMS (TFA3) MH+ 440, rt = 2.44 min.
4.2. 6-(4-r(E)-3-(6-Aminopvridin-3-vl)acrvlovlamino1-3-fluorophenvl>-2-ethvlamino-N-
r2-(piperidin-1-v0ethyrinicotinamide
0.187 g (0.43 mmol) of the compound obtained in stage 4.1 is dissolved in 15 ml of
propionitrile. 0.074 g (0.43 mmol) of 2-amino-5-bromopyridine and 0.11 ml (0.64 mmol) of
DIPEA are added. The mixture is degassed with argon for 30 minutes and then 0.01 g
(0.04 mmol) of Pd(OAc)2 and 0.022 g (0.07 mmol) of tri(ortho-tolyl)phosphine are added. The
mixture is brought to reflux for 3 h. After returning to ambient temperature, the mixture is
diluted with DCM and filtered through a Whatman filter. The filtrate is evaporated and the

residue is purified by flash chromatography, 85/15/0.2 DCM/CH3OH/20% NH4OH. 0.120 g
(53%) is obtained.

0.25 g (0.65 mmol) of the compound obtained in stage 1.3 is dissolved in 20 ml of DCM, and
0.27 ml (1.95 mmol) of triethylamine is added. The reaction medium is cooled in an ice bath
and 0.163 g (0.97 mmol) of (E)-3-(pyridin-3-yl)acryloyl chloride is added dropwise. Stirring is
carried out at ambient temperature for 18 h. The organic solution is washed with a 10%
NaOH solution, dried over Na2S04 and filtered and the filtrate is evaporated. The residue is
purified by flash chromatography, Si02, C18, CH3OH/H20 50/50 - 90/10. 0.035 g (10.4%) is
obtained.
Example 6: 6-{4-r3-(6-Aminopvridin-3-vlmethvl)ureido1-3-fluorophenvl)-2-ethylamino-N-
T2-(1-oxvpiperidin-1-vl)ethvnnicotinamide (compound No. 45)


6.1. f5-f3-(4-l6-Ethvlamino-5-r2-(1 -oxypiperidin-1 -vl)ethvlcarbamovllpyridin-2-vD-2-
fluorophenvl)ureidomethvllpyridin-2-vl)carbamic acid tert-butyl ester
0.35 g (0.55 mmol) of [5-(3-{4-[6-ethylamino-5-(2-(piperidin-1-yl)ethylcarbamoyl)pyridin-2-yl]-
2-fluorophenyl}ureidomethyl)pyridin-2-yl]carbamic acid tert-butyl ester is suspended in 35 ml
of DCM and 10 ml of CHCI3. The suspension is cooled with an ice bath and 0.105 g (0.61
mmol) of meta-chloroperbenzoic acid is added. The mixture is stirred under cold conditions
for 0.5 h and then at ambient temperature for 2 h. The organic phase is washed with an
NaHCO3 solution, then with H20 and then with a saturated NaCI solution. It is dried over
Na2S04, filtered and evaporated. The residue is purified by flash chromatography on neutral
Al203, DCM/CH3OH - 98/2 to 92/8. 0.340 g (94.7%) is obtained. LCMS (TFA3) MH+ 651, it =
2.07 min.
6.2. 6-f4-r3-(6-Aminopvridin-3-vlmethvl)ureido1-3-fluorophenyl)-2-ethvlamino-N-r2-(1-
oxypiperidin-1-vl)ethvnnicotinamide
0.328 g (0.5 mmol) of the compound obtained in stage 6.1 is dissolved in 20 ml of
CH2CI2. The solution is cooled with an ice bath and 0.85 ml (11.1 mmol) of TFA is added.
The mixture is stirred at ambient temperature for 44 h. It is evaporated and the residue is
taken up in a 10% Na2CO3 solution and extracted with DCM. The organic phase is dried
over Na2S04, filtered and evaporated. The residue is purified by flash chromatography on
neutral Al203, DCM/CH3OH - 95/5 to 88/12. 0.213 g (76.9%) is obtained.
1H NMR of the compounds in Table 1
The chemical shifts 5 are given in ppm.
Compound No. 2: (400 MHz) 1.22 (t, 3 H), 1.35 - 1.81 (m, 6 H), 2.54 - 3.16 (m, 6 H), 3.45 -3.57
(m, 4 H), 4.13 (d, 2 H), 5.88 (s, 2 H), 6.44 (d, 1 H), 7.02 - 7.14 (m, 2 H), 7.35 (dd, 1 H), 7.85 - 7.92
(m, 2 H), 7.98 (d, 1 H), 8.16 (dd, 1 H), 8.35 (t, 1 H), 8.61 (br. s., 1 H), 8.75 (s, 1 H).
Compound No. 3: (250 MHz) 1.22 (t, 3 H), 1.32 - 1.60 (m, 6 H), 2.40 - 2.65 (m, 6 H), 3.29 -3.46
(m, 2 H), 3.58 (m, 2 H), 4.13 (d, 2 H), 5.84 (s, 2 H), 6.44 (d, 1 H), 7.03 (t, 1 H), 7.35 (dd, 1 H), 7.88
(d, 1 H), 8.00 - 8.19 (m, 2 H), 8.25 - 8.39 (m, 1 H), 8.50 - 8.63 (m, 2 H), 8.68 (s, 1 H), 8.75 (t, 1
H).
Compound No. 4: (250 MHz) 1.22 (t, 3 H), 1.32 - 1.60 (m, 6 H), 2.40 - 2.65 (m, 6 H), 3.29 -3.46
(m, 2 H), 3.58 (m, 2 H), 4.13 (d, 2 H), 5.84 (s, 2 H), 6.44 (d, 1 H), 7.03 (t, 1 H), 7.35 (dd, 1 H), 7.88
(d, 1 H), 8.00 - 8.19 (m, 2 H), 8.25 - 8.39 (m, 1 H), 8.50 - 8.63 (m, 2 H), 8.68 (s, 1 H), 8.75 (t, 1
H).

Compound No. 5: (250 MHz) 1.28 - 1.65 (m, 6 H), 2.32 - 2.47 (m, 6 H), 3.35 - 3.52 (m, 2 H),
4.13 (d, 2 H), 5.84 (s, 2 H), 6.44 (d, 1 H), 7.02 (t, 2 H), 7.26 - 7.52 (m, 4 H), 7.75 (d, 2 H), 7.82 -
8.04 (m, 3 H), 8.16 (d, 1 H), 8.34 (t, 1 H), 8.53 (s, 1 H), 8.69 (t, 1 H),11.06(s, 1 H).
Compound No. 6: (250 MHz) 0.97 (d, 6 H), 1.21 (t, 3 H), 1.57 (br. s., 1 H), 2.58 - 2.87 (m, 3H),
3.23 - 3.34 (m, 2 H), 3.43 - 3.61 (m, 2 H), 4.13 (d, 2 H), 5.84 (s, 2 H), 6.44 (d, 1 H), 6.99 (t, 1 H),
7.16 (d, 1 H), 7.35 (dd, 1 H), 7.80 - 8.10 (m, 4 H), 8.28 (t, 1 H), 8.34 - 8.48 (m, 2 H), 8.51 (d, 1 H).
Compound No. 7: (250 MHz) 1.22 (t, 3 H), 2.66 (t, 2 H), 2.89 - 3.17 (m, 8 H), 3.31 - 3.42 (m, 2H),
3.45 - 3.61 (m, 2 H), 4.13 (d, 2 H), 5.84 (s, 2 H), 6.44 (d, 1 H), 6.98 (t, 1 H), 7.17 (d, 1 H), 7.35
(dd,1 H), 7.83 - 8.03 (m, 4 H), 8.28 (t, 1 H), 8.34 - 8.46 (m, 2 H), 8.50 (d, 1 H).
Compound No. 9: (250 MHz) 0.49 - 0.60 (m, 2 H), 0.77 - 0.94 (m, 2 H), 1.29 - 1.57 (m, 6 H),
2.28 - 2.48 (m, 6 H), 2.99 - 3.11 (m, 1 H), 3.31 - 3.42 (m, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44
(d, 1 H), 7.03 (t, 1 H), 7.36 (dd, 1 H), 7.88 (d, 1 H), 8.05 - 8.23 (m, 2 H), 8.28 - 8.38 (m, 1 H), 8.50
- 8.64 (m, 2H), 8.69 (s, 1 H), 8.77 (d, 1 H).
Compound No. 10: (250 MHz) 1.27 - 1.70 (m, 6 H), 2.49 - 2.87 (m, 6 H), 3.40 - 3.58 (m, 2 H),
4.14 (d, 2 H), 5.84 (s, 2 H), 6.44 (d, 1 H), 7.07 (t, 1 H), 7.15 (t, 1 H), 7.36 (dd, 1 H), 7.40 - 7.50 (m,
2 H), 7.77 (d, 2 H), 7.88 (d, 1 H), 8.03 (dd, 1 H), 8.13 (dd, 1 H), 8.38 (t, 1 H), 8.63 (d, 1 H), 8.81 -
9.04 (m,2H),11.15 (s, 1 H).
Compound No. 11: (250 MHz) 1.20 (t, 3 H), 1.29 - 1.66 (m, 6 H), 2.11 - 2.47 (m, 6 H), 3.25 -3.40
(m, 2 H), 3.42 - 3.62 (m, 2 H), 4.11 (d, 2 H), 5.76 (s, 2 H), 6.43 (d, 1 H), 6.61 (br. s., 1 H), 6.97 (d,1
H), 7.12 (d, 1 H), 7.35 (d, 1 H), 7.62 (d, 1 H), 7.77 - 8.05 (m, 3 H), 8.28 - 8.48 (m, 2 H), 8.91 (s, 1
H).
Compound No. 12: (250 MHz) 1.22 (t, 3 H), 1.57 - 1.86 (m, 4 H), 2.43 - 2.52 (m, 4 H), 2.57 (t,
2H), 3.29 - 3.43 (m, 2 H), 3.43 - 3.60 (m, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 6.99 (t, 1
H), 7.15 (d, 1 H), 7.35 (dd, 1 H), 7.80 - 8.04 (m, 4 H), 8.28 (t, 1 H), 8.35 - 8.48 (m, 2 H), 8.51 (br.
s., 1 H).
Compound No. 13: (250 MHz) 1.22 (t, 3 H), 2.75 (d, 3 H), 3.43 - 3.66 (m, 2 H), 4.13 (d, 2 H), 5.83
(s, 2 H), 6.44 (d, 1 H), 6.98 (t, 1 H), 7.15 (d, 1 H), 7.35 (dd, 1 H), 7.82 - 8.04 (m, 4 H), 8.28 (t, 1 H),
8.35 - 8.62 (m, 3 H).

Compound No. 14: (250 MHz) 1.22 (t, 3 H), 3.27 (s, 3 H), 3.35 - 3.62 (m, 6 H), 4.13 (d, 2 H), 5.83
(s, 2 H), 6.44 (d, 1 H), 6.97 (t, 1 H), 7.15 (d, 1 H), 7.37 (dd, 1 H), 7.82 - 8.07 (m, 4 H), 8.28 (t, 1 H),
8.50 (br. s., 3 H).
Compound No. 16: (400 MHz) 1.22 (t, 3 H), 2.56 (t, 2 H), 2.66 - 2.75 (m, 4 H), 2.82 - 3.04 (m,
4H), 3.34 - 3.41 (m, 2 H), 3.45 - 3.60 (m, 2 H), 4.13 (d, 2 H), 5.87 (s, 2 H), 6.44 (d, 1 H), 6.99 (t, 1
H), 7.15 (d, 1 H), 7.35 (dd, 1 H), 7.82 - 7.99 (m, 4 H), 8.27 (t, 1 H), 8.34 - 8.47 (m, 2 H), 8.50 (d, 1
H).
Compound No. 17: (250 MHz) 1.22 (t, 3 H), 1.29 - 1.62 (m, 6 H), 2.04 (s, 3 H), 2.29 - 2.47 (m,
6H), 3.30 - 3.41 (m, 2 H), 3.44 - 3.60 (m, 2 H), 4.13 (d, 2 H), 5.62 (s, 2 H), 6.96 (t, 1 H), 7.16 (d, 1
H), 7.22 (s, 1 H), 7.76 (s, 1 H), 7.82 - 8.06 (m, 3 H), 8.28 (t, 1 H), 8.33 - 8.46 (m, 2 H), 8.48 (d, 1
H).
Compound No. 18: (250 MHz) 0.32 - 0.57 (m. 1 H), 0.78 (d, 6 H), 1.18 (t, 3 H), 1.35 - 1.70 (m, 5
H), 2.39 (t, 2 H), 2.79 (d, 2 H), 3.22 - 3.38 (m, 2 H), 3.41 - 3.56 (m, 2 H), 4.09 (d, 2 H), 5.78 (s, 2
H), 6.39 (d, 1 H), 6.92 (t, 1 H), 7.11 (d, 1 H), 7.30 (dd, 1 H), 7.74 - 7.98 (m, 4 H), 8.23 (t, 1 H), 8.28
- 8.42 (m, 2 H), 8.44 (d, 1 H).
Compound No. 19: (250 MHz) 1.11 (d, 6 H), 1.02 - 1.32 (m, 3 H), 1.21 (t, 3 H), 1.39 - 1.73 (m, 3
H), 2.37 - 2.51 (m, 2 H), 2.59 - 2.78 (m, 2 H), 3.11 - 3.29 (m, 2 H), 3.42 - 3.59 (m, 2 H), 4.13 (d, 2
H), 5.83 (s, 2 H), 6.44 (d, 1 H), 6.97 (t, 1 H), 7.16 (d, 1 H), 7.35 (dd, 1 H), 7.83 - 8.01 (m, 4 H), 8.28
(t, 1 H), 8.35-8.59 (m, 3 H).
Compound No. 20: (250 MHz) 0.94-1.13 (m, 4 H), 1.22 (t, 3 H), 1.30-1.68 (m, 6 H), 2.41 -2.65
(m, 6 H), 3.31 - 3.68 (m, 4 H), 5.70 (s, 2 H), 6.43 (d, 1 H), 6.67 (br. s., 1 H), 7.16 (d, 1 H), 7.29 (d,1
H), 7.73 - 8.07 (m, 4 H), 8.19 - 8.34 (m, 1 H), 8.42 (br. s., 2 H), 8.54 (s, 1 H).
Compound No. 21: (250 MHz) 1.13 (t, 3 H), 1.27 - 1.69 (m, 6 H), 2.16 - 2.47 (m, 6 H), 3.32 -3.43
(m, 4 H), 4.11 (d, 2 H), 5.81 (s, 2 H), 6.43 (d, 1 H), 6.61 - 6.82 (m, 2 H), 7.23 (d, 2 H), 7.35 (d, 1H),
7.87 (s, 1 H), 7.92 (d, 1 H), 8.27 (br. s., 1 H), 8.41 (br. s., 1 H), 9.03 (s, 1 H).
Compound No. 22: (250 MHz) 1.19 (t, 3 H), 1.30 - 1.64 (m, 6 H), 2.31 -2.50 (m, 6 H), 3.32 -3.42
(m, 2 H), 3.41 - 3.58 (m, 2 H), 4.13 (d, 2 H), 5.84 (s, 2 H), 6.44 (d, 1 H), 6.89 - 7.06 (m, 2 H), 7.35
(dd, 1 H), 7.70 - 7.83 (m, 1 H), 7.88 (d, 1 H), 7.96 (d, 1 H), 8.09 (t, 1 H), 8.35 (t, 1 H), 8.43 (t, 1 H),
8.67 (d, 1 H).

Compound No. 23: (250 MHz) 1.22 (t, 3 H), 1.33 - 1.68 (m, 6 H), 2.52 - 2.92 (m, 6 H), 3.15 -3.27
(m, 2 H), 3.34 - 3.50 (m, 2 H), 4.12 (d, 2 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 6.80 - 6.90 (m, 2 H). 6.94
(t, 1 H), 7.35 (dd, 1 H), 7.48 (d, 1 H), 7.52 - 7.66 (m, 2 H), 7.78 - 7.93 (m, 2 H), 8.13 - 8.37 (m, 2
H), 8.43 (d, 1 H).
Compound No. 24: (250 MHz) 0.39 - 0.51 (m, 2 H), 0.51 - 0.59 (m, 2 H), 0.59 - 0.75 (m, 2 H),
0.75 - 0.90 (m, 2 H), 2.68 - 2.86 (m, 1 H), 2.86 - 3.09 (m, 1 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44
(d, 1 H), 6.98 (t, 1 H), 7.21 (d, 1 H), 7.35 (dd, 1 H), 7.83 - 8.13 (m, 4 H), 8.29 (t, 1 H), 8.38 - 8.65
(m, 3 H).
Compound No. 25: (250 MHz) 0.35 - 0.55 (m, 2 H), 0.69 - 0.84 (m, 2 H), 1.41 - 2.01 (m, 8 H),
2.85 - 3.05 (m, 1 H), 4.13 (d, 2 H), 4.13 - 4.26 (m, 1 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 6.98 (t, 1 H),
7.22 (d, 1 H), 7.35 (dd, 1 H), 7.84 - 8.08 (m, 4 H), 8.22 - 8.37 (m, 2 H), 8.44 - 8.57 (m, 2 H)
Compound No. 26: (250 MHz) 0.37 - 0.55 (m, 2 H), 0.71 - 0.83 (m, 2 H), 0.89 (t, 3 H), 1.18-1.41
(m, 2 H), 1.41 - 1.63 (m, 2 H), 2.84 - 3.05 (m, 1 H), 3.21 (q, 2 H), 4.13 (d, 2 H), 5.86 (s, 2 H), 6.45
(d, 1 H), 6.98 (t, 1 H), 7.23 (d, 1 H), 7.36 (dd, 1 H), 7.83 - 8.09 (m, 4 H), 8.29 (t, 1 H), 8.39 - 8.68
(m, 3H)
Compound No. 27: (250 MHz) 1.22 (t, 3 H), 1.29 - 1.58 (m, 6 H), 2.28-2.47 (m, 6 H), 3.30 -3.41
(m, 2 H), 3.43 - 3.62 (m, 2 H), 4.37 (d, 2 H), 7.16 (d, 1 H), 7.23 (t, 1 H), 7.39 (dd, 1 H), 7.69 - 7.79
(m, 1 H), 7.82 - 8.03 (m, 3 H), 8.26 (t, 1 H), 8.31 - 8.46 (m, 2 H), 8.49 (dd, 1 H), 8.56 (d, 1 H), 8.64
(d,1H).
Compound No. 28: (250 MHz) 1.22 (t, 3), 1.23 - 1.6 (m, 6), 2.30 - 2.50 (m, 6), 2.75 (d, 3), 3.34
(m, 2), 3.52 (qui, 2), 4.13 (d, 2), 6.39 (q, 1), 6.43 (d, 1), 6.98 (t, 1), 7.16 (d, 1), 7.37 (dd,1), 7.80-
8.02 (m, 4), 8.28 (t, 1), 8.37 (t, 1), 8.41 (t, 1), 8.49 (d, 1).
Compound No. 29: (250 MHz) 1.22 (t, 3 H), 1.29 - 1.60 (m, 6 H), 2.31 - 2.47 (m, 6 H), 3.00 (s,
6H), 3.26 - 3.42 (m, 2 H), 3.45 - 3.60 (m, 2 H), 4.18 (d, 2 H), 6.64 (d, 1 H), 7.01 (s, 1 H), 7.16 (d, 1
H), 7.49 (dd, 1 H), 7.81 - 8.01 (m, 3 H), 8.06 (d, 1 H), 8.28 (t, 1 H), 8.33 - 8.46 (m, 2 H), 8.51 (d, 1
H)
Compound No. 30: (250 MHz) 1.22 (t, 3 H), 1.30 - 1.63 (m, 6 H), 2.29 - 2.47 (m, 6 H), 3.29 -3.40
(m, 2 H), 3.44 - 3.63 (m, 2 H), 4.22 (d, 2 H), 5.32 (s, 2 H), 6.86 (s, 1 H), 7.03 - 7.22 (m, 2 H), 7.71
(s, 1 H), 7.79 - 8.02 (m, 4 H), 8.28 (t, 1 H), 8.33 - 8.51 (m, 2 H), 8.58 (s, 1 H)

Compound No. 31: (500 MHz) 1.23 (t, 3 H), 1.34 - 1.43 (m, 2 H), 1.45 - 1.57 (m, 4 H), 2.31 -2.49
(m, 6 H), 3.31 - 3.39 (m, 2 H), 3.46 - 3.59 (m, 2 H), 4.43 (d, 2 H), 7.17 (d, 1 H), 7.27 (t, 1 H), 7.62 -
7.76 (m, 1 H), 7.88 (dd, 1 H), 7.91 - 8.02 (m, 2 H), 8.24 (t, 1 H), 8.38 (t, 1 H), 8.42 (t, 1 H), 8.46 (s,
1H), 8.49 (d, 1 H), 8.69 (d, 1 H)
Compound No. 32: (400 MHz) 1.22 (t, 3 H), 1.33 - 1.61 (m, 6 H), 2.31 (s, 3 H), 2.51 (s, 6 H), 3.34
- 3.43 (m, 2 H), 3.46 - 3.60 (m, 2 H), 4.34 (d, 2 H), 7.16 (d, 1 H), 7.21 (t, 1 H), 7.54 (s, 1 H), 7.87
(d, 1 H), 7.90 - 8.05 (m, 2 H), 8.21 - 8.29 (m, 1 H), 8.29 - 8.37 (m, 2 H), 8.37 - 8.49 (m, 2 H), 8.62
(d, 1H)
Compound No. 33: (250 MHz) 1.22 (t, 3 H), 1.31 - 1.59 (m, 6 H), 2.22 - 2.47 (m, 6 H), 3.29 -3.41
(m, 2 H), 3.53 (m, 2 H), 5.67 (s, 2 H), 6.45 (d, 1 H), 7.17 (d, 1 H), 7.51 (dd, 1 H), 7.80 - 8.05 (m,
4H), 8.27 (t, 1 H), 8.41 (d, 2 H), 8.70 (br. s., 2 H).
Compound No. 34: (400 MHz) 1.22 (t, 3 H), 1.40 (d, 2 H), 1.53 (quin, 4 H), 2.41 - 2.60 (m, 6H),
2.45 (s, 3 H), 3.34 - 3.42 (m, 2 H), 3.47 - 3.57 (m, 2 H), 4.32 (d, 2 H), 7.11 - 7.21 (m, 2 H), 7.23
(d, 1H), 7.61 (dd, 1 H), 7.87 (d, 1 H), 7.90 - 8.03 (m, 2 H), 8.25 (t, 1 H), 8.41 (s, 3 H), 8.60 (d, 1 H)
Compound No. 35: (400 MHz) 1.22 (t, 3 H), 1.32 - 1.45 (m, 2 H), 1.64 - 1.78 (m, 2 H), 2.06 (t,
2H), 2.43 (t, 2 H), 2.64 - 2.77 (m, 2 H), 3.32 (s, 2 H), 3.37 - 3.48 (m, 1 H), 3.48 - 3.57 (m, 2 H),
4.13 (d, 2H), 4.52 (d, 1 H), 5.83 (s, 2 H), 6.43 (d, 1 H), 6.97 (t, 1 H), 7.15 (d, 1 H), 7.34 (dd, 1 H),
7.86 (d, 2 H), 7.89 - 7.99 (m, 2 H), 8.27 (t, 1 H), 8.33 - 8.45 (m, 2 H), 8.49 (d, 1 H)
Compound No. 36: (250 MHz) 0.94-1.15 (m, 1 H), 1.22 (t, 3 H), 1.30-1.52 (m, 1 H), 1.52-1.69
(m, 1 H), 1.69 - 1.97 (m, 3 H), 2.44 (t, 2 H), 2.62 - 2.77 (m, 1 H), 2.85 (dd, 1 H), 3.28 - 3.39 (m,
2H), 3.39 - 3.62 (m, 3 H), 4.13 (d, 2 H), 4.56 (d, 1 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 6.99 (t, 1 H), 7.16
(d, 1H), 7.35 (dd, 1 H), 7.82 - 8.03 (m, 4 H), 8.28 (t, 1 H), 8.33 - 8.46 (m, 2 H), 8.51 (d, 1 H)
Compound No. 37: (400 MHz) 0.99 (d,12), 1.22 (t, 3), 2.51 (m, 2), 2.99 (m, 2), 3.19 (q, 2), 3.53
(qui, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d,1), 6.97 (t, 1), 7.15 (d, 1), 7.34 (dd, 1), 7.80 - 8.00 (broad
unresolved peak, 4); 8.27 (t, 1), 8.37 (t, 1), 8.42 - 8.54 (broad unresolved peak, 2)
Compound No. 38: (400 MHz) 1.22 (t, 3), 1.40 (m, 2), 1.82 (m , 2), 2.12 (t, 2), 2.44 (t, 2), 2.72 (m,
2), 3.15 (sep, 1), 3.22 (s, 3), 3.32 (m, 2), 3.52 (qui, 2), 4.15 (d, 2), 5.84 (s , 2), 6.43 (d,1), 6.97 (t, 1),
7.15 (d, 1), 7.34 (dd, 1), 7.80 - 8.00 (m, 4), 8.27 (t, 1), 8.37 (t, 1), 8.40 (t, 1), 8.49 (d,1).

Compound No. 39: (250 MHz) 1.22 (t, 3 H), 1.30-1.57 (m, 6 H), 1.66 (t, 2 H), 2.18-2.41 (m,
6H), 3.16 - 3.29 (m, 2 H), 3.40 - 3.60 (m, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 6.97 (t, 1
H), 7.15 (d, 1 H), 7.35 (del, 1 H), 7.81 - 8.03 (m, 4 H), 8.28 (t, 1 H), 8.36 - 8.58 (m, 3 H).
Compound No. 40: (400 MHz) 1.22 (t, 3), 1.30 - 1.59 (m, 10), 2.23 (t, 2), 2.28 (br. s., 4), 3.23 (q,
2); 3.52 (qui, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.99 (t, 1), 7.14 (d, 1), 7.34 (dd, 1), 7.82 - 8.00
(m, 4), 8.26 (t, 1), 8.43 (m, 2), 8.51 (br. s. 1).
Compound No. 41: (400 MHz) 1.22 (t, 3 H), 2.14 (s, 3 H), 2.18 - 2.49 (m, 10 H), 3.31 - 3.39 (m, 2
H), 3.44 - 3.58 (m, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.43 (d, 1 H), 6.97 (t, 1 H), 7.15 (d, 1 H), 7.34
(dd, 1 H), 7.81 - 7.89 (m, 2 H), 7.89 - 7.98 (m, 2 H), 8.27 (t, 1 H), 8.32 - 8.45 (m, 2 H), 8.49 (d, 1
H)
Compound No. 42: (250 MHz) 1.22 (t, 3 H), 2.02 (br. s., 1 H), 2.27 - 2.38 (m, 4 H), 2.41 (t, 2H),
2.62 - 2.74 (m, 4 H), 3.22 - 3.41 (m, 2 H), 3.44 - 3.59 (m, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44
(d,1H), 7.00 (t, 1 H), 7.16 (d, 1 H), 7.35 (dd, 1 H), 7.82 - 8.02 (m, 4 H), 8.28 (t, 1 H), 8.33 - 8.46
(m, 2 H), 8.51 (d, 1 H)
Compound No. 43: 1H NMR (500 MHz, d6-DMSO) 6 ppm 1.24 (t, 3 H), 1.35 - 1.44 (m, 2 H), 1.51
(quin, 4 H), 2.33 - 2.50 (m, 6 H), 3.33 - 3.41 (m, 2 H), 3.50 - 3.59 (m, 2 H), 6.48 - 6.56 (m, 3 H),
6.86 (d, 1 H), 7.22 (d, 1 H), 7.49 (d, 1 H), 7.66 (dd, 1 H), 7.90 - 8.06 (m, 3 H), 8.16 (d, 1 H), 8.31 (t,
1 H), 8.41 (q, 2 H), 9.88 (s, 1 H).
Compound No. 44: 1H NMR (250 MHz, d6-DMSO) 8 ppm 1.23 (t, 3 H), 1.31 -1.64 (m, 6 H), 2.23 -
2.47 (m, 6 H), 3.29 -3.41 (m, 2 H), 3.46 - 3.65 (m, 2 H), 7.21 (s, 1 H), 7.26 (d, 1 H), 7.51 (dd, 1 H),
7.69 (d, 1 H), 7.93 - 8.13 (m, 4 H), 8.31 (t, 1 H), 8.37 - 8.47 (m, 2 H), 8.62 (d, 1 H), 8.85 (d, 1 H),
10.17 (s,1H).
Compound No. 45: 1H NMR (250 MHz, d6-DMSO) 5 ppm 1.22 (t, 7 H), 1.96 - 2.26 (m, 2 H), 3.16
(d, 4 H), 3.40 (t, 2 H), 3.52 (ddt, 2 H), 3.71 (d, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 7.07
(t. 1 H), 7.13 (d, 1 H), 7.35 (dd, 1 H), 7.73 (d, 1 H), 7.80 - 7.96 (m, 3 H), 8.28 (t, 1 H), 8.55 (br. s., 2
H), 11.05 (br. s., 1 H)

The compounds in Table I have the chemical names (obtained from the Autonom® software):
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (compound No. 1)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2,5-difluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide (No. 2)
■ 2-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-4-(ethylamino)pyrimidine-5-
carboxylic acid [2-(piperidin-1-yl)ethyl]amide (No. 3)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-cyclopropylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide (No. 4)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-phenylamino-N-[2-(piperidin-
1-yl)ethyl]nicotinamide (No. 5)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-
(isopropylamino)ethyl]nicotinamide (No. 6)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(1,1-dioxothiomorpholin-4-
yl)ethyl]-2-(ethylamino)nicotinamide (No. 7)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-(2-hydroxy-
ethyl)nicotinamide (No. 8)
■2-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-4-
(cyclopropylamino)pyrimidine-5-carboxylic acid [2-(piperidin-1-yl)ethyl]amide (No. 9)
■ 2-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-4-(phenylamino)pyrimidine-5-
carboxylic acid [2-(piperidin-1-yl)ethyl]amide (No. 10)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2-fiuorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (No. 11)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(pyrrolidin-1-
yl)ethyl]nicotinamide (No. 12)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-methyl-
nicotinamide (No. 13)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-(2-methoxy-
ethyl)nicotinamide (No. 14)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(azepan-1-yl)ethyl]-2-
(ethylamino)nicotinamide (No. 15)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(1-oxo-
thiomorpholin-4-yl)ethyl]nicotinamide (No. 16)
■ 6-{4-[3-(6-Amino-5-methylpyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide (No. 17)

■644-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(cis-3,5-dimethylpipericiin-
1-yl)ethyl]-2-(ethylamino)nicotinamide (No. 18)
■6^4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(cis-2,6-dimethylpiperidin-
1-yl)ethyl]-2-(ethylamino)nicotinamide (No. 19)
■6-(4-{3-[2-(6-Aminopyridin-3-yl)ethyl]ureido}-3-fluorophenyl)-2-ethylamino-N-[2-(piperidin-
1-yl)ethyl]nicotinamide (No. 20)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2,6-difluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide (No. 21)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2,3-difluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide (No. 22)
■4'-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-ethylamino-3'-fluorobiphenyl-4-carboxylic acid
[2-(piperidin-1-yl)ethyl]amide (No. 23)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-cyclopropyl-2-
(cyclopropylamino)nicotinamide (No. 24)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-cyclopentyI-2-
(cyclopropylamino)nicotinamide (No. 25)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-butyl-2-
(cyclopropylamino)nicotinamide (No. 26)
■ 2-Ethylamino-6-{3-fluoro-4-[3-(pyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (No. 27)
■ 2-Ethylamino-6-{3-fluoro-4-[3-(6-(methylamino)pyridin-3-ylmethyl)ureido]phenyl}-N-[2-
(piperidin-1-yl)ethyl]nicotinamide (No. 28)
■ 6^4-[3-(6-(Dimethylamino)pyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide (No. 29)
■ 6-{4-[3-(5-Aminopyridin-3-ylnnethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (No. 30)
■ 2-Ethylamino-6-{3-fluoro-4-[3-(5-fluoropyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (No. 31)
■ 2-Ethylamino-6-{3-fluoro-4-[3-(5-methylpyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (No. 32)
■ 6-{4-[3-(6-Aminopyridin-3-yl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (No. 33)
■ 2-Ethylamino-6-{3-fluoro-4-[3-(6-methylpyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yi)ethyl]nicotinamide (No. 34)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(4-hydroxy-
piperidin-1-yl)ethyl]nicotinamide (No. 35)

■6H;4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(3-hydroxy-
piperidin-1-yl)ethyl]nicotinamide (No. 36)
■644-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fIuorophenyl}-N-[2-(diisopropylamino)ethyl]-2-
(ethylamino)nicotinamide (No. 37)
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(4-methoxy-
piperidin-1-yl)ethyl]nicotinamide (No. 38)
■6^4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[3-(piperidin-1-
yl)propyl]nicotinamide (No. 39)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[4-(piperidin-1-
yl)butyl]nicotinamide (No. 40)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(4-
methylpiperazin-1-yl)ethyl]nicotinamide (No. 41)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperazin-1-
yl)ethyl]nicotinamide (No. 42)
■ 6-{4-[(E)-3-(6-Aminopyridin-3-yl)acryloylamino]-3-fluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethy!]nicotinamide (No. 43)
■ 2-Ethylamino-6-{3-fluoro-4-[(E)-3-(pyridin-3-yl)acryloylamino]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide (No. 44)
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(1-oxy-
piperidin-1-yl)ethyl]nicotinamide (No. 45)
The compounds described in Table I have formed the subject of pharmacological trials which
make it possible to determine the anticancer activity. They were tested in vitro on the HCT116
tumour line (ATCC-CCL247). The cell proliferation and viability were determined in a test
using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-
tetrazolium (MTS) according to Fujishita T. et al., Oncology, 2003, 64(4), 399-406. In this test,
the mitochondrial ability of the living cells to convert MTS to a coloured compound is
measured after incubating the test compound for 72 hours. The concentration of compound
which results in a 50% loss of cell proliferation and viability is denoted IC50.
For the compounds of Table I, an IC50<1000 nM (1 uM) is found with regard to the HCT116
line. Some compounds (for example Nos. 1, 5, 11,19, 27) even exhibit an activity <1 nM.

CLAIMS
1. Compound of formula (I):

in which:
• Z and Z' represent N or CH;
• x is an integer having the value 1 or 2, representing the number of fluorine atom(s)
attached to the central phenyl nucleus;
• L represents a -CH=CH- or -(CH2)nNH- group in which the NH group is attached to the
C=O and n is an integer having the value 0,1 or 2;
• R1 represents a hydrogen atom or a (C1-C6)alkyl, (C3-C6)cycloalkyl or phenyl group;
• R'1 represents a hydrogen atom or a (C1-C6)alkyl group;
• R2 represents:

- a (C3-C6)cycloalkyl group;
- a (C1-C6)alkyl group, optionally substituted by:
o one or more hydroxyl or (C1-C4)alkoxy groups;
o an -NRaRb group in which Ra and Rb represent, independently of one another,
a hydrogen atom or a (C1-C6)alkyl group or form, together with the nitrogen atom to
which they are connected, a (C4-C6)heterocycloalkyl group optionally comprising,
in the ring, the -S(O)q- group with q= 0,1 or 2 or the -NH- or -N(C1-C4 alkyl)- group
and being optionally substituted by one or more substituent(s), which are identical
to or different from one another when there are several of them, chosen from an
-OH, (C1-C4)alkoxy or (C1-C4)alkyl group;
• R3 represents at least one substituent of the pyridine nucleus chosen from a hydrogen
atom, a fluorine atom, a (C1-C4)alkyl group or an -NRcRd group in which Rc and Rd
represent a hydrogen atom or a (C1-C4)alkyl group.
2. Compound according to Claim 1, in which R1 represents the cyclopropyl group or the
phenyl group or a (C1-C6)alkyl group and R'1 represents a hydrogen atom.
3. Compound according to Claim 1, in which R'1 represents a hydrogen atom.

4. Compound according to Claim 1 to Claim 3, in which R2 represents:
- the cyclopropyl or cyclopentyl group;
- a (C1-C6)alkyl group, optionally substituted by:
o one or more -OH or (C1-C4)alkoxy group(s);

5. Compound according to one of the preceding claims, in which R3 is in the 5 and/or 6
position on the pyridine nucleus.
6. Compound according to one of the preceding claims, in which the number of R3
substituents is equal to 1 and/or R3 is in the 5 or 6 position on the pyridine nucleus.
7. Compound according to one of Claims 1 to 6, in which R3 is -NH2.
8. Compound according to one of the preceding claims, in which n is equal to 1 or L
represents the -CH=CH- group in the E or Z form.
9. Compound according to one of the preceding claims, in which Z and Z' respectively
represent N and CH, CH and CH or N and N.

10. Compound according to one of the preceding claims, in which x has the value 1.
11. Compound according to Claim 1 of formula (I"):

in which R1 represents a (C1-C4)alkyl group, R2 represents a (C1-C6)alkyl group
optionally substituted by an -NRaRb group in which Ra and Rb form, together with the
nitrogen atom to which they are connected, the (C4-C6)heterocycloalkyl group
optionally comprising, in the ring, the -S(O)q- group with q= 0, 1 or 2 or the -NH- or
-N(C1-C4 alkyl)- group, x is an integer having the value 1 or 2, representing the
number of fluorine atom(s) attached to the central phenyl nucleus, and R3 is as
defined in one of Claims 1 and 5 to 7.
12. Compound according to Claim 11, in which the (C4-C6)heterocycloalkyl group is
chosen from the pyrrolidinyl, piperidinyl, piperazinyl, N-(C1-C4 alkyl)piperazinyl,
azepanyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl,
3-hydroxypiperidinyl or 4-hydroxypiperidinyl, 4-methoxypiperidinyl, c/s-3,5-
dimethylpiperidinyl or cis-2,6-dimethylpiperidinyl group.
13. Compound according to one of Claims 1 to 12, in which x has the value 1 and the
fluorine atom is in the 3 position.
14. Compound according to any one of the preceding claims, in the form of the base or of
an addition salt with an acid or in the form of a hydrate or of a solvate.
15. Compound according to Claim 1, chosen from one of the following:
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2,5-difluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide

■2-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-4-(ethylamino)pyrimidine-5-
carboxylic acid [2-(piperidin-1-yl)ethyl]amide
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-cyclopropylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-phenylamino-N-[2-(piperidin-
1-yl)ethyl]nicotinamide
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fIuorophenyl}-2-ethylamino-N-[2-
(isopropylamino)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-yImethyl)ureido]-3-fluorophenyl}-N-[2-(1,1 -dioxothiomorpholin-4-
yl)ethyl]-2-(ethylamino)nicotinamide
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-(2-hydroxy-
ethyl)nicotinamide
■2-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-4-
(cyclopropylamino)pyrimidine-5-carboxylic acid [2-(piperidin-1 -yl)ethyl]amide
■ 2-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-4-(phenylamino)pyrimidine-5-
carboxylic acid [2-(piperidin-1-yl)ethyl]amide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(pyrrolidin-1-
yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylarnino-N-methyl-
nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyI)ureido]-3-fluorophenyl}-2-ethylamino-N-(2-methoxy-
ethyl)nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(azepan-1-yl)ethyl]-2-
(ethylamino)nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(1-oxo-
thiomorpholin-4-yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Amino-5-methylpyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(cis-3,5-dimethylpiperidin-
1-yl)ethyl]-2-(ethylamino)nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(cis-2,6-dimethylpiperidin-
1-yl)ethyl]-2-(ethylamino)nicotinamide
■ 6-(4-{3-[2-(6-Aminopyridin-3-yl)ethyl]ureido}-3-fluorophenyl)-2-ethylamino-N-[2-(piperidin-
1 -yl)ethyl]nicotinamide

■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2,6-clifluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-2,3-difluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide
■4'-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-ethylamino-3'-fluorobiphenyl-4-carboxylic acid
[2-(piperidin-1 -yl)ethyl]amide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-cyclopropyl-2-
(cyclopropylamino)nicotinamide
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-cyclopentyl-2-
(cyclopropylamino)nicotinamide
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-butyl-2-
(cyclopropylamino)nicotinamide
■ 2-Ethylamino-6-{3-fIuoro-4-[3-(pyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 2-Ethylamino-6-{3-fluoro-4-[3-(6-(methylamino)pyridin-3-ylmethyl)ureido]phenyl}-N-[2-
(piperidin-1-yl)ethyl]nicotinamide
■ 6-{4-[3-(6-(Dimethylamino)pyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide
■ 6-{4-[3-(5-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 2-Ethylamino-6-{3-fluoro-4-[3-(5-fluoropyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 2-Ethylamino-6-{3-fluoro-4-[3-(5-methylpyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-yl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 2-Ethylamino-6-{3-fluoro-4-[3-(6-methylpyridin-3-ylmethyl)ureido]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-yimethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(4-hydroxy-
piperidin-1-yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(3-hydroxy-
piperidin-1-yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-N-[2-(diisopropylamino)ethyl]-2-
(ethylamino)nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(4-methoxy-
piperidin-1-yl)ethyl]nicotinamide

■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylarnino-N-[3-(piperidin-1-
yl)propyl]nicotinamide
■6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[4-(piperidin-1-
yl)butyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(4-
methylpiperazin-1-yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethylamino-N-[2-(piperazin-1-
yl)ethyl]nicotinamide
■ 6-{4-[(E)-3-(6-Aminopyridin-3-yl)acryloylamino]-3-fluorophenyl}-2-ethylamino-N-[2-
(piperidin-1-yl)ethyl]nicotinamide
■2-Ethylamino-6-{3-fiuoro-4-[(E)-3-(pyridin-3-yl)acryloylamino]phenyl}-N-[2-(piperidin-1-
yl)ethyl]nicotinamide
■ 6-{4-[3-(6-Aminopyridin-3-ylmethyl)ureido]-3-fluorophenyl}-2-ethy!amino-N-[2-(1-oxy-
piperidin-1-yl)ethyl]nicotinamide
in the form of the base or of an addition salt with an acid or in the form of a hydrate or a
solvate.
16. Compound of formula:

in which L represents a -CH=CH- or -(CH2)n-NH- group in which the NH group is
attached to the C=O, R3 is as defined in Claim 1 and Claim 5 to Claim 7 and K and K'
represent a hydrogen atom, an alkyl group or an aryl group which are optionally
connected to one another to form, together with the boron atom and the two oxygen
atoms, a 5- to 7-membered ring optionally substituted by at least one (C1-C4)alkyl
group or to which is optionally fused, over two consecutive carbon atoms on the said
ring, a phenyl group.
17. Compound according to Claim 13, characterized in that -B(OK)(OK') represents one
of the following groups:


18. Compound of formula

or of formula

in which R1, R'1, R2, R3, Z, Z' and x are as defined in one of Claims 1 to 10.
19. Medicament, characterized in that it comprises a compound according to one of
Claims 1 to 15.
20. Pharmaceutical composition, characterized in that it comprises a compound
according to one of Claims 1 to 15 and at least one pharmaceutically acceptable
excipient.
21. Compound according to Claim 1 to Claim 15, as anticancer drug.

22. Use of a compound according to one of Claims 1 to 15 in the manufacture of a
medicament intended for the treatment or prevention of a cancer.
23. Use of a compound chosen from the following list:



as intermediate in the preparation of a compound as defined in one of Claims 1 to 15.

The present invention relates to nicotinamide derivatives of formula (I), to compositions containing same, and to
the therapeutic use thereof, in particular as anticancer drugs. The invention also relates to the method for preparing said
compounds, as well as to some of the intermediate products.