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21)Application Number: KE/P/2009/ 000903

(22) Filing Date: 09111/2007

(30)    Priority data:  0609812  10111/2006  FR

(86)  PCT data PCT/FR07/001851 09111/2007 WO 2008/065282 05/06/2008

(73) Owner: SANOFI-AVENTIS of  174 Avenue de France, F-75013 Paris, France

(72)    Inventors:  TABART, Michel of c/o Sanofi-Aventis 174 Avenue de France F-75013 Paris, France; BJERGARDE, Kirsten of c/o Sanofi-Aventis Mailstop 1580 E. Hanley Blvd  Tucson, AZ 85737-9525, U.S.A.; PATEK, Marcel of c/o  Sanofi-Aventis Mailstop 1580 E. Hanley Blvd Tucson,  AZ 85737-9525, U.S.A.; DODSON, Mark of c/o Sanofi-  Aventis Mailstop 1580 E. Hanley Blvd Tucson, AZ  85737-9525, U.S.A.; MAUGER, Jacques of c/o Sanofi- Aventis Mailstop 1580 E. Hanley Blvd Tucson, AZ  85737-9525, U.S.A. and NAIR, Ani! of c/o Sanofi-  Aventis Mailstop 1580 E. Hanley Blvd Tucson, AZ 85737-9525, U.S.A.

(74)    Agent/address for correspondence: Kaplan & Stratton Advocates, P.O. Box40111-00IOO, Nairobi

(54)Title: SUBSTITUTED PYRAZOLES, COMPOSITIONS CONTAINING THESE, METHOD OF PRODUCTION AND USE

(57) Abstract: The present invention relates to new chemical compounds, particularly to substituted pyrazoles, compositions containing these, and their use as drugs.

SUBSTITUTED PYRAZOLES. COMPOSITIONS CONTAINING THESE. METHOD OF

PRODUCTION AND USE

The  present  invention  relates  especially  to  novel  chemical  compounds,  particularly

substituted    pyrazoles,  to  compositions   containing  them,   and   to   their   use   as

medicaments.

More particularly, and according to a first aspect, the invention relates to novel specific substituted pyrazoles with anticancer activity, via modulation of the activity of proteins, in

10    particular kinases.

Prolein kinases are a family of enzymes that catalyse the phosphorylation of hydroxyl

groups of specific residues of proteins such as tyrosine, serine or.threonine residues.

Such phosphorylations can .largely modify the function of proteins; thus, protein kinases

15    play an important role in regulating a wid~ .~ariety of cell.processes, especially including metabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among the various cellular functions in which the activity of a protein kinase is involved, certain processes represent attractive targets for• treating cancer diseases and also other diseases.
20

Thus, one of the objects of the present invention is to propose compositions with cinticancer activity, by• acting in particular with respect to kinases. Among the kinases for

which a modulation of activity is desired, mention may be made of KDR, Tie2, VEGFR-1, PDGFR, FGFR and FL T1. The kinases KDR and/or Tie2 are preferred.

25

These products correspond to lhe general formula (I) below:
t
Ar...-L

R~,a,N__.(
~    j'    R 4b

R,,X/'1()-R,    (I)-
N-N_
R,

Formula (I)

in which:


1)    A and Ar are independently selected from the group consisting of: aryl, heteroaryl, substituted aryl, substituted heteroaryl;

2)    L is selected from the group consisting of: NH-CO-NH and 0-CO-NH;

3)    R1 is selected from the group consisting of: H, R,, COR,, SO,R,, in which R6 is chosen from H, OR7, NR,R9, alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, in which R, is chosen from H,

phenyl and alkyl, and in which Ra and R, are independently selected from the group

consisting of H, alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted

aryl, heteroaryl and substituted heteroaryl, or alternatively Ra and R9 are linked together

J0    to form a saturated 5- to 8-membered ring containing from 0 to 3 heteroatoms chosen

from 0, S and N;

4)    X is selected from the group consisting of: 0 and NH;

5)    R3 is selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl;

t5    6)  R.a is selected from the,group consisting of: Hand (C1-C4)alkyl;

7)    R4b is selected from the group consisting of: Hand (C1-C4)alkyl;
8)    R, is selected From the group consisting of: H, halogen, R10, CN, O(R10), OC(O)(R10), OC(O)N(R10)(R11), OS(O,)(R10), N(R10)(R11), N=C(R10)(R11), N(R10)C(O)(R11),

N{R10)C(O)O(R11),    N(R12)C(O)N(R10)(R11),   N(R12)C(S)N{R10)(R11),   N{R1D)S(O,)(R"),

20    C(O)(R10). C(O)O(R10), C(D)N(R10)(R11), C(=N(R11))(R10), C(=N(OR11))(R10), S(R,,), S(O)(R10), S(O,)(R;o), S(O,)O(R"), S(O,)N(R10)(R11); in•which each R10, R11, R.12 is

independently selected from the gr9up consisting of•H, alkyl, alkylene, ?lkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted
25    heterocyclyf.
When R1 is H, the two tautomeric for~s,. indicated below form part of the' invention:
    Ar/L            Arl   
R4a,  A            R.;a,  ~           
o    N    R 4b    -~    O    N    R 4b   
~    ~    R,        \\    ) -        R   
R J-x~ Y        -- R;--/--y- 7r    s   
    N-~                ~-N           

30    In the products of fonnula (1), R, is advantageously H.
 
In the products of formula (I), R, is advantageously H and X is advantageously NH, or alternatively R3 is advantageously methyl and X is advantageously 0.

    In the products of formula (I), R5 is advantageously H.           
    A substituent Ar according to the invention rnay be chosen frorn phenyl, pyridyl, thienyl,   
    fury/ and pyrro/y/, substituted with R's,in which R' has the same definition as R    5    •   
    5           
10    In the products of formula (1), Ar-L-A is advantageously:           

X_rX3

--{.~;x,
XI\
L-A

in which each X1, X2, X3 and X4 is indeJ2e~_dently chosen from N and C-R', in which R'.a
5
has the same definition as R5•

15
More particularly, R',may be selected from the group consisting of H, F, Cl, methyl, NH2,
OCF3 and CONH,. A substituent Ar is advantageously a phenyl in which R' is H.
5

A substituent A according to the invention may be selected from the group consisting of

20    ph~nyl, pyridyl, pyrimidyl, thienyl, fury!, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzothiazolyl; optionally substituted.

-More particularly, a substituent A according to the invention may be selected from the

25    group consisting of phenyl, pyrazolyl and isoxazolyl; optionally substituted. A substituent A is advantageously optionally substituted phenyl.

Among the products of fonnula (I) that are subjects of the present invention, mention

may be made especially of a first group of products tor which R,, and R,, are H, and A,

30    Ar, L, R,, X, R, and Rs are as defined above.

Among the products of the first group, mention may be made especially of a first subgroup of products for which:

1)    A and Ar are optionally substituted phenyls;
 

2)    Lis selected from the group consisting of: NH-CO-NH and 0-CO-NH;

3)    X is NH and R3 is H, or alternatively X is 0 and R, is methyl;

4)    R1, R,,, R.> and Rs are H.

Among this first subgroup, mention may also be made of a subgroup of products for

which:

1)    A and Ar are optionally substituted phenyls;

2)    L is NH-CO-NH;

3)    X is NH and R, is H;

10    4)  R1,  R4,   R40 and Rs are H.

Among the products of the first subgroup, mention may be made especially of a second

subgroup of products for which:

1)  A is an optionally substituted phenyl and Ar is an optionally substituted pyridine;

15    2)  Lis selected from the group consisting of: NH-CO-NH and 0-CO-NH;

3)    X is NH and R3 isH, or altematively X is 0 and R, is methyl;
4)    R1,  R.,, R40 and Rs are H.

Among  this second subgroup,  mention  may  be  made  especially oF a  subgroup  of

20    products for which:

1)    A is an optionally substituted phenyl and Ar is an optionally substituted pyridine;

2)    L is NH-CO-NH;

3)    X is NH and R, is H.

4)    R, R,,, R,, and R5 are H.

25

Among the products of formula (I) that are subjects .of the present invention, mention may be made especially of a second group of products for which R,, is H, R,, is (C1-C4)alkyl, and A, Ar, L, R,, X, R, and-R5 are as defined above.

30    Among the products of the second group, mention may be made especially of a first subgroup of products For which:
1)    -A and Ar are optionally substituted phenyls;

2)    Lis NH-CO-NH;

3)    X is NH and R, is H;

35    4)  R,, R,, and Rs are H;

5)    R,,is methyl.
 
Among the products of formula (I) that are subjects of the present invention, mention may be made especially of a third group of producls for which R,, is (C1-C4)alkyl, R,0 is

H, and A, Ar, L, R1, X, R3 and Rs are as defined above.

Among the products of the third group, mention may be made especially of a first subgroup of products for which:
1)    A and Ar are optionally substituted phenyls;

2)    L is NH-CO-NH;

10    3)  X is NH and R, isH;

4)    R1, R,, and Rs are H;

5)    R,, is methyl.

Among the products of the third group, mention may be made especially of a second

15    . subgroup of products for which:

1)    A and Ar are optionally substituted phenyls;

2)    Lis NH-CO-NH;
3)    X is NH and R3 is H;
4)    R, R,0 and Rs are H; 20 5) R,, is ethyl.

A.    may be substituted with one or more substituents selected from the gi"oup consisting

of:  H,  F,  Cl,  Br,  I,  OH,  SH,  S03M,  COOM,  COO-alkyl,  CON(R14)(R15),   CN,  N02,

N(R14)CO(R15),  N(R14)(R15),  alkyl, haloalkyl, alkyi-OH, alkyi-N(R14)(R,), alkyi(R16),  alkyl-25    COOM,  alkyi-S03M,  cycloalkyl,  alkylene,  alkynyl, aryl,  heteroaryl,  0-alkyl,  0-aryl, 0-heteroaryl, S-alkyl, S-aryl and S-heteroaryl,  each being  optionally sub.stituted wit[l a

. substituent chosen from alkyl, halogen, 0-alkyl and N(R14)(R15); in which R14 and R15 are independently chosen from H, alkyl, alkyi-OH, haloalkyl, alkyi-NH2, alkyi-COOM and alkyi-S03 M; in which, when R14 and R, are simultaneously other than H, may be

30    bonded to form a 5- to ?-membered ring comprising from 0 to 3 heteroatoms chosen

from 0, Nand S; in which M isH or a cation of an alkali metal chosen from Li, Na and K; and in which R16 is H or an optionally substituted non-aromatic heterocycle, containing from 2 to 7 carbon atoms, and 1 to 3 heteroatoms chose; from N, 0 and S. When A is disubstituted, the two substituents may be linked together to form a 5- to ?-membered

35    ring containing from 0 to 3 heteroatoms chosen from N, 0 and S.

A may also be substituted  with  one  or more substituents selected  from the  group
 
mentioned above, also including SiMe3, S-CHFJ and SF5 .

More particularly, A may be chosen from phenyl, pyrazolyl or isoxazolyl, substituted with at least one group chosen from H, halogen, alkyl, haloalkyl, 0-alkyl, COO-alkyl and 0-haloalkyl. A substituent A is advantageously selected from the group consisting of: phenyl, 2-fiuoro-5-(trifluoromethyl)phenyl, 2-fiuorophenyl, 2-methoxyphenyl, •2-fluoro-3-(trifluoromethyl)phenyl, 3-methoxyphenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-(trifiuoromethoxy)phenyl, 3-methoxycarbonylphenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-(trifiuoromethyl)phenyl, 3,5-dimethoxyphenyl, 3-methylphenyl,

10 4-methoxyphenyl, 4-fluorophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 4-(difiuoromethoxy)phenyl, 2-chioro-4-(trifluoromethyl)phenyl, 4-methylphenyl, 2,5-dimethyl phenyl, 3,4-dimethylphenyl, 2-methylphenyl, 3-ethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3-fiuorophenyl, 2-methoxy-5-methylphenyl, 2,5-dimethoxyphenyl, 3-chloro-4-(difluoromethoxy)phenyl, 2,5-difluorophenyl and 4-methyl-

15    3-(trifluoromethyl)phenyl.

A substituent A is more advantageously selected from the group consisting of: 2-chloro-

5-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-5-trifluorome\hylphenyl, 3-trimethylsilyl-4-fluorophenyl, 3-trifluoromethoxyphenyl, 4-

20    trifluoromethylpyrid-2-yl, 4-methoxypyrid-2-yl, 3-trifluoromethyl-4-chlorophenyl, 2-chloro-5-triflu~romethylphenyl, 3-trifluoromethylsulfanylphenyl, 3-isopropylphenyl, 3-isopropyl-4-fluorophenyl, 3-pentafluorosulfanylphenyl, 2-methoxy-5-tert-butylphenyl, 4-isopropylphenyl, 2-chloro-4-isopropylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-4-trifluororilethylphenyl, 2-fluoro-4-methylphenyl, 2-chloro-4-methylphenyl and 2-chloro-5-

25    methylphenyl.

The present invention also compris.es the subjects corresponding to combinations of the subgroups mentioned above.

30    The products according to the invention may be:

1)    in non-chiral form, or

2}    in racemic form, or

3)    enriched in one stereoisomer, or

4)    enriched in one enantiomer:

35    and may optionally be salified.
 
The present invention also relates to pharmaceutical compositions comprising a product according to the invention in combination with. a pharmaceutically acceptable excipient according to the chosen mode of administration. The pharmaceutical composition may be in solid or liquid form or in the fonn of liposomes.

Among the solid compositions that may be mentioned are powders, gel capsules and

tablets. Among the oral fonms that may also be included are solid forms protected with

respect to the acidic medium of the stomach. The supports used for the solid forms consist especially of mineral supports, for instance phosphates or carbonates, or organic•

10    supports, for instance lactose, celtuloses, starch or polymers. The liquid forms consist of solutioris, suspensions or dispersions. They contain as dispersive support either water or an organic solvent (ethanol, NMP or the like) or mixtures of surfactants and of solvents, or of complexing agents and of solvents.

15    The liquid forms will preferably be injectable and, as a result, will have a formulqtion that" is acceptable for such a use.

Routes  of  administration  that  are  acceptable  by  injection  include  intravenous,

intraperitoneal, intramuscular and subcutaneous routes, th~ intravenous route usually

20 •  being preferred.

The  administered dose  of the  compounds  of the  invention  will  be  adapted  by the .

practitioner as a function of the route of administration to the patient and of the patient's

condition.

25

The products of the invention are useful as inhibitors of a rea.ction catalysed by a kinase.

KDR and/or Tie2 are kinases for which the products of the invention will be particularly

useful as inhibitors.

30    The reasons for which these kinases are chosen are given below:

KDR

KDR (Kinase insert Domain Receptor), also known as VEGF-R2 (Vascular Endothelial

35    Growth Factor Receptor 2), is expressed solely in endothelial cells. This receptor binds to the angiogenic growth factor VEGF, and thus selVes as a transduction signal mediator

via the activation of its intracellular kinase domain. The direct inhibition of the kinase activity of VEGF-R2 makes it possible to reduce the phenomenon of angiogenesis in the
presence of exogenous VEGF (Vascular Endothelial Growth Factor) (Strawn et al., Cancer Research, 1996, val. 56, p.3540-3545). This process has especially been demonstrated using VEGF-R2 mutants (Millauer et al., Cancer Research, 1996, val. 56, p.1615-1620). The VEGF-R2 receptor appears to have no other function in adults than that associated with the angiogenic activity of VEGF. In addition to this central role in the

dynamic  angiogenic  process,  recent  results  suggest  that  the  expression  of  VEGF

contributes toWards the swvival• of tumoral cells after chemotherapy and radiotherapy,

10    underlining the potential synergy of KDR inhibitors with other agents (Lee et al. Cancer Research, 2000, val. 60, p.5565-5570).

Tie2

15    Tie-2 (TEK) is a memb.er of a family of tyrosine kinase receptors, which is specific to endothelial cells. Tie2 is the first receptor with tyrosine kinase activity for which both the agonist (angiopoietin 1 or Ang1), which stimulates the autophosphorylation of the receptor and cell signalling [S. Davis et al. (1996) Cell 87, 1161-1169], and the antagonist (angiopoietin 2 or Ang2) [P.C. Maisonpierre et al. (1997) Science 277, 55-60]

20    are .known. Angiopoietin 1 can. synergize with VEGF in the final stages of neoangiogenesis [Asahara T. Circ. Res. (1998) 233-240]. Knock-out experiments and transgenic manipulations of the. expression of Tie2 or of Ang1 lead. to animals that

present vascularization defects [D.J. Dumont et al. (1994) Genes Dev. 8, 1897-1909 and c. Suri (1996) Cell 87, 1171-1180]. The binding of Ang1 to its receptor leads to

25    autophosphorylation of the kinase domain of Tie2, which is essential for neovascularization and also for the recruitm~nt an~ interaction of blood vessels with the pericytes and smooth muscle cell~; these phenomena contribute towards the maturation and stability of tbe newly formed•blood vesses [P.C. Maisonpierre et al. (1g97). Science

277, 55-60]. Lin et al. (1997) J. Clin. Invest. 100, 8: 2072-2078 and Lin P. (1998) PNAS

30    95, 8829-8834 have shown an inhibition of tumour growth and vascularization, and also a reduction in lung metastases, during adenoviral infections or injections of the extracellular domain of Tie-2 (Tek) into models of melanoma and breast tumour xenografts.

35    For the reasons that follow, the Tie2 inhibitors may be used in situations in which neovascularization or angiogenesis takes place inappropriately, i.e. in cancers in
 
general, but also in particular cancers such as Kaposi's sarcoma or infantile haemoangioma, rheumatoid arthritis, osteoarthritis and/or the associated pain, inflammatory diseases of the intestine such as haemorrhagic rectocolitis or Grahn's disease, eye pathologies such as age-related macular •degeneration, diabetic retinopathies, chronic inflammation and psoriasis.

Angiogenesis is a process of generation of new blood capillaries from pre-existing blood vessels. Tumoral angiogenesis (formation of new blood vessels), which is essential for tumoral growth, is also one of the essential factors of metastasic dissemination
10    (Oncogene. 2003 May 19; 22(20):3172-9; Nat. Med. 1995 Jan; 1(1):27-31).

This neovascularization is due to the migration and then the proliferation and differentiation of endothelial "cells under the influence of angiogenic factors secreted by
cancer cells and stromal cells (Recent Prog. Harm. Res. 2000; 55:15-35; 35-6).

15

The angiopoietin 1ffie2 receptor system plays a predominant. role in the maturation of blood vessels by allowing the recruitment of periendothelial cells to st~bilize the vessel
(Cell. 1996 Dec. 27; 87(7): 1161-9, Recent Prog. Harm. Res. 2004; 59:51-71). Thus, it has been shown that the administration of the soluble recombinant form of the

20    extracellular domain of the Tie2 receptor (exTek) inhibits tumoral angiogenesis in models of murine tumours, and also metastasic growth (Proc. Nat! Acad. Sci. USA. 1998 Jul 21;95(15):8~29-34; Cancer lmmunol. lmmunother. 2004 Jul; 53(7):600-8). IQ endothelial cells in culture, stimulation of Tie2 activates the Pl3 kinase route; of p42/p44 routes involved in cell proliferation and migration; of the synthesis of PAF.(Cell Signal.
25    2006 Apr 14; ahead of print), a route involved in pro-inflamm0tory activity. Stimula!ion of Tie2 stimulates the Akt route and inhibits apoptosis (Exp. Cell Res. 2004 Aug. 1; 298(1 ): 167-77), a transduction route known for its importance in cell survival.

The addition of exTek (soluble receptor of Tie2) inhibits the fon11ation of pseudotubules

30    of endothelial cells on Matrigel (Cancer lmmunol. lmmunother. 2004 Jul; 53(7): 600-8). These studies indicate that the Tie2/angiopoietin system is necessary during the first stages of formation of vascular buds in adult tissues i3fld that one function of the Tie2 receptor is to increase the survival of endothelial cells during the formation of blood

vessels. Furthermore, angiopoietin-1 stimulates the proliferation of lymphatic endothelial

35    cells and also lymphangiogenesis (development of new lymphatic vessels), a favoured route of access for metastasic growth (Blood. 2005 Jun 15; 105(12): 4649-56).

Angiogenesis processes also play a predominant role in the progression of numerous

solid  tumours.  Furthermore,  it  has  been  shown  that  the  probability  of  onset  of

metastases  increases  very  greatly  as  the  vascularization  of  the  primary  tumour

increases (Br. J. Cancer. 2002 May 20; 86(10): 1566-77.

The potential role of pro-angiogenic agents in leukaemias and lymphomas has also more recently been documented. Specifically, it has been reported in general that cell clones in these pathologies maY be either naturally destroyed by the immune system, or

10    revert to an angiogenic phenotype that favours their survival and then their proliferation.

This change in phenotype is induced by an overexpression of angiogenic factors especially by the macrophages and/or mobilization of these factors from the extracellular matrix (Thomas DA, Giles FJ, Cortes J, Albitar M, Kantarjian HM., Acta Haematot., (2001), vol207, pp .. 106-190.

15

There is a correlation between the angiogenesis process of bone marrow and "extramedullar disease•s" in CML (chronic myelomonocytic leukaemia). Various studies demonstrate that the inhibition of angiogenesis might represent a treatment of choice in
this. pathology (Leuk. Res. 2006 Jan; 30(1): 54-9; Histol. Histopathol. 2004 Oct.; 19(4):

20    1245-60). Furthermore; it is strongly suggested that activation of the 'l'ie2/angiopoietin system is involved in the development of angiogenesis of bone marrow in the case of patients suffering from multiple ll]Yeloma (Blood. 2003 Jul15; 102(2): 6~8-45.

Rheumatoid arthritis (RA) is a chronic disease whose aetiology is unknown. Although it'

25    affects many or.gans, the m.ost se:vere form of RA is progressive synovial inflammation of the joints resulting in their destruction. Angioge~esis appears to substantially affect progression of this pathology. Thus, it has been shown that activation of Tie2 regulates angiogenesis ia synovial tissues, promoting the development of rheumatoid arthritis
(Arthritis Rheum. 2003 Sep; 48(9): 2461-71 ).

30

It has also been shown that an overexpression of angiopoietin-1 and of Tie2 in the Synovial tissues of patients suffering from osteoarthritis is correlated to active
neovascularization (Shahrara S et at., Arthritis Res. 2002; 4(3)). Thus, it has been shown

that by blocking the activation of Tie2 by using an adenovirus that produces exTek

35    (soluble Tie2 receptor), an inhibition of angiogenesis, of the development of arthrosis and protection against bone degradation are obtained in a mouse model in which the


arthrosis is induced with collagen (Arthritis Rheum. 2005 May; 52(5):1346-B).

IBDs (inflammatory bowel disease) comprise two forms of chronic inflammatory diseases

of the intestine: UC (ulcerative colitis) and Grahn'sdisease (CD). IBDs are characterized

by an immune dysfunction that is reflected by an inappropriate production of inflammatory cytokines, inducing the establishment of a local microvascular system. This angiogenesis of inflammatory origin results in a vasoconstriction-induced intestinal
ischaemia (lnflamm. Bowel Dis. 2006 Jun; 12(6):515-23).

I 0 Eye pathologies in relation with neovascularization phenomena, such as age-related macular degeneration, are responsible for a large majority of the cases of blindness in

developed    countries.  The  molecular  signals  that  control  the  neovascularization

phenomena in the eye, such as VEGFs or angiopoietins, are targets of choice for these

pathologies (Campochiaro PA Expert Opin. Bioi. Ther. 2004 Sep; 4(9)). Thus, it has

15    been shown that blocking the activation of Tie2 by using an adenovirus thai produces exTek (soluble Tie2 receptor) inhibrrs•retinol and choroid neovascularization, which is the most common cause of loss of vision (Hum~ Gene Ther. 2001 Jul1; 12(10):1311-21).

A product in  accordance  with  the  invention  may be  used  for the manufacture  of a

20    medicament that is useful for treating a pathological conditton, in particular a cancer.

By virtue of th~ir low toxicity and their pharmacological and biological properties, t~e compOunds of the present invention find their application in the treatment of any

carcinoma having a substantial degree of vascularization or inducing metastases, or,

25    finally, in patllologies of the type such as lymphomas and leukaemias.

These compounds represent a treatment of choice either alone or in combination with _a suitable chemotherapy or radiotherapy and/or in combination with .other compounds having anti-angiogenic activity, for instance VEGF or FGF inhibitors. Thus, the products
30    of general formula (I) are especially useful for treating or preventing a pathological condition, characterized in that the product is administered alone or in combination with other active principles, especially anticancer agents Such as cytotoxic, cytostatic, anti-angiogenic or anti-metastasic products.

35    The compounds of the present invention may thus be administered alone or as a mixture wrth other anticancer agents. Among the possible combinations that may be mentioned
 




12

are:

•    alkylating   agents   and  especially  cyclophosphamide,   melphalan,   ifosfamide,

chlorambucil,  busulfan,  thiotepa,  prednimustine,  carmustine,  lomustine,  semustine,

streptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine

platinum derivatives such as, especially, cisplatin, carboplatin or oxaliplatin

•    antibiotics such as, especially, bleomycin, mitomycin •ardactinomycin

•    antimicrotubule  agents  such  as,  especially,  vinblastine,  vincristine,. vindesine,

vinorelbine and taxoids (paclitaxel and docetaxel)

•    anthracyclines such as, especially, doxorubicin, daunarubicin, idarubicin, epirubicin,

10    mitoxantrone and losoxantrone

•   group I and II topoisamerase inhibitors such as etoposide, tenipaside, amsacrine,

irinotecan, topotecan and tomudex

•    fluoropyrimidines such as 5-f\uorouracil, UFT and floxuridine

•    cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-15 mercaptomurine and 6-thioguanine
adenosine analo9ues such as pentostatin, cytarabine or f\udarabine phosphate

    •   methotrexate and folinic •acid
    •   various  enzymes  and  compounds  such  as  L-asparaginase,  hydroxyurea,  trans-
    retinoic acid, suramine, dexrazoxane, amifostine and herceptin, and  also oestrogen-
20    ba~ed and androgenio hormones  .
    •   antivascular agents such as•combretastatin derivatives, for example CA4P, chalcone
    or colchicine derivatives, for ex~mple ZD6126, and prodrugs thereof  .

•    anti-angiogenic agents such as bevacizumab, sorafenib or sunitinib malate

•    therapeutic agents that inhibit other tyrosine kinases, such as imatinib, gefitinib and 25 erlotinib.

When the compounds of the p~esent invention are combined with another treatment or with a radiation treatment, these treatments may then be administered simultaneously, separately or sequentially. The treatment will be adapted by the practitioner as a function

30    of the disease to be trealed. Definitions

The term "halogen''refers to an element chosen from F, Cl, Brand I.

35

The term ~'alkyl" refers to a linear or branched saturated hydrocarbon-based substituent


containing from 1 to 6 carbon atoms. The substituents methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimelhylethyl, pentyl, 1-methylbulyl, 2-methylbulyl, 3-methylbutyl, 1, 1-dimethylpropyl, 1,2-dimelhylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpenlyl, 2-melhylpentyl, 1-ethylbutyl, 2-ethylbutyl and 3,3-dimelhylbulyl are examples of alkyl substituents.

The  term  "alkylene11    refers  to  a  linear  or  branched  hydrocarbon-based  substituent

containing one or rJ:lore unsaturafions, and containing from 2 to 6 carbon atoms. The

substituents  ethylenyl,  1-methylethylenyl,  prop-1-enyl,  prop-2-enyl,  Z-1-methylprop-1-

10    enyl, E-1-methylprop-1-enyl, Z-1 ,2-dimethylprop-1-enyl, E-1 ,2-dimethylprop-1,enyl, but-1,3-dienyl, 1-methylidenylprop-2-enyl, Z-2-melhylbut-1, 3-dienyl, E-2-methylbul-1 ,3-dienyl and 2-methyl-1-methylidenylprop-2-enyl are examples of alkylene substiluents.

The  term  "alkynyl"  refers  to  a  linear  or  branched  hydrocarbon-based  substituent

15    containing at least two unsaturations borne by a pair of vicinal carbon ~.toms, and containing from 2 to 6 carbon atoms: The substiluents ethynyl; prop-1-ynyl; prop-2-ynyl; and but-1-ynyl are examples of alkynyl substiluents.

The term "aryl" refers to a monocyc!ic or polycyclic aromatic substituent containing from

20    6 to 14 carbon atoms. The substituenls phenyl, naphth+yl; naphth-2-yl; anlhracen-9-yl; 1,2,3,4-telrahydronaphth-5-yl; and 1,2,3,4-tetrahydronaphth-6-yl are examples of aryl substituents.

The  term "heteroaryl" refers to a monocyclic or polycyclic heteroaromatic substituent

25    containing from 1 to 13 carbon atoms and from 1 to 4 heteroatoms. The sub~tituents pyrrol-1-yl; pyrrol-2-yl; pyrrol-3-yl; furyl; thienyl; imidazolyl.; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; 1,2,4-triazolyl; oxadiazolyl; thiadiazolyl; letrazolyl; pyridyl; pyrimidyl;

pyrazinyl; 1,3,5-triazinyl; indolyl; benzo[b]furyl; benzo[b]thienyl; indazolyl; benzimidazolyl;

azaindolyl;  quinolyl;  Jsoquinolyl; carbazolyt;  and  acridyl  are  examples  of  heteroaryt

30    substituents.

The term "heteroatom" refers herein to an at least div8'1entatom other than carbon. N; 0; S; and Se are examples of heteroatoms.

35    The term "cyctoatkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon-based substituent containing from 3 to 12 carbon atoms. The substituents 'cyctopropyl;

cyclobutyl; cyclopentyl; cyclopentenyl; cyclopentadienyl; cyclohexyl; cyclohexenyl; cycloheptyl; bicyclo[2.2.1]heptyl; cyclooctyl; bicyclo[2.2.2]octyl; adamantyl; and perhydronaphthyl are examples of cycloalkyl substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon-

based substituent containing from 1 to 13 carbon atoms and from 1 to 4 heteroatoms.

Preferably, the saturated or partially unsaturated cyclic hydrocarbon-based substituent

will be monocycfic and will contain 4 or 5 carbon atoms and 1 to 3 heteroatoms.

10    The term 11substituted" refers to one or more substituents other than H, for example halogen; alkyl; aryl; heteroaryl, cycloalkyl; heterocyclyl; alkylene; alkynyl; OH; 0-alkyl; 0-
alkylene; 0-aryl; 0-heteroaryl; NH,; NH-alkyl; NH-aryl; NH-heteroaryl; N-alkyl-alkyl',in which alkyl'and alkyl are two identical or different alkyls; SH; S-alkyl; S-aryl; S(02)H;
8(02)-alkyl; S(O,)-aryl; SO,H; SO,-alkyl; SO,-aryl; CHO; C(O)-alkyl; C(O)-aryl; C(O)OH;

15    C(O)O-alkyl; C(O)O-!'ryl; OC(O)-alkyl; OC(O)-~ryl; C(O)NH 2; C(O)NH-alkyl; C(O)NH-aryl; NHCHO; NHC(O)-alkyl; NHC(O)-aryl; NH-cycloalkyl; NH-heterocyclyl.

A subject of the present invention is also the process for preparing the products of general formula (I) below:



(I)

20
in which R1, Ra, R.b. Rs, X, Ar, L and A are as• defined above, characterized in that a

product of general formula (II) below:
.    NH
R'i'-x~R5 (II)
N-N
'R,

in which R' is R3 or a precursor of R3, and X, R1, R and R  are as defined above, reacts
3    3    5

25    with a product of formula (Ill) below:
0

K',..L'ArJlR,b(Ill)
 


in which R,,, Ar, L and A are as defined above, to give the product of general formula (I).

A subject of the present invention is also,  as intermediate products, the products of

general formula (II), for which R',, X, R, and R5 are as defined above, and also lhe

producls of general formula (Ill), for which Ar, L and A are as defined above.

A subject of the present invention is also the process for preparing the intermediate

products of general fonmula (II) : . :gR    (II)

5
N-1'{
R,
10    in which  R',  X,  R  and  Rs are  as defined above,  characterized in that a product of

3 1 general formula (IV) below:
R~'5
-    OH
R;-N,fi"    (IV)

0

in which R, and R5 are as defined above, reacts with a product of general formula (V)

below:
R',----X-Gp (V)
15
in which Gp is a protecting group, X and R'3 are as defined above, to give the product of general formula (II).

A subject of the present invention is also the process for preparing the intermediate

20    products of general formula (Ill) below:
0

A_..-L-...,ArJlR,b  (Ill)

in which R,,, Ar and A are as defined above, and L is NH-CO-NH, characterized in that a

product of general fonmula (VI) below:
0
(-Ar-NH2    (VI)•

R,b

25    in which R,0, Ar is as defined above, reacts with a product of general formula (VII) below:

,FN\ (VII) 0 A


in which A is as defined above, to give the product of general formula (Ill).

A subject of the present invention is also a process for preparing the products of general

formula(!)
t
Ar..-L
R4a,N__(

~    / R4 b
R''XR)-R, (I)
N-"(
R,

in which R,  R3,  R,,  R,,,R,, X, Ar and A are as defined above, and L is NHCONH,

characterized in that a product of general formula (VIII) below:

Ar-NH2
~R4 a,r_ . ( R,b
R'i'~R, (VIII)
N-1'\
R,

in which R' is R3 or a precursor of R3,  and X, R~< %, ~a. ~b and R  are .as defined
3    5

10    above, reacts with 'lproduct 9fformula (VII) below:
FN\ (VII) 0 A

in which A is as defined above, to give the product of general formula (I')below
t
Ar_.....L

R4a'.N--(
~  l   R,b
.R'''X")\)-5 R  (I')
N-1>(
R,

in which the precursor R'3 is transformed into R, in order to obtain the product of general 15_ formula (I).

A subject of the present invention is also the process for preparing the intermediate products of general formula (VIII)
 

in which R'3is R3 or a precursor of R3, and Ar, X, R,, R3, ~a. R;b and R5 are as defined
above, characterized in that a product of general formula (IX) below:
__z,-No,

R'i'MR,R,b(IX)

N-1'(

R,

undergoes a reduction to give a product of general formula (VIII).

A subject of the present invention is also the process for preparing th~ intermediate

products of general formula (IXa)

Ar-ND:z
R  a, -- \
R'    ~ 4    r R,b
i'x"\\) - R, (IXa)
N-1'\
R,

10    in which R'3 .is R3 or a precursor of R,, R,, is (C1-C4)alkyl, and R.o isH, and X, R.1, R3 and R5 are as defined above, characterized in that a product of general formula (IXc) below:




in which R'3is R3 or a precursor of R3, R;e and R;b are H, and X, R,, R3 and Rs are as

15    defined above, undergoes an aminoalkylation to give a product of general formula (IXa) above.

A subject of the present invention is also the process for preparing the intermediate products of general formula (IXc)
 


in which R' is R3 or a precursor of R3, ~a and ~bare H, and Ar, X, R1. R3 and Rs are as
3

defined above, characterized in that a product of general formula (II) below:
~• lH'
R'i'-K)\)-5R (II)

N-N,

R,

in which R', X, R1 and R are as defined above, reacts with a product of general formula
3    5

(Xc) below:
0
)--Ar-N02    (Xc)

R4b

in which R,0 is H and Ar is as defined above, to give a product of general formula (lXc)

above.

10

A subject of the present inve~tion is also the process for preparing the intermediate

products of general formula (lXb)

in which R'3 is R3 or a precursor of R,, R,, isH, and R,0 is (C1-C4)alkyl, and Ar, X, R, R3

15    and R5 are as defined above, characterized in that a product of general fonmula (II) below:
~ t'
R'i'x~)-R 5      (II)

N-N
'R,

in which R', X, R1 and Rs are as defined above, reacts with a product of general formula
3

(Xb) below:

0
j'--Ar-N0  (Xb)
2

R 4b

in which R.b is (C1-C4)alkyl and Ar is as defined above, and then undergoes a reduction to give a product of general formula (IXb) above.

The  starting  materials  used  are commercially available or are  prepared  by  methods

known to those skilled in the art.

The term "protecting group Gp" means a group that makes it possible, on the one hand,

fo protect reactive functions such as a hydroxyl or an amine during a synthesis, and, on

10    the other hand, to regenerate the intact reactive function at the end of the synthesis.

Examples of protecting groups and of protection and deprotection methods are given in "Protective Groups in Organic Synthesis", Green et al., 2m:1 Edition (John Wiley & Sons,
Inc., New York).

15    The term "precursor of R3" means a group which makes it possible to generate, at the end of the reaction or synthesis, a.group R3. It is, for example, a -CH2-Rink resin when X is NH, or a 2,4-dimethoxybenzyl group.

The product according to the invention may be prepared using conventional methods of

20    organic chemistry. Scheme 1 below illustrates the methods used for the preparation of Examples 1 to 31. In this respect, it shall not constitute a limitation of the scope of the invention, as regards the methods far preparing the claimed compounds.

Rink Resin            H1•Ar•L•A•CHO(Iil)   
r~H (v)        ~       
fmoc    1• Plperidlne/DMF        r: JNaBH3CNIOCE   
+    2-HOB(I'DIC~MFr~~    MeOHIAcOH
Q    3-SnC12/DMF    N-u    2-TFNDCM    (i')   
                   
        (il)           
HN    OH  (iv}               

25    0

1-    Preparation of the intermediate resin (ii)

The Rink resin (v) is swollen in DMF. The DMF is filtered off and then replaced with a

50% solution of piperidine in DMF. After stirring for 30 minutes at room temperature, the

mixture is filtered and the resin is then successively washed with DMF, methanol and

DMF

Next, a solution of 3 equivalents of 4-nitro-3-pyrazo\ecarboxy\ic acid (iv), 3 equivalents of HOB! (hydroxybenzotriazole) and 3 equivalents of diisopropy\carbodiimide (DIG) in DMF

is added .to the resin. The mixture is stirred overnight at room temperature  and the

reaction mixture is then removed by filtration. The resin is washed three times with DMF,

twice with methanol and five times with DMF. The resin is then treated with molar lin

chloride (SnC12) solution overnight at room temperature. The reaction mixture is removed

10    by filtration. The resin is washed five times with DMF, twice with methanol, three times with DCM (dichloromethane) and twice with ether, and then dried under vacuum to give the resin (ii).

2-    Preparation of the products (i')by reductive amination

15

In a vial, the resin (ii) is swollen in dichloroethane (DCE). 3 equivalents .of aldehyde (iii)' dissolved in DMF are added, followed by 5 equivalents of sodium cyanoborohydride in
methanol containing 10% acetic acid. The mixture is maintained at 80°C for 2 hours.

After cooling, the reaction medium is filtered and the resin is washed successively twice

20    with methanol, thcee times .with DCM (dichloromethane), twice with methanol and three times with DCM. The final products are obtained by cleavage with a trifiuoroacetic acid/DCM solution (50/50) at room temperature for two hours. The product is isolated by filtration and evaporation of the solvent. The product (i')is purified either by normal-phase liquid chromatography or by preparative LC/MS.
25

Materials and methods

LC/MS an.alytical method A:

30    The analysis is performed on a Waters ZQ model mass spectrometer in negative and positive electrospray mode (range from 10 to 1200 amu) connected to an Agilent HP
1100 HPLC instrument. The separation is performed on a Waters Xbridge C18 column (3X50 mm, 2.5 ~m particie diameter) maintained at 60°C, USing an acetonitrile/water

gradient containing 0.1% (v/v) of fonmic acid and at a flow rate of 1.1 ml/minute. The

35    gradient rises from 5% to 100% acetonitrile over 5 minutes, is maintained at 100% for 30 seconds and is then returned to 5% over 1 minute. The total separation time is

7 minutes. In addition to the mass spectroscopy analysis, a UV detection (diode array) is performed at wavelengths of from 210 to 400 nm, along with an ELSD measurement (evaporative light scatlering) using a Sedere Sedex 85 instrument.

LC/MS analytical method B:

The analysis is performed on a Waters model ZQ mass spectrometer in negative and

positive e\ectrospray mode (range from 10 to 1200 amu) connected to a Waters Alliance

HT instrument.  The  separation  is  performed  on  a Waters  Atlantis  dC18  column  of

10    (2.1x50 mm, 5 ~m particle diameter) maintained at 25°C, using an acetonitrile/water gradient containing 0.1% (v/v) of trifluoroacetic acid and at a flow rate of 0.5 mVminute. The gradient rises from 5% to 85% acetonitrile over 5 minutes, and is then maintained at 90% for 1 minute. The total separation time is 7 minutes. In addition to the mass spectroscopy analysis, a UV detection (diode array) is performed at wavelengths of from
15    210 to 400 nm.

LC/MS Method preparative C:

The products are purified by preparative LC/MS using a Waters Fractionlynx system

20    composed of a Waters model 600 pump for the gradient, a Waters model 515 pump for the regeneration, a Waters Reagent Manager pump, a model• 2700 auto-injector, two
Lab Pro model Theodyne switches, a Waters diode array detector, a Waters ZMD model mass spectrometer and a model 204 fraction collector. The instrument is run by the
Waters FractionLynx•software. At the outlet of the separation column, 1/1000 of the flow

25    is diverted by means of an LC Packing Accurate splitter; this fiowis mixed with m'ethanol (fiow rate 0.5 m\/minute) and sent to the detectors:% is sent to ihe diode array andy, to
the mass spectrometer; the rest of the fiow (999/1 000) is sent to the fraction collector. The product is collected if the mass peak is observed by Fra~tionLynx, otherWise the fiow is directly discarded. The molecular formulae of the products are transferred to the

30    Fractionlynx software and the product is collected when the mass peaks [M+H]'and [M+Na]'are detected. The fractions are collected in vials, which are evaporated in a Jouan model RC10.10 rotary evaporator. The weight of product obtained is determined by measuring the w~ight of the vial after evaporation of the solvent. The information regarding the columns and the gradients used is given for each example in the fo!!owing
35    section.


LC/MS analytical method D:

The analysis is performed on a Waters SQD mass spectrometer in negative and positive

electrospray mode (range from 10 to 1200 amu) connected to a Waters Alliance HT

instrument. The separation is performed on a BEH column (2.1 x50 mm, 1. 7 ~m particle

diameter) maintained at 25°C, using an acetonitrile/water gradient containing 0.1% (v/v) of tr.ifluoroacetic acid and at a flow rate of 1 ml/minute. The gradient rises from 5% to 100% acetonitrile aver 2 minutes. 1n.addition to the mass spectroscopy analysis, a UV
detection (diode array) is perlonmed at wavelengths offrom 210 to 400 nm.

10

Example 1: 4-([3-phenyl]carbamoyl}oxy)benzyl]amino}-1 H-pyrazole-3-carboxamide

trifluoroacetate





Preparation of the resin (ii):

15    30 g of Rink resin (PolymerLab; 0.99 mmol/g) is swollen in 150 ml of DMF. After stirring for 10 minutes, tne DMF is filtered off and replaced with 150 ml of a solution of piperidine in DMF .(50/50, v/v). The mixlure is stirred for 1 hour and then fillered. The resin is washed successively with•five times 150 ml'ofDMF, twice 150 ml of methanol and three times 150 ml of DMF. Next, a solution of 14.1 g of 4-nitro-3-pyrazolecarboxylic acid

20    (90 mmol, 3 eq.) and 13.8 g of HOSt (90. mmol, 3 eq.) in 150 ml of DMF is added to the resin, immediately followeo by 13.8 ml of DIG (90 mmol; 3 eq.). The mixture is stirred for 16 hours at room temperature. The solution is filtered and !he resin is washed

successively with five times 150 ml of DMF, twice 150 ml of methanol, three times 150 ml of DMF ~nd then with 150 ml of a 1M SnCI2 solution (33 g in 150 ml). The mixture

25    is stirred at room temperature for 24 hours and is then filtered, and the resin is washed with five times 150 ml of DMF, twice 150 ml of methanol, three times 150 ml of DCM and twice 150 ml of ethyl ether. After drying under vacuum, 31 g of intermediate resin (ii) are isolated.
Preparation of Example 1:

30    100 mg of resin (ii) are swollen in 0.3 ml of DCE, and 72 mg of phenylcarbamic acid 3-fonmylphenyl ester (0.3 mmol; -3 eq.) dissolved in 0.2 ml of DMF are then added, followed by 33 mg of sodium cyanoborohydride (0.5 mmol; -5 eq.). The mixture is


heated at 80'Cfor 1 hour, and then filtered after cooling to room temperature. The resin is then washed successively with twice 1 ml of MeOK, five times 1 ml of DMF, three times 1 ml of MeOK and five times 1 ml of DCM. The product is cleaved by treating the resin with 1 ml of a 50/50 TFNDCM solution. The solution is evaporated and the crude product obtained is directly purified by preparative KPLC. 2.4 mg of expected product 1 are obtained (yield= 5%). ([M+H]+): 352). RT= 2.49 min (Method A)

Example 2a: 4-{[3-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl)amino)benzyl]-amino}-1H-pyrazole-3-carboxamide trifiuoroacetate.and Example 2b: 4-{[3-(([2-

10    fluoro-5-(trifl uoromethyl)phenyl] carbamoyl)amino )benzyl]amino)-1 H-pyrazole-3-carboxamide hydrochloride
~F~/CIH
0    H__)=/  )--- )=/ l'F
H,Ni-§~N    O    ~
N
H

Preparation of 1-(2-fluoro-5-lrifluoromethylpheny/)-3-(3-formylphenyl)urea:

A mixture of 484 mg of 3-aminobenzaldehyde (4 mmol) (polymerized form) and 290 ~I of

15    2-fluoro-5-trifiuoromethylphenyl isocyanate in 4 ml of DCE is treated in a GEM Discover microwave oven at 100'Cfor 10 minutes (power 90). After cooling, the mixture i~ poured

into 100 ml of saturated potassium hydrogen sulfate solution .and extracted with "twice 50 ml of ;thyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. 740 mg of the expected aldehyde (yield = 57%) are
20    obtained in an LC/MS purity of 82%. The crude product is used directly for the following steps. ([M+K]+): 327. RT= 4.28 min (acetonitrile/water gradient from 30% to 90%-Method B).
Preparation of Example 2a:

Example 2a was prepared according to the method described for Example  1,."starting 25    with   1   g   of  resin   (ii),   520   mg   of  1-(2-fluoro-5-trifluoromethylphenyl)-3-(3-fonnylphenyl)urea (1.6 mmol, 2 eq.) and 264 mg of sodium cyanoborohydride (4 mmol; -5 eq.). After puriFication by preparative HPLC, product 2a is obtained (ElMS ([M+H]+):
437. RT= 3.45 min. (Method A).

Preparation of Example 2b:

30    Example 2b was prepared according to the method described for Example 1, starting with 1 g of resin (ii), 520 mg of 1-(2-fluoro-5-trifluoromethy/phenyl)-3-(3-formy/phenyl)urea (1.6 mmo/, 2 eq.) and 264 mg of sodiul)l cyanoborohydride (4 mmo/;

-5 eq.). After filtration and evaporation, 301 mg of crude product are isolated (LC/MS purity 83%). The crude product is purified on a column of silica using a DCM/MeOH mixture (90/10) as eluent. 151 mg of pale yellow solid are isolated (43% yield). The product is dissolved in 2 ml of MeOH and is converted into its hydrochloride salt by addition of a 4N solution of HCl in dioxane. After evaporation, the product Z£ is isolated in the form of a pale yellow solid. (ElMS ([M+H]+): 437. RT= 3.45 min. (Method A).

1H NMR (06-MeOD) (600 MHz): 4.62 (s, 2H); 7.19 (d, 1H); 7.36 (2s, 2H); 7.40 (m, 1H); 7.49 (m, 1H); 7.76 (s, 1H); 7.78 (s, 1H); 8.62 (m, 1H)

10    Example 3:   4-[(3-([(2-fluorophenyl)carbamoyl]amino }benzyl)amino ]-1 H-pyrazole-

3~carboxamide trifluoroacetate


Preparation of 1-(2-fluordphenyV-3-(3-formy/phenyljurea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-

15    benzaldehyde (4 mmol) (polymerized form) and 548 mg of 2-fluorophenyl isocyanate in 4 ml of DCE. After cooling, the mixture is poured into 100 ml of saturated potassium hydrogen sulfate solution and extracted with twice 50 ml of ethyl acetate. The combined organic.phases are. washed with water, dried over sodium sulfate and evaporated. 864 mg of the expected aldehyde are isolated.in the form of a gum, in an LC/MS purity of

20    77%. A Cl)'stallizedfraction is obtained after trituration from ethyl ether. 165 mg of solid are isolated ([M+H]+): 259. RT= 4.28 min (acetonitrile/water gradient from 5% to 85%-

Method B).

Preparation of Example 3:

Example 3 was prepared according to the method described far Example 1, starting with is   200 mg of resin (ii),  104 mg of 1-(2-fiuorophenyl)-3-(3-formylphenyl)urea (0.4 mmal, 2 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 33 mg of product 3 are isolated. (yield= 43%). ElMS ([M+H]+): 369.

RT= 3.70 min (acetonitrile/water gradient from 5% to 85%- Method A).
 

Example 4: 4-[(3-{[(2-methoxyphenyl)carbamoyl]amino}benzyl)amino]-1 H-

pyrazole-3-carboxamide trifluoroacetate
- 0}--rO-
y~    0

~ Ht    )!oH
H,N'n    F  F

N-N
H

Preparation of 1-(2-methoxypheny0-3-(3-formy/pheny/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 597 mg of 2-methoxyphenyl isocyanate (4 mmol) in 4 ml of DCE. 300 mg of crude expected aldehyde are isolated and used directly in thefollowingstep. ([M+H]+): 271. RT= 5.14 min (acetonitrile/water gradient from 30% to 90%- Method B).
10    Preparation of Example 4:

Example 4 was prepared according to the method described for Example 1, starting •with 200 mg of resin (ii), 162 mg of 1-(2-methoxyphenyl)-3-(3-formylphenyl)urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 10.4 mg of product 4 are isolated. (yield = 11 %). ElMS ([M+H]+): 381.
15    RT= 3.84 min (acetonitrile/water gradient from 5% to 85%- Method A).

Example 5: 4-{[3-({[2-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}amino)benzyl]-amino}-1 H-pyrazole-3-carboxamide trifluoroacetpjate

F
0-L.    F
0    HN Y~r~

H2N~
N-N
H

20    Preparation of 1-(2-fluoro-3-trifluoromethy/pheny/)-3-(3-formy/pheny/)urea:

The product was prepared es described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized fonm) and 820 mg of 2-fiuoro-3-trifiuoromethylphenyl isocyanate (4 mmol) in 4 ml of DCE. 300 mg of crude expected

aldehyde are isolated and used directly in the following step. ([M+H]+): 327. RT ; 4.21 min (acetonitrile/water gradient from 30% to 90% -Method B).
Preparation of Example 5:

Example 5 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 195 mg of 1-(2-fluoro-3-trinuoromethy\pheny\)-3-(3-formy\pheny\)-urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 31.4 mg of product 5 are isolated. (yield; 29%). ElMS ([M+H]+): 437. RT; 3.33 min (acetonitrile/water gradient from 5% to 100%- Method A).

10    Example 6: 4-[(3-{[(3-methoxypheny\)carbamoy\]amino}benzyl)amino]-1H-pyrazoJe .. 3..carboxamide trifluoroacetate

Preparation of.1-(3-met/Joxyphenyl}-3-(3-formylphenyl)urea:

The product was prepar.ed as described in Example 2, starting with 484 mg of 3-amino-

15    benzaldehyde (4 mmol) (polymerized forTl)) and 597 mg of 3-methoxypheny\ isocyanate (4 mmol) in 4 ml of DCE. 598 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 271. RT; 5.05 min (acetonitrile/water gradient from 30% to 90%- Method B).
Prapaiation of Example •6:

20    Example 6 was prepared according to the method described for Example 1, starting with 200 m~ of resin (ii), 162 mg of 1-(3-methoxypheny\)-3-(3-formy\pheny\)urea (0.6 mmo\, 3 eq.) and 66 mg of sodium cyanoborohydride {1 mmo\; -5 eq.). After purification by preparative HPLC, 17 mg of product 6 are isolated. (yield; 17%). ElMS ([M+H]+): 381. RT; 2.47 min (acetonitrile/water gradient from 5% to 100%- Method A).
25

Example 7: 4-{[3•({[3-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)benzyl]•

amino}-1H-pyrazofe-3-carboxamide trifluoroacetate

FPr~- IF 0 - F F
0    HN Y~~~ 0
H2N~   \)loH
N-N F F H

Preparation of 1-(3-lluoro-5-trinuoromethyiphenyl)-3-(3-formylpheny/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized fonm) and 597 mg of 3-ftuoro-5• trifluoromethylphenyl isocyanate (4 mmol) in 4 ml of DCE. 924 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 327. RT= 4.48 min (acetonitrile/Water gradient from 30% to 90% • Method B).
I 0    Preparation of Example 7:

Example 7 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 196 mg of 1•(3-fluoro-5-trifluoromethyfphenyl)-3•(3-formylphenyl)• urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 33.6 mg of product 7 are isolated. (yield= 31 %). ElMS

15    ([M+H]+): 437. RT= 3.55 min (acetonitrile/wafer gradient from 5% to 100%- Method A).

Example 8: 4-{[3•({[4-(trifluoromethoxy)phenyl]carbamoyl)amino)benzyl]amino}-

1 H-pyrazole-3-carboxamide trif/uoroacetate
[,~
0    ¢ F
0HN Y~~~F,~
H,N~    F'\'OH

N•N
H

20    Preparation of 1-(4-trifluoromethoxypheny/)-3-(3-formylphenyljurea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino• benzaldehyde (4 mmol) (polymerized fonm) and 812 mg of 4-trifluoromethoxyphenyl

isocyanate (4 mmol) in 4 ml of DCE. 558 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+ ): 325. RT= 4.13 min (acetonitrile/water gradient from 30% to 90% - Method B).
Preparation of Example 8:

Example a was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 195 mg of 1-(4-frifiuoromethoxyphenyl)-3-(3-formylphenyl)urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After pilriffcation by preparative HPLC, 26.3 mg of product 8 are isolated. (yield = 24%). ElMS ([M+H]+): 435. RT= 3.34 min (acetonitrile/water gradient from 5% to 100%- Method A).

10

Example 9: methyl 3-{[(3-{[(3-carbamoyt-1 H-pyrazol-4-yl)amina]methyl)phenyl)-

carbamoyl]amino}benzoate trifluoroacetate

0"}-N~p

y-~ H

~ H~•    0
H2N'-n    VaH
N-~    F  F

Preparation of 1-(3-methoxycarbony/)-3-(3-fonmy/pheny/)urea.

•15 The product was prepared as described in .Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized farm) and 812 mg of methyl 3-isocyanobenzoate (4 mmol) in 4• ml of o•cE. 695 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 299. RT= 2.94 min (acetonitrile/water gradient from 30% to 90% -Method 8).
20    Preparation of Example 9:

Example 9 was prepared according to the method described for Example 1, starting with

200 !"g of .resin (ii); 180 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 25.3 mg of product 9 are isolated. (yield = 24%). ElMS ([M+H]+): 409. RT= 2.67 min
25    (acetonitrile/water gradient from 5% to 100%- Method A).

Example 1O: 4-{[3-( {[4-(trifluoromethyl)phenyl]carbamoyl}amino )benzyl] amino }-1 H-

pyrazole-3-carboxamide trifluoroacetate
Preparation of 1-(3-fonnylphenyl)-3-(4-trifluoromethylphenyDunea:

The product was prepared as •described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized fonm) and 748 mg of 4-trifiuoromethylphenyl isocyanate •(4 mmol) in 4 ml of DCE. 696 mg of crude expected aldehyde are isolated and used dfrectly in the following step. ([M+H]+): 309. RT= 4.14 min (acetonitrile/water gradient from 30% to 90% -Method B).
10    Preparation of Example 10:

Example 10 W?S prepared according to the method descr[bed for Example 1, starting with 200 mg of resin (ii), 185 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium

cyanoborohydride (1 mmol; -5 eq.). After purification by preparativ~ HPLC, .20.9 mg of

product  10  are  isolated.  (yield  =  19%).  ElMS  ([M+l:i]+):  419.  RT=  3.33  min

15    (acetonitrile/water gradient from 5% to 100%- Method A).

Example 11: 4-{[3-( {[3-(trifluoromethyl)phenyl]carbamoyl}amino )benzyl]amino}-1 H-pyrazofe .. 3-carboxamide trifluoroacetate
0   HN Ya~~~Pi,?t
H2N~    \"oH
N-N    F  F
H

20    Preparation of 1-(3-formy/pheny/)-3-(3-trifluoromethy/phenyDurea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized fonm) and 748 mg of 3-trifiuoromethylphenyl isocyanate (4 mmol) in 4 ml of DCE. 744 mg of crude expected aldehyde are isolated

and used directly in the following step. ([M+H]+): 309. RT= 4.04 min (acetonitrile/water gradient from 30% to 90% - Method B).
Preparation of Example 11:

Example 11 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 185 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 25.9 mg of product 11 are isolated. (yield = 24%). ElMS ([M+H]+): 419. RT= 3.25 min (acetonitrile/water gradient from 5% to 100%- Method A).

10    Example 12: 4-{[3-({[2-(trifluoromethyl)phenyl]carbamoyl}amino)benzyl]amino}-1H-pyrazole-3-carboxamide trifluoroacetate
o}-PfF
0    HN Y ~   0
H,N~    )loH

N-N    F  F
H

Preparation of 7-{3-formylphenyl)-3-(2-trifluoromethy/pheny/)urea:

The product"was prepar~d as described in Example 2, starting with 484 mg of 3-amino-

15    benzaldehyde (4 mniol) (polymerized form) and 748 mg of 2-trifiuoromethylphenyl isocyanate (4 mmol) in 4 ml of DCE. 744 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 309. RT= 5.51 min (acetonitrile/water gradient from 30% to 90% - Method B).
Preparation of E_xampje 12:

20    Example 12 was prepared according tp the method described for Example 1, starting with. 200 mg of resi~ (ii), 185 mg •of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohYctride (1 mmol; -5 eq.). After purification by preparative HPLC, 17.5 mg of product 12 are isolated. (yield = 16%). ElMS ([M+H]+): 419. RT= 2.64 min (acetonitrile/water gradient from 5% to 100% -Method A).

25


Exam pie 13: 4-[(3-{[(3,5-dimethoxyphenyl)carbamoyl]amino)benzyl)amino]-1 H-

pyrazole-3-carboxamide trifluoroacetate

    I
    op-o
    \
o'}-~
0   HN Y~    0
H2N~    \)loH
N-N    F  F
H   

Preparation of 1-(3-formylphenyl)-3-(3,5-dimethoxypheny/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 717 mg of 3,5-dimethoxyphenyl isocyanate•(4 mmol) in 4 ml of DCE. 893 mg of crude expected aldehyde are isolated and used directly in theJ~IIowing step. ([M+H]+): 301. RT= 2.99 min (acetonitrile/water gradient from 30% to 90% -Method B).
I 0    Preparation of Example 13:

Example 13 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 180 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After puriflcation by p~eparative HPLC,'14.9 mg of product 13 are isolated.' (yield = 14%). ElMS ([M+H]+): 411. RT,; 4.61 min
15    (acetonitrile/water gradient from 5% to 85%- Method A).

Example 14: 4-[(3-{[(3-methylp henyl)carbamoyl]amino}benzyl)amino]-1 H-pyrazole-

3-carboxamide trifluoroacetate
~~~~
H,N-<0    }F    o-
Na    d

N,~    Fx;'OH

20    Preparation of 1-(3-formylpheny/)-3-(3-to/yi)Drea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 533 mg of 3-tolyl isocyanate (4 mmol) in 4 ml of DCE. 629 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 255. RT= 3.27 min (aceto~itrile/water gradient from 30% to
 

90% - Method B).

Preparation of Example 14:

Example 14 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 153 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 17 mg of product 14 are isolated. (yield = 18%). ElMS ([M+H]+): 365. RT= 4.66. min (acetonitrile/water gradient from 5% to 85% - Method B).

Example 15: 4-[(3-{[(4-methoxyphenyl)carbamoyl]amino}benzyl)amino]-1 H-

10    pyrazole-3-carboxamide trifluoroacetate
        0
0    Hp?-L
H,N~    )    \__(
l1    F.Rl
~        Fx; ~OH
Preparation of 1-(3-formylphenyl)-3-(4-methoxyphenyl)urea:

The product was prepared as described in Example 2; starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 597 mg of 4-methoxyphenyl isocyanate

15    (4 mmol) in 4 ml of DCE. 747 mg of crude expected aldehyde are isolated and used dir~c!ly in ihe follo_.;ing step. ([M+H]+): 271. RT= 2.53 min (acetonitrile/water gradient from 30% to 90% - Method B).

Preparation of Example 15:

Example 15 was prepared according to the method described for Example 1, starting

20    with 200 mg of resin (ii), 162 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 2.6 mg of product 15 are isolated. (yield = 3%). ElMS ([M+H]+): 381. RT= 4.3 min (acetonitril~/water gradient from 5% to 85% - Method B).

25    Example 16: 4-[(3-{[( 4-fluorophenyl)carbamoyl]amino)benzyl)amino]-1 H-pyrazole-

3-carboxamide trifluoroacetate
o    ptL
H,N-{  )    \__(
l)    F
'~    FvFOH
 




33

Preparation of 1-(3-formy/pheny/)-3-(4-ffuoropheny/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 548 mg of 4-fluorophenyl isocyanate (4 mmol) in 4 ml of DCE. 760 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+Hj+): 259. RT= 2.86 min (acetonitrile/water gradient from 30% to 90%- Method B).
Preparation of Example 16:

Example 16 was prepared according to the method described for Example 1, starting with 200 mg of resin (il), 155 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium

10    cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 0.6 mg of product 16 are isolated. (yield = 1%). ElMS ([M+H]+): 369. RT= 4.44 min (acetonitrile/water gradient from 5% to 85%- Method B).

Example 17: 4-{[3-{{[4-chloro-3-{trifluoromethyl)phenyl]carbamoyl}amino)benzyl]-

15    amino}-1H-pyrazole-3-carboxamide trifluoroacetate
    -  J--H
0    n-~~.F
H,N--<  }F    "L(i
N'!:)    ~    Cl F F
'~    F.FOH   

Preparation of 1-(3-formy/pheny/)-3-(3-trifluoro-4-ch/orophenyljurea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-

benzaldehyde    (4 mmol)   (polymerized   form)   and   886   mg   of   4-chloro-3-

20    trifluorofluorophenyl isocyanate (4 mmol) in 4 ml of DCE. 117 mg of crude expected

aldehyde are isolated and used directly in the following step. ([M+H]+): 343. RT= 4.66 min (acetonitrile/water gradient from 30% to 90%- Method B).

Preparation of Example 17:

Example 17 was prepared according to the method described. for Example 1, starting

25    with 200 mg of resin (ii), 206 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 7.3 mg of product 17 are isolated. (yield = 6%)._ ElMS ([M+H]+): 453. RT= 5.38 min (acetonitrile/water gradient from 5% to 85% -Method B).
 




34

Example 16: 4-{[3•({[4•(difluoromethoxy)phenyJ]carbamoyJ}amino)benzyl]amino}•

1 H~pyrazole~3-carboxamide trifiuoroacetate
P,_~
o    L:~ ~ k
H2N-< }    'L(
lJ    F;  R    o
N    ->(  'OH   F--(
H    F  F    F

Preparation of 1•(3'formylphenyl)-3-(4-difiuoromethoxyphenyl)urea:

The•product was prepared as described in Example 2, starting with 464 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 741 mg of 4-difluoromethoxyphenyl isocyanate (4 mmol) in 4 ml of DCE. 640 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 307. RT= 3.39 min (acetonitrile/water gradient from 30% to 90% •Method B).
10    •Preparati~n of Example 18:

Example 18 was prepared according to the method described for Example -r,-•starting

with 200 mg of resin (ii), 184 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 28.9 mg of product 16 are isolated. (yield = 27%). ElMS ([M+H]+): 417. RT= 4.9 min

15    (acetonitrile/water gradient from 5% to 85%- Method B).

Example 19: 4-{[3'(([2-chloro-4-(trifluoromethyl)phenyl]carbamoyl}amino}benzyl]•

amino }-1 H-pyrazole-3-carboxamide trifluoroacetate

(), _ O~~    Cl
H,N_z }F  ~ t-f
l)    )/OH  ~F
~    F  F    F

20    Preparation of 1-(3-formy/pheny/)•3•(2-ch/oro-4-trifiuoromethylpheny/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 886 mg of 2-cholro-4-

trifluoromethylphenyl  isocyanate  (4 mmol)  in 4 ml  of DCE.  1 g  of crude  expected

aldehyde is isolated and used directly in the following step. ([M+H]+): 343. RT = 4.66 min

25    (acetonitrile/water gradient from 30% to 90%- Method B).

Preparetion of Example 19:
 




35

Example 19 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 206 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 24.3 mg of product 19 are isolated. (yield = 22%). ElMS ([M+H]+): 453. RT= 5.36 min (acetonitrile/water gradient from 5% to 85% -Method B).

Example 20: 4-[(3-{[(4-methylphenyl)carbamoyl]amino}benzyl)amino]-1 H-pyrazole-

3Mcarboxamide trifluoroacetate
p-J-Mq
H,N~/ FO~
{)    XoH
H    F

10    Preparation of 1-(3-formy/pheny/)-3-(4-to/y/)urea:

The product was prepar!3.d as described h Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 533 mg of 4-tolyllsocyanate (4 mmol) in
4 ml of DCE. 683 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+HJ+): •255. RT = 3.16 min (acetonitrile/water gradient from 30% to

15    90% -Method B).

Pr~paration of Example 20:

Example 20 was prepared according to the method described for Example 1, starting

with 200 mg of resin (ii), 153 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 15.3 mg of

20    product 20 are isolated. (yield = 16%). ElMS ([M+H]+): 365. RT= 4.58 min (acetonitrile/water gradient from 5% to 85%- Method B).•

Example 21: 4-[(3•{[(2,5-dimethylphenyl)carbamoyljamino}benzyl)amino]•1H•

pyrazoleM3-carboxamide trifluoroa~etate
P)L~
\\.t.i~)=(
H2N--<0   /~ •.    y
Nl!J\    F. R
~    F~ 'OH
25

Preparation of 1-(3-formy/phenylj-3-(2,5-dlme/hy/pheny/)urea;
 




36

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 589 mg of 2,5-dimethylphenyl isocyanate (4 mmol) in 4 ml of DCE. 660 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 269. RT= 3.39 min (acetonitrile/water gradient from 30% to 90% - Method B).
Preparation of Example 21:

Example 21 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 161 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 26.7 mg of

10    product 21 are isolated. (yield = 27%). ElMS ([M+H]+): 379. RT= 4.68 min (acetonitrile/water gradient from 5% to 85%- Method B).

Example 22: 4-[(3-{[(3,4-dimethylphenyl)carbamoyl]ami no}benzyl)amino)-1 H-

pyrazole-3-carboxamide trifiuoroacetate
r=L 0)--H
H,N__;z  }Y  ~ h
Nl()    F, R  ~
~    F-\ "OH
15

/?reparation of 1-(~-formytpheny/)-3-{3,4-dimethy/phany/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4'mmol) (polymerized form) and 589 mg of 3,4-dimethylphenyl isocyanate (4 mmol) in 4 ml of DCE. 621 mg of crude expected aldehyde are isolated

20    and used directly in the following step. ([M+H]+): 269. RT= 3.55 min (acetonitrile/water gradient from 30% to 90% - Method B).
Preparation of Example 22:

Example 22 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 161 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium

25    cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 32 mg of product 22 are isolated. (yield = 32%). ElMS ([M+H]+): 379. RT= 4.8 min (acetonitrile/water gradient from 5% to 85%- Method B).
 




37

Example 23: 4-[(3-{[(2-methylphenyl)carbamoyl]amino}benzyl)amino]-1H-pyrazole-

3~carboxamide trifluoroacetate
-  J--H
(}-~>=;
0    u
H,N-'( }_JJ
l3    :x;oH°
N,~

Preparation of 1-(3-formy/pheny/)-3-(2-to/yl)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-

benzaldehyde (4 mmol) (polymerized form) and 533 mg of 2-tolyl isocyanate (4 mmol) in 4 ml of DCE. 621 mg of crude expected aldehyde are isolated and used directly in the following step. {[M+H]+): 255. RT= 5.14 min (acetonitrile/water gradient from 30% to 90% - Method B).
I 0    Preparation of Example 23

Example 23 was prep!!red according to the method described for Example 1, starting with 200 mg of resin (ii), 153 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative KPLC, 16.7 mg of product 23 are isolated. (yield = 17%). ElMS ([M+H]+): 365. RT= 4.5 min
15    (acetonitrile/water gradient from 5% to 85'/o-Method B).

Example 24: 4-[(3-{[(3-ethylphenyl)carbamoyl]amino)benzyt)amino]-,i H-pyrazole-3-

carboxamide trifluoroacetate    -    )L   
0           
           
H,Ni--§~Y~ ~   
r ~    F    o   
N,N    F)(loH   
H        F   

20    Preparation of 1-(3-formy/phenyl)-3-(3-ethy/pheny/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 589 mg of 3-ethylphenyl isocyanate {4 mmol) in 4 ml of DCE. 732 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 255. RT= 5.51 min (acetonitrile/water gradient
25    from 30% to 90% - Method B).

Preparation of Example 24 :

Example 24 was prepared according to the method described for Example 1, starting
 




38

with 200 mg of resin (ii), 160 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmo/; -5 eq.). After purification by preparative HPLC, 12.2 mg of product 24 are isolated. (yield = 12%). ElMS ([M+H]+): 365. RT= 4.5 min (acetonitrile/water gradient from 5% to 85% - Method B).

Example 25: 4-([3-({[3,5-bis(trifluoromethy/)phenyl]carbamoyl}amino)benzyl]•

amino}~1 Hppyrazole-3-carboxamide trifluoroacetate
-  ~~
H,N~ /~Y~ F()_ ;F
lJ    0    F~ I'F
'N    F,JL    F
H    F'\~OH

Preparation of 1-(3-formy/pheny/)-3-(3,5-bis-trifluoromethy/phenyf)urea:

10    The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzald~hyde (4 mmol) (polymerized form) and 1.02 g of 3,5-bis-trifluoromethy/pheny/ isocyanate (4 mmol) in 4 ml of DCE. 489 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 377. RT= 5.05 min (acetonitrile/water gradient from 30% to 90% - Method 8).

15    Prapara_tion of Example 25:

.Example 25 was. prepared according_ to the method described for Example 1, starting with 200 mg of• resin (ii), 225 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification l)y preparative HPLC, 3.3 mg of product 25 are isolated. (yield = 4%). ElMS ([M+H]+): 365. • RT= 4.5 min

20    (acetonitrile/water gradient from 5% to 85%- Method B).

Example 26: 4-[(3-{[(3-fluoropheriyl)carbamoyl]amino}benzyl)amino]-1 H-pyrazole-

3-carboxamide ~rifluoroacetate
0    ()--.~)-M)=_

H,N-< }F \_}-F l) v
'~    F   F  OH

25    Preparation of 1-(3-formyfpheny/)-3-(3-fluoropheny/)urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 548 mg of 3-fluorophenyl isocyanate
 




39

(4 mmol) in 4 ml of DCE. 723 mg of crude expected aldehyde are isolated and used directly in the following step. [M+H]+): 259. RT= 4.04 min (acetonitrile/water gradient from 30% to 90% - Method B).
Preparation of Example 26:

Example 26 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 155 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After purification by preparative HPLC, 23.5 mg of product 26 are isolated. (yield =• 25%). ElMS ([M+H]+): 369. RT= 4.7 min (acetonitrile/water gradient from 5% to 85% -Method B).
10

Example 27: 4-[(3-([(2-methoxy-5-methylphenyl)carbamoyl)amino}benzyl)amino)-

1 H-pyrazole-3-carboxamide trifluoroacetate
o p-1-~o-
H,Nt(    (\ ;j
N/~    F.Jl
'N    X  ~OH
H    F   F

Preparation of 1-(3-formy/phenyl)-3-(2-methoxy-5-methy/pheny/)urea:

15    The product was prepared as described in Example 2, startinQ with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 653 ,mg of 2-methoxy-5-methylphenyl
isocyanate (4 mmol) in 4 ml of DCE. 797 mg of crude expected aldehyde are isolated

~nd used directly in the following step. ([M+H]+): 285. RT= 2.94 min (acetonitrile/water gradient from 30% to 90% - Method B).

20    Preparation of Example 27:

Example 27 was prepared according to the method tlescribed for Example 1, starting

with 200 mg of resin (il), 170 mg of urea (0,6 mmol, 3 eq.) and 66 mg of sodium • cyanoborohydride (1 mmol; -5 eq,). After purification by preparative HPLC, 20 mg of product 27 are isolated. (yield = 25%). ElMS ([M+H]+): 395. RT= 5 min

25    (acetonitrile/water gradient from 5% to 85%- Method B).
 




40

Example 28: 4•[(3-{[(2,5•dimethoxyphenyl)carbamoyl]amino)benzyl)amino]•1H•

pyrazole-3-carboxamide trifluoroacetate
0    (}--~~H'>=<'b
H,N-z /HF     y
N~ di.  -o
'N    .)(  •oH
H    F  F

Preparation of 1,(3•formylphenyl)-3•(2,5•dimethoxyphenyl)urea:

The product was prepared•as described in Example 2, starting with 484 mg of 3-amino• benzaldehyde (4 mmol) (polymerized form) and 717 mg of 2,5-dimethoxyphenyl isocyanate (4 mmol) in 4 ml of DCE. 853 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+HJ+): 301. RT= 4.14 min (acetonitrile/water gradient from 30% to 90% •Method B).
10    Preparation of Example 28:

Example 28 was prepared according to the method described for Exampl~ .1, starting

with 200 mg  of resin  (ii), 170 mg of urea (0.6 mmol,  3 eq.)  and  66 mg of sodium

cyanoborohydride (1 mmol; -seq.). After purification by preparative HPLC, 11.8 mg of

product  28  are  isolated.  (yield  =  12%).  ElMS  ([M+H]+):  411.  RT=  4.72  min

15    (acetonitrile/water gradient from 5% to 85% •Method B).

Examp.le 29: 4•([3•({[3•chloro•4•(difluoromethoxyphenyl]carbamoyl}amino)benzyl]• amino}-1 H-pyrci.zole-3-carboxamide trifluoroacetate•
'11~~-0~ tro
'N    F>!oH   F--(
H    F    F

20    Preparation of 1-(3-formy/pheny/)-3-(3-ch/oro-4-difluoromethoxyphenyl}urea:

The product was prepared as described in Example 2, starting with 484 mg of 3-amino-benzaldehyde (4 mmol) (polymerized form) and 878 mg of 3-chloro-4-difluoromethoxyphenyl,isocyanate (4 mmol) in 4 ml of DCE. 936 mg of crude expected aldehyde are isolated and used directly in the following step. ([M+H]+): 341. RT= 4.21

25    min (acetonitrile/water gradient from 30% to 90% •Method B).

Preparation of Example 29:
 




41

Example 29 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 204 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). Alter purification by preparative HPLC, 8.3 mg of product 29 are isolated. (yield = 7%). ElMS ([M+H]+): 451. RT= 5.36 min (acetonitrile/water gradient from 5% to 85%- Method B).

Example 30: 4-[(3-{[(2,5-difiuorophenyl)carbamoyl]amino}benzyl)amino]-1 H-

pyrazole-3-carboxamide trif/iJoroacetate






10    Preparation of 1-(3'formylpheny/)-3-(2,5-dinuorophenyl}urea:

The producl was prepared as described in Example 2, starting•with 484 mg of 3-amino-benzaldehyde (4 mmoJ) (polymerized form) and 620 mg of 2,5-difluorophenyl isocyanate (4 mmol) in 4 ml of DCE. 952 mg of crude expected aldehyde are isolated and used
.directly in the following step. ([M+H]+): Z77. RT= 4.13 min _(acetonitrile/water gradient

15    from 30% to 90%- Method B).

Preparation of Example 30:

Example 30 was prepared according to the method described for Example 1, starting

with. 200 mg of resin (ii),  167 mg of urea (0.6 mmol,  3 eq.) and 66  mg of sodium

cyanoborohydride (1 mmol; -5 eq.). Alter purification by preparative HPLC, 14.1 mg of

20    product 30 are isolated. (yield = 14o/;). ElMS• ([M+H]+): • 387: RT= 4.82 min (acetonitrile/water gradient from 5% to 85%- Method B).

Example 31: 4-{[3-({[4-methyl-3-(trifluoromethyl)phenyl]carbamoyl}amino)benzyl]-

amino }-1 H-pyrazole-3-carboxamide trifluoroacetate
u_J--H
H,Ntl0y-t)~
Fs(-{

    'N    F
25    H   

Preparation of 1-(3-formy/pheny/)-3-(4-methy/-3-trifuoromethy/pheny/)urea
 




42








The urea was prepared in the following manner: 3 g of 3-nitrobenzaldehyde (20 mmol), 3.4 ml of ethylene glycol (60 mmol) and 0.3 g of para-toluenesulfonic acid dissolved in 250 ml of toluene are boiled for 4 hours and the mixture is then poured into 100 ml of saturated sodium bicarbonate solution and extracted with twice 50 ml of ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated under vacuum. The crude product is directly hydrogenated in 20 ml of THF in the presence of 160 mg of platinum oxide in a Parr flask. After hydrogenation for
4 hours at roorh temperature, the reaction mixture is filtered ihrough Celite. To avoid any 10 degradation, the aniline obtained is left dissolved in the THF at a c6ncEmtration of

10 mmol/20 ml and used in this form for the formation of the urea.

2 ml of the aniline solution (1 mmol) are treated with 200 mg of !1-methyl-3-trifluoromethylphe.nyl isocyanate for 4 hours at room t~mperature. The mixture is poured into 100 ml of •10% HCl solution and extracted with •twice 50 ml of ethyl acetate. The

15    combined organic phases are washed .with water, dried• over sodium sulfate and evaporated un.Per vacuum. 320 •mg of expected pro~uct are isolated in the form of a
solid. _(quantitative yield) ElMS ([M+H]+): 323. RT= 4.37 min (acetonitrile/water gradient from 30% to 90%- Method B).
Preparafi?n of Example 31:

20    Example 31 was prepared according to the method described for Example 1, starting with 200 mg of resin (ii), 193 mg of urea (0.6 mmol, 3 eq.) and 66 mg of sodium cyanoborohydride (1 mmol; -5 eq.). After puriftcation by preparative HPLC, 36.7 mg of product 31 are isolated. (yield = 34%). ElMS ([M+H]+): 433. RT= 4.64 min (acetonitrile/water gradient from 5% to 85%- Method B).
25

Example 32: methy14-{[3•({[2-fiuoro-5-(trifiuoromethyl)phenyl]carbamoyl}amino)-

benzyl]amino}•1H-pyrazole-3-carboxylate trifiuoroacetate
 




43

'Ko0 HN_p-~H0h
N~ ~  F, ~ F-(J--l

~    F.x;:-oH - .    F F

Compound 32 was prepared by direct reductive amination of methyl 4-amino-3-pyrazolecarboxylate. A solution of 44 mg of methyl 4-amino-3-pyrazolecarboxylate (0.31 mmol) and 100 mg of 1-(2-fiuoro-5-trifluoromethylphenyl)-3-(3-fonnylphenyl)urea (see Example 2) in a mixture of 0.6 ml of DCE and 0.5 ml of DMF is treated with a solution of 59 mg of sodium cyanoborohydride in 0.5 ml of methanol and 0.05 ml of

acetic acid. The mixture is stirred for 2 hours at ao~c and then cooled and poured into

20 ml of water. The mixture is extracted with twice 20 ml of ethyl acetate. The combined

organic phases are washed with water, dried over sodium sulfate and evaporated under

10    vacuum. After purification by preparative HPLC, 20.8 mg of product 32 are Isolated. (yield; 12%). EI~S ([M+H]+): 452. RT; 5.52 min.(acetonitril.e/water gradient from 5% t~ 85%- Method B).

Example 33: 4-(1-{3-i3-(2-fluoro-5-trifluoromethylphenyl)ureldo]phenylethylamino}-15 1 H-pyrazole-3-carboxamide trifluoroacetate (1 :1)







Preparation of 1-(3-acetylphenyl)'3-(2-fiuoro-5-trifiuoromethylphenyl)urea:

A mixture of 181 mg of 3-aminoacetophenone (1.34 mmol) and 275 mg of 2-fluoro-5-trifiuoromethylpheny/ isocyanate (1.34 mmol) in 1 ml of TiiF is. stirred at room

20    temperature for 1 hour and then evaporated. The solid is taken up in ether and filtered off. 307 mg of expected ketone (yield ; 69%) are isolated in an LC/MS purity of 87%. The crude product is used directly in the following step. ([M+H]+ ): 341. Ret. time: 6.06 min (Method A).
 



44

Preparation of Example 33:

450 mg of resin I (0.45 mmol) are swollen in 2 ml of DCE, and 307 mg of 1-(3-acetylphenyl)-3-(2-fluoro-5-trifluoromethylphenyl)urea (0.9 mmol; 2 eq.) dissolved in 2 ml of DMF are then added, followed by 149 mg of sodium cyanoborohydride (2.25 mmol; 5 eq.). The mixture is treated In a GEM Discover microwave oven at 100"C for 10
minutes (power 90). The resin is then washed successively with twice 2 ml of MeOH, three times 2 ml of dichloromethane, twice 2 ml of MeOH and three times 2 ml of

dichloromethane. The product is cleaned by treating the resin with 4 ml of a 50150

trifluoroacetic"acid/dichloromethane solution. The solution is evaporated and the crude

10    product obtained is purified directly by HPLC preparative. After freeze-drying, 13.5 mg of expected product are obtained (white solid, yield= 5%). ([M+H)+): 451). RT: 4.77 min (Method A)

Example 34: •4•({3-[3•(2-fluoro•5-trifluoromethylphenyl)ureido)benzyl}methyl-

15    amino)-1 H-pyrazole-3-carboxamide





A solution of 0.14 ml of 1-fiuoro-2-isocyanato-4-trifiuoromethylbenzene is added at 20"C to a solution of 0.25 g of 4-[(3-aminobenzyl)methylamino)-1H-pyrazole-3-carboxamide in 25 ml of anhydrous THF. The reaction medium is stirred for 12 hours at 20"C and then.
20• diluted with 100 ml of ethyl acetate. The organic phase is washed with 50 ml of distilled water, and is then separated out by settling of the phases, dried over magnesium sulfate

and. evapora.ted  to  dryness  under  reduced  pressure.  The  residue  obtained  is

chromatographed on a column of silica (15 g of Merck cartridge silica with a particle size of 15 to 45 ~m. column diameter 2.2 em, 5 ml fractions, flow rate of 10 ml/min, eluent

25    95/5 dichloromethane/methanol - by volume). Fractions 35 to 95 are combined and evaporated to dryness under reduced pressure. 0.02 g of 4-({3-[3-{2-fiuoro-5-

trifiuoromethylphenyt)ureido)benzyl)methylamino)-1 H-pyrazole-3-carboxamide is obtained in the fonm of a solid. {[M+H)+): 451). RT: 3.55 min {Method A)

4-[(3-Aminobenzyl)methylamino)-1 H-pyrazole-3-carboxamide is obtained in the following 30 manner:
 




45

3.6 g of tin chloride dihydrate are added portionwise at 20°C to a solution of 1.26 g of 4-[methyl(3-nitrobenzyl)amino]-1H-pyrazole-3-carboxamide in 90 ml of absolute ethanol.
The reaction medium is stirred for 15 hours at 20°C, and then brought to dryness under

reduced pressure. The residue is taken up in .500 ml of a 90/10 methylene chloride/methanol mixture (by volume) and 500 ml of saturated potassium hydrogen carbonate solution. This medium is stirred at 20°C for 2 hours and then filtered. The solid obtained after filtration is extracted twice with a mixture of 100 ml of 90/10 methylene chloride/methanot (by volume), and the liquid phases are combined and separated by settling. The aqueous phase is extracted with twice 200 ml of methylene chloride, and

10    the organic phases are combined, washed with 300 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. 0.6 g of 4-[(3-aminobenzyl)methylamino]-1H-pyrazole-3-carboxamide is obtained in the form of a cream-coloured foam. ([M+H]+): 246). RT: 0.3 min (Method
A)

15    4-[Methyl(3-nitrobenzyl)amino]-1H-pyrazole-3-carboxamide .is prepared in the following manner:
4.45 g of para-toluenesulfonic acid monohydrate are added to a solution of 2.49 g of 4-

[methyl(3-nitrobenzyl)amino]-1 H-pyrazole-3-carboxylic  acid  2,4-dimethoxybenzylamide

in 30 .ml of toluene, and the reaction medium is then heated at the reflux temperature of

20    the toluene for 17 hours. After cooling the reaction medium to room•temperature, 15 ml of methanol are added, followed by 700 ml of ethyl•acetate and finally 300 ml of distilled • water. The pH of this medium is adjusted to a value of 11 by adding 100 ml of aqueous 1N sodium hydroxide solution. This solution is filtered, the solid is extracted twice with 30 ml of ethyl acetate, and the liquid phases are combined and then separated by

25    settling of the phases. The aqueous phase is extracted with twice 200 ml of methylene chloride, the organic phases are combined, washed with 300 ml of saturated aqueo~s
sodium  chloride  solution,  dried  over  magnesium  sulfate,  filtered .and  evaporated  to

dryness under reduced pressure. 1.41 g of 4-[methy1(3-nitrobenzy/)amino]-1H-pyrazole-3-carboxamide are obtained .in the fonn of a beige-ooloured solid melting at 166°C.

30    ([lvl+H]+): 276). RT: 2.61 min (Method A)

4-[Methy/(3-nitrobenzyl)amino]-1 H-pyr~zole-3-carboxylic acid 2,4-dimethoxybenzylamide is obtained in the following manner:

A  solution  of  1.61  g  of  4-(3-nitrobenzylamino)-1H-pyrazole-3-carboxylic  acid  2,4-

dimethoxybenzylamide,  1.25  g  of  paraformaldehyde  and  0.94  g  of  anhydrous

35    magnesium sulfate in 70 ml of glacial acetic acid is stirred at room temperature for
 




46

4 hours. 1.23 g of sodium cyanoborohydride are then added portionwise to this solution.

The reaction medium is stirred for 2 hours at room. temperature, and then poured onto

300 ml of aqueous SN sodium hydroxide solution and 120 g of crushed ice, the pH being adjusted to 11. 300 ml of saturated sodium chloride solution are then added: This solution is filtered and the solid is washed three times with 60 ml of distilled water. The solid thus collected is air-dried. 1.51 g of 4-(methyl(3-nitrobenzyl)amino]-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide are obtained in the form of a pale yellow solid. ([M+H]+): 426). RT: 3.87 min (Method A).

4-(3-Nitrobenzylamino)-11'1-pyrazole-3-carboxylic acid   2,4-dimethoxybenzylamide   is

10    obtained in the following manner:

8.2 g of 3-nitrobenzaldehyde and 5.9 g of anhydrous magnesium sulfate are added to a solution of 15.43 g of 4-amino-1H-pyrazole-3-carboxylic acid-2,4-dimethoxybenzylamide

•hydrochloride  and  7.01   g  of  diisopropylethylamine  in  490  ml  of  anhydrous

tetrahydrofuran. The reaction medium is refluxed for 1 hour •30 minutes, allowed to cool
15    to 20oc and'then cooled to 5°C using an ice bath. 15.5 gof sodium cyanoborohydride

are added portionwise to the cream~coloured suspension obtained. The-rei3.ction medium is stirred for 5 minutes at soc and then allowed to wa.rm to room temperature. It is left stirring at room temperature for 20 hours. The cloudy orange-brown solution obtained is
poured into 1500 ml of distilled water. 1000 ml of dichloromethane are added to the light-

20    brown milky solution obtained. After stirring, •followed by separating out the chloromethylene phase by settling, the aqueous phase is re-extracted with twice 500 ml of dichloromethane. The organic phases are combi~ed and then washed with 500 ml of

saturated  aqueous  sodium  chloride  solution,  dried  Over magnesium  sulfate, •filtered

through paper and then  brought to dryness on a rotary evaporator (temp.  40oc P:

2~ 15 mbar). 27.19 g of a tacky yellow solid are obtained, which product is recrystallized from 360 ml of refluxing acetoritrile. A first crop of 7.7 g of 4-(3-nitrobenzylamino)-1H-pyrazole-3-carboxylic acid 2.4-dimethoxybenzylamide is obtained in the form of a yellow solid.
The acetonitrile filtrate is recovered and then brought to dryness on a rotary evaporator

30    (temp. 40°C P: 15 mbar). 19.7 g of a tackyochre-coloured mass are obtained, which product is triturated at 20°C with 50 ml of acetonitrile for 1 hour. The suspension obt~ined is filtered through a No. 3 sinter funnel and washed with twice 15 ml of

acetonitrile. After drying in air and then in a Heraeus oven (temp. 40°C P: 0.2 mbar), a second crop of 6.59 g of 4-(3-nitrobenzylamino)-1 H-pyrazole-3-carboxylic acid 2,4-

35    dimethoxybenzylamide is obtained in the form of a yellow solid. ([M+H]+): 412). RT: 3.93 min (Method A)
 




47

4-Amino-1H-pyrazole-3-carboxylic acid  2,4-dimethoxybenzylamide is  prepared  in  the

following manner:

27.64 g of tin chloride dihydrate are added portionwise to a suspension of 10.72 g of 4-nitro-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide in 600 ml of absolute
ethanol. The reaction medium is stirred for 48 hours at 20°C. The clear brown solution obtained is brought to dryness on a rotary evaporator. The clear brown foam obtained is
taken up in 700 ml of a 90/10 by volume a mixture of methylene chloride/methanol.

700 ml of saturated  aqueous sodium  hydrogen  carbonate  solution are  added to the

brown solution obtained. The cream-coloured suspension obtained •is stirred for 1 hour at

10    room temperature. 30 g of Clarcel Flo are added to the suspension and the mixture is then stirred for 10 minutes at room temperature. The resulting mixture is filte'red and the
filter cake is washed with twice 250 ml of a 90/10 by volume a mixture of methylene

chloride/methanol. The solid is drained by suction and the filtrate is recovered and then

transferred into a separating funnel. The chloromethylene phase is separated out by

15    settling and the aqueous phase is then re-extracted with twice 250 ml" of dichloromethane. •The organic phases are combined and then dried over magnesium sulfate, filtered through paper and then brought to dryness on a rotary evaporator. 8.53 g of 4-amino-1 H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide are obtained in the form of a pale pink solid. ([M+H]+]: 277). RT: 2.36 min (Method A)

20    4-Nitro-1H-pyrazole-3-carboxylic acid. 2,4-dimethoxybenzylamide• is obtained in the following manner:
23 g of 2,4-dimethoxybenzylamine and then 20.04 g of 98% 4-nitro.-3-pyrazolecarboxylic

acid are added to a solution of 28.76 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

hydrochloride and 20.27 g of 1-hydroxybenzotriazole in 100 ml of dimethylformamide.

25"    The reaction medium is stirred for at. room temp~rature for ~0 ho~rs. The clear yellow

solution obtained is then poured into 1000 ml of distilled water. A white suspensiop is obtained, which is left at room temperature for 1 hour. The suspen~ion is filtered and the filter cake is washed with three times 250 ml of. distillea water. The solid obtained is

drained by suction• and dried in air and then in a Heraeus oven under vacuum (temp.

30    40oc P: 0.2 mbar). 40.65 g of a white solid are obtained, which product is triturated in 750 ml of refiuxing isopropanol for 20 minutes. The suspension obtained is cooled in a bath of water + ice for 2 hours, and then filtered off. The filter cake is washed with twice

100 ml of isopropanol and then twice 100 ml of isopropyl ether. The solid obtained is

dried in air and then in a Heraeus oven (temp. 40°C P: 0.2 mbar). 32.16 g of 4-nitro-1H-

35    pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide are obtained in the form of a white solid melting at 204°C. ([M+H]+): 307). RT: 3.12 min
 



48


Example 35:  4-(ethyl{3•[3•(2-fiuoro-5-trifiuoiomethylphenyl)ureido]benzyl)amino)•

1H•pyrazole-3-carboxamide





4-(Ethyl-(3•[3•(2-fluoro-5-trifluoromethylphenyl)ureido]benzyl)amino)•1H-pyrazole-3-

carboxamide is prepared by condensing 1-fluoro-2-isocyanato-4-trifluoromethylbenzene

with    4-[(3-aminobenzyl)ethylamino]-1 H-pyrazole-3-carboxamide   according   to   the

procedure described in Example 34, the latter derivative itself being prepared from 4•[(3•

nitrobenzyl)ethylamino]-1 H-pyrazole-3-carboxamide  according  to  the  procedure  also

10    described in Example 34.

4-[(3-Nitrobenzyl)ethylamino]-1 H-pynazole-3-carboxamide is obtained in the following manner:
A solution of 2.2 g of 4-amino•1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide

hydrochloride and 1.3 ml of diisopropylethylamlne in 70 ml of THF is stirred for five

15    minutes, and 1.2 g of 3-nitrobenzaldehyde and Q.85 g of magnesium sulfate are then added to this solution. The reaction medium is refluxed for one hour and, after cooling to
45'C,74 g"of sodium triaoetoxyborohydride are added portionwise and the mixture is refluxed for a further three hours. Since not all the starting material has disappeared,

after cooling to 45'C,7.4 g of sodium triacetoxyborohydride are added portionwise, and

20    the mixture is refluxed for a further two hours. After cooling the reaction medium to room temperature, it is poured into 350 ml of distilled water. The pale yellow milky solution thus obtained is brought to pH 8-9 by adding 60 ml of aqueous 2N sodium hydroxide solution. 250 ml of dichloromethane are added and, after separation of the phasee by settling and then extraction of the aqueous phase with twice 150 ml of dichloromethane,

25    the organic phases are combined, washed with 250 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 3.19 g of a tacky oil are obtained, which product is-chromatographed on a column of silica (90 g of Merck cartridge silica with a particle size
of 15 to 45 ~m. column diameter 4.7 em, 15 ml fractions, flow rate of 18 ml/min, eluent

30    70/30 ethyl acetate/cyclohexane- by volume). Fractions 34 to 110 are combined and evaporated to dryness under reduced pressure. 2.22 g of 4-[(3-nitrobenzyl)ethylamino]-
 



49

1H-pyrazole-3-carboxamide are obtained in the form of a yellow foam. ((M+Hj+): 453). RT: 4.02 min (Method A)

Example 36: 4-({3-(3-(2-chloro•5-trifluoromethylphenyl)ureido]benzyl}methyl•

amino)-1 H-pyrazole-3-carboxamide




4-({3-[3-(2-Chloro-5-trifiuoromethylphenyl)ureido]benzyl)methylamino)-1H-pyrazole-3-

carboxamide is obtained by condensing 1-chloro-2-isocyanato-4-trifluoromethylbenzene

with    4-[(3-aminobenzyl)methylamino]-1H-pyrazole-3-carboxamide  according   to   !he

10    procedure described in Example 34. (lM+H]+ ): 467). RT: 3.81 min (Method A)

Example 37: 4•{3•(3-(4•trifluoromethylpyrid-2•YI)ureido]benzylamino}•1H•pyrazole•

3-carboxamide




15

88 ~I of triethylamine and 0.18 g of phenyl (4-trifiuoromethylpyrid-2-yl)carbamate are

added  at  20'C to  a solution  of  0.12  g  of 4-(3-aminobenzylamino)-1H-pyrazole-3-

carboxamide in 5 ml of anhydrous THF. The reaction medium is heated in a mic~owave

reactor for 20 minutes and, after cooling, is diluted wi!h 25 ml :of ethyl acetate. The

20    organic phase is washed wilh twice 15 ml of distilled water and then separated out by settfing of the phases, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is chromatographed on a column of silica (15 g

of Merck cartridge silica with a parjicle size of 15 to 45 ~m. column diameter 2.2 em,

3.5 ml fractions,  flow rate of 7 ml/min, ethyl acetate eluent).  Fractions 36 to 60 are

25    combined and evaporated to dryness under reduced pressure. 0.06 g of 4-{3-[3-(4-trifluoromethylpyrid-2-yl)ureido]benzylamino}-1 H-pyrazole-3-carboxamide is obtained In the fonn of a white solid. ([M+Hj+): 420). RT: 0.78 min (Method D).
 




50

Phenyl (4-trifluoromethylpyrid-2-yl)carbamate is prepared in the following manner:

0.81 ml of pyridine is added to a solution of 2-amino-4-trifluoromethylpyridine in 65 ml of anhydrous tetrahydrofuran, the reaction mixture is cooled to 5°C, and 0.95 ml of phenyl chloroformate is then added at this temperature. After stirring for 2 hours at 5oc, the
reaction mixture is a!fowed to warm to room temperature and is then poured into 20 ml of

distilled water and maintained at a temperature of 20°C. 50 ml of ethyl acetate are then

added, the phases are separated by settling and the aqueous phase is extracted twice

with 20 ml of ethyl acetate. The organic phases are_ combined, dried aver magnesium

sulfate, filtered and then evaporated to dryness. The solid obtained is triturated in 10 ml

10    of diisopropyl ether. 1.07 g of phenyl 4-trifluoromethylpyrid-2-yl)carbamate are obtained in the form of a white solid melting at 161°C. ([M+H]): 281). Rt:4.30 MIN (Method A)

Example 38: 4-{3-[3-(4-methoxypyrid-2-yl)u rei do]benzyl amino)-1 H-pyrazole-3-carboxamide




15

Example 39: (RS)-4-(1-{3-[3-(2-chloro-4-trifluoromethytphenyl)ureido]phenyl)ethyl-

amino)-1 H-pyrazole-3-carbOxamide trifluoroacetate

20







Exemples 40 to 58, described in Table A below, are obtained or could be obtained by

25    condensing the corresponding isocyanates with 4-[(3-aminobenzyl)amino]-1 H-pyrazole-3-carboxemide according to the procedure described in Example 34.
 



51

                                                    Table A               
                                                                   
                                                                   
            Example                    Structure        [M+H]+    RT(min)   
            No.                            !Method Dl       
                                                           
    40                ~~v\\xo0I...,:::F        403    0.78   
                                H                           
                                                                   
    41                1J""~cYY'C(-oI-"0        419    0.91   
                                   
                                H                           
                                                           
                                           
    42                ~~v\#-01y..,;::        453    0.96   
                                H    ,,               
                                                           
                                                               
                                                                   
                                        Q    01..-.::;               
    43                jd""~        442    n.d.   
                                   
                                H    -1'-               
    44        ~    or. ....,        435    n.d.   
                               
                    i/vYQH               
                                                y,               
                                                               
    45                                0I"""'F        453    0.92   
                                ir-v\-~a               
                                H                           
                                               
    46                H        0   • /  -"F        454    n.d.   
                                1J~m~-<'               
                                               
                                               
                                                F               
                                                           
    47                i>vYQ        451    0.91   
                                               
                                H        -.~f               
                                                F               
 




52

                                                                       
    48                    #    0    .&    393        0.86           
                            ~v~H                               
                                                                       
                                                                       
    49                ~NH~    411                n.d.   
                                                           
                                                                   
                        ~    "'">    HH    ,\   F                               
                                        F                               
    50                H    VYif.    477                n.d.   
                                               
                                                                       
                                                           
    51                i?~    437        0.96           
    52                ~""u\0-1...,~    393        0.86           
                            H                                           
                                                                   
                        ~        HH    0                               
    53            •9"'urey    428                n.d.   
                                                                       
    54                    . d0    14    383        0.74           
                            ~~v~~                               
                            H                                           
                                                       
    55                ~ ...v~~u0INF    437        0.89           
                                                           
                            H            F                               
    56                    "'0    {    383        0.74           
                            ~""U%H                               
    57                ~NH~"'01"'    399        0.8           
                            H                                           
 



53

58    i>~v~~HI""01-"'      399             0.81

n.d. not determined

Determination of the activity of the compounds •experimental protocols

1.    KDR

The inhibitory effect of the compounds is determined in an in vitro test of phosphorylation

of substrate with the enzyme KDR via a scintillation technique (96-well plate, NEN).

10    The cytoplasmic domain of the human KDR enzyme was cloned in the form of a GST fusion in the pFastBac bacu!ovlrus expression vector. The protein was expressed in the
SF21 cells and purified to about 60% homogeneity.

The KDR kinase activity is measured in 20 mM MOPS, 10 mM MgCI2,  10 mM MnCI2,

15    1 mM OTT, 2,5'mMEGTA, 10 mM b-glycerophosphate, pH= 7.2, in the presence of 10 mM MgCI2, 100 ~m Na,VO,, 1 mM NaF. 10 ~I of the compound are added to 70 ~I of

kinase buffer containing 100 ng of KDR enzyme at 4"C. The•reaction is lnitiafed by adding 20 ~I of solution containing 2 ~g of'substrate (SH2-SH3 fragment of PtCy expressed in the form of a GST fusion protein), 2 ~Ci of y''P[ATP]and 2 ~m of cold

20    ATP. After incubation for 1 hour at 37"C, the reaction is stopped by adding 1 volume (100 ~I) of 200 mM EDTA. The incubation buffer is removed, and the wells are washed three times with 300 ~I of PBS. The radioactivity in each '!'•IIis. measured using a Top Count NXT radioactivity counter (Packard).

25    The background noise fs determined by measuring the radioactivity in four different wells containing radioactive ATP and the substrate alone.

A total activity control is mea~ured in four different wells containing all the reagents (r"P-[ATP], KDR and substrate PLCy), but in the absence of compound,

30

The inhibition of the KDR activity with the compound of the invention is expressed as a percentage of inhibition of the control activity determined in the absence of compound.
 




54

Compound  SU5614 (Calbiochem) (1  ~M) is included  in each  plate as an inhibition

control.

2.    Tie2

The  coding  sequence  of  human  Tie2 • corresponding  to  the  amino  acids  of  the

intracellular domain 776-1124 was generated by PCR using the eDNA isolated from a

human  placenta  as  a  model.  This  sequence  was  introduced  into  a  pFastBacGT

baculovirus expression vector in the form of a GST fusion protein.

10

The inhibitory effect of the molecules is detenmined in a test of phosphorylation of PLC with Tie2 in the presence of GST-Tie2 purified to about 60% homogeneity. The substrate is composed of the SH2-SH3 fragments of PLC expressed in the form of a GST fusion

protein.

15

The kinase activity of Tie2 is measured in a MOPS 20mM pH 72"buffer, containing 10 mM MgCI2 , 10 mM MnCI,, 1 mM DTI, 10 mM of glycerophosphate. In a 96-well

FlashPiate plate maintained on ice, a reaction mixture is deposited, cqmposed of 70 l-JL

of kinase buffer containing 100 ng of enzyme GST-Tie2 per well. Next, 10 ~L of the test .

20    -molecule diluted in DMSO•to a maximum concentration of 10% are added. For a given concentration, each measurement is performed four times. The reaction is initiated by

adding 20 ~I of solution containing 2 ~g of GST-PLC, 2 ~m of cold ATP and 1 ~Ci of B"P[ATP]. After incubation for one hour at 37°C, the reaction is stopped by adding 1 volume (100 ~I) of 200 mM EDTA. After removal of the incubation buffer, the wells are

25    washed three times with 300 ~L of PBS. The radioactivity is measured on a MicroBeta1450 Wallac.

The inhibition of the Tie2 activity is calculated and expressed as a percentage of inhibition relative to the control activity determined in the absence of compound.

30

Results:

The compounds of the examples of the invention have a concentration that inhibits 50% of the kinase activity generally of between 0.1 nM and 2 ~M on KDR and/or Tie2,

35    preferably between 0.1 nM and 500 nM and more preferentially between 0.1 nM and 50 nM. The values in Table 1 below are given as illustrations.
 



55


Examnle    KDR    Tie2
       
2a    6    20
7    4.5    72.7
       
9    21.6    4510.4
13    11.6    1461.9
       
32    64.1    1000.8
 







AMENDED CLAIMS

1.  Product of general formula (I) below:







Formula (I)

in which:

1)    A and Ar .are independently selected from the group consisting of: aryl, heteroaryl, substituted aryl, substituted heteroaryl;

2)    Lis selected from the group consisting of: NH-CO-NH and O;CO-NH;

10 3) R1 is selected from the group consisting of: H, R,, COR,, S02R6 , in which R6 is chosen from H, OR,, NR,R9, alkyl, cycloalkyl, heterocyclyl, substituted

heterocyclyl, aryl, substituted aryl, heteroaryl and substituted 'heteroaryl,in which R7 is chose~ from H, phenyl and alkyl, and in which Ra and R9 are independently

selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, substituted

15    heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or alternatively Ra and R9 are linked together to form a saturated 5- to 8-membered ring containing from 0 to 3 heteroatoms chosen from 0, S and N;

4)    X is selected from the group consisting of: 0 and NH;

5)    R, is selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl,

20    substituted cycloalkyl;

6)    R.,, is selected from the group consisting of: Hand (C1-C4)alkyl;

7)    R., is selected from the group consisting of: H and (C1-C4)alkyl;
8)    R,  is  selected  from  the  group  consisting  of:  H,  halogen,  R10,  CN,  O(R10),
OC(O)(R10),    OC(O)N(R10)(R11 ),     OS(O,)(R10),   N(R10)(R,),   N=C(R10)(R11 ),

25    N(R10)C(O)(R,), N(R10)C(O)O(R,), N(R,)C(O)N(R10)(R,), N(R1,JC(S)N(R10)(R11 ), N(R,)S(02)(R11 ), C(O)(R10), C(O)O(R10), C(O)N(R10)(R11 ), C(=N(R11))(R10), C(=N(OR,))(R,), S(R10), S(O)(R10), S(O,)(R10), S(02)0(R 10), S(02)N(R10)(R11 ); in which each R10, R11 , R, is independently selected from the group consisting of H, alkyl, alkylene, alkynyl, aryl, heteroaryl, cycloalkyl,
 





2

heterocyclyl,    substituted   alkyl,   substituted   alkylene,   substituted   alkynyl,

substituted  aryl,  substituted  heteroaryl,  substituted  cycloalkyl  and  substituted

heterocyclyl.

2.  Product according to Claim 1, characterized in that R4a and R4b are H.

3.    Product according to Claim 1, characterized in that R., is H and R., is (C1-C4)alkyl.

4.    Product according to Claim 1'•characterizedin that R4,  is (C1-C4)alkyl and R,. is H.

10

5.    Product according to any one of Claims 1 to 4, characterized in that R1 is H.

6.    Product according to any one of Claims 1 to 5, characterized in that ~ is H and X is

NH .

.15

7.  Product according to any one of Claims 1 to 5, characterized in that~ is methyl and

XisO.

8.  Product acCording to any one of Claims 1 to 7, characterized in that R5 is H.

20

9.  Product according to any one of Claims 1 to 8, characterized in that Lis NHCONH.

10. Product according to any one of Claims 1 to 9, characterized in thatAr-L-A is:
x -x,
----{~X,
xi\
L-A
25    in which each X , X2,  ~and .>4 is independently chosen from N and C-R',  in which R'
1 5 5 has the same definition as Rs.

11. Product according to Claim 10, characterized in that R' is selected from the group
5

consisting of H, F, Cl, methyl, NH,, OCF, and CONH,.

30

12. Product  according  to  Claim  9,  characterized  in  that  A is  chosen  from  phenyl,

pyrazolyl and isoxazolyl; optionally substituted.

13. Product according to any one of Claims 1 to 12, characterized in that A is substituted
 






with one or more substituents selected from the group consisting of: H, F, Cl, Br, I, OH,
SH,    S03M,   COOM,   COO-alkyl,   CON(R14)(R15),     CN,   N02,     N(R14)CO(R15),

N(R14)(R15), alkyl, haloalkyl, alkyi-OH, alkyi-N(R,;)(R15), alkyi(R16), alkyi-COOM, alkyi-S03M, cycloalkyl, alkylene, alkynyl, aryl, heteroaryl; 0-alkyl, 0-aryl, 0-heteroaryl, S-alkyl, S-aryl and S-heteroaryl, each being optionally substituted with a substituent

chosen from alkyl, halogen, 0-alkYI and N(R,.)(R15); in which R14 and R15 are independently chos~n from H, alkyl, alkyi-OH, haloalkyl, alkyi-NH2 , alkyi-COOM and

alkyi~S03M; in which, when R14 and R1s are simultaneously other than H, may be bonded to form a 5- to 7-membered. ring comprising from 0 to 3 heteroatoms chosen

10    from 0, Nand S; in which M isH or a cation of an alkali metal chosen from Li, Na and K; and in which R16 is H or an optionally substituted non-aromatic heterocycle, containing from 2 to 7 carbon atoms, and 1 to 3 heteroatoms chosen from N, 0 and S; when A is
di~ubstituted, the two substituents may be linked together to form a 5- to 7-membered ring containing from •a to 3 heteroatonis chosen from N, 0 and S.

15

14.    Product according to Claim 13, characterized in that A is sub~tituted with one or more substituents selected from the said group, also including SiMe3, S-CHFa and SF5•

15.    Product according to any ~me of the preceding claims, characterized-in that it is:

20    4-{[3-phenyl]carbamoyl}oxy)benzyl]amino )-1 H-pyrazole-3-carboxamide trifluoroacetate; 4-{[3-({[2-fluoro-5-(trtnuoromethyl)phenyl]carbamoyl}amino)benzyl]amino)-1 H-pyrazole-3-carboxamide hydrochloride;
4-[(3-{[(2-fluorophenyl)carbamoyl]amino)benzyl)amino]-1 H-pyrazole-3-carboxamide

trifluoroacetate;

25    4-[(3-{[(2-methoxyphenyl)carbamoyl]amino)benzyl)amino]-1 H-pyrazole-3-carboxamide trifluoroacetate;
4-{[3-({[2-fluoro-3-(trifluoromethyl)phenyl]carbamoyl}amino)benzyl]amino)-1 H-pyrazole-

3-carboxamide trifluoroacetate;

4-[(3-{[(3-methoxyphenyl)carbamoyl]amino)benzyl)amino]-1 H-pyrazole-3-carboxamide

30    trtnuoroacetate; 4-{[3-({[3-fluoro-5-(trtnuoromethyl)phenyl]carbamoyl)amino)benzyl]amino)-1 H-pyrazole-

3-carboxamide trifluoroacetate;

4-{[3-({[4-(trifluoromethoxy)phenyl]carbamoyl}amino }benzyl]amino)-1 H-pyrazole-3-

carboxamide trifluoroacetate;

35    methyl3-{[(3-{[(3-carbamoyi-1H-pyrazol-4-yl)amino]methyl}phenyl)carbamoyl]-amino}benzoate trifluoroacetate;
 






4-{[3-({[ 4-(trifiuoromethyl)phenyl]carbamoyl}amino)benzyl]amino }-1 H-pyrazole-3-

carboxamide trifluoraacetate;

4-{[3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)benzyl]amino }-1 H-pyrazole-3-

carboxamide trifluoroacetate;

4-{[3-({[2-(trifiuoromethyl)phenyl]carbamoyl}amino)benzyl]amino }-1 H-pyrazole-3-

carboxamide trifluoroacetate;

4-[(3-{[(3,5-dimethoxyphenyl)carbamoyl]amino }benzyl)amino]-1 H-pyrazole-3-

carboxamide trifluoroacetate;

4-[(3-{[(3-methylphenyl)carbamoyl]amino }benzyl)amino ]-1 H-pyrazole-3-carboxamide

10    trifluoroacetate;

4-[(3-{[( 4-methoxyphenyl)carbamoyl]amino }benzyl)amino]-1 H-pyrazole-3-carboxamide trifluoroacetate;
4-[(3-{[(4-fluorophenyl)carbamoyl]amino)benzyl)amino]-1H-pyrazole-3-carboxamide trifluoroacetate;
1.5    4-{[3-({[ 4-chloro-3-(trifluoromethyl)phenyl]carbamoyl)amin6 )benzyl]amino)-1 H-pyrazoie-

3-carboxamide trifluoroacetate;

4-{[3-({[4-( difluoromethoxy)phenyl]carbamoyl}amino)benzyl] amino }-1 H-pyrazole-3-

carboxamide trifluoroacetate;

4-{[3-({[2-chloro-4"-(trifluoromethyl)phenyl]carbamoyl)amino)benzyl]amino}-1 H-pyrazol_e-

20    3-carboxamide trifluoroacetate;.

4-[(3-{[( 4-methylphenyl)carbamoyl]amino }benzyl)amino ]-1 H-pyrazole-3-carboxamide trifluoroacetate;
4-[(3-{[(2,5-dimethylphenyl)carbamoyl]amino)benzyl)amino]-1 H-pyrazole-3-carboxamide

trifluoroacetate;

25    4-[(3-{[(3,4-dimethylphenyl)carbamoyl]amino)benzyl)amino ]-1 H-pyrazole-3-carboxamide trifluoroacetate;
4-[(3-{[(2-methylphenyl)carbamoyl]amino}benzyl)amino]-1 H-pyrazole-3-carboxamide trifluoroacetate;
4-[(3-{[(3-ethylphenyl)carbamoyl]amino )benzyl)amino]-1 H-pyrazole-3-carboxamide

30    trifluoroacetate; 4-{[3-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl)amino)benzyl]amino )-1 H-pyrazole-3-carboxamide hifluoraacetate;
4-[(3-{[(3-fluorophenyl)carbamoyl]amino }benzyl)amino]-1 H-pyrazole-3-carboxamide

trifluoroacetate;

35    4-[(3-{[(2-methoxy-5-methylphenyl)carbamoyl]amino}benzyl)amino]-1 H-pyrazole-3-carboxamide trifluoroacetate;
 







4-[(3-{[{2, 5-dimethoxyphenyt)carbamoyt]amino)benzyt)amino]-1 H-pyrazole-3-

carboxamide trifluoroacetate;

4-{[3-({[3-chloro-4-(difluoromethoxyphenyl]carbamoyl)amino)benzyijamino)-1H-pyrazole-

3-carboxamlde trifluoroacetate;

4-[(3-{[(2,5-difluorophenyl)carbamoyl]amino)benzyl)amino ]-1 H-pyrazole-3-carboxamide

trifluoroacetate;

4-{[3-({[4-methyl-3-(trifiuoromethyl)phenyl]carbamoyl}amino)benzyl]amino}-1 H-pyrazole-

3-carboxamide trifluoroacetate;

methyl 4-([3-({[2-fiuoro-5-(trifiuoromethyl)phenyl]carbamoyl)amino)benzyl]amino )-1 H-

10    pyrazole-3-carboxylate trifluoroacetate.

16. Product according to any one of the preceding claims, characterized in that it is:

4-(1-{3-[3-(2-fiuoro-5-trifiuoromethylphenyl)ureido]phenylethylamino}-1 H-pyrazole-3-

Carboxamide trifluoroacetaie;

15    4-({3-[3-(2-fiuoro-5-tniluoromethylphenyl)ureido)benzyl}methylamino)-1 H-pyrazole-3-carboxamide;

4-(ethyl-{3-[3-(2-fiuoro-5-trifiuoromethylphenyl)ureido]benzyl}amino)-1 H-pyrazole-3-

carboxamide;

4-({3-[3-(2-chloro-5-trifiuorome\hylphenyl)ureido ]benzyl}methylamino}-1 H•pyrazole-3-

20    carboxamide~

4-{3-[3-(4-trifiuoromethylpyrid-2-yl)ureido]benzylamino)-1 H-pyrazole-3-carboxamide; 4-{3-[3-( 4-methoxypyrid-2-yl)ureido ]benzylamino}-1 H-pyrazole-3-carboxamide; 4-{[3-({[3-chloro-4-fiuorophenyl]carbamoyl}amino)benzyl]amino}-1 H-pyrazole-3-
carboxamide;

25    4-{[3-({[3,4-dichlorophenyl]carbamoyl}amino}benzyl]amino)-1 H-pyrazole-3-carboxamide; 4-{[3-({[3-chloro-5-trifiuoromethylphenyl]carbamoyl)amino)benzyl]amino)-1 H-pyrazole-3-carboxamide;
4-{[3-({[3-trimethylsiiyl-4-fiuorophenyl]carbamoyl}amino)benzyl]amino}-1 H-pyrazole-3-

carboxamide;

30    4-{[3-({[3-trifiuoromethoxyphenyl]carbamoyl}amino)benzyl]amino }-1 H-pyrazole-3-carboxamide~

4-{[3-({[3-tlifiuoromethyl-4-chlorophenyl]carbamoyl)amino)benzyl]amino)-1 H-pyrazole-3-carboxamide;

4-{[3-({[2-chloro-5-trifiuoromethylphenyl]carbamoyl)amino)benzyl]amino)-1 H-pyrazole-3-

35    carboxamide;

4-{[3-({[3-trifluoromethylsulfanylphenyl]carbamoyl}amino)benzyl]amino)-1 H-pyrazole-3-
 






carboxamide;

4-{[3-({[3-isopropylphenyl]carbamoyl}amino)benzyl]amino }-1 H-pyrazole-3-carboxamide; '4-{[3-({[3-isopropyl-4-fluorophenyl]carbamoyl)amino)benzyl]amino}-1H-pyrazole-3-
carboxamide;

4-{[3-({[3-penlafluorosulfanylphenyl]carbamoyl)amino )benzyl]amino)-1 H-pyrazole-3-

carboxamide;

4-{[J-({[2-methoxy-5-tert-butylphenyl]carbamoyl)amino)benzyl]amino)-1 H-pyrazole-3-

carboxamide;

4-{[3-({[4-isopropylphenyl]carbamoyl)amino)benzyl]amino)-1 H-pyrazole-3-carboxamide;

10    4-{[3-({[2-chloro-4-isopropylphenyl]carbamoyl}amino)benzyl]amino}-1 H-pyrazole-3-carboxamide;
4-{[3-({[2-fluoro-5-methylphenyl]carbamoyl)amino)benzyl]amino}-1 H-pyrazole,3-carboxamide;
4-{[3-({[2-fluoro-4-trifluoromethylphenyl]carbamoyl)amino)benzyl]amino}-1 H-pyrazole-3_-

1~ carboxamide; 4-{[3-({[2-fluoro:4-methylphenyl]carbamoyl}amino}benzyl]amino)-1 H-pyrazole-3-

carboxamide;

4-{[3-({[2-chloro-4-methylphenyl]carbamoyl}amino)benzyl]amino)-1 H-pyrazole-3-

carboxamide;

20    4-{[3-({[2-chloro-5-methylphenyl]carbamoyl)amino)benzyl]amino}-1 H-pyrazole-3, carboxamide;
(RS)-4-(1-{3-[3-(2-chloro-4-trifluoromethylphenyl)ureido ]phenyl)ethylamino)-1 H-pyrazole-

3-carboxamide.

25    17. Product according to any one of the preceding claims, characterized in that it is:

1) in non-chiral form, or 2} in racemic form, or
3} enriched in one stereoisomer, or 4) enriched in one enantiomer;
30    and in that it is optionally salified.

18. Pharmaceutical composition comprising a product according to any one of Claims 1

to 17, in combination with a pharmaceutically acceptable excipient.

35    19. Use of a product according to any one of Claims 1 to 17, as an agent for inhibiting one or more reactions catalysed by a kinase.
 





7

20. Use of a product according to Claim 19, in which the kinase is chosen from KDR and

Tie2.

21. Use of a product according to any one of Claims 1 to 20, for the manufacture of a

medicament that is useful for treating a pathological condition.

22. Use according to Claim 21, characterized in that the pathological condition is cancer.

10    23. Process for preparing the products of general formula (lb) below:
r
ArL

~ .Jw-ZR,b
R;'x"\()-R s    (lb)
N-N
'R,

in  which  R1,  R3,  ~b. Rs,  X,  Ar,  L and A are  as  defined in  Claim  1,  and  ~a is  H,

characterized in that a product of general formula (II) below:
~ t'
R','x'\()s -R(II)

N-i'!_

R,

15    in which R'3 is RJ or a precursor of R3, and X, R,, RJ and Rs are as defined in Claim 1, reacts with a product of formula (Ill) below:
0

A_..-L-.._ArJlR ,b   (Ill)

in which  R4b,  Ar,  L and A  are as  defined in  Claim  1, to give the  product of general

formula (lb).

20

24.    Process for preparing the products of general formula (I) below:

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