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DERIVATIVES OF AZAINDAZOLE OR DIAZAINDAZOLE TYPE AS
MEDICAMENT
The present invention relates to azaindazole and diazaindazole fused bicyclic
5 derivatives, as well as to the therapeutic use of same, notably in the treatment of cancer,
inflammation and neurodegenerative diseases such as Alzheimer's disease, as well as to
methods for synthesizing same.
Protein kinases are enzymes that play a key role in cell signal transduction. They
10 are involved in physiological processes such as cell proliferation, mitosis,
differentiation, cell invasion and mobility, and apoptosis, for example.
Deregulation of the physiological mechanisms controlled by protein kinases is
central to the appearance and development of many pathologies, notably including
cancers. It is of particular note that many oncogenes and proto-oncogenes correspond to
15 protein kinases.
Consequently, these enzymes are seen to play an important role during the
various stages of tumor development and thus they constitute important pharmaceutical
targets for cancer treatments.
Tyrosine kinase receptors (TKRs) form a particular class of protein kinases
20 among which, among others, mention may be made of ALK, EGFR, Her2, PDGFR, Kit,
VEGFR, IGFR, FGFR, Trk, Axl, Mer, Met, Ron and Ret. In this subfamily, ALK is
regarded as a particularly relevant target because it is genetically modified in certain
tumor pathologies and thus acquires an oncogenic nature. More precisely, chromosomal
translocations leading to the production of fused protein kinases (ALK-X) which are
25 then constitutively activated cause the development of certain cancers. ALK in
oncogenic form is expressed by various tumor pathologies of different histological
types. These pathologies are thus ALK-dependent. ALK in oncogenic form exists only
in tumor cells and is not expressed by normal cells. For this reason, this protein kinase
provides the opportunity to specifically target ALK-dependent tumor tissues while
30 saving heahhy tissues from significant toxic effects (Ott G.R. et al. Anticancer Agents
Med. Chem., 2010,10(3), 236-49).
Several cases of chromosomal translocations involving ALK, related to cancer
pathologies, have already been documented. For example, the fusion protein NPM-ALK
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is associated with anaplastic large-cell lymphoma (ALCL) for which an optimal
treatment remains to be developed. Similarly, the fusion protein EML4-ALK is
associated with tumor development in a subpopulation of patients suffering from nonsmall
cell lung cancer. Mutated forms of ALK have also been observed in
5 neuroblastoma.
c-Src is also a protein kinase whose activation state proved to be negatively
correlated with the survival of patients suffering from various forms of cancer,
including non-small cell lung cancer (Byers LA. et ai, Clin. Cancer Res. 2009, 15(22),
6852-6861).
10 For this reason, and because of its involvement in many key mechanisms such as
cell cycle progression, adhesion, proliferation, migration and control of apoptosis, this
protein is also regarded as a target of interest in oncology.
It has been shown in particular that the inhibition of this target, by both
biochemical and pharmacological means, induced effects such as a reduction in cell
15 proliferation, a stopping of the mitotic cycle and a slowing of tumor growth in vivo. In
the particular case of non-small cell lung cancer, the inhibition of c-Src by an inhibitor
(dasatinib) led to the observation, in vitro, of inhibition of the migration and the
invasion of the cells concerned.
Nevertheless, in terms of the control of tumor cell proliferation, it has been
20 proposed that c-Src inhibition alone only induces a partial and/or transitory
pharmacological response.
Consequently, there continues to be a need for inhibitors with a composite mode
of action that are capable of intervening at several targets, in particular at several targets
25 of the same signaling pathway, proposed as being more effective, with an improved
therapeutic index and less likely to give rise to phenomena of compensation, resistance
or therapeutic escape.
The compounds of the present invention thus have the property of inhibiting or
30 modulating the enzymatic activity of protein kinases in general and ALK and c-Src in
particular. Consequently, said compounds can be used as drug in the treatment of
proliferative diseases such as cancer.
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3
Additional indications in inflammation or in affections of the central nervous
system may also be pursued.
More particularly, the present invention thus has as an object a compound of
5 following general formula (I):
R2
N-K3
II N
' • H
(I)
or a pharmaceutically acceptable sah or solvate of same, a tautomer of same, a
stereoisomer or a mixture of stereoisomers of same in any proportions, such as a
mixture of enantiomers, notably a racemic mixture,
10 wherein:
- Yi and Y4 each represent, independently of each other, a CH group or a nitrogen
atom,
- Y2 represents a nitrogen atom or a CH or C-X-Ar group,
- Y3 represents a nitrogen atom or a C-X-Ar or C-W group,
15 on the condition that:
• at least one and at most two Yi, Y2, Y3, and Y4 groups represent a nitrogen
atom,
• Y2 and Y4 cannot represent a nitrogen atom at the same time,
• when Y2=C-X-Ar, then Y3 represents a nitrogen atom or a C-W group, and
20 • when Y3=C-X-Ar, then Y2 represents a nitrogen atom or a CH group,
- Ar represents an aryl or heteroaryl group optionally substituted by one or more
! groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-
C6)haloalkoxy, (Ci-C6)halothioalkoxy, CN, NO2, ORn, SR12, NRnRw, CO2R15,
CONRieRiv, SO2R18, SO2NR19R20, COR21, NR22COR23, NR24SO2R25, and
25 R26NR27R28 and/or optionally fiised to a heterocycle.
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- X represents a divalent group selected from O, S, S(0), S(0)2, NR4, S(NR4),
S(0)(NR4), S(0)2(NR4), NR4S, NR4S(0), NR4S(0)2, CH2, CH2S, CH2S(0),
CH2S(0)2, SCH2, S(0)CH2, S(0)2CH2, CH2CH2, CH=CH, C=C, CH2O, OCH2,
NR4CH2, and CH2NR4,
5 - W represents an R5, SR5, OR5 or NR5R6 group,
- U represents a CH2 or NH group, one or more hydrogen atoms which may be
replaced by a (Ci-C6)alkyl group,
- V represents C(0), C(S) or CH2,
- n represents 0 or 1,
10 - Ri represents a hydrogen atom, or an OR? or NRyRg group,
- R2 represents a hydrogen atom, an optionally substituted heterocycle, NO2, OR9 or
NR9R10,
- R3, R4, Rii to R25 and R27 to R28 each represent, independently of each other, a
hydrogen atom or a (Ci-C6)alkyl group,
15 - R5 and Re each represent, independently of each other, a hydrogen atom or a (Ci-
C6)alkyl, optionally substituted aryl or optionally substituted benzyl group,
- R7, Rg, R9 and Rio each represent, independently of each other, a hydrogen atom or
an optionally substituted (Ci-C6)alkyl or (C3-Ci2)cycloalkyl group or an optionally
substituted heterocycle, and
20 - R26 represents (Ci-C6)alkyl.
In the preceding definitions, all the combinations of substituents or variables are
possible insofar as they lead to stable compounds.
25 The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "(Ci-Ce) alkyl" refers to saturated linear or branched hydrocarbon
chains comprising 1 to 6 carbon atoms. It may be a methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, ^ec-butyl, tert-butyl, pentyl or hexyl group.
The term "(Ci-C6)alkoxy" refers to a (Ci-Ce) alkyl chain linked to the rest of the
30 molecule via an oxygen atom. As an example, mention may be made of methoxy,
ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy groups.
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I
The term "(Ci-C6)thioalkoxy" refers to a (Ci-Ce) alkyl chain linked to the rest of
the molecule via a sulfur atom. As an example, mention may be made of thiomethoxy,
thioethoxy, thiopropoxy, thioisopropoxy, thiobutoxy or thio-tert-butoxy groups.
The term "(Ci-C6)haloalkyl" refers to a (Ci-Ce) alkyl chain such as defined
5 above wherein one or more hydrogen atoms are replaced by a halogen atom such as
defined above. It may be in particular a trifluoromethyl group.
The term "(Ci-C6)haloalkoxy" refers to a (Ci-C6)alkoxy chain such as defined
above wherein one or more hydrogen atoms are replaced by a halogen atom such as
defined above. It may be in particular a trifluoromethoxy group.
10 The term "(Ci-C6)halothioalkoxy" refers to a (Ci-C6)thioalkoxy chain such as
defined above wherein one or more hydrogen atoms are replaced by a halogen atom
such as defined above. It may be in particular a trifluorothiomethoxy group.
The term "(C3-Ci2)cycloalkyl" refers to cyclic hydrocarbon systems comprising
fi^om 3 to 12 carbon atoms and comprising one or more rings, in particular fused rings.
15 As an example, mention may be made of an adamantyl or cyclohexyl group.
The term "aryl" refers to an aromatic hydrocarbon group preferably comprising
fi-om 6 to 14 carbon atoms and comprising one or more fiised rings, such as, for
example, a phenyl or naphthyl group. Advantageously, it is a phenyl group.
The term "heteroaryl" refers to a cychc aromatic group comprising 5 to 7 atoms
20 included in the ring or a bicyclic aromatic group comprising 8 to 11 atoms included in
the rings, wherein 1 to 4 of the atoms included in the rings are a heteroatom selected
independently fi^om sulfiir, nitrogen and oxygen atoms, and wherein the other atoms
included in the rings are carbon atoms. Examples of heteroaryl groups include fliryl,
thienyl, pyridinyl, and benzothienyl groups.
25 The term "heterocycle" refers either to a stable monocycle containing from 4 to
7 cyclic atoms, or to a stable bicycle containing from 8 to 11 cyclic atoms, which may
be either saturated or unsaturated, wherein 1 to 4 of the cyclic atoms are a heteroatom
selected independently from sulfur, nitrogen and oxygen atoms, and wherein the other
cyclic atoms are carbon atoms. As an example, mention may be made of fijran, pyrrole,
30 thiophene, thiazole, isothiazole, oxadiazole, imidazole, oxazole, isoxazole, pyridine,
piperidine, pyrazine, piperazine, tetrahydropyran, pyrimidine, quinazoline, quinoline,
quinoxaline, benzofiiran, benzothiophene, indoline, indolizine, benzothiazole.
k
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benzothienyl, benzopyran, benzoxazole, benzo[l,3]dioxole, benzisoxazole,
benzimidazole, chromane, chromene, dihydrobenzofuran, dihydrobenzothienyl,
dihydroisoxazole, isoquinoline, dihydrobenzo[l,4]dioxane, imidazo[l,2-a]pyridine,
furo[2,3-c]pyridine, 2.3-dihydro-l/f-indene, [l,3]dioxolo[4,5-c]pyridine, pjTTolo[l,2-
5 c]pyrimidine, pyrrolo[l,2-a]pyrimidine, tetrahydronaphthalene, benzo[b][l,4]oxazin.
In the context of the present invention, "optionally substituted" means that the
group in question is optionally substituted by one or more substituents which may be
selected in particular from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-
C6)haloalkoxy, (Ci-C6)halothioalkoxy, CN, NO2, ORn, SR]2, NR13R14, CO2R15,
10 CONR16R17, SO2R18, SO2NR19R20, COR21, NR22COR23, NR24SO2R25, and R26NR27R28,
wherein Rn to R28 are such as defined above.
In the present invention, "pharmaceutically acceptable" refers to that which is
use&l in the preparation of a pharmaceutical composition that is generally safe,
nontoxic and neither biologically nor otherwise undesirable and that is acceptable for
15 veterinary and human pharmaceutical use.
"Pharmaceutically acceptable salt or solvate" of a compound refers to salts and
solvates which are pharmaceutically acceptable, as defined herein, and which has the
desired pharmacological activity of the parent compound.
Acceptable salts for the therapeutic use of the compounds of the present
20 invention include the conventional nontoxic salts of the compounds of the invention
such as those formed from pharmaceutically acceptable organic or inorganic acids or
from pharmaceutically acceptable organic or inorganic bases. As an example, mention
may be made of saks derived from inorganic acids such as hydrochloric acid,
hydrobromic acid, phosphoric acid and sulfuric acid, and those derived from organic
25 acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fiimaric
acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid,
benzoic acid, salicylic acid, toluenesulfonic acid, methanesulfonic acid, stearic acid and
lactic acid. As an example, mention may be made of salts derived from inorganic bases
such as soda, potash or calcium hydroxide and salts derived from organic bases such as
30 lysine or arginine.
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These salts may be synthesized from the compounds of the invention containing
a basic or acidic part and the corresponding acids or bases according to conventional
chemical methods well known to the person skilled in the art.
Acceptable solvates for the therapeutic use of the compounds of the present
5 invention include conventional solvates such as those formed during the last step of the
preparation of the compounds of the invention due to the presence of solvents. As an
example, mention may be made of solvates due to the presence of water or ethanol.
In the context of the present invention, "stereoisomer" refers to a geometric
! isomer or an optical isomer.
10 Greometric isomers result from the different position of substituents on a double
bond which can then have a Z or E configuration.
j Optical isomers result notably from the different position in space of substituents
I on a carbon atom comprising four different substituents. This carbon atom thus
I constitutes a chiral or asymmetrical center. Optical isomers include diastereoisomers
15 and enantiomers. Optical isomers that are mirror images of each other but are nonsuperimposable
are enantiomers. Optical isomers that are not mirror images of each
i
other are diastereoisomers.
I In the context of the present invention, "tautomer" refers to a constitutional
isomer of the compound obtained by prototropy, i.e., by migration of a hydrogen atom
20 and a change in location of a double bond. The different tautomers of a compound are
generally interconvertible and are in equilibrium in solution in proportions which may
vary according to the solvent used, the temperature or the pH.
According to a first embodiment, Y4=N.
25 Y2=C-X-Ar and Y3 preferably represents a C-W group.
In particular:
- Yi=CH or N, and advantageously CH,
- Y2=C-X-Ar,
- Y3=C-W, and
30 - Y4=N.
According to a second embodiment, Yi and/or Y4 represent a nitrogen atom.
In this case, Y2 and Y3 preferably do not represent a nitrogen atom.
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In particular:
- Yi and/or Y4 = N,
- Y2=CH or C-X-Ar, and
- Y3=C-W or C-X-Ar.
5 Advantageously, X represents a divalent group selected from O, S, S(0), S(0)2,
NR4, CH2, CH2S, CH2S(0), CH2S(0)2, NHS(0)2, SCH2, S(0)CH2, S(0)2CH2,
S(0)2NH, CH2CH2, CH=CH, C=C, CH2O, OCH2, NEL,CH2, and CH2NR4.
In aprticular, X represents a divalent group selected from S, S(0), S(0)2, NR4,
CH2, CH2S, CH2S(0), CH2S(0)2, NHS(0)2, SCH2, S(0)CH2, S(0)2CH2, S(0)2NH,
10 CH2CH2, C=C, CH2O, OCH2, NR4CH2, and CH2NR4.
More particularly, X may be selected from S, S(0), S(0)2, CH2, CH2S,
CH2S(0), CH2S(0)2, NHS(0)2, SCH2, S(0)CH2, S(0)2CH2, S(0)2NH, CH2CH2,
CH=CH, and C=C.
In particular, X may be selected from S, S(0)2, CH2, SCH2, S(0)2CH2,
15 S(0)2NH, CH2S, CH2S(0)2, NHS(0)2, CH2CH2, and C=C.
X may notably be selected from S, S(0), S(0)2, NR4, CH2, SCH2, S(0)CH2,
S(0)2CH2, S(0)2NH, CH2CH2, C=C, OCH2, and NR4CH2; notably from S, S(0)2, CH2,
SCH2, S(0)2CH2, S(0)2NH, CH2CH2, and C=C, wherein the first atom of these groups
is bound to atom C of the C-X-Ar chain.
20 X may be in particular S, S(0)2, SCH2, S(0)2CH2, S(0)2NH, CH2S, CH2S(0)2,
or NHS(0)2; and notably S, S(0)2, SCH2, S(0)2CH2, or S(0)2NH, wherein the first atom
of these groups is bound to atom C of the C-X-Ar chain.
Advantageously, Ar represents a heteroaryl group, such as pyridine, or an aryl
group, such as phenyl, optionally substituted by one or more groups selected from a
25 halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci-
C6)halothioalkoxy, CN, NO2, ORu, SR12, NR13R14, CO2R15, CONRieRiv, SO2R18,
SO2NR19R20, COR21, NR22COR23, and NR24SO2R25; and/or optionally fused to a
heterocycle.
More particularly, Ar may represent an aryl group, such as phenyl, optionally
30 substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-
C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci-C6)halothioalkoxy, CN, NO2, ORn, SR12,
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NR13R14, CO2R15, CONR16R17, SO2R18, SO2NR19R20, COR21, NR22COR23, and
NR24SO2R25.
Ar may notably represent an aryl group, such as phenyl, optionally substituted
by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl,
5 and CONRieRn, and in particular from a halogen atom such as fluorine, (Ci-C6)alkyl
such as methyl, and CONRisRi? such as CONH2.
Ar can also represent a pjridine group.
Ar may notably be selected from the following groups:
) ) J J J
0 H N
10 , \ = / , ^' , \ = / , and
notably from the following groups.
>• p- 0°^- 5: >• s
5 » 3 9 5 5
and
in particular, from the following groups:
h^-b-0^- ^:
15 F ,/ ,CI ,and\=/ .
Ar may advantageously represent the group:
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^ ^
I F
i
I W may advantageously represent an R5, SR5, OR5 or NRsRe group, and
j preferably R5, OR5 or NR5R6, with R5 and Re representing, independently of each other,
a hydrogen atom or a (Ci-C6)alkyl group.
5 W may represent in particular H, OMe, Me, OH or NH2, and notably H.
Advantageously, R3 represents a hydrogen atom.
U may represent more particularly a CH2 or NH group.
I Advantageously, n may represent 0.
I V may represent more particularly a C(0) or C(S) group, and advantageously a
i
10 C(0) group.
According to a particular embodiment of the invention;
- R3=H,
- U=CH2 0rNH,
- V=C(0) or C(S), and notably C(0), and
15 - n=0 or 1, and notably 0.
According to another particular embodiment of the invention:
- V=C(0) or C(S), and notably C(0), and
- n=0.
According to still another particular embodiment of the invention:
20 - R3=H,
- V=C(0) or C(S), and notably C(0), and
- n=0.
Ri may represent more particularly a hydrogen atom or an NRyRg group, with
25 R7 notably representing a hydrogen atom and Rs notably representing an optionally
substituted (C3-Ci2)cycloalkyl group or an optionally substituted heterocycle.
The (C3-Ci2)cycloalkyl group may be in particular a cyclohexyl. It may be
substituted by one or more halogen atoms. It may be in particular the group:
%
%
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The heterocyclic group may be in particular a tetrahydropyran, notably
unsubstituted. It may thus be the following group:
5 Ri may thus represent more particularly one of the following groups:
• ^ \ / •^' \ A
H, /*^ \ / and /^ \ ^ F; and notably H and
^-\ P ^^ P
f^ \ ' ; and advantageously ^^ \ f
R2 may represent more particularly an optionally substituted heterocycle
10 (notably substituted by (Ci-C6)alkyl or NH2), NO2 or NR9R10, with notably R9=Rio=H
or else R9 and Rio each represent H or an optionally substituted (Ci-C6)alicyl.
R2 may represent in particular an optionally substituted heterocycle, notably
substituted by (Ci-C6)alkyl or NH2. The heterocycle may be in particular a heterocycle
with 5 or 6 members comprising at least one nitrogen atom, and in particular one or
15 two. The heterocycle may thus be selected from piperazine, piperidine and pyrrolidine.
R2 may notably represent one of the following groups:
—5-N N
NH2, NH(CH2)3NMe2, NMe(CH2)3NMe2, NO2, \ /
,NH2
\ / , and ^^"""^ ; and notably NH2, NO2,
.NH2
—|-N N— ~r\ ^— ~^ \ J
\ ' , > ' , and ^""^ ; and in
I
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—i-H N —^-( N
particular \ / , and \ / ; and more particularly I
—?-N N
^ \ — /
The compounds of the present invention may be selected from the compounds
5 cited in the following table:
o JiO o I ^o
I 14-2 Y T T JL N w "-1" f ] T I N W
I \ ^ l ^ CI ( /
I 14-11 Y ] T JL N W 15 ^ ^ M ' O
F " F "^
S /—^
F \__N F
i
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30-1 [Tj ^TTY^N \X ^"-^ d'^VV^N ( /
H ^-^ ^N^N N-^
30-12 I T T T ^ N O 30-a T J T T^N W
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I \ \ \ \ T^
A 0 jr? --^^^
V ^^N N^ y N N
F \ \ ~o r^o I
30-70 f T I l^N W 30-71 f T f l^N W
H H , ) I H , ^
J HN-O J HN-O
N F
30-13 ''Y^Y^'^Y^N O 3"-1* F^^'^^^^Y^'T^ W
T " Y i "^"^ XI
30-17 V^O N^ VA 30.18 y k /O N ^ )rI O / O i. ,r HN"^ J
30-19 V - 0 N^^ V \ 3„.,, y ^ O N^^ Q
%
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30-21 'V^^°v'^^V-i F l 30-22 ^>A^0 N , J fX
N /? HN-\ /° ^ H N - \ /°
30-23 ^'^^^v^Ov^N^ ^ ^ 30.24 y V Y I P ' N C J
^. ^ V ^« Q
30-29 YT T r^N V i 30-30 J^ J IpN V i
I l^*^ ^^
O /"^O ^ F ^ O / ^
I J H N - \ / FvUF ^ H N - \/
3.-3, "VT'TVN Q "^ u X^jd" Q
WO 2012/101239 PCT/EP2012/051283
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I n^^ ..A 'f^-o I \ J HNO I a H N - - \ / HN--\/ ^-^
3.-35 f-^-^YV-. U »-^' F X T id" Q
O f^O J HN--V/
30-43 A^N^N^^ V \ 30^, N ^ T T^N O
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F
30^7 1 T 1 I ^N V-s/ 30-48 |l 1 -^ \=<
T "^ H' /^ " r
'^ V-N N-
\ /
- 0 no
V-N N—
\ /
O / ^O ^ F _ 0 _/ P
30-51 fYYr^NQ ''-'' r j ' T ' HQ
30-53 ^S,^N^J )/ % 30-54 /Sv^N-J ZT^
30-55 I O' T r^N V i ^""^^ F O" T O Vi
\ - -N \^N
\ %
t
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I I i i , H.^-^" I I AP j\2p I
30-59 o' T IP'^'N \ J I 30-60 0 T j T ^ \ 1
V-N \—N
30-61 t J O' Y IT^N i J 30-62 SJ ° L L -^ VJ!
30-63 L J o' T 11 \ \ i 30-64 ^ ^*^^N Vx
F H / ) V-N^
V - N ^
O J ^0 ^ J^ HN-\ /
I I " Q I I A„ " o^ I
V
i
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i
3... ^^'t^
The present invention also has as an object a compound according to the
invention of formula (I) such as defined above, to be used as a drug, notably intended
for the treatment of cancer, inflammation and neurodegenerative diseases such as
5 Alzheimer's disease, in particular cancer.
The present invention also relates to the use of a compound of formula (I) such
as defined above, for the manufacture of a drug, notably intended for the treatment of
cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease, in
particular cancer.
10 The present invention also relates to a method for the treatment of cancer,
inflammation and neurodegenerative diseases such as Alzheimer's disease, in particular
cancer, comprising the administration to a person in need thereof of an effective dose of
a compound of formula (I) such as defined above.
The cancer may be more particularly in this case colon cancer, breast cancer,
15 kidney cancer, liver cancer, pancreatic cancer, prostate cancer, glioblastoma, non-small
cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, diffuse B-cell
lymphoma or anaplastic large-cell lymphoma.
The present invention also relates to a compound according to the invention of
20 formula (I) such as defined above, to be used as a drug intended for the treatment of a
disease associated with a kinase, and in particular a tyrosine kinase such as the kinases
ALK, Abl and/or c-Src, and in particular ALK. The disease may be in particular
associated with ALK and at least one other kinase, for example Abl or c-Src, in
particular ALK and c-Src.
25 The present invention also has as an object a compound according to the
invention of formula (I) such as defined above, to be used as a kinase inhibitor, and in
particular an inhibitor of tyrosine kinases such as ALK, Abl and/or c-Src, and in
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I particular ALK. The compounds according to the invention may notably be used as an
I inhibitor of ALK and at least one other kinase, for example Abl or c-Src. Preferentially,
the compounds according to the invention are inhibitors of ALK and c-Src.
In the context of the present invention, "disease associated with a kinase" or
5 "kinase-associated disease" refers to any diseases, and in particular diseases related to
deregulation of cell proliferation, in particular cancers, due to deregulation of the
expression or activity of said kinase compared to its normal state of expression or
activity. Deregulation of the expression of said kinase may be modification of the
sequence expressed or modification of the quantity of protein expressed. These
10 deregulations may lead to changes in cells which may, in particular, result in
proliferative disorders including cancers. Preferentially, according to the invention,
kinase-associated diseases may be cancers related to deregulation of ALK and/or c-Src
activity such as, for example, colon cancer, breast cancer, kidney cancer, liver cancer,
pancreatic cancer, prostate cancer, glioblastoma, non-small cell lung cancer,
15 neuroblastoma, inflammatory myofibroblastic tumors, diffuse B-cell lymphoma and
anaplastic large-cell lymphoma.
According to the invention, the expression "inhibitor of kinases" or "kinase
inhibitor" refers to molecules that are able to interact with the kinase and to reduce its
activity. Preferentially, the use of a kinase inhibitor according to the invention makes it
20 possible to suppress the activity of said kinase.
The present invention also relates to a pharmaceutical composition comprising
at least one compound of formula (I) such as defined above, and at least one
pharmaceutically acceptable excipient.
25 The pharmaceutical compositions according to the invention may be formulated
notably for oral administration or for injection, wherein said compositions are intended
for mammals, including humans.
The active ingredient may be administered in unit dosage forms of
administration, in mixture with standard pharmaceutical carriers, to animals or to
30 humans. The compounds of the invention as active ingredients may be used in doses
ranging between 0.01 mg and 1000 mg per day, given in a single dose once per day or
administered in several doses throughout the day, for example twice a day in equal
I I
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doses. The dose administered per day advantageously is between 5 mg and 500 mg,
even more advantageously between 10 mg and 200 mg. It may be necessary to use
doses outside these ranges as determined by the person skilled in the art.
The pharmaceutical compositions according to the invention may further
5 comprise at least one other active ingredient, such as an anticancer agent.
The present invention also has as an object a pharmaceutical composition
comprising:
(i) at least one compound of formula (I) such as defined above, and
(ii) at least one other active ingredient, such as an anticancer agent,
10 as a combination product for simultaneous, separate or sequential use.
The present invention also relates to a pharmaceutical composition such as
defined above to be used as a drug, notably intended for the treatment of cancer,
inflammation and neurodegenerative diseases such as Alzheimer's disease, in particular
cancer.
15
The present invention also has as an object method for the preparation of the
compounds of formula (I) according to the invention.
According to a first embodiment, the present invention relates to a method for
20 the preparation of a compound of formula (I) according to the invention wherein
V=C(0) or C(S), preferably C(0), and notably U=CH2, comprising the following
successive steps:
(al) coupling between a compound of following formula (A):
NHz
^ " (A)
25 wherein Yi, Y2, Y3 and Y4 are such as defined above, and R29 represents a
hydrogen atom or an N-protecting group,
with a compound of following formula (B): I
i
i
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23
R2
^ t
V
^^ (B)
wherein Ri, R2, U and n are such as defined above, V=C(0) or C(S), and
R3o=OH or a leaving group such as CI,
to yield a compound of following formula (C):
R2
^ I
NH
II N
5 "" (C)
wherein Yi, Yj, Y3, Y4, Ri, R2, R29, U and n are such as defined above and
V=C(0) or C(S),
(bl) optionally substitution of the nitrogen atom bound to V of the compound of
formula (C) obtained in the preceding step with an R3 group other than H and/or
10 deprotection of the nitrogen atom carrying an R29 group representing an Nprotecting
group to yield a compound of formula (I) with V=C(0) or C(S), and
(cl) optionally forming of a salt of the compound of formula (I) obtained in the
preceding step to yield a pharmaceutically acceptable salt of same.
15 In the context of the present invention, "N-protecting group" refers to any
substituent that protects the NH or NH2 group against undesirable reactions such as the
N-protecting groups described in Greene, "Protective Groups in Organic Synthesis"
(John Wiley & Sons, New York (1981)) and Harrison et al, "Compendium of Synthetic
Organic Methods", Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996). N-protecting groups
20 include carbamates, amides, N-alkylated derivatives, amino acetal derivatives, Nwo
2012/101239 PCT/EP2012/051283
24
benzylated derivatives, imine derivatives, enamine derivatives and N-heteroatom
derivatives. In particular, the N-protecting group consists of formyl, acetyl, benzoyl,
pivaloyl, phenyl sulfonyl, trityl (triphenylmethyl), tert-hutyl, benzyl (Bn), tbutyloxycarbonyl
(BOC), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, p-
5 nitrobenzyl-oxycarbonyl, trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), 9-
fluorenylmethyloxycarbonyl (Fmoc), trifluoro-acetyl, benzyl carbamates (substituted or
not) and the like. It may be in particular a trityl, tert-hutyl or BOC group.
In the context of the present invention, "leaving group" refers to a chemical
group which may be easily displaced by a nucleophile during a nucleophilic substitution
10 reaction, wherein the nucleophile is more particularly an amine, and notably a primary
or secondary amine. Such a leaving group may be more particularly a halogen atom
such as a chlorine atom, a mesylate (CH3-S(02)0-), a triflate (CF3-S(0)20-) or a
tosylate (p-Me-C6H4-S(0)20-).
Step (al):
15 Coupling between (A) and (B) may be carried out by techniques well known to
the person skilled in the art.
When R3o=OH, the coupling may be carried out under peptide coupling
conditions. It may thus be carried out in the presence of a coupling agent such as
diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), l-(3-
20 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole
(CDI), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
(HBTU), 2-(lH-benzotriazole-l-yl)-l, 1,3,3-tetramethyluronium tetrafluoroborate
(TBTU) or 0-(7-azobenzotriazol-l-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate
(HATU); optionally combined wdth a secondary coupling agent such as N-
25 hydroxysuccinimide (NHS), N-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-
4-oxo-l,2,3-benzotriazole (HOOBt), l-hydroxy-7-azabenzotriazole (HAt) or Nhydroxysulfosuccinimide
(sulfo NHS). Peptide coupling may moreover be carried out in
an aprotic solvent such as tetrahydrofuran, dioxane and dichloromethane.
When R30 is a leaving group such as CI, coupling may be carried out in the
30 presence of a base such as pyridine, triethylamine or diisopropylethylamine (DIPEA).
The reaction may be carried out in an aprotic solvent such as tetrahydrofuran, toluene or
dichloromethane, or in a base solvent such as pyridine.
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The compounds of formula (A) and (B) can be prepared by the methods
described in further detail below.
Step (b\):
In the context of the present invention, "deprotection" refers to the process by
5 which a protecting group is eliminated once the selective reaction is completed. Certain
protecting groups may be preferred over others due to their convenience or their relative
ease of elimination.
The deprotection step may be carried out under conditions well known to the
person skilled in the art.
10 The substitution step may also be carried out by techniques well known to the
person skilled in the art. If necessary, functionalities that may be sensitive to the
reaction conditions of the substitution step may be protected beforehand and then
I deprotected once substitution is carried out.
I Thus, if a step of deprotection of the nitrogen atom carrying an R29 group
15 representing an N-protecting group and a step of substitution of the nitrogen atom
bound to V with an R3 group must be carried out, the order in which these two steps are
carried out will depend on the reaction conditions of each of these steps.
Moreover, it may also be necessary to carry out additional steps of
functionalization of the molecule by techniques known to the person skilled in the art.
20 Step (cl):
This step may be carried out in the presence of a pharmaceutically acceptable
organic or inorganic acid or a pharmaceutically acceptable organic or inorganic base
such as defined above.
25 According to a second embodiment, the present invention relates to a method for
the preparation of a compound of formula (I) according to the invention wherein
V=CH2, and notably U=CH2, comprising the following successive steps:
(a2) reducing amination reaction between a compound of formula (A) such as defined
above and an aldehyde of following formula (D):
••
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26
R2
° (D)
wherein Ri, R2, U and n are such as defined above,
to yield a compound of following formula (E):
NH
II N
(E)
5 wherein Yi, Y2, Y3, Y4, Ri, R2, R29, U and n are such as defined above,
(b2) optionally deprotection of the nitrogen atom carrying an R29 group representing
an N-protecting group and/or substitution of the nitrogen atom bound to V with
an R3 group other than H of the compound of formula (E) obtained in the
preceding step to yield a compound of formula (I) with V=CH2, and
10 (c2) optionally forming of a salt of the compound of formula (I) obtained in the
preceding step to yield a pharmaceutically acceptable salt of same.
Step (a2):
This step is carried out in the presence of a reducing agent such as a borohydride
15 and in particular NaBH4, NaBH(0Ac)3 or NaBHsCN.
This reaction is more particularly carried out at room temperature, i.e., at a
temperature ranging between 15°C and 40°C, in particular between 20°C and 30°C.
The reaction may be typically carried out in a solvent such as dichloroethane
(DCE), tetrahydrofliran (THF) or acetonitrile, optionally in the presence of water, acetic
20 acid or trifluoroacetic acid.
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I
i
27
The compounds of formula (A) and (D) can be prepared by the methods
described in further detail below.
Step ("b2): see step (bl)
Step (c2): see step (cl)
5
According to a third embodiment, the present invention relates to a method for
the preparation of a compound of formula (I) according to the invention wherein
V=C(0) or C(S), n=l and U=NH, comprising the following successive steps;
(a3) coupling between a compound of formula (A) such as defined above and a
10 compound of following formula (F):
R2
(F)
wherein Ri and Ri are such as defined above and Z=0 or S,
to yield a compound of following formula (G):
R2 a-
NH
NH
^ " (G)
15 wherein Yi, Y2, Y3, Y4, Ri, R2, R29, and Z are such as defined above,
(b3) optionally deprotection of the nitrogen atom carrying an R29 group representing
an N-protecting group and/or substitution of the nitrogen atom bound to V with
an R3 group other than H of the compound of formula (G) obtained in the
preceding step to yield a compound of formula (I) with V=C(0) or C(S), n=l
20 and U=NH, and
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28
(c3) optionally forming of a salt of the compound of formula (I) obtained in the
preceding step to yield a pharmaceutically acceptable salt of same.
Step (a3V
5 This step may be carried out under conditions well known to the person skilled
in the art.
A polar or non-polar protic solvent may be more particularly used such as
dichloromethane, acetone, acetonitrile, tetrahydrofuran or dioxane.
The compounds of formula (A) and (F) can be prepared by the methods
10 described in fiirther detail below.
Step (b3V see step (bl)
Step (c3\. see step (cl)
Once the compound of formula (I) is obtained by any one of the preceding
15 methods, it may be separated from the reaction medium by techniques well known to
the person skilled in the art, and notably by evaporation of the solvent, crystallization
and filtration, etc.
The compound obtained may be purified if necessary by techniques well known
to the person skilled in the art, and notably by high-performance liquid chromatography
20 (HPLC), silica gel chromatography, recrystallization when the compound is crystalline,
etc.
Thus, the compounds of formula (I) according to the present invention can be
prepared by the various methods summarized in diagrams la and lb below.
wo 2012/101239 PCT/EP2012/051283
I 29
Method A I Ri
precursors - ^ J ^ ^ | ^^
• (>i) \ \ : <'"' {IV) R| (V) jR, • Rj ^ '
Rj=H or N-protecting group " " * '" Method £
R„ - Hal, OMe, S02M9 .. .^ ^ R?
Method fi sL=N - r q;: Method £ „„ : \i.^,
I ^'^xy^yCN ^ ' ^ x y ^ , J ^ I Methods ^'^x. ^ . J
i precursors " I3 I _ " l ^ X ^ \ ^3„A^'
T4 Ri Y4 "; i Y4 "^
i (vi) (VII) Rj j (I) R]
Ri = NO2, halogen, OH, OMe, SMe, S(0)Me, SOzMe, OMs, OTf or OTs Method £
Rj = H or N-protecting group R2
V.
Ar ^'^
(0 "
Diagram la
.Methods pS^ors \ 'XjT^'
I precursors _ / V " _ / Y ^ " ^ / V C j M s M i _ V«3
I Ao ^ Yr^° - 'lY'
W N NH2 W N NH2 W N NH2 W'^N*^NH2
NH2
_ J N a N 0 2 _ ^ ' - V ' N ^ C N RjNHNH2 ^ ' V ^ T ^ N
Hal® w'^N*^Hal W^N*^N
(lie) (Vc) Rj
Diagram 4
The optionally functionalized 3-amino-6-iodopyrazine-2-carboxamides are
25 typically obtained in two steps from the corresponding methyl 3-aminopyrazine-2-
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32
carboxylates by iodination in the presence of N-iodosuccinimide or molecular iodine
optionally in the presence of a cofactor such as KIO3, AgCOaCFs, Ag2S04, AICI3,
CuCU or HgO, followed by a conversion reaction of the methyl ester function into
I
I carboxamide, notably by the use of ammonia in a polar solvent such as water, methanol
5 or THF at temperatures varying between 0°C and 100°C. The carboxamide function of
the optionally flinctionalized 3-amino-6-iodopyrazine-2-carboxamide is then converted
into nitrile by the use of dehydration agents such as, in particular, CCl4/PPh3, SOCI2,
PhS02Cl, P2O5, TsCl, COCI2, DCC/py (N,N'-dicyclohexylcarbodiimide/pyridine) or
(C0C1)2 used as the case may be in the presence of an organic base such as pyridine.
10 The preferred method involves the use of phosphorus oxychloride in
dimethylformamide (DMF). Deprotection of the dimethylformimidamide function is
carried out by treatment with acid such as aqueous hydrochloric acid or any other
reagent with equivalent properties. Formation of the pyrazole ring is carried out by a
Sandmeyer reaction, well known to the person skilled in the art, followed by a reaction
15 in the presence of a hydrazine, flinctionalized or not, under conditions as described in
the methods above. Alternatively, the diazonium salt, an intermediate of the Sandmeyer
reaction, may be reduced by the use, for example, of tin chloride in an acid medium or
any other equivalent agent, in order to form a hydrazine fiinction that can undergo
intramolecular cyclization under the effect of heat.
20 Method A3:
Method A3 aims at obtaining derivatives of general formula (V) featuring a
variable function in position 6 of the pyrazolopyridine bicycle. It is detailed in
diagram 5 below.
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33
0 mz
1*^2 A CN
(MB] ^ H . ^ W « OH. NHj, Alk. Ai, CHjAr
m) H 1 or 2 (Vd) "^
W = OH. QAIIi. NHi NHMk. Alk. Ai. 01^^-
Rj=H or N-protecting group
(Alk=(Ci-C6)alkyl, Ar=aryl, CH2Ar=benzyl, H=halogen)
Diagram 5
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34
Reaction of the cyanothioacetamide with ethyl 3-ethoxyacrilates variously
substituted according to methods described notably by Litrivnor et al. in Russ. Chem.
Bull., 1999, 48(1), 195-196 and Tsann-Long Su etal. in J. Med. Chem., 1988, 31, 1209-
1215 make it possible to yield access, in two steps, to ethyl 5-cyano-6-
5 (methylthio)nicotinates carrying a variable functionality in position 2. These syntheses
are typically carried out, for the first step, in an anhydrous polar solvent such as, for
example, ethanol at a temperature ranging between 0°C and 70°C in the presence of an
organic base such as methylmorpholine, triethylamine, DIPEA (N,Ndiisopropylethylamine)
or DBU (l,8-diazabicyclo[5,4,0]undec-7-ene). The second step
10 of intramolecular cyclization and of alkylation is typically carried out by the heating to a
temperature ranging between 20°C and 100°C of a solution of the intermediate
thioamidate in a polar solvent, for example ethanol in the presence of a suitable
alkylating agent such as alkyl halide or dialkyl sulfate.
The 5-cyano-6-(methylthio)nicotinic acids substituted in position 2 are typically
15 obtained by saponification of the corresponding ethyl esters according to methods well
known to the person skilled in the art, notably by the use of hot lithium hydroxide.
Decarboxylation of these compounds is carried out by heat treatment in a high boilingpoint
solvent such as diphenylether at a temperature ranging between 150°C and 250°C.
Halogenation reactions principally aim at obtaining iodinated, brominated or
20 chlorinated derivatives, more particularly iodinated derivatives. The latter are typically
obtained by a molecular iodine treatment in the presence of a silver salt such as, for
example, Ag2S04 in a polar solvent such as ethanol at a temperature ranging between
0°C and 70°C. Alternative methods, notably those based on other salts such as KIO3,
AgCOzCFa, AICI3, CuCb or HgO, or other iodination agents such as N-
25 iodosuccinimide, are also considered. The conceivable bromination methods typically
rely on agents such as N-bromosuccinimide or dibromine according to methods well
known to the person skilled in the art.
In the case in which W=OH (tj^jically resulting fi-om the use of diethyl 2-
(ethoxymethylene)malonate), the corresponding compounds are protected by an
30 alkylation reaction. This reaction is notably carried out by the use of methyl iodide or
bromomethane, and silver carbonate in dioxane, THF, acetonitrile or acetone, or any
other equivalent agent such as dimethylsulfate. The 5-halo-2-(methyhhio)
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35
nicotinonitriles obtained are subjected to oxidation of their thiomethoxy function,
typically by the use of m-CPBA (m-chloroperbenzoic acid), oxone or any other
equivalent agent, to lead to the formation of the corresponding sulfoxide. These
compounds, which may contain variable quantities of the corresponding sulfone, are
5 engaged in a reaction in the presence of an optionally substituted hydrazine to form the
corresponding 5-halogeno-pyrazolo[3,4-b]pyridin-3-amine carrying a variable
functionality in position 6.
MethodA4:
Method A4 aims at obtaining derivatives of general formula (V) from the
10 compounds of general formula (m) via intermediate formation of compounds of
formula (IV). These compounds are typically obtained by the pathway presented in
diagram 6. The following references illustrate the method used; Gueiffier et al.
Heterocycles, 1999, 51(7), 1661-1667; Gui-Dong Zhu etal. Bioorg. Med. Chem., 2007,
75, 2441-2452.
15
Halv^Yi .CH3 Hal.^Yi CH3 Hal.^Yi
•^•¥4 NH2 "^yC^m [Base] Y4 N
(Ilia) \ O^CHa (IVa) cT '^"^
^ NO2 NH2
H a l ^ Y i , ^ ^ Hal^^i^ H a l ^ i^
J! I N [NO2I J! I N [Red] J! [ N
T4 ^ U ^ U y^
(IVb) (Ve)
Diagram 6
The compounds of general formula (Ilia), acetylated beforehand by one or
20 another of the methods well known to the person skilled in the art, are subjected to the
action of isoamyl nitrite, sodium nitrite or any other equivalent organic or inorganic
nitrite, in water or acetic acid, for periods typically varying from 1 to 3 days at
temperatures varying between 0°C and 40°C. The compounds of general formula (IVa)
thus obtained are deprotected in acidic conditions, for example by the use of
25 hydrochloric acid, before being subjected to the action of nitration agents such as
concentrated nitric acid or potassium nitrate in sulfuric acid at temperatures varying
between 0°C and 25°C.
I
I .
i
1 ' '
i
j
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36
It should be noted that the direct conversion of compounds of general formula
(Ilia) into deprotected compounds (IVb) is possible in general.
The nitropyrazoles thus obtained are typically reduced into aminopyrazoles of
general formula (Ve) by the use of SnCl2 in hydrochloric acid. Alternative methods
5 include the use of iron, zinc or tin in acidic conditions and methods of catalytic
hydrogenation in the presence of complexes of platinum, nickel or Pd/C under an
atmosphere of hydrogen or in the presence of equivalent agents such as cyclohexadiene,
cyclohexene, sodium borohydride or hydrazine.
10 Method B:
According to method B, the compounds of formula (I) are obtained by the
preliminary synthesis of compounds of general formula (VI) characterized by a
functionalized heterobicyclic ring possessing an exocyclic amine. These compounds are
obtained via the synthesis of intermediates of general formula (VI).
15 Method Bl:
Method Bl is represented in diagram 7 below, with W notably representing H,
(Ci-C6)alkyl, aryl or benzyl.
W Y4 NO2 W Y4 NO2 W Y4 NO2 W Y4 NO2
NH2
W Y4 NH2 2. [Red] W Y4 N
1 . [ 0 N 0 - ] \ RjNHNHsy^ ^'^'"^^
2. [Hal-] Ar>^S N CN
A «L (VIb)
W Y4 Hal
20 Diagram 7
The 3-nitro-6-thioxo-l,6-dihydropyridin-2-carbonitrile and 3-nitro-6-thioxo-l,6-
dihydropyrazine-2-carbonitrile derivatives, optionally functionalized in position 5, are
typically obtained from the corresponding 2,6-dichloro-3-nitropyridines or 2,6-dichlorot
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3-nitropyrazines by the successive reactions of a cyanide salt, such as copper cyanide, in
a high boiling-point polar solvent such as N-methylpyrrolidone at temperatures ranging
between 100°C and 200°C; followed by the reaction of aqueous sodium hydrosulfite in
a polar solvent. These compounds are then alkylated, for example by the use of a
5 substituted benzyl bromide, in basic medium, according to methods well known to the
person skilled in the art. The preferred protocol includes the use of an aprotic and
I anhydrous polar solvent such as acetone carrid at its boiling point and an organic base
I such as pyridine, triethylamine or DIPEA, or an inorganic base such as sodium,
I potassium or calcium carbonate. Reactions for reducing the nitro function in amine are
10 preferentially carried out by the use of SnCla in hydrochloric acid. Alternative methods
include the use of iron, zinc or tin in acidic conditions and methods of catalytic
hydrogenation in the presence of complexes of platinum, nickel or Pd/C under an
atmosphere of hydrogen or in the presence of equivalent agents such as cyclohexadiene,
cyclohexene, sodium borohydride or hydrazine.
15 In certain cases, the product of the reduction reaction, in addition to having a
primary amine, has a carboxamide function resulting from hydrolysis of the nitrile
function. In this case, isolation of the corresponding 3-aminopicolinonitriles or 3-
aminopyrazine-2-carbonitriles may be carried out by dehydration of the carboxamide
into nitrile via the use of phosphorus oxychloride in the presence of DMF or any other
20 method well known to the person skilled in the art. Lastly, formation of the
aminopyrazole ring is carried out preferentially by the formation of a diazonium,
obtained by the successive reaction at low temperature of isoamyl nitrite, sodium nitrite
or any other equivalent organic or inorganic nitrite, in water, hydrochloric acid, acetic
acid or sulfliric acid, at temperatures varying between 0°C and 20°C, followed by its
25 reduction into hydrazine and intramolecular cyclization activated by heating of the
reaction medium. The reduction reaction is preferentially carried out with tin chloride in
acidic conditions but may also be carried out by catalytic hydrogenation or any other
I method well known to the person skilled in the art. In an alternative to this last step, it is
conceivable that the intermediate diazonium undergoes a Sandmeyer reaction during
30 which this functional group is substituted by a halogen atom, such as iodine, by the
reaction of an adequate salt, such as Nal. If this option is preferred, formation of the
i
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38
aminopyrazole ring is carried out by the use of a hydrazine, fiinctionalized or not, in a
polar solvent such as ethanol at temperatures varying between 25°C and 150°C.
Method B2:
Alternatively, it is possible to take advantage of an aromatic nucleophilic
5 substitution reaction to functionalize the pyridine or pyrazine ring in position 6. In this
case the nucleophiles used are phenols, thiophenols, benzyl alcohols or thiobenzyl
I alcohols as well as anilines or benzylamines, fiinctionalized or not. The general reaction
diagram 8a is presented below, notably with W=H, (Ci-C6)alkyl, aryl or benzyl.
W Y4 NO2 [base] W Y4 NO2 W Y4 NHj
(Vic) (Vid)
NH2
W - ^ Y ^ N H ^ 2. [Red] W^Y^^N^ (Vllb)
(VId) \ . ^ ^
1, [ 0 N 0 - ] \ ^ /^,NHNH2
2. [Hal-] Ar'^YV^^
10 W-^Yrnal (^'^)
Diagram 8a
In the case in which X=0 or S, the 6-chloro-3-nitropicolinonitriles and 6-chloro-
3-nitropyrazine-2-carbomtriles, optionally substituted in position 5, are reacted in the
15 presence of the suitable nucleophile, alcohol or thiol, in a polar solvent such as
acetonitrile in the presence of an inorganic base such as potassium or sodium carbonate.
Solvents such as DMSO (dimethylsulfoxide), DMF (dimethylformamide), acetone, THF
(tetrahydrofliran) or pyridine may also be considered. If necessary, these reactions may
be catalyzed by the action of copper and may also be carried out without solvent.
20 Typically, the preferred protocol involves temperatures ranging between 20°C and
150°C.
Alternatively, the use of bases such as pyridine, DIPEA, diisopropylamine,
triethylamine, DBU, potassium tert-butylate, NEts or NaH is also possible.
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39
In the case in which X=N, toluene is a preferred solvent and triethylamine (NEt3) the
base of choice.
The following steps, up to the compounds of general formula (Vllb), are
identical to those documented in method Bl above.
5 Method B3:
Method B3, presented in diagram 8b below, is a variant of method B2
characterized by a first step resulting from a catalytic coupling reaction between a
benzyl boronate, in acid or ester form, and a 6-chloro-3-nitropicolinonitrile or 6-chloro-
3-nitropyrazine-2-carbonitrile derivative. It is also well known to the person skilled in
10 the art that catalytic coupling reactions using alternative catalysts and benzyl derivatives
are also possible. Among these, the Stille reaction, based on tin complexes, or those
based on organozinc compounds may be considered.
W ^ Y f ^ N 0 2 °> w'^vf^NO^
(Vlf)
NH2
[Red] ^ A r - ^ ^ ^ . r ^ ^ 1[ONO-] ^ A r ^ ^ ^ - Y - ^^
W^Y4 NH2 2. [Red] W'^Y4 N
(VIg) (Vile)
15 Diagram 8b
An optionally substituted 2-benzyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane is
obtained beforehand, for example from the corresponding benzyl chloride and
octamethyl-bi-dioxaborolane in dioxane in the presence of potassium acetate and
20 Pt(dppf)Cl2 (dppf=l,r-bis(diphenylphosphino)ferrocene). This compound is brought
together with a 6-chloro-3-nitropicolinonitrile, a 6-chloro-3-nitropyrazine-2-carbonitrile
optionally substituted in position 5 or a 5-chloro-2-nitronicotinonitrile optionally
substituted in position 6 and a palladium catalyst such as Pd(dppf)Cl2 or Pd(PPh3)4, an
organic base such as triethylamine or an alcoholate, or an inorganic base such as
25 sodium, potassium or cesium carbonate in a solvent such as toluene, benzene, THF or
dioxane. The preferred reaction temperatures are between 20°C and 100°C. The
products of these reactions correspond to substituted 6-benzyl-3-nitropicolinonitrile, 6-
i
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40
benzyl-3-nitropyrazine-2-carbonitrile or 5-benzyl-2-mtronicotinonitrile derivatives for
which the following transformation steps are reproduced from method Bl above.
Method B4:
Method B4, presented in diagram 9 below, gives access to pyrazolopyridine and
5 pyrazolopyrazines bicycles featuring optionally fiinctionalized aryl sulfonamide
functions, with Ri=(Ci-C6)alkyl and notably W=H, (Ci-C6)alkyl, aryl or benzyl.
? ^ R.^o^,o OH ' ^ r ^ V r
ClOzS^Y, J»p 1.ArNHRi/[base]^ ^ Y ^ N ' ^ Y ^ ' T O ^ T ^ ' ^ ' ^ Y ^ ' T O
W ' ^ N ' ^ C I 2.LiOH Ri '^'W'^N*^CI ^' '^'w'^N^^CI
LJL V Y, CN RiNHNHz SAM-S>^YI^ ' iXtT ' Vs, J,x>
(Vlh) ^' '^'W^N^^CI (Vlld) ^ ^ R.
Diagram 9
10
The ethyl 2-chloro-5-(chlorosulfonyl)nicotinate derivatives required for this
I reaction sequence may be obtained according to the methods described by Levett P.C. et
I al. Org, Proc. Res. Dev., 2002, 6(6), 767-772; WO 01/98284 and WO 2008/010964.
The formation of sulfonamides is typically carried out by mixing the 2-chloro-5-
15 (chlorosulfonyl)nicotinate of interest with a primary or secondary aniline, optionally
fiinctionalized, in an aprotic solvent such as dichloromethane, THF, acetone or
acetonitrile in the presence of an organic base such as triethylamine (NEts), pyridine or
DIPEA. The use of an inorganic base such as sodium or potassium carbonate may also
be considered. The optimal reaction temperatures are between 0°C and 70°C.
20 The saponification reaction of the product thus obtained, notably by the use of
lithium hydroxide in a THF/water mixture, gives access to the corresponding 2-chloro-
5-(N-phenylsulfamoyl)nicotinic acids.
The corresponding acid chlorides are prepared by treatment with thionyl
chloride in toluene under reflux or by any other dehydrochlorination method well
25 known to the person skilled in the art. The reaction of these intermediates with aqueous
ammonia makes it possible to form optionally fiinctionalized 2-chloro-5-(Nw
o 2012/101239 PCT/EP2012/051283
41
phenylsulfamoyl)nicotinamides which are then engaged in a dehydration reaction,
notably by the use of POCI3, at a temperature ranging between 75°C and 150°C. The
alternative use of agents such as P2O5 or trifluoroacetic anhydride and pyridine may also
be considered.
5 Lastly, these derivatives of general formula (Vlh) are reacted in the presence of
a hydrazine, functionalized or not, in a polar solvent such as ethanol at temperatures
varying between 25°C and 150°C to form the corresponding derivatives of general
formula (Vlld).
Method B5:
10 Method B5, presented in diagram 10 below, gives access to pyrazolopyridine
bicycles featuring optionally functionalized benzyl ether functions, notably with W=H,
(Ci-C6)alkyl, aryl or benzyl.
W N [base] W N W N
6
e
NH2
(Vli) (Vile)
15 Diagram 10
The method described below is inspired by the work of J. Baldwin et al, J.
Heterocyclic. Chem., 1980, 17(3), 445-448. The 5-hydroxynicotinonitrile derivatives,
optionally functionalized in position 6, are alkylated, typically by the use of an
20 optionally functionalized benzyl halide in the presence of a base. The preferred method
requires the use of an aprotic polar solvent such as DMF and a base such as NaH. The
optimal reaction temperatures are between 20°C and 100°C. Alternatively, the solvents
which may be used include, for example, THF, DMSO, dioxane, acetonitrile,
dichloromethane or acetone and bases such as *BuOK, DIPEA, pyridine, triethylamine,
25 DBU or sodium, potassium or cesium carbonate.
Oxidation of the pyridine ring into pyridine-N-oxide is typically carried out by
use of m-CPBA in dichloromethane at room temperature. Nevertheless, many
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alternative methods are conceivable, notably those based on the use of sodium
percarbonate in the presence of a rhenium catalyst, sodium perborate in the presence of
acetic acid or the urea-hydrogen peroxide complex.
Treatment of these pyridine-N-oxide derivatives with phosphorus oxychloride
5 leads to the formation of the corresponding 2-chloronicotinonitriles (VI).
Their reaction under heat with a hydrazine, flinctionalized or not, in a polar
solvent such as isopropanol or ethanol leads to the formation of the pyrazolopyridine
bicycles (Vile) sought.
Method B6:
10 Method B6, presented in diagram 10a below, gives access to optionally
functionalized pyrazolop5Tidine and pyrazolopyrazine bicycles featuring with reversed
sulfonamide functions, notably with W=H, (Ci-C6)alkyl, aryl or benzyl.
\ Ar Ar
0=S=0 0=S=0 NH2
W ^ N ^ ^ C I [base] w"^N*^CI W-^N^^N
(vy) (viif) '^'
15 Diagram 10a
Le method described below consists in forming a sulfonamide function from an
aromatic amine and an arylsulfonyl halide, or any other equivalent reagent, in the
presence of a base, which can optionally be introduced as solvent or co-solvent.
Alternatively, the arylsulfonyl halide or its equivalent can be generated in situ.
20 Their reaction under heat with a hydrazine, functionalized or not, in a polar
solvent such as isopropanol or ethanol leads to the formation the desired
\ pyrazolopyridine and pyrazolopyrazine bicycles (Vnf).
Method C:
j 25 Method C aims at the preparation of compounds of general formula (XI) as
described in diagram 1.
Method CI:
Method CI, presented in diagram 11 below, is intended for the preparation of
pyrazolopyridines and pyrazolopyrazines functionalized at position 6 with Rn=halogen,
i
I
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mesylate, tosylate or triflate, X=0, S, NH, N-(Ci-C.)alkyl, and optionally CH2 for (Xc)
and (Xd), and Rj=H or N-protecting group.
This method can also be used to carry out the synthesis of molecules comprising
a diatomic X group corresponding notably to an ArX group representing: -ArCHaNH-, -
I 5 ArCH2N(R4)-, -ArCHjO-, -ArCH2S-, -ArCHzCHz-, -ArCHCH-, or -ArCC-.
I ^Yi CN ^Yi CN ^Yi CN
X X JL X * Ar X X
(IXa) (Xa)
(IXb) (Xb)
NH2
fr\^^_m__^ ^Yi CN RjNHNH, ^ f ^ ' r ^N
^^^X^N^^SMe ^ ^ - X ^ N ^ S - ^^^X^^N^N
(Xc) (Xd) l°/iou2 (XIa)
Diagram 11
10 The 6-hydroxy-2-(methylthio)nicotinonitriles or 5-hydroxy-3-(methylthio)
pyrazine-2-carbonitriles are subjected to a dehydrochlorination reaction, typically in the
presence of phosphorus oxychloride, with or without solvent, at temperatures varying
between 70°C and 180°C. If a solvent is used, a high boiling-point non-polar solvent
such as toluene or xylene will be preferred. Alternatively, it is possible to activate the 6-
15 hydroxy-2-(methylthio)nicotinonitriles and 5-hydroxy-3-(methylthio)pyrazine-2-
carbonitriles by their derivation into sulfonic esters via the formation of the
corresponding tosylates, mesylates or triflates. If this option is preferred, the use of
tosyl, mesyl or triflyl chlorides in a solvent such as toluene, dichloromethane, THF,
acetonitrile, acetone or dioxane in the presence of an organic or inorganic base gives
20 access to these derivatives.
The 6-chloro-2(methylthio)nicotinonitriles and 5-chloro-3-(methylthio)pyrazine-
2-carbonitriles respectively obtained, or their sulfonic ester analogues if this option is
preferred, are then reacted with a nucleophile such as a phenol, an aniline or a
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thiophenol in the context of aromatic nucleophilic substitution. In this case, the reaction
is carried out in a polar solvent such as DMSO, DMF, acetone, THF or acetonitrile, in
the presence of a base such as potassium ^er^butylate or NaH. If necessary, these
reactions may be catalyzed by the action of copper and may also be carried out without
5 solvent. Typically, the preferred protocol involves temperatures ranging between 20°C
and 150°C.
Alternatively, the use of organic bases such as pyridine, diisopropylamine,
triethylamine or DBU, or inorganic bases such as sodium or potassium carbonate is also
possible.
10 Alternatively, the compounds of formula (IXb) may give rise to a catalytic
coupling reaction such as a Suzuki reaction. In this case, these compounds are brought
together with an optionally substituted 2-benzyl-4,4,5,5-tetramethyl-l,3,2-
dioxaborolane already described in preceding method B3, a palladium catalyst such as
Pd(dppf)Cl2 or Pd(PPh3)4, an organic base such as triethylamine or an alcoholate, or an
15 inorganic base such as sodium, potassium or cesium carbonate in a solvent such as
toluene, benzene, THF or dioxane. The preferred reaction temperatures are between
20°C and 100°C.
The derivatives obtained by one or another of these methods are then oxidized,
typically by the use of m-CPBA or oxone to form the corresponding methyl sulfoxides
20 or methyl sulfones. These compounds, sometimes obtained as mixtures, are used as-is in
the aminopyrazole ring formation reaction by use of an optionally substituted hydrazine
in a polar solvent such as ethanol at temperatures varying between 25°C and 150°C.
Alternatively, it is possible to modify the reaction sequence, notably by
reversing the synthesis steps.
25 Method C2:
Method C2, presented in diagram 12 below, is intended for the preparation of
pyrazolopyridines and pyrazolopyridazines functionalized at position 6 with X=0, S,
NH, N-(Ci-C.)alkyl, or CH2 and Rj=H or N-protecting group.
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NH2 NH2
jM I • 1! JL ^ i! JL
H O ' ' ^ ^ * ^ S M e 2.RjNHNH2 H O ' ' ^ ^ ^ N CI^'^^^^'^N
(Xlla) (Xllla) '^i (XlVa)'^J
NH2
*• . II N
(Xlb) Rj
Diagram 12
The 6-hydroxy-4-(methylthio)nicotinonitrile or 6-hydroxy-4-(methylthio)
5 pyridazin-3-carbonitrile derivatives are oxidized, typically by the use of m-CPBA or
oxone to form the corresponding methyl sulfoxides or methyl sulfones. These
compounds, sometimes obtained as mixtures, are used as-is in the aminopyrazole ring
formation reaction by use of an optionally substituted hydrazine in a polar solvent such
as ethanol at temperatures varying between 25°C and 150°C.
10 The pyrazolopyridines and pyrazolopyridazines thus obtained are subjected to a
dehydrochlorination reaction, typically in the presence of phosphorus oxychloride, with
or without solvent, at temperatures varying between 70°C and 180°C. If a solvent is
used, a high boiling-point non-polar solvent such as toluene or xylene will be preferred.
The optionally substituted 6-chloro-pyrazolo[4,3-c]pyridin-3-amine and 6-chloro-
15 pyrazolo[4,3-c]pyridazin-3-amine respectively obtained are then reacted with a
nucleophile such as a phenol, an aniline or a thiophenol in the context of aromatic
I nucleophilic substitution. In this case, the reaction is carried out in a polar solvent such
I as DMSO, DMF, acetone, THF or acetonitrile, in the presence of a base such as
potassium ter^butylate or NaH. If necessary, these reactions may be catalyzed by the
20 action of copper and may also be carried out without solvent. Typically, the preferred
protocol involves temperatures ranging between 20°C and 150°C.
Alternatively, the use of organic bases such as pyridine, diisopropylamine,
triethylamine or DBU, or inorganic bases such as sodium or potassium carbonate is also
possible.
25 Alternatively, the compounds of formula (XlVa) may give rise to a catalytic
coupling reaction such as a Suzuki reaction. In this case, these compounds are brought
together with an optionally substituted 2-benzyl-4,4,5,5-tetramethyl-l,3,2-
I
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dioxaborolane described above in preceding method B3, a palladium catalyst such as
Pd(dppf)Cl2 or Pd(PPh3)4, an organic base such as triethylamine or an alcoholate, or an
inorganic base such as sodium, potassium or cesium carbonate in a solvent such as
toluene, benzene, THF or dioxane. The preferred reaction temperatures are between
5 20°C and 100°C.
Method C3:
Method C3, presented in diagram 12a below, is a variant of method CI based on
the regioselective functionalization of 2,6-dichloronicotinonitrile either by an anionic
nucleophile such as a phenate or a thiophenate, or by an organometallic such as a
10 benzylzinc chloride. In the latter case, the reaction is catalyzed for example with a
palladium(n) complex. The transformation of the chloronicotinonitrile thus obtained in
the corresponding p3Tazolopyridine, in the case where Yi = CH, is carried out as
previously described in method Al.
I NH2
/ Y i .CN ,^^1 CN ^Yi J
0 1 ArXH.base ., 1 I RjNHNHz f T ^N
Rj
NH,
^ Y i . ^ CN ,^Yi CN ^Yi J
I 1 ArCHzZnCI . J| 1 RjNHNHz ^ J T ^N
' Ri
15 Diagram 12a
Method D:
These methods have as an object the synthesis of compounds of general formula
(I) or (VII) by the use of various catalytic coupling methods.
20 Method Dl:
Method Dl, presented in diagram 13 below, makes use of the coupling reaction
as described in J.A.C.S., 1984, 106, 158 between an organozinc compound prepared in
situ and an aryl bromide catalyzed by palladium complexes.
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« T^N + Ar-^ZnC! ^ '^^ T T ^N
Rj Rj
Rj=H or N-protecting group •
Diagram 13
The optionally substituted 3-amino-diazaindazoles or 3-amino-azaindazoles are
5 brought together with a zinc benzyl chloride, optionally substituted, in an aprotic polar
solvent such as THF or dioxane, in the presence of a catalytic quantity of a palladium
complex such as (dppf)2PdCl2 €112012. The coupling reaction is carried out at
temperatures ranging between 25°C and 100°C.
Method D2:
i 10 Method D2, presented in diagram 14 below, makes use of the coupling reaction
\ as described by GueifFier A. et ai. Tetrahedron, 2006, 62, 6042-6049, between a thiol,
in particular a thiophenol or a benzylthiol, and an aryl iodide catalyzed by copper
complexes.
N-R3 N-f*3
R, R,
Rj=H or N-protecting group
R2
n = Oor 1 V
:>(
15
Diagram 14
•
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This reaction is typically carried out in a high boiling-point polar solvent such as
2-propanol in the presence of a catalytic quantity of polyethylene glycol, a metal salt
such as copper iodide (Cul) and an excess of an inorganic base such as potassium
carbonate, calcium carbonate or sodium carbonate. The reaction temperatures typically
5 vary between 50°C and 100°C.
Method D3:
Method D3, presented in diagram 15 below, makes use of the coupling reaction
as described by Sonogashira, K. et al. in Tetrahedron Lett., 1975, 16, 4467-4470
between an acetylene derivative and an aryl halide catalyzed by copper and palladium
10 complexes.
Rj R) .
Rj=H or N-protecting group
I Rs
R.-Hor ^ ^ ^ ^
n = 0 or ! v\-
Diagram 15
15 Such a reaction is typically carried out by the reaction under an inert atmosphere
of a heteroaryl halide with a stoichiometric quantity of an optionally substituted
ethynylbenzene in the presence of a catalytic quantity of a palladium complex, for
example PdCl2(PPh3)2 or Pd(PPh3)4, a catalytic quantity of a copper salt, for example
Cul, and an organic base such as triethylamine or DIPEA, or an inorganic base such as
20 potassium or cesium carbonate. The protocol generally involves reaction temperatures
ranging between 20°C and 45°C in solvents including DMF, THF, dioxane or diethyl
ether.
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Method E:
The protocols of method E aim at functionalizing the exocyclic amine of
arainopyrazole rings by their reaction with an intermediate featuring an electrophile
function, optionally generated in situ, such as acid chloride, an isocyanate, a
5 isothiocyanate or an aldehyde.
Method El:
Method El, presented in diagram 16 below, aims at the transformation of the
primary exocyclic amine function of aminopyrazole compounds into an amide function.
•• N + ^ ^ . ^ *•• •• N
R 0^ ' R
^j OH ^j
Rj=H or N-protecting group
10
Diagram 16
These compounds are synthesized via the corresponding 3-aminopyrazole by the
addition of adequate acid chloride prepared beforehand by the use of oxalyl chloride
15 and a catalytic quantity of DMF in a solvent such as tetrahydrofuran. These acid
chlorides may be obtained by the use of alternative methods, such as those based on the
use of thionyl chloride or phosphorus oxychloride, well known to the person skilled in
the art. The condensation of acid chlorides on aminopyrazoles is typically carried out in
an aprotic solvent such as tetrahydrofuran, toluene or dichloromethane in the presence
20 of a base such as DIPEA, pyridine or triethylamine.
Alternatively, the use of a base as a solvent, in particular pyridine, is a
possibility.
Alternatively, this type of reaction may be conducted in a biphasic system
according to the well-known Schotten-Baumann method.
I
y • *
j WO 2012/101239 PCT/EP2012/051283
50
Alternatively, formation of the amide bond may be carried out from the
corresponding 3-aminopyrazole and the acid of interest by the use of peptide coupling
conditions using reagents such as HOBt (hydroxybenzotriazole), TBTU (O-
(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), HATU (2-(lH-7-
5 azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate), EDCI (1-
ethyl-3-(3-diraethylaminopropyl)carbodiimide) or carbonyldiimidazole at a temperature
ranging between -20°C and 100°C in an aprotic solvent such as tetrahydrofiiran,
dioxane, dichloromethane or any solvent with similar properties.
Method E2:
10 Derivatives characterized by the presence of a secondary amine in position 3 of
the aminopyrazole ring are synthesized by a reducing amination reaction according to
diagram 17 below.
NH2 NH
R, R,
Rj=H or N-protecting group
R2
Rk = Hor ^ ^ „
"^
Diagram 17
15
Reducing amination reactions are typically carried out by mixing adequate
stoichiometric quantities of aminopyrazole and aldehyde in a solvent such as DCE
(dichloroethane), THF or acetonitrile, optionally in the presence of a quantity of water,
TFA (trifluoroacetic acid) or acetic acid, by adding successive fractions of a reducing
20 agent such as NaBH4, NaBH(OAc)3 or NaBHsCN. These reactions are typically carried
out at room temperature.
Method E3:
Derivatives carrying a 3-ureido or 3-thioureido function are obtained by the
reaction, presented in diagram 18 below, of an aminopyrazole with an isocyanate or
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isothiocyanate obtained according to methods well known to the person skilled in the
art.
R2
c ^^
NH2 Ki 2^
^YH V 7 NH
R2 Rj
Rj=H or N-protecting group
Z= Oor S
Diagram 18
5
In a typical reaction, the reaction mixture is prepared in a polar or non-polar
aprotic solvent such as dichloromethane, acetone, DMF, DMA, acetonitrile, THF or
dioxane carried at temperatures varying between 20°C and the boiling point of the
chosen solvent. If necessary, recourse to a weakly nucleophilic organic or inorganic
10 base may prove to be necessary. In this case, sodium hydride is a possible option.
Method F: post-synthetic deprotections and modifications
Method Fl: deprotections
The trifluoroacetate protecting groups are removed by the action of an organic
15 base such as triethylamine or pyridine in a polar solvent such as methanol, ethanol or
THF at the reflux temperatures of the solvents used.
The tert-huty\ or trityl protecting groups carried by the pyrazole rings are
displaced by the action of a strong acid, typically TFA, in a non-polar solvent such as
dichloromethane or DCE.
20
• » <
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Method F2: alkyne reductions
*'"-ss>^ N'Rs N-R3
Rj Rj
Rj=H or N-protecting group
RJ
i
Diagram 19
5
Reactions for reducing diaryl alkynes into diaryl alkanes are typically carried out
by catalytic hydrogenation, under hydrogen pressure, in the presence of catalysts such
as Pt02, Pt, Pd/C, Ni or Rh. Alternatively, the use of DIBAL-H (diisobutylaluminum
hydride) in the presence or the absence of a catalyst such as Cp2TiCl2 is conceivable.
10 Method F3: oxidation of sulfides into sulfones and sulfoxides
Rl * Rj ' Ri
Rj=H or N-protecting group
R. = Hor V-^y^„
Diagram 20
15 Oxidation reactions of sulfides into sulfoxides are typically carried out via the
use of oxone in a mixture of polar solvents such as THF/MeOH or DMF/water. The
optimal reaction temperatures are typically between 25°C and 50°C.
• *
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53
Many alternative methods are available, and some give the possibility of
producing semi-oxidized derivatives, namely sulfoxides. Such alternative methods
include the use of m-CPBA, KMn04/Mn02 in dichloromethane, H2O2 (30%) in a
biphasic medium and the presence of a phase transfer catalyst or a catalyst in the form
5 of a urea complex (UHP).
The combined use of H2O2 and metal complexes such as Sc(0Tf)3 promotes
partial oxidation derivatives.
Other known methods include, for example, the use of CAN/NaBrOs
(CAN=ceric ammonium nitrate).
10
The examples which follow illustrate the invention without limiting its scope in
any way.
EXAMPLES
15 The following abbreviations are used:
DMSO Dimethylsulfoxide
EI Electron impact
ES Electrospray
LCMS Liquid chromatography - mass spectrometry
20 mg milligram
mL milliliter
NMR Nuclear magnetic resonance
I. Synthesis of the compounds according to the invention
25
Examples of method Al
Example 1; 5-iodo-lH-pyrazoIo[3,4-b]pyridine-3-amine
NH2
'^ H
30
* 1 '
• t
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Example la; 2-hydroxy-5-iodonicotinonitrile
9 g (0.5 eq) of N-iodosuccinimide at room temperature is added to a solution of 10 g
(83 mmol) of 2-hydroxynicotinonitrile in 150 ml of anhydrous dimethylformamide. The
reaction mixture is stirred at 60°C. After 30 minutes of stirring, 9g (0.5 eq) of N-
5 iodosuccinimide is added and then the reaction mixture is stirred at 60°C for 5 hours.
The solvent is evaporated and the precipitate formed is filtered, rinsed with water and
with diethyl ether and then dried under vacuum to yield 18.5 g (90%) of 2-hydroxy-5-
iodonicotinonitrile in the form of a beige powder.
LCMS (EI, m/z): (M+1) 246.93
I 10 ^H NMR: 6H ppm (400 MHz, DMSO): 12.79 (IH, s, OH), 8.36 (IH, d, CHarom), 8.04
(IH, d, CHarom).
Example lb; 2-chloro-5-iodonicotinonitriie
30.7 ml (329 mmol) of phosphorus oxychloride at 0°C and 6 drops of sulfuric acid are
added to 9 g (6.6 mmol) of 2-hydroxy-5-iodonicotinonitrile. The reaction mixture is
15 heated at 110°C for 5 hours and then at room temperature overnight. The reaction
mixture is poured in a beaker containing ice and a little water, and a precipitate is
formed. The mixture is allowed to gradually return to room temperature and then is
filtered and rinsed with water. The solid is dried to yield 6.8 g (70%) of 2-chloro-5-
iodonicotinonitrile.
20 LCMS (EI, m/z): (M+1) 265.45
'H NMR: 5H ppm (400 MHz, DMSO): 9.61 (IH, d, CHarom), 9.14 (IH, d, CHarom).
Example 1; 5-iodo-lH-pyrazolo[3,4-b]pyridine-3-amine
Hydrazine (3.86 ml, 79 mmol) is added at room temperature to 7 g (26.5 mmol) of a
solution of 2-chloro-5-iodonicotinonitrile in 25 ml of propan-2-ol. The reaction mixture
25 is heated at 85°C for 7 hours and then at room temperature overnight. The suspended
solid is fihered, rinsed with isopropanol and then with ether and dried in an oven at
50°C to give 6 g (87%) of 5-iodo-lH-pyrazolo[3,4-b]pyridine-3-amine.
LCMS (EL m/z): (M+1) 260.95
^HNMR: 8Hppm (400 MHz, DMSO): 12.12 (IH, bs, NH), 8.51(1H, d, CHarom), 8.45
30 (lH,d, CHarom), 5.64 (2H,bs,NH2).
•
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55
The following compounds were obtained according to the same method.
NH2
Ex.** W Rj Compound name Yield Mass MH*
T T ^ t-butyl l-^^'-^-butyl-5-iodo-lH-pyrazolo[3,4-b]pyridin- ~ ^ 317.05
^ 3-amme
1-3 Me H 5-iodo-6-methyl-lH-pyrazolo[3,4-b]pyridin-3- ^^^^^ 215 02
amine ^ '
** 'HNMR, DMS0-d6, Ex. 1-2; 8.55 (IH, bs, CPIamm), 8.42 (IH, bs, CHarom), 6.33 (IH,
bs, CHarom), 1.57 (9H, s, CH).; 1-3: 11.92 (IH, s, NH), 8.55 (IH, s, CHa„,m), 5.59 (2H,
5 bs, NH2), 2.66 (3H, s, CH3).
Example 2: 5-bromo-lH-pyrazolo[3,4-b]pyridine-3-amine
NH2 "TV" N N
'^ H
Example 2a; 2-methoxy-nicotinonitrile
10 4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction
medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2-
chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25°C for
16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After returning to
room temperature, the precipitate obtained is filtered, rinsed with water and then dried
15 at 50°C to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid.
LCMS (EI, m/z): (M+1) 135.04
^H NMR: 6H ppm (400 MHz, DMSO): 8.46-8.48 (IH, dd, CHarom), 8.25-8.27 (IH, dd,
CHarom), 7.17-7.20 (IH, dd, CHarom), 3.99 (3H, S, CH3).
Example 2b; 5-bromo-2-methoxy-nicotinonitrile
20 12.23 g (149 mmol) of sodium acetate and then 7.66 ml (149 mmol) of bromine at 0°C
are added to 10 g (74.6 mmol) of a solution of 2-methoxy-nicotinonitrile in 29 ml of
acetic acid. The reaction mixture is heated at 70°C overnight. After returning to room
temperature, the reaction medium is added to an ice bath and the precipitate obtained is
filtered, rinsed with water and then dried at 50°C to yield 11.6 g (73%) of 5-bromo-2-
25 methoxy-nicotinonitrile in the form of a white solid.
1
* t 1
i
I wo 2012/101239 PCT/EP2012/051283
56
LCMS (EI, m/z): (M+1) 214.95
^H NMR: 6H ppm (400 MHz, DMSO): 8.61 (IH, d, CHan,m), 8.60 (IH, d, CHarom), 3.98
(3H, s, CH3)
Example 2: 5-bromo-lH-pyrazolo[3,4-b]pyridine-3-amine
5 35 ml (23.47 mmol) of hydrazine is added at room temperature to 5 g (23.47 mmol) of
5-bromo-2-methoxynicotinonitrile. The reaction medium is carried at 100°C for
3 hours. After returning to room temperature, the precipitate obtained is filtered, rinsed
with water and then dried at 50°C to yield 3.6 g (72%) of 5-bromo-lH-pyrazolo[3,4-
b]pyridine-3-amine in the form of a yellow solid.
I 10 LCMS (EI, m/z): (M+1) 214.05
I ^H NMR; 5H ppm (400 MHz, DMSO): 12.18 (IH, s, NH), 8.38 (IH, d, CHarom), 8.37
(IH, d, CHarom), 5.66 (2H, S, NH).
Examples of method A2
15
Example 3; 5-iodo-lH-pyrazolo[3,4-b]pyrazine-3-amine
NH2
'^ H
Example 3a; methyl 3-amino-6-iodopyrazine-2-carboxylate
1.5 equivalents of N-iodosuccinimide are added at room temperature to 5 g (32.7 mmol)
20 of a methyl 3-aminopyrazine-2-carboxylate solution in 25 ml of dimethylformamide.
The reaction medium is heated at 65°C for 1 hour, added together with 0.5 equivalents
of N-iodosuccinimide and maintained at 65°C for 24 hours. After returning to room
temperature, the solvent is evaporated and then the product is extracted several times
with dichloromethane. The organic phases are combined, washed with 10% sodium
25 bisulfite solution, dried on magnesium sulfate and concentrated to yield 8 g (88%) of
methyl 3-amino-6-iodopyrazine-2-carboxylate in the form of a yellow solid.
LCMS (EI, m/z): (M+1) 280
^HNMR: SHppm (400 MHz, DMSO): 8,50 (IH, s, CHarom), 7.50 (2H, bs, NH2), 3.20
(3H, s, CH3).
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Example 3b: 3-amino-6-iodopyrazine-2-carboxainide
30 ml of ammonia in water is added under magnetic stirring to 15 g (53.8 mmol) of a
solution of methyl 3-amino-6-iodopyrazine-2-carboxylate in 150 ml of methanol. The
reaction medium is stirred at 25°C for 48 hours. After evaporation of the solvents, the
5 precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 12.50 g
of 3-amino-6-iodopyrazine-2-carboxamide (88%) in the form of a beige solid.
LCMS (EI, m/z): (M+1) 265.02
' H N M R ; 5Hppm (400 MHz, DMSO): 8.35 (IH, s, CHarom), 7.85 (IH, bs, NH), 7.60
(3H,bs,NH),3.25(3H,s,CH3)
10 Example 3c; N'-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethylformimidamide
13.59 ml (146 mmol) of phosphorus oxychloride is added drop by drop at 0°C to 11 g
(41.7 mmol) of a solution of 3-amino-6-iodopyrazine-2-carboxamide in 80 ml of
dimethylformamide. The reaction mixture is stirred at room temperature overnight and
then poured in a beaker containing ice and a little water. The pH is adjusted to 8 with
15 IN soda solution; a precipitate is formed. The mixture is allowed to gradually return to
room temperature and then the solid formed is filtered, rinsed with water and dried at
50°C to yield 10.50 g of N'-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethyl
formimidamide (84%) in the form of a beige solid.
LCMS (EI, m/z): (M+1) 302.07
20 ^H NMR: 5H ppm (400 MHz, DMSO): 8.69 (IH, s, CHan>m), 8.67 (IH, s, CHe,hyi), 3.20
(3H, s, CH3), 3.11 (3H,s,CH3).
Example 3d; 3-amino-6-iodopyrazine-2-carbonitrile
77 ml (77 mmol) of 1 M hydrochloric acid solution is added to 7.7 g (25.6 mmol) of N'-
(3-cyano-5-iodopyrazin-2-yl)-N,N-dimethylformimidamide. The reaction medium is
25 heated at 50°C for 4 hours and then stirred at room temperature overnight. The
precipitate formed is filtered, rinsed with water and dried at 50°C to yield 6 g (95%) of
3-amino-6-iodopyrazine-2-carbonitrile in the form of a beige solid.
LCMS (EI, m/z): (M+1) 247.0
'H NMR: 5H ppm (400 MHz, DMSO): 8.49 (IH, s, CHarom), 7.53 (2H, bs, NH2).
30 Example 3e: 3-chloro-6-iodopyrazine-2-carbonitrile
64.3 ml of hydrochloric acid is added at -5°C to 7.7 g (31.3 mmol) of 3-amino-6-
iodopyrazine-2-carbonitrile. At this temperature, a sodium nitrite solution (4.32 g,
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62.6 mmol) dissolved in 9 ml of water is added to the reaction mixture and is stirred for
4 hours at -50°C and then at room temperature overnight. Another equivalent of sodium
nitrite is added to the reaction mixture and the precipitate formed is filtered, rinsed with
water and dried at 50°C to yield 3.65 g (44%) of 3-chloro-6-iodopyrazine-2-carbonitrile
5 in the form of a beige solid.
LCMS (EI, m/z): (M+1) 266.49
^H NMR: 5H ppm (400 MHz, DMSO); 9.13 (IH, s, CHaram)
Example 3; 5-iodo-lH-pyrazolo[3,4-b]pyrazine-3-ainine
0.74 ml (9.8 mmol) of hydrazine is added to 2.6 g (9.80 mmol) of a solution of 3-
10 chloro-6-iodopyrazine-2-carbonitrile in 15 ml of butanol. The reaction mixture is heated
at 110°C for 5 hours and then left at room temperature overnight. The suspended solid
is filtered, rinsed with butanol and then dried in an oven at 50°C to yield 2.2 g (86%) of
5-iodo-lH-pyrazolo[3,4-b]pyrazine-3-amine in the form of a brown solid.
LCMS (EI, m/z): (M+1) 262.02
15 ^H NMR: 5H ppm (400 MHz, DMSO): 12.59 (IH, bs, NH), 8.60 (IH, d, CHarom), 5.83
(2H, bs, NH2).
Examples of method A3
20 Example 4; 5-iodo-6-methoxy-lH-pyrazolo[3,4-b]pyridin-3-amine
NH2
MeO N N
Example 4a: ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate
Ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate is obtained by following the
procedure of Ya. Yu. Yakunin et al, Russian Chemical Bulletin, 1999, 48(1), 195-6
25 with a total yield of 34%.
LCMS (EI, m/z): (M-1) 237.22
' H N M R : SHppm (400 MHz, DMSO): 12.72 (IH, bs, OH), 8.40 (IH, s, CHarom), 4.29
(2H, q, CH2), 2.64 (3H, s, CH3), 1.30 (3H, t, CH3).
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Example 4b: 5-cyano-2-hydroxy-6-(methyIthio)nicotinic acid
4.16 g (2 eq) of lithium hydroxide monohydrate is added at room temperature to a
solution of 11.8 g (49.5 mmol) of ethyl 5-cyano-2-hydroxy-6-(methylthio)mcotinate in
100 ml of ethanol and 100 ml of water. The reaction mixture is stirred at 60°C for
5 2 hours. The ethanol is evaporated and 1 N aqueous soda is added. The aqueous phase is
washed with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen
chloride (pH=l). The precipitate formed is filtered, rinsed with water and with diethyl
ether and then dried under vacuum to yield 9.9 g (95%) of 5-cyano-2-hydroxy-6-
(methylthio)nicotinic acid in the form of a brown powder.
10 LCMS (EI, m/z): (M-1) 209.09
^HNMR; 5H ppm (400 MHz, DMSO): 8.32 (IH, s, CHan,m), 2.61 (3H, s, CH3).
Example 4c; 6-hydroxy-2-(methylthio)nicotinonitriIe
A solution of 6 g (28.5 mmol) of 5-cyano-2-hydroxy-6-(methylthio)nicotinic acid in
35 ml of diphenyl ether is stirred at 250°C for 4 hours. After returning to room
15 temperature, 100 ml of cyclohexane is added and the reaction medium is triturated for
30 minutes. The solid formed is filtered, rinsed thoroughly with cyclohexane and then
dried under vacuum to yield 2.87 g (60%) of 6-hydroxy-2-(methylthio)nicotinonitrile in
the form of a brown powder.
LCMS (EI, m/z): (M+1) 167.12
20 'H NMR: 5H ppm (400 MHz, DMSO): 12.16 (IH, bs, OH), 7.92 (IH, d, CHarom), 6.46
(IH, d, CHaiom), 2.59 (3H, s, CH3).
Example 4d: 6-hydroxy-5-iodo-2-(metliylthio)nicotinonitrile
6 g (1.6 eq) of silver sulfate and 4.58 g (1.5 eq) of iodine are added successively to a
solution of 2 g (12 mmol) of 6-hydroxy-2-(methylthio)nicotinonitrile in 200 ml of
25 ethanol. The reaction medium is stirred at room temperature for 2 hours. The solid is
filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and
then taken up in ethyl acetate. The organic phase is washed with water three times, dried
on magnesium sulfate and evaporated to yield 3.18 g (90%) of 6-hydroxy-5-iodo-2-
(methylthio)nicotinonitrile in the form of a yellow powder.
30 LCMS (EI, m/z): (M+1) 292.93
^HNMR: 5Hppm (400 MHz, DMSO): 12.96 (IH, bs, OH), 8.38 (IH, s, CHarom), 2.62
(3H, s, CH3).
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Example 4e; 5-iodo-6-inethoxy-2-(inethylthio)nicotinonitrile
905 |xl (2 eq) of methyl iodide and 2.1 g (1.05 eq) of silver carbonate are added
successively to a solution of 2.12g (7.26 mmol) of 6-hydroxy-5-iodo-2-
(methylthio)nicotinonitrile in 20 ml of 1,4-dioxane. The reaction medium is stirred at
5 60°C for 5 hours. The solid is filtered and the residue rinsed thoroughly with methanol.
The filtrate is evaporated and the residue purified by silica column chromatography (4:6
dichloromethane/cyclohexane as eluent) to yield 1.52 g (68%) of 5-iodo-6-methoxy-2-
(methylthio)nicotinonitrile in the form of a white powder.
LCMS (EI, m/z): (M+1) 306.95
10 ^H NMR: 5H ppm (400 MHz, DMSO): 8.50 (IH, s, CHarom), 4.04 (3H, s, CH3), 2.63
(3H, s, CH3).
Example 4f: 5-iodo-6-methoxy-2-(methylsulfinyI)nicotinoiiitrile
1.42 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.6 g
(5.23 mmol) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in 20 ml of
15 dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl
acetate is added and the organic phase is washed with saturated sodium bicarbonate
solution, dried on magnesium sulfate, filtered and evaporated to yield 1.63 g (97%) of
5-iodo-6-methoxy-2-(methylsulfinyl)nicotinonitrile in the form of a white powder
which may also contain 5-iodo-6-methoxy-2-(methylsulfonyl)nicotinonitrile in small
20 proportions (<20%). If necessary, the mixture is used as-is in the following steps.
LCMS (EI, m/z): (M+1) 322.95
^HNMR: 6Hppm (400 MHz, DMSO): 8.86 (IH, s, CHaiom), 4.05 (3H, s, CH3), 2.95
(3H, s, CH3).
Example 4; 5-iodo-6-methoxy-lH-pyrazolo[3,4-b]pyridin-3-amine
25 294 nl (1.2 eq) of hydrazine monohydrate is added to a solution of 1.63 g (5.05 mmol)
of 5-iodo-6-methoxy-2-(methylsulfinyl)nicotinonitrile in 30 ml of 2-propanol. The
reaction medium is stirred at 80°C for 9 hours. After returning to room temperature, the
solid formed is filtered and rinsed with 2-propanol to yield 1.14 g (78%) of 5-iodo-6-
methoxy-l//-pyrazolo[3,4-b]pyridin-3-amine in the form of a white powder.
30 LCMS (EI, m/z): (M+1) 291.00
^HNMR: 5Hppm (400 MHz, DMSO): 11.87 (IH, s, NH), 8.49 (IH, s, CHarom), 5.49
(2H, bs, NH2), 3.90 (3H, s, CH3).
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Example 5: 5-iodo-lH-pyrazoIo[3,4-b]pyridine-3,6-dianiine
NH2
Example 5a; 4-methylmorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5-
mercaptopenta-2,4-dienoate
5 4-methylmorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5-mercaptopenta-2,4-dienoate
is prepared according to the procedure described by V.D. Dyachenko et al. Chemistry
of Heterocyclic Compounds, 2005, 41(4), 503-10 with a yield of 50%.
^HNMR: 5Hppm (400 MHz, DMSO): 9,60 (IH, bs, NH), 8.66 (IH, s, CH), 8.33 (IH,
bs, NH), 7.43 (IH, bs, NH), 4.08 (2H, q, CH2), 3.82-4.02 (2H, m, CH2), 3.55-3.78 (2H,
10 m, CH2), 3.24-3.42 (2H, m, CH2), 3.98-3.17 (2H, m, CH2), 2.81 (3H, s, CH3), 1.19 (3H,
t, CH3).
Example 5b; ethyl 2-amino-5-cyano-6-(methyIthio)nicotinate
2.73 ml (1 eq) of methyl iodide is added to a solution of 14.2 g (43.8 mmol) of 4-
methylmorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5-mercaptopenta-2,4-dienoate in
15 78 ml of iV,A'-dimethylformamide. The reaction mixture is stirred at room temperature
for 1 hour and then at 75°C for 20 hours. After returning to room temperature, water is
added and the solid formed is filtered and dried under vacuum to yield 10.31 g (100%)
of ethyl 2-amino-5-cyano-6-(methylthio)iiicotinate in the form of a beige powder.
LCMS (EI, m/z): (M+1) 238.20
20 ^H NMR: 5H ppm (400 MHz, DMSO): 8.25 (IH, s, CHarom), 8.19 (IH, bs, NH), 7.99
(IH, bs, NH), 4.27 (2H, q, CH2), 2.58 (3H, s, CH3), 1.31 (3H, t, CH3).
Example 5c; 2-amino-5-cyano-6-(methylthio)nicotinic acid
3.08 g (2 eq) of lithium hydroxide monohydrate is added at room temperature to a
solution of 8.7 g (36.7 mmol) of ethyl 2-amino-5-cyano-6-(methylthio)nicotinate in
25 87 ml of ethanol and 87 ml of water. The reaction mixture is stirred at 60°C for 2 hours.
The ethanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed
with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride
(pH=l). The precipitate formed is filtered, rinsed with water and with diethyl ether and
then dried under vacuum to yield 7.67 g (quantitative) of 2-amino-5-cyano-6-
30 (methylthio)nicotinic acid in the form of a brown powder.
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LCMS (EI, m/z): (M+1) 210.16
' H N M R : 6Hppm (400 MHz, DMSO): 13.28 (IH, bs, CO2H), 8.21 (IH, s, CHarom),
8.13 (2H, bs, NH2), 2.57 (3H, s, CH3).
Example 5d; 6-aiiiino-2-(niethylthio)nicotinonitrile
5 A solution of 3 g (14.3 mmol) of 2-amino-5-cyano-6-(methylthio)nicotinic acid in 30 ml
of diphenyl ether is stirred at 255°C for 60 hours. After returning to room temperature,
60 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The
1 solid formed is filtered and then rinsed thoroughly with cyclohexane. The solid is
redissolved in ethyl acetate and then the organic phase is washed with water, dried on
[ 10 magnesium sulfate, filtered and then evaporated to yield 1.32 g (55%) of 6-amino-2-
I (methylthio)nicotinonitrile in the form of a brown powder.
I LCMS (EI, m/z): (M+1) 166.13
^H NMR: 5H ppm (400 MHz, DMSO): 7.58 (IH, d, CHarom), 7.12 (2H, bs, NH2), 6.20
I (lH,d, CHarom), 2.51 (3H,S,CH3).
15 Example 5e; 6-amino-5-iodo-2-(methylthio)nicotinonitrile
3.75 g (1.5 eq) of silver sulfate and 2.85 g (1.4 eq) of iodine are added successively to a
solution of 1.32 g (8.02 mmol) of 6-amino-2-(methylthio)nicotinonitrile in 65 ml of
ethanol. The reaction medium is stirred at room temperature for 3 hours. The solid is
filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and
20 redissolved in ethyl acetate. The organic phase is washed with water three times, dried
on magnesium sulfate and evaporated to yield 1.89 g (81%) of 6-amino-5-iodo-2-
(methylthio)mcotinonitrile in the form of a brovwi powder.
LCMS (EI, m/z): (M+1) 291.99
' H N M R : SHppm (400 MHz, DMSO): 8.13 (IH, s, CHarom), 7.19 (IH, broad flat
25 singlet, NH2), 2.51 (3H,s,CH3).
Example 5f; 6-amino-5-iodo-2-(methylsulfinyl)nicotinonitrile
1.77 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.89 g
(6.51 mmol) of 6-amino-5-iodo-2-(methylthio)nicotinonitrile in 60ml of
dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl
30 acetate is added and the organic phase is washed with saturated sodium bicarbonate
I solution, dried on magnesium sulfate, filtered and evaporated to yield 1.5 g (75%) of 6-
amino-5-iodo-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which
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may also contain 6-aniino-5-iodo-2-(methylsulfonyl)nicotinonitrile in small proportions
(<20%). If necessary, the mixture is used as-is in the following steps.
LCMS (EI, m/z): (M+1) 307.98
^HNMR: 5Hppm (400 MHz, DMSO): 8.45 (IH, s, CHaiom), 7.70 (2H, broad flat
5 singlet, NHj), 2.84 (3H, s, CH3).
Example 5; 5-iodo-lB[-pyrazolo[3,4-b]pyridine-3,6-diainine
275 |J1 (2 eq) of hydrazine monohydrate is added to a solution of 872 mg (2.84 mmol) of
6-amino-5-iodo-2-(methylsulfmyl)nicotinonitrile in 11 ml of 2-propanol. The reaction
medium is stirred at 80°C for 3 hours. Water is added and the product is extracted with
10 ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and evaporated.
The residue is triturated in a minimum of diisopropyl ether. The solid is filtered to yield
523 mg (67%) of 5-iodo-lH-pyrazolo[3,4-b]pyridin-3,6-diamine in the form of a brown
powder.
LCMS (EI, m/z): (M+1) 276.00
15 'H NMR; 5H ppm (400 MHz, DMSO): 11.23 (IH, s, NH), 8.26 (IH, s, CHarom), 6.11
(2H, bs, NH2), 5.25 (2H, bs, NH2).
Examples of method Bl
20 Example 6; 5-(3,5-difluorobenzylthio)-lH-pyrazolo[4,3-b]pyridin-3-amine
F
H
Example 6a; 6-chloro-3-nitropicolinoiiitrile
2,6-Dichloro-3-nitropyridine (5.18 mmol, 1 g) is mixed with 5 ml of N-methyl-2-
pyrrolidinone in a microwave reactor. The reaction mixture is heated at 180°C for 15
25 minutes (6 bars). The crude reaction product is dissolved in ethyl acetate, filtered and
washed several times using an aqueous phase. The organic phase is collected, dried on
magnesium sulfate and dry concentrated. The crude product thus obtained is purified by
silica gel chromatography (heptane/AcOEt) to yield, after concentration, 0.62g (65%) of
a brown oil.
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^HNMR: 5H ppm (400 MHz, DMSO): 8.81 (IH, d, CHarom), 8.18 (IH, d, CH^^).
Example 6b; 3-nitro-6-thioxo-l,6-dihydropyridine-2-carbonitrile
One equivalent of NaSH:H20 is added to a solution of 6-chloro-3-nitropicolinonitrile
(5.45 mmol, 1 g) in 20 ml of EtOH. The color turns orange. The reaction medium is
5 stirred at room temperature for 30 minutes. The crude reaction product is then
concentrated, redissolved in ethyl acetate and extracted several times using an acidic
aqueous phase (1 N HCl) and then a neutral phase. The organic phase is concentrated
and the crude reaction product recrystallized in acetone to yield 0.64 g (79%) of yellow
crystals.
10 ^H NMR: 5H ppm (400 MHz, DMSO): 8.71 (IH, d, CHarom), 8.27 (IH, d, CHarom).
Example 6c; 6-(3,5-difluorobenzylthio)-3-nitropicolinonitrile
A mixture of 3-nitro-6-thioxo-l,6-dihydropyridin-2-carbonitrile (4.42 mmol, 1.34g),
3,5-diflurobenzylbenzylbromide (8.83 mmol, 1.828 g), and K2CO3 (11.04 mmol,
1.525 g) in 5 ml of acetone is heated at 70°C for 10 hours and then evaporated under
15 reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane)
to yield 1.33 g (98%) of the expected product.
LCMS (ES-): m/z 306 (M-H+).
'HNMR: 5H ppm (400 MHz, DMSO): 8.53 (IH, d, CHarom), 7.91 (IH, d, CHarom), 7.21
(2H, m), 7.17 (IH, m), 4.55 (2H, CH2).
20 Example 6d; 3-amino-6-(3,5-difluorobenzylthio)picolinamide
A mixture of 6-(3,5-difluorobenzylthio)-3-nitropicolinonitrile (0.05 g, 0.163 mmol) and
Pt02 (0.739 mg, 3.25 |imol) in 10 ml of MeOH is placed under stirring at atmospheric
pressure of hydrogen for 2 hours. The catalyst is filtered, the solution is concentrated
and the residue thus obtained is purified by silica gel chromatography (AcOEt/heptane)
25 to yield, after concentration, 0.04 g (83%) of white crystals.
LCMS (ES+) m/z: 296 (MH+).
^H NMR: 6H ppm (400 MHz, DMSO): 7.84 (IH, broad s, NH), 7.40 (IH, broad s, NH),
7.14 (IH, d, CHarom), 7.08 (4H, m, CHarom), 6.80 (2H, broad s, NH2), 4.43 (2H, s, CH2).
Example 6e; 3-amino-6-(3,5-difluorobenzylthio)picolinonitrile
30 A mixture of 3-amino-6-(3,5-difluorobenzylthio)picolinoamide (2.37 mmol, 0.7 g) and
P2CI5 (9.48 mmol, 1.346 g), 20 ml of toluene and 1 ml of ionic solvent (l-butyl-3-
methylimidazolium tetrafluoroborate) are placed in a microwave reactor and then heated
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at 140°C for 30 minutes. The crude reaction product is then concentrated under reduced
pressure and the orange crystals thus obtained are redissolved in ethyl acetate and
washed using saturated aqueous NaHCOa solution. The organic phase is dried on
magnesium sulfate and then concentrated to yield 0.7 g of a brown oil. This crude
5 reaction product is purified by silica gel chromatography (AcOEt/heptane + 0.1% of
NEts) to yield, after concentration, 0.15 g (23%) of orange crystals.
^H NMR: 5H ppm (400 MHz, DMSO): 7.73 (IH, d, CHarom), 7.25 (2H, m, CHarom), 7.18
(IH, m), 6.85 (IH, d), 5.43 (2H, CH2).
Example 6; 5-(3,5-difluorobenzylthio)-lH-pyrazolo[4,3-b]pyridin-3-amine
10 A solution cooled to 0°C of NaN02 in 3 ml of water is added drop by drop to a solution
at 0°C of 3-amino-6-(3,5-difluorobenzylthio)picolinonitrile (1.587 mmol, 0.44g) in
15 ml of 6 N HCl solution. After 15 minutes, a solution cooled to 0°C of SnCl2-2H20
diluted in 4 ml of 12 N HCl is added drop by drop. The reaction medium is then stirred
at 25°C for 1 hour. The solution is extracted with ethyl acetate and then washed using
15 saturated NaHCOs solution and then saturated NaCl solution. The organic phase is
collected, dried on magnesium sulfate and then concentrated under reduced pressure.
The residue is purified by silica gel chromatography (AcOEt/heptane) to yield, after
concentration of the organic phases, 0.07 g (15%) of black crystals.
'H NMR: 5H ppm (400 MHz, DMSO): 11.64 (IH, s, NH), 7.63 (IH, d, CHarom), 7.21
20 (2H,m, CHarom), 7.13 ( l H , d , CHarom), 7.04 (lH,m, CHarom), 5.38 (2H, S,NH2), 4.51
(2H, s, CH2).
The following compounds are obtained by a similar method:
NH2
25
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I Ex.** I Arif I W I Y4 I Rj I Compound names I Yield I MassMH+ I
c 1 5-(2,5-difluorobenzylthio)-lH- 5%
6-2 " ^ N ^ ^ H CH H 293.0
ll pvrazolo[4,3-b]pyridin-3-anmie 4 steps
Clv_A^^ 5-(2,5-dichlorobenzylthio)-lH- 3%
6-3 7| ^ H CH H 324.9
y ^l pyTazolo[4,3-b]pyridin-3-ainine 4 steps
** ^HNMR: 5H ppm (400 MHz, DMSO): 6-2: 11.65 (IH, s, NH), 7.64 (IH, dd,
CHarom, J=8.8Hz), 7.42-7.51 (IH, m, CHarom), 7.20-7.25 (IH, m, CHarom), 7.14 (IH,
dd, CHarom, J=8.8Hz), 7.01-7.11 (IH, m, CHarom), 5.37-5.41 (2H, m, NH2), 4.49 (2H,
s). 6-3: 11.65 (IH, s, NH), 7.83 (IH, m, CHarom), 7.61 (IH, dd, CHarom, J=8.8Hz),
5 7.50 (IH, m, CHarom), 7.28-7.32 (IH, m, CHarom), 7.10 (IH, dd, CHarom, J=8.8Hz),
7.01-7.11 (IH, m, CHarom), 5.42 (2H, s, NH2), 4.47 (2H, s).
Examples of method B2
10 Example 7; 5-(3,5-dichlorophenylthio)-lH-pyrazolo[4,3-b]pyridin-3-amine
NHj
CI
Example 7a: 6-(3,5-dichIorophenylthio)-3-nitropicolinonitrile
A mixture of 6-chloro-3-nitropicolinonitrile (3.70g, 0.02 mol), 3,5-dichlorobenzenethiol
(3.60 g, 0.02 mol) and K2CO3 (5.6 g, 0.04 mol) in 100 ml of acetonitrile is carried at
15 70°C for 16 hours. The crude reaction product is diluted in an ethyl acetate fraction and
washed using an aqueous phase. The organic phase is dried with sodium sulfate and the
residue is purified by silica gel chromatography (AcOEt/petroleum ether) to yield 5.4 g
(80%) ofa yellow solid.
Example 7b; 3-amino-6-(3,5-dichlorophenylthio)picolinonitrile
20 10 ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio)-3-
nitropicolinonitrile (3.4 g, 0.01 mol) in 50 ml of methanol under stirring. The reaction
medium is refluxed, added together with 1.68 g (0.03 mol) of iron and stirred for 10
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minutes. After returning to room temperature, the reaction mixture is added together
with 100 ml of ethyl acetate and 50 ml of water. The pH is adjusted to 10 using 30%
soda solution and the organic phase is extracted and then dried on anhydrous sodium
sulfate before being concentrated. The residue is purified by silica gel chromatography
5 (ethyl acetate/petroleum ether) to yield, after concentration of the fractions, 2.82 g
(91%) ofa yellow solid.
LCMS (m/e): 296(M+H+). %.
Example 7; 5-(3,S-dichlorophenylthio)-lH-pyrazolo[4,3-b]pyridin-3-amine
A solution of 350 mg of NaN02 (5.07 mmol) in water (2 ml) is added to a stirring
10 solution of 1.5 g of 3-amino-6-(3,5-dichIorophenylthio)picolinonitrile (5.07 mmol) in
100 ml of 50% sulfiiric acid at 0°C. The mixture is stirred for 20 minutes at 0-5°C. A
solution of 2.9 g of SnCl2-2H20 (12.7 mmol, 2.5 eq) in hydrochloric acid (12 N
solution, 10 ml) is then added and the solution is stirred for 1 hour at room temperature.
The solid formed is filtered and then washed twice with 20 ml of water. The solid is
15 suspended in 100 ml and the pH is adjusted to 10 by adding 30% soda solution. The
organic phase is separated and then dried on anhydrous sodium sulfate before being
concentrated under vacuum. A light yellow solid is obtained after recrystallization in
ethyl acetate (470 mg, 34%).
LCMSm/z311(M+H^).
20 'H NMR: 5H ppm (400 MHz, DMSO): 11.91 (IH, bs, NH), 7.79 (IH, d, CHarom), 7.55
(IH, s, CHarom), 7.36 (2H, s, CHa«m), 7.33 (IH, m, CHan,™), 5.42 (2H, s, NH2).
The following compounds are obtained by a similar method:
NH2
25
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I Ex,** I ArX IY41WI Rj I Compound names I Yield i MassMH'^ I
.
I 5-(3,5-difluorobenzyloxy)-lH-
7-1 A. CH H H 28% 277
[| ] pyrazolo[4,3-b]pyridin-3-amine
1 5-(3,5-di£luorophenylthio)-lH- 33%
7-2 ( ^ CH H H 278,9
II 1^ pyrazolo[4,3-b]pyTidin-3-ainine 3 steps
_
^ . ' ^ F 5-(2,4-difluorophenylthio)-lH- 24%
7-3 f 7 CH H H 279,0
\ ^ pyrazolo[4,3-b]pyridin-3-amine 3 steps
F
_
,As^CI 5-(2,4-dichlorophenylthio)-lH- 24%
7-4 f ] CH H H 311,0
\jsi^ pyrazolo[4,3-b]pyridm-3-amine 3 steps
CI
FNJ 1 5-(2-(trifluoromethyl)phenylthio)-lH- 17%
7-5 F - ^ Y S CH H H J ^ J 3JJ Q
|l J pyrazolo[4,3-b]pyridm-3-amme 3 steps
1 5-(3,5-difluorophenylthio)-lH- 6%
7-6 if^ N H H 279,9
II I pyrazolo[3,4-b]pyrazm-3-ainme 7 steps
_
,As^ci 5-(2,4-dicWorophenylthio)-lH- 4%
7-7 I ] N H H 311,9
^ss^ pyrazolo[3,4-b]pyrazm-3-amme 7 steps
CI
F P
FvJ 1 5-(2-(trifluoromethyl)phenylthio)-lH- 6%
7-8 F ^ S r S N H H } jy y J 3^^^
|l J pyrazolo[3,4-b]pyTazm-3-amine 7 steps
1 5-(3,5-F 5-(5-chloro-2-(trifluoromethyl)benz\'loxy)- 8%
7-12 [ f ' V ' ^ F CH H H 343.1
|l J lH-pyrazolo[4,3-b]pyridm-3-ainine 3 steps
CI
] 5-(pyridm-3-ylmethoxy)-lH-pyrazolo[4,3- 6%
7-13 -/"^^ ^H H H 342.1
[| ^ b]pyridin-3-amine 3 steps
** ^H NMR: 5H ppm (400 MHz, DMSO): 7-1: 11,61 (IH, s large, NH), 7,73 (IH, d,
CHarom), 7,24 (2H; m, CHarom), 7,18 (IH, m, CHarom), 6,86 (IH, d, CHarom). 7-2:
11.95 (IH, si, NH), 7.78 (IH, d, CHarom, J=11.6Hz), 7.33 (IH, d, CHarom, J=11.6Hz),
7.19 (IH, t, CHarom), 7.04 (2H, 2d, CHarom, J=8.8Hz), 5.51 (2H, s, NH2). 7-3: 11.80
5 (IH, si, NH), 7.70 (IH, d, CHarom, J=8.8Hz), 7.60 (IH, t, CHarom), 7.49 (IH, q,
CHarom), 7.27-7.33 (IH, m, CHarom), 7.11 (IH, d, CHarom, J=8.8Hz), 5.41 (2H, s,
NH2). 7-4: 11.93 (IH, si, NH), 7.80 (IH, d, CHarom, J=11.6Hz), 7.62 (IH, d, CHarom,
J=11.6Hz), 7.40 (IH, dd, CHarom, J=11.2Hz), 7.29 (IH, d, CHarom, J=11.6Hz), 7.1
(IH, s, CHarom), 5.51 (2H, s, NH2). 7-5: 11.86 (IH, si, NH), 7.87 (IH, d, CHarom,
10 J=9.6Hz), 7.73 (IH, d, CHarom, J=11.6), 7.50-7.68 (2H, m, CHarom), 7.44 (IH, d,
CHarom, J=10.4Hz), 7.11 (IH, d, CHarom, J=11.6Hz), 5.46 (2H, s, NH2). 7-6: 12.66
(IH, si, NH), 8.52 (IH, s, CHarom), 7.12-7.20 (IH, m, CHarom), 7.02-7.10 (2H, m,
CHarom), 5.90 (2H, s, NH2). 7-7: 12.70 (IH, s, NH), 8.52 (IH, s, CHarom), 7.60 (IH,
d, CHarom, J=8.8Hz), 7.38 (IH, dd, CHarom, J=8.4Hz), 7.12 (IH, s, CHarom), 5.92
15 (2H, s, NH2). 7-8: 12.66 (IH, s, NH), 8.39 (IH, s, CHarom), 7.84 (IH, d, CHarom,
J=7.6Hz), 7.58 (IH, t, CHarom), 7.50 (IH, t, CHarom), 7.34 (IH, d, CHarom, J=7.6Hz),
5.87 (2H, s, NH2). 7-9: 11,57 (IH, s, NH), 7,74 (IH, d, Charom, J=9Hz), 7,25 (3H, m,
CHarom), 6,88 (IH, d, Charom, J=9Hz), 5,44 (2H, s), 5,08 (2H, s). 7-10: 11,58 (IH, s,
I
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NH), 7.73 (IH, d, CHarom, J=12.0Hz), 7.48-7.58 (IH, m, CHarom), 121-131 (2H, m,
CHarom), 6.85 (IH, d, CHarom, J=12.0Hz), 5.44 (2H, s, CH), 5.10 (2H, si, NH2). 7-11:
11.60 (IH, si, NH), 7.70-7.77 (2H, m, CHarom), 7.57 (IH, d, CHarom, J=11.2Hz),
7.40-7.50 (IH, m, CHarom), 6.89 (IH, d, CHarom, J=12.0Hz), 5.48 (2H, s, CH), 5.06
5 (2H, si, NH2). 7-12: 11.60 (IH, si, NH), 7.91 (IH, s, CHarom), 7.83 (IH, d, CHarom,
J=11.2Hz), 7.75 (IH, d, CHarom, J=12.0Hz), 7.66 (IH, d, CHarom, J=9.6Hz), 6.88 (IH,
d, CHarom, J=12.0Hz), 5.58 (2H, s, CH), 5.01 (2H, si, NH2). 7-13: 11.56 (IH, si, NH),
8.77 (IH, s, CHarom), 8.55 (IH, s, CHarom), 7.96 (IH, d, CHarom, J=10.4Hz), 7.72
(IH, d, CHarom, J=12.0Hz), 7.42 (IH, dd, CHarom, J=10.0Hz), 6.83 (IH, d, CHarom,
10 J=11.6Hz), 5.45 (2H, s, CH), 5.15 (2H, si, NH2).
Example 8; N5-(3,5-difluorophenyl)-lH-pyrazolo[4,3-b]pyridine-3,5-diamine
H NH2
F
Example 8a; 6-(3,5-difluorophenylamino)-3-nitropicoIinonitrile
15 A mixture of 6.5 g of 6-chloro-3-nitropicolinonitrile (0.065 mol) and 6.2 g of 3,5-
difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70°C for 5 hours. The
crude reaction product is diluted in an ethyl acetate fraction and washed using saturated
NaCl solution. The organic phase is dried with sodium sulfate and the residue purified
by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow
20 solid.
Example 8b; 3-amino-6-(3,5-difluorophenylamino)picolinonitrile
10 ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenyhhio)-3-
nitropicolinonitrile (3.9 g, 0.0141 mol) in 150 ml of ethanol under stirring. The reaction
medium is refluxed, added together with 2.4 g of iron (0.0423 mol) and stirred at 80°C
25 for 1 hour. After returning to 0°C the pH is adjusted to 8 using 1 N soda solution and
the reaction medium is filtered on Celite. The reaction mixture is added together with
100 ml of ethyl acetate and 50 ml of methanol. The organic phase is extracted and the
aqueous phase is extracted several times by ethyl acetate fractions. The organic phases
are combined and then dried on anhydrous sodium sulfate before being concentrated to
30 yield, after concentration, 2.3 g (66%) of a brown solid.
!
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Example 8; 5-(3,5-difluorophenylamino)-lH-pyrazolo[4,3-b]pyridin-3-ainine
A solution of 713 mg of NaNOz (10.3 mmol) in water (5 ml) is added, drop by drop, to
a stirring solution of 2.3 g of 3-amino-6-(3,5-difluorophenylamino)picolinonitrile
(9.4 mmol) in 100 ml of 6 N hydrochloric acid at 0°C. The mixture is stirred for 20
5 minutes at 0-5°C. A solution of 5.3 g of SnCl2-2H20 (23.5 mmol, 2.5 eq) in
hydrochloric acid (12 N solution, 30 ml) is then added drop by drop and the solution is
stirred for 1 hour at room temperature. The reaction medium is then cooled at 0°C and
basified to pH 8 using 30% soda solution. The mixture is extracted with ethyl acetate
and washed using saturated NaCl solution and the organic phase is dried on anhydrous
10 sodium sulfate before being concentrated under vacuum. The residue is purified by
silica column chromatography (AcOEt). A light yellow solid is obtained (530 mg,
22%).
LCMS: m/z 262 (M+H^).
' H N M R : SHppm (400 MHz, DMSO): 11.47 (s, IH), 9.45 (s, IH), 7.65 (m, 3H), 6.87
15 (d, IH, J=7.8 Hz), 6.60 (m, IH), 5.09 (s, 2H).
The following compounds are obtained by a similar method:
NH2
Ex.** I Arte IY41WI Rj I Compound names I Yield I Mass MH* I
HN"
F ^ ^ ^ N-(2,5-difluorophenyl)-lH- 4%
8-1 T ^ CH H H 262.0
Vi*** pyrazolo[4,3-b]pyridine-3^-diamine 4 steps
F
CI^A^ N-(2,5-dichlorophenyl)-lH- 9%
8-2 y ^ CH H H 294.0
• s ^ pyrazolo[4,3-b]pyridine-3,5-diamine 4 steps
CI
** ' H N M R : 5Hppm (400 MHz, DMSO): 8-1: 11.46 (IH, s, NH), 8.75-8.82 (2H, m,
20 CHarom), 7.65 (IH, dd, CHarom, J=9,2Hz), 7.19-7.31 (2H, m, CHarom), 6.67-6.63
(IH, si, CHarom), 5.06 (2H, s, NH2). 8-2: 11.58 (IH, si, NH), 8.65 (IH, s, CHarom),
8.35 (IH, s, CHarom), 7.69 (IH, d, CHarom, J=12.0Hz), 7.45 (IH, d, CHarom,
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J=11.6Hz), 7.24 (IH, d, CHarom, J=12.0Hz), 6.96 (IH, dd, CHarom, J=11.2Hz), 5.03
(2H, si, NH2).
Example of method B3
5
Example 9; 5-(3,5-difluorobenzyl)-lH-pyrazolo[4,3-b]pyridin-3-amine
NH2
•--^ ^sji*>^N
F
This compound can be prepared from the following intermediates, according to method
B3.
10 Example 9a; 2-(3,5-difluorobenzyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane
Example 9b; 6-(3,5-difluorobenzyl)-3-nitropicolinonitrile
Example 9c: 3-amino-6-(3,5-difluorobenzyl)picolinonitriIe
Example of method B4
15
Example 10; 3-amino-N-(3,5-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5-
sulfonamide
F
N N
^ H
Example 10a; 5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinic acid
20 2.74 g (9.64 mmol) of ethyl 2-chloro-5-(chlorosulfonyl)nicotinate in solution in 20 ml
of anhydrous dichloromethane is added, drop by drop at 0°C, to a mixture of 623 mg
(4.82 mmol) of 3,5-difluoroaniline and 1.68 ml (12.05 mmol) of triethylamine diluted in
10 ml of anhydrous dichloromethane. The solution is stirred at room temperature for
3 hours. The solvent is evaporated to yield a light brown solid. The solid is triturated in
25 20 ml of methanol, filtered and then rinsed with 3 ml of methanol to yield 2.85 g of a
white solid.
This solid is redissolved in 25 ml of tetrahydrofuran and is added together with a
solution of 0.421 g (10.04 mmol) of lithium monohydrate hydroxide in 10 ml of water.
ft
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The reaction mixture is left under stirring for 3 hours at 35°C and then diluted in water,
acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase
is collected, dried on sodium sulfate, fihered and concentrated to yield 1.12 g of 5-(N-
(3,5-difluorophenyl)sulfamoyl)nicotinic acid in the form of an orange solid
5 (yield=67%).
'HNMR: 5H ppm (400 MHz, DMSO); 8.91 (IH, s, CHarom), 8.51 (IH, s, CHarom), 7.02
(IH, dd, CHan,m), 6.83 (2H, d, CHarom).
Example 10b; 2-chIoro-5-(N-(3,5-difluorophenyI)suIfamoyI)nicotinamide
0.288 ml (3.87 mmol) of thionyl chloride and a drop of DMF are added successively to
10 0.450 g (1.29 mmol) of 2-chloro-5-(N-(3,5-difIuorophenyl)sulfamoyl)nicotinic acid in
5 ml of anhydrous toluene. The mixture is placed under stirring, at reflux of toluene, for
2 hours. The acid chloride reaction mixture is then added drop by drop to an iced
solution, under stirring, of 4.5 ml of 25% ammonium hydroxide. A release of gas is
observed. The reaction medium is left under stirring at room temperature for 30
15 minutes. The reaction medium is extracted several times with ethyl acetate. The
combined organic phases are dried on anhydrous sodium sulfate and then concentrated.
0.315 g of 2-chloro-5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinamide in the form of a
light brown solid is obtained (yield=72%).
'H NMR: 5 H ppm (400 MHz, DMSO); 11.18 (IH, bs, NH), 8.86 (IH, s, CHarom), 8.22
20 (IH, s, CHarom), 8.21 (IH, bs, NH), 7.98 (IH, bs, NH), 6.96 (IH, dd, CHarom), 6.79 (2H,
U, V'Harom).
Example 10c; 6-chloro-5-cyano-N-(3,5-difluorophenyl)pyridine-3-sulfonamide
3.4 ml (36.2 mmol) of phosphoryl chloride and a drop of concentrated sulfuric acid are
added to 0.315 g (0.906 mmol) of 2-chloro-5-(N-(3,5-difluorophenyl)
25 sulfamoyl)nicotinamide. The reaction mixture is stirred for 2 hours at 90°C and then
added drop by drop to ice. The brown solid is filtered, rinsed with water and then dried
under vacuum. 0.217 g of 6-chloro-5-cyano-N-(3,5-difluorophenyl)pyridine-3-
sulfonamide is obtained in the form of a light brown solid (yield=72%).
^H NMR: 5H ppm (400 MHz, DMSO): 11.34 (IH, bs, NH), 9.04 (IH, s, CHarom), 8.92
I 30 (IH, S, CHarom), 7.03 (IH, dd, CHarom), 6.85 (2H, d, CHarom).
Example 10; 3-amino-N-(3,5-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5-
sulfonamide
• > •
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0.377 ml (2.63 mmol) of 35% hydrazine is added to 0.217 g (0.658 mmol) of 6-chloro-
5-cyano-N-(3,5-difluorophenyl)pyridine-3-sulfonamide diluted in 6 ml of isopropanol.
The solution is heated at 75°C for 2 hours. The solvent is evaporated to yield 0.214 g of
3-amino-N-(3,5-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5-sulfonamide in the form
5 ofa yellow solid (yield=100%).
^HNMR: 5H ppm (400 MHz, DMSO): 8.74 (IH, d, CHarom), 8.68 (IH, d, CHarom), 6.88
(IH, dd, CHan,„,), 6.80 (2H, d, CHarom), 6.04 (2H, bs, NH).
Examples of method BS
10
Example 11; 5-(3,5-difluorobenzyloxy)-lH-pyrazolo[3,4-b]pyridin-3-amine
F
1 1 1 ,^"2
This compound can be prepared from the following intermediates, according to method
B5.
15 Example 11a; 5-hydroxynicotinonitrile
A mixture of Ig of 5-methoxynicotinonitrile (7.46 mmol) and 8.62 g of pyridine
hydrochloride is heated at 200°C for 2 hours. The crude reaction product is diluted in a
water fraction several times with diethyl ether. The aqueous phase is basified by adding
sodium bicarbonate and then extracted again with diethyl ether. The organic phase is
20 dried and then concentrated to yield 850 mg of 5-hydroxynicotinonitrile (95%) in the
form ofa beige solid.
LCMS: m/z 120,94 (M+H^.
' H N M R : 6H ppm (400 MHz, DMSO): 10,79 (s, IH), 8,46 (s, IH, CHarom.), 8,42 (s,
IH, CHarom.), 7,60 (s, IH, CHarom.).
25 Example lib; 5-(3,5-difluorobenzyloxy)nicotinonitrile
876 mg (2 eq) of sodium hydride is added gradually at 0°C under nitrogen to a solution
of 865 mg of 5-hydroxynicotinonitrile (7.2 mmol) in 15 mL of dimethylacetamide. The
mixture is stirred 10 min at 0°C before adding 2.24 g (1.5 aq) of 3,5-difluorobenzyl
bromide. The mixture is placed under stirring for 2.5 additional hours before being
30 diluted in an ethyl acetate fraction and being washed with aqueous fractions. The
»
*
J. *
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75
organic phases are isolated, dried and concentrated. The solid residue obtained is
recrystallized in methanol to yield 1.1 g (68 % of 5-(3,5-difluorobenzyloxy)
nicotinonitrile in the form of a beige powder.
LCMS: m/z 247.11 (M+H^).
5 'H NMR: 5 H ppm (400 MHz, DMSO): 8,69 (s, IH, CH), 8,65 (s, IH, CH), 8,08 (s, IH,
CH), 7,26 (m, 3H, CH), 5,28 (d, 2H, CH2).
Example lie; 3-cyano-5-(3,5-difluorobenzyIoxy)pyridine 1-oxide
224 mg of m-CPBA is added at 0°c to a solution in acetonitrile of 250 mg of 5-(3,5-
difluorobenzyloxy)nicotinonitrile. The reaction medium is stirred for 20 hours while a
10 precipitate is formed progressivelt. this solid is then filtered and washed to yield 200 mg
(75%) of 3-cyano-5-(3,5-difluorobenzyloxy)pyridine 1-oxide in the form of a white
powder.
LCMS: m/z 263,06 (M+H^.
Example lid; 2-chloro-5-(3,5-difluorobenzyloxy)nicotinonitrile
15 A mixture of 650 mg of 3-cyano-5-(3,5-difluoroben[zyloxy)pyridine 1-oxide in 2.3 mL
of POCI3 added with few drops of H2SO4 is heated at 110°C for lh30. The crude
reaction medium is then poured in ice and the precipitate thus formed is isolated by
filtration and dried under vacuum to yield 600 mg of a beige solid in the form of a
mixture of regioisomers comprising mainly the desired 2-chloro-5-(3,5-
20 difluorobenzyloxy)mcotinonitrile which is used without further purification.
LCMS: m/z 281,02 (M+rf").
Example 11; 5-(3,5-difluorobenzyloxy)-lH-pyrazolo[3,4-b]pyridin-3-amine
313 mg of hydrazine hydrate (5 eq) is added to a solution of 1.6 g of 2-chloro-5-(3,5-
difluorobenzyloxy)nicotinonitrile (450 ^mol) in 10 mL of propan-2-ol. The reaction
25 mixture is heated at 100°C for 6 hours. After return to room temperature leading to a
precipitation, the crude reaction medium is filtered, the solid is removed and the filtrate
is dry evaporated. It is then purified by chromatography on a silica column eluted with a
gradient of ethyl acetate and methanol, whereas the more polar fraction is isolated,
concentrated and suspended again in a small fraction of methanol under stirring. The
30 solid thus obtained is isolated and dried to yield 221 mg of 5-(3,5-difluorobenzyloxy)-
lH-pyrazolo[3,4-b]pyridin-3-amine in the form of a beige solid wich is used without
further purification.
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76
LCMS: m/z 277,07 (M+H^.
Example of method B6
5 Example 11 bis; N-(3-amino-lH-pyrazoIo[3,4-b]pyridin-5-yl)-3,5-difluorobenzene
sulfonamide
I F
i l l H NH2
N N
^ H
Exam p i e 11 b i s-a; N-(6-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzene-
10 sulfonamide
1.132 g (5.32 mmol) of 3,5-difluorobenzene-l-sulfonyle chloride is added under argon
to a solution of 545 mg (3.55 mmol) of 5-amino-2-chloronicotinotrile in 20 mL of an
anhydrous 1:1 mixture of THF and pyridine. The reaction medium is heated to 70°C for
3 hours and let 12 additional hours under stirring at room temperature. The solvent is
15 dry evaporated and the crude reaction product is redissolved in ethyl acetate and washed
with several aqueous fractions. The organic phase is dried on magnesium sulfate,
filtered, concentrated and then purified by silica gel chromatography to yield 784 mg
(67%)ofN-(6-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzene-sulfonamide.
' H N M R : 5H ppm (400 MHz, DMSO) : 11,39 (IH, si, NH), 8. 34 (IH, m, CHarom),
20 8,10 (IH, m, CHarom), 7,67 (IH, m, CHarom), 7,59 (2H, m, CHarom).
Example llbis; N-(3-amino-lH-pyrazolo[3,4-b]pyridin-5-yl)-3,5-difluorobenzenesulfonamide
1.786 g (35.7 mmol) of hydrazine hydrate is added under argon to a solution of 784 mg
(2.38 mmol) of N-(6-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzene-sulfonamide in 6
25 mL of ethanol. The solution is heated to 100°C for 20 hours and then cooled to room
temperature. The solvent is evaporated to yield 810 mg ofN-(3-amino-lH-pyrazolo[3,4-
b]p3Tidin-5-yl)-3,5-difluorobenzene-sulfonamide (100%) which is used without further
purification in the following steps.
LCMS: m/z 326,07 (M+H").
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Example of method CI
Example 12; N6-(2,4-difluorophenyI)-lH-pyrazolo[3,4-b]pyridine-3,6-diamine
NH2
H H
5 This compound can be prepared from the following intermediates, according to method
CI.
Example 12-a; 5-cyano-6-(methyIthio)pyridin-2-yl trifluoromethanesulfonate
15.26 mL (1.2 eq) of potassium 2-methylpropan-2-olate and then 9.03 g (1.2 eq) of
l,l,l-trifluoro-A/-phenyl-A'-(trifluoromethylsulfonyl)methanesulfonamide are added
10 dropwise to a solution of 3.5 g (21.06 mmol) of 6-hydroxy-2-(methylthio)nicotinonitrile
I in 180 mL of tetrahydrofurane under nitrogen. The reaction mixture is stirred at room
temperature for 2h45. Water is added and the product is extracted with ethyl acetate.
The organic phase is dried on anhydrous magnesium sulfate, filtered and evaporated to
yield an orange solid. The product is purified on a silica gel column (eluent:
15 cyclohexane/dichloromethane 5:5) to yield 5.31 g (85%) of 5-cyano-6-
(methylthio)pyridin-2-yl trifluoromethanesulfonate in the form of a yellow solid.
'HNMR: 5H ppm (400 MHz, DMSO): 8,57 (IH, d, CH), 7,52 (IH, d, CH), 2.59 (3H, s,
CH3).
Example 12-b; 6-(2,4-difluorophenylamino)-2-(methylthio)nicotinonitrile
20 0.81 mL (1.2 eq) of ,4-dif!uoroaniline and 1.53 g (1.4 eq) of cesium(I) carbonate are
added under nitrogen to a solution of 2 g (6.71 mmol) of 5-cyano-6-
(methylthio)pyridin-2-yl trifluoromethanesulfonate in 30 mL of 1,4-dioxane. The
medium is degased for 5 minutes under argon before adding 0.25 g (0.06 eq) of de 2,2'-
bis(diphenylphosphino)-l,l'-binaphthyl and 0.08 g (0.04 eq) of (1E,4E)-1,5-
25 diphenylpenta-l,4-dien-3-one, palladium(II) complex. The reaction medium is stirred at
100°C for 2 hours. After return to room temperature, ethyl acetate and brine are added.
The organic phase is dried on anhydrous magnesium sulfate, fitered and evaporated.
The residue obtained is purified on silica gel chromatography (eluent: cyclohexane/ethyl
acetate 8:2 then 7:3) to yield 1.52 g (82%) of 6-(2,4-difluorophenylamino)-2-
30 (methylthio)nicotinonitrile in the form of a white solid.
wo 2012/101239 PCT/EP2012/051283
78
LCMS (IE, m/z): (M+1) 278,06.
' H NMR: 5H ppm (400 MHz, DMSO): 9,57 (IH, s, NH), 7,73-7,86 (2H, m, CH), 7,28-
7,44 (IH, m, CH), 7,02-7,18 (IH, m, CH), 6,60 (IH, d, CH), 2.41 (3H, s, CH3).
Example 12; N6-(2,4-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-3,6-diamine
5 769 mg (3.12 mmol) of m-chloroperbenzoic acid (mCPBA) is added under argon to a
stiring solution of 786 mg (2.83 mmol) of 6-(2,4-difluorophenylamino)-2-
(methy]thio)nicotinonitrile in 25 mL of dichloromethane. The reaction medium is stirred
1 hour at room temperature before adding a fraction of ethyl acetate and washed this
organic phase with a NaHCOs saturated solution. The combined organic phases are
10 dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved
again in 10 mL of propanol and 2 equivalents of hydrazine hydrochloride in water are
added. The mixture is heated at 90°C for 6 hours before being diluted in water and
extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and dry
evaporated before being purified by silica gel chromatography to yield 495 mg of N6-
15 (2,4-difIuorophenyI)-lH-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yelloworange
solid (67%).

CLAIMS
1. A compound of following general formula (I):
R2
IM-R3
•* H
5 " (I)
or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a
stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture
of enantiomers, notably a racemic mixture,
10 wherein;
- Yi and Y4 each represent, independently of each other, a CH group or a nitrogen
atom,
- Y2 represents a nitrogen atom or a CH or C-X-Ar group,
- Y3 represents a nitrogen atom or a C-X-Ar or C-W group,
15 on the condition that:
• at least one and at most two Yi, Y2, Y3, and Y4 groups represent a nitrogen
atom,
• Y2 and Y4 caimot represent a nitrogen atom at the same time,
• when Y2=C-X-Ar, then Y3 represents a nitrogen atom or a C-W group, and
20 • when Y3=C-X-Ar, then Y2 represents a nitrogen atom or a CH group,
- Ar represents an aryl or heteroaryl group optionally substituted by one or more
groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl„ (Ci-
C6)haloalkoxy, (Ci-C6)halothioalkoxy, CN, NO2, ORu, SRn, NRIJRM, CO2R15,
CONRieRn, SO2R18, SO2NR19R20, COR21, NR22COR23, NR24SO2R25, and
25 R26NR27R28 and/or optionally fused to a heterocycle.
!
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- X represents a divalent group selected from O, S, S(0), S(0)2, NR4, S(NR4),
S(0)(NR4), S(0)2(NR4), NR4S, NR4S(0), NR4S(0)2, CH2, CH2S, CH2S(0),
CH2S(0)2, SCH2, S(0)CH2, S(0)2CH2, CH2CH2, CH=CH, C^C, CH2O, OCH2,
NR4CH2, and CH2NR4,
5 - W represents an R5, SR5, OR5 or NR5R6 group,
- U represents a CH2 or NH group, one or more hydrogen atoms which may be
replaced by a (Ci-C6)alkyl group,
- V represents C(0), C(S) or CH2,
- n represents 0 or 1,
10 - Ri represents a hydrogen atom, or an OR7 or NRyRg group,
- R2 represents a hydrogen atom, an optionally substituted heterocycle, NO2, OR9 or
NR9R10,
- R3, R4, Rii to R25 and R27 to R28 each represent, independently of each other, a
hydrogen atom or a (Ci-C6)alkyl group,
15 - R5 and R6 each represent, independently of each other, a hydrogen atom or a (Ci-
C6)alkyl, optionally substituted aryl or optionally substituted benzyl group,
- R7, Rs, R9 and Rio each represent, independently of each other, a hydrogen atom or
an optionally substituted (Ci-C6)alkyl or (C3-Ci2)cycloalkyl group or an optionally
substituted heterocycle, and
20 - R26 represents a (Ci-C6)alkyl group.
2. The compound according to claim 1, characterized in that;
- Yi and/or Y4 = N,
- Y2=CH or C-X-Ar, and
25 - Y3=C-W or C-X-Ar.
3. The compound according to either claim 1 or claim 2, characterized in that X
represents a divalent group selected from S, S(0), S(0)2, NR4, CH2, CH2S, CH2S(0),
CH2S(0)2, CH2O, CH2NR4, NHS(0)2, SCH2, S(0)CH2, S(0)2CH2, S(0)2NH, OCH2,
30 NR4CH2, CH2CH2, CH=CH, and C=C; notably from S, S(0), S(0)2, NR,, CH2, SCH2,
S(0)CH2, S(0)2CH2, S(0)2NH, CH2CH2, C^C, OCH2, and NR4CH2; in particular from
•
I
I »
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S, S(0)2, CH2, SCH2, S(0)2CH2, S(0)2NH, CH2CH2, and C=C, wherein the first atom
of these groups is bound to atom C of chain C-X-Ar.
4. The compound according to any one of claims 1 to 3, characterized in that Ar
5 represents an aryl group, such as phenyl, optionally substituted by one or more groups
selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci-
C6)halothioalkoxy, CN, NO2, ORn, SR12, NR13R14, CO2R15, and CONRigRn, SO2R18,
SO2NR19R20, COR21, NR22COR23 or NR24SO2R25; or a pyridine group.
10 5. The compound according to claim 4, characterized in that Ar represents a group
selected from the following groups:
5 ) J 5 )
CF3
15 6. The compound according to any one of claims 1 to 5, characterized in that W
represents an R5, SR5, OR5 or NRsRe group, with R5 and Re representing, independently
of each other, a hydrogen atom or a (Ci-C6)alkyl group.
7. Compound according to any one of claims 1 to 6, characterized in that:
20 - R3=H,
- U=CH2or]SIH,
- V=C(0) or C(S), and notably C(0), and
- n=0 or 1, and notably 0.
25 8. The compound according to any one of claims 1 to 7, characterized in that Ri
represents a hydrogen atom or an NRyRg group, with R? representing a hydrogen atom
I
f •
wo 2012/101239 PCT/EP2012/051283
155
and Rs representing an optionally substituted (C3-Ci2)cycloalkyl group or an optionally
substituted heterocycle.
9. The compound according to claim 8, characterized in that Ri represents one of
5 the following groups:
H, >^ \ / and - ^ N / F.
10. The compound according to any one of claims 1 to 9, characterized in that Ri
represents NO2, NR9R10 or a heterocycle optionally substituted by (Ci-C6)alkyl or NH2-
10
11. The compound according to claim 10, characterized in that R2 represents one of
the following groups;
—l-N N
NH2, NH(CH2)3NMe2, NMe(CH2)3NMe2, NO2, \ /
,NH2
\ / ,and ^ -^
15
12. The compound according to any one of claims 1 to 11, characterized in that it is
selected from the following compounds:
i
\ •
I *
wo 2012/101239 PCT/EP2012/051283
156
0 J^O O JT^O
H N - \ ^ ^— 9' HN--\y ^—
14-2 YT T i^N w i'*-!® (\ T I N C=(
s F F "^
F \^N^ J H
"^ F \^fg
H2N^O P H N - \ 7 ° L^ O ^^,jr^O
[ HN-\ / ^— I ^ Jl H N - \ /
30-1 r J If JP^ VJ( ^"-^ /Y'V^ f/
" Q " " O
\ \-N
s
!
wo 2012/101239 PCT/EP2012/051283
157
\ H^AT-O^^^ I \ H.AT^° I
^ o J^o o , , ^ 0
\—N 30-10 ^ ^ ^ ^ ^ ' " V S 30-n ' T T ' Y V NQ
30-12 'Y^'YV^N Q 30-a 'YY'I^NQ
F (^^/ F ^m^
I F
HN-A^ J /**VNH2
N
I
f ^
wo 2012/101239 PCT/EP2012/051283
158
o _/^o p
30-69 XJ XX;' ^ 27-2 'Y^^'YV, Q
T H , Y "-N-^N N-S^
27-3 ^ O^Y V N Q 27-4 jfS JpVi, Q
H N - \ J H " ' ^ ' V^
30-73 ^YT'jfr^N Q "«>- ' T T ' T V N U
o r^o o /"^o
30-70 'TT'rt^N Q 30-71 ' r y ' j r VN Q
\ 30-72 F>Y^V^\ T T^N \ J 27-5 , J r\N \s=<
^ F
i
1 »
WO 2012/101239 PCT/EP2012/051283
159
/? HN-C° I o no
30-17 V ^ V ^ rS 30-18 V ^ ° Y M M V)
30-19 V ^ ° Y ^ ^ K , r ? 30-20 V^°>''^«r-i YS
30-21 V^^°Y^*r^ ffl 30-22 kA/O^v-N^ F S
N /9 HM'^ ? ^ HN-X7
30-23 k A / 0 N ^ VA 30.24 ' Y Y V ' ^ T ^ N O
^y^—M \ ^^r ^i^ N M—X I " Q I I - " Q I
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160
\ 0 r^o I \ 0 r^o I
J H N - \ / A H N - \ /
H N - \ j ^-^ HNA J ^—
30-25 YJ T IHN V i 30-26 Y T T T^N V4
T H p) F H ^-^
H N - \ J HN-\ / ^'^
30-27 Y T X O M ^"-^^ T T T T^N v i
_ - _ _ - o r^o
A HN-\_7 J^ HN-\ /
H N - \ j ^ ^ HN-\y ^-^
30-29 Y Y Y o Vi 3«-3o Y Y T jIjN Q
».3. "YYVYQ '"^ uYc^"M
F>4'F J H N - \ J Jf H N - V /
T HN-Aj ^-^ HN-\ / ^-^
" Y ^ " Q
^S^N^ Y\ S,^NY( YS
30-37 p 1 L £> \ Y 30-38 ri I L L^^ VA
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f HN-\ /° P F H N - \ j°
H HN-\7 ^-^ ^, H HNA-U
30-41 F..^^N N_4 y\ 30^2 /L.N N^ y-^
y ^« ^ ^ T ^« Q
O /"^O 0 / ^p
P Jl HN-\ / ^ H N - V/
F
0 /^ P L\ J HN-\ /
F^^^^v'*ri Tl
^ - ^ / N T > < V'-/ N T ><
30-55 T d' Y o vi ^"-^^ T d' Y r^N w
X-N V-N
\ 11 J^ ,0 HN-\ / — A J^ P HN-\/ ^-^
30-59 d' Y T^N \J 30-60 d' Y T^N \J
O " O
\ 30-61 XXo^T^T^N O 30-62 kJ °'T iC^ Vi
< >
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163
\ 0 r^o ^ I o r^o I
30-65 r T PN v i '"^' lAc?' X r^-^ v i
o j^o o r^o ^ HN-\/ _, J HN-X J
CI ^ ^ P HN-\/ ^^ ^ HN^\/
O \X " O
N ! o no
31-1 ^ X^^ ^^
13. A compound according to any one of claims 1 to 12, for use as a drug.
14. A compound according to any one of claims 1 to 12, for use as a drug intended
5 for the treatment of cancer, inflammation and neurodegenerative diseases such as
Alzheimer's disease, in particular cancer.
15. A compound according to any one of claims 1 to 12, for use as an inhibitor of
kinases such as ALK, Abl and/or c-Src.
10
16. A compound according to any one of claims 1 to 12, for use as a drug intended
for the treatment of a disease associated with a kinase such as ALK, Abl and/or c-Src.
17. A pharmaceutical composition comprising at least one compound of formula (I)
15 according to any one of claims 1 to 12, and at least one pharraaceutically acceptable
excipient.
18. The pharmaceutical composition according to claim 17, further comprising at
least one other active ingredient such as an anticancer agent.
!
r 1
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19. A pharmaceutical composition comprising:
(i) at least one compound of formula (I) according to any one of claims 1 to 12, and
(ii) at least one other active ingredient, such as an anticancer agent,
as a combination product for simuhaneous, separate or sequential use.
5
20. A method for the preparation of a compound of formula (I) according to any one
of claims 1 to 12, wherein V=C(0) or C(S), preferably C(0), and notably U=CH2,
comprising the following successive steps:
(al) coupling between a compound of following formula (A):
NHz
10 ^"^ (A)
wherein Yi, Y2, Y3 and Y4 are as defined in claim 1, and R29 represents a
hydrogen atom or an N-protecting group,
with a compound of following formula (B):
^/
V
R30 (B)
15 wherein Ri, R2, U and n are as defined in claim 1, V=C(0) or C(S), and R3o=OH
or a leaving group such as CI,
to yield a compound of following formula (C):
r t
wo 2012/101239 PCT/EP2012/051283
165
R2
NH
II N
>4 R29
(C)
wherein Yi, Y2, Y3, Y4, Ri, R2, U and n are as defined in claim 1, R29 is such as
defined above and V=C(0) or C(S),
(bl) optionally substitution of the nitrogen atom bound to V of the compound of
5 formula (C) obtained in the preceding step with an R3 group other than H and/or
deprotection of the nitrogen atom carrying an R29 group representing an Nprotecting
group to yield a compound of formula (I) with V=C(0) or C(S),
(cl) optionally forming of a salt of the compound of formula (I) obtained in the
preceding step to jdeld a pharmaceutically acceptable salt of same.
10
21. A method for the preparation of a compound of formula (I) according to any one
of claims 1 to 12, wherein V=CH2, and notably U=CH2, comprising the following
successive steps:
(a2) reducing amination reaction between a compound of formula (A) such as defined
15 in claim 20 and an aldehyde of following formula (D):
R2
° (D)
wherein Ri, R2, U and n are as defined in claim 1,
to yield a compound of following formula (E):
1 >
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R2 a-
NH
N
R29
(E)
wherein Yi, Y2, Y3, Y4, Ri, R2, U and n are as defined in claim 1 and R29 is such
as defined in claim 20,
(b2) optionally deprotection of the nitrogen atom carrying an R29 group representing
5 an N-protecting group and/or substitution of the nitrogen atom bound to V with
an R3 group other than H of the compound of formula (E) obtained in the
preceding step to yield a compound of formula (I) with V=CH2, and
(c2) optionally forming of a salt of the compound of formula (I) obtained in the
preceding step to yield a pharmaceutically acceptable salt of same.
10
22. A method for the preparation of a compound of formula (I) according to any one
of claims 1 to 12 wherein V=C(0) or C(S), n=l and U=NH, comprising the following
successive steps:
(a3) coupling between a compound of formula (A) such as defined in claim 1 and a
15 compound of following formula (F):
R2
N
(F)
wherein Ri and R2 are such as defined above and Z=0 or S,
to yield a compound of following formula (G):
f
I 1
I
w o 2012/101239 PCT/EP2012/051283
167
R2
NH
NH
M N
R29 (G)
wherein Yi, Y2, Y3, Y4, Ri and R2 are as defined in claim 1, R29 is such as
defined in claim 20 and Z is such as defined above,
(b3) optionally deprotection of the nitrogen atom carrying an R29 group representing
5 an N-protecting group and/or substitution of the nitrogen atom bound to V with
an R3 group other than H of the compound of formula (G) obtained in the
preceding step to yield a compound of formula (I) with V=C(0) or C(S), n=l
and U=NH, and
(c3) optionally forming of a salt of the compound of formula (I) obtained in the
10 preceding step to yield a pharmaceutically acceptable sah of same.
>
• r
NH
NH
R29 (Q)
wherein Yi, Y2, Y3, Y4, R% and Rj are as defined in claim 1, R29 is such as
defined in claim 20 and Z is such as defined above,
(b3) optionally deprotection of the nitrogen atom carrying an R29 group representing
5 an N-protecting group and/or substitution of the nitrogen atom bound to V with
an R3 group other than H of the compound of formula (G) obtained in the
preceding step to yield a compound of formula (I) with V=C(0) or C(S), n=l
and U=NH, and
(c3) optionally forming of a salt of the compound of formula (I) obtained in the
10 preceding step to yield a pharmaceutically acceptable salt of same.