NZ737314B2 - 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as jak inhibitors - Google Patents
2-(pyrazolopyridin-3-yl)pyrimidine derivatives as jak inhibitors Download PDFInfo
- Publication number
- NZ737314B2 NZ737314B2 NZ737314A NZ73731416A NZ737314B2 NZ 737314 B2 NZ737314 B2 NZ 737314B2 NZ 737314 A NZ737314 A NZ 737314A NZ 73731416 A NZ73731416 A NZ 73731416A NZ 737314 B2 NZ737314 B2 NZ 737314B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- group
- amino
- pyrazolo
- piperidinyl
- fluoro
- Prior art date
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- PWNLEGTUORZMTM-UHFFFAOYSA-N 3-pyrimidin-2-yl-1H-pyrazolo[4,3-b]pyridine Chemical class N1=CC=CN=C1C1=NNC2=CC=CN=C12 PWNLEGTUORZMTM-UHFFFAOYSA-N 0.000 title claims abstract description 86
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 210
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- 238000005457 optimization Methods 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
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- 239000003182 parenteral nutrition solution Substances 0.000 description 1
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- ATGAWOHQWWULNK-UHFFFAOYSA-I pentapotassium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [K+].[K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O ATGAWOHQWWULNK-UHFFFAOYSA-I 0.000 description 1
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- 239000011574 phosphorus Substances 0.000 description 1
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- 229920001296 polysiloxane Polymers 0.000 description 1
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- 238000001556 precipitation Methods 0.000 description 1
- 229960002794 prednicarbate Drugs 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000006233 propoxy propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- LFCWHDGQCWJKCG-UHFFFAOYSA-N pyrazin-2-ylmethanol Chemical compound OCC1=CN=CC=N1 LFCWHDGQCWJKCG-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- NDRLPYIMWROJBG-UHFFFAOYSA-M pyridin-1-ium-1-amine;iodide Chemical compound [I-].N[N+]1=CC=CC=C1 NDRLPYIMWROJBG-UHFFFAOYSA-M 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- ZFCHNZDUMIOWFV-UHFFFAOYSA-M pyrimidine-2-carboxylate Chemical compound [O-]C(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-M 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960001068 rolapitant Drugs 0.000 description 1
- 108010025791 sarilumab Proteins 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 108010040425 secukinumab Proteins 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- 239000006190 sub-lingual tablet Substances 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- FRHOQDDDDFBHGW-UHFFFAOYSA-N tert-butyl N-piperidin-1-ylcarbamate Chemical compound CC(C)(C)OC(=O)NN1CCCCC1 FRHOQDDDDFBHGW-UHFFFAOYSA-N 0.000 description 1
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Abstract
New 2-(pyrazolopyridin-3-yl)pyrimidine derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
Description
-(PYRAZOLOPYRIDINYL)PYRIMIDINE DERIVATIVES AS JAK INHIBITORS
FIELD OF THE INVENTION
The present ion s to novel compounds having JAK inhibitory activity. This
invention also relates to pharmaceutical compositions containing them, processes for
their preparation and their use in the treatment of several disorders.
BACKGROUND OF THE INVENTION
Cytokines have critical functions in regulating many aspects of immunity and
mation, ranging from the development and differentiation of immune cells to the
suppression of immune responses. Type I and type II cytokine receptors lack intrinsic
enzymatic activity e of mediating signal transduction, and thus require
association with ne kinases for this purpose. The JAK family of kinases comprises
four different members, namely JAK1, JAK2, JAK3 and TYK2, which bind to type I and
type II cytokine receptors for controlling signal transduction (Murray PJ, (2007). The
JAK-STAT signalling pathway: input and output integration. J Immunol, 178: 2623).
Each of the JAK kinases is selective for the receptors of certain cytokines. In this
regard, JAK-deficient cell lines and mice have validated the ial role of each JAK
protein in receptor ling: JAK1 in class II cytokine receptors (IFN and IL-10 ),
those sharing the gp130 chain (IL-6 family) and the common gamma chain (IL-2, IL-4,
IL-7, IL-9, IL- 15 and IL-21) (Rodig et al. (1998). Disruption of the JAK1 gene
demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced
biological response. Cell, 93:373; Guschin et al. (1995). A major role for the protein
tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to
interleukin-6. EMBO J. 14: 1421; Briscoe et al. (1996). Kinase-negative mutants of
JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral
state. EMBO J. 15:799); JAK2 in hematopoietic factors (Epo, Tpo, GM-CSF, IL-3, IL-5)
and type II IFNs (Parganas et al., (1998). JAK2 is essential for ling through a
variety of cytokine ors. Cell, 93:385); JAK3 in receptors sharing the common
gamma chain (IL-2 family) (Park et al., (1995). Developmental defects of lymphoid cells
in JAK3 kinase-deficient mice. Immunity, 3:771; Thomis et al., (1995). Defects in B
lymphocyte maturation and T cyte activation in mice lacking JAK3. Science,
270:794; Russell et al., (1995). Mutation of JAK3 in a partient with SCID: ial role
of JAK3 in lymphoid development. Science, 270:797); and Tyk2 in the receptors of IL-
12, IL-23, IL-13 and type I IFNs (Karaghiosoff et al., . Partial impairment of
cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., (2000).
Tyk2 plays a restricted role in IFNg signaling, although it is ed for ILmediated
T cell function. Immunity, 13:561; shi et al., (2006). Human Tyrosine kinase 2
ency reveals its ite roles in multiple cytokine signals involved in innate and
acquired immunity. Immunity, 25:745).
Receptor stimulation leads sequentially to JAK activation by orylation, receptor
phosphorylation, STAT protein recruitment and STAT activation and dimerization. The
STAT dimer then functions as a transcription factor, translocating to the s and
activating the transcription of multiple response genes. There are seven STAT ns
identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Each
particular cytokine receptor associates preferentially with a particular STAT protein.
Some associations are independent of cell type (ex: IFNg- STAT1) while others may be
cell type dependent y PJ, (2007). The JAK-STAT signaling pathway: input and
output integration. J Immunol, 178: 2623).
The phenotype of deficient mice has provided insights on the function of each JAK and
the cytokine receptors signaling through them. JAK3 associates ively with the
common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
cytokines. By virtue of this exclusive association, JAK3 knock out mice and common
gamma chain deficient mice have an identical phenotype (Thomis et al., (1995).
Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3.
Science, 270:794; DiSanto et al., . Lymphoid pment in mice with a
targeted deletion of the interleukin 2 receptor gamma chain. PNAS, 92:377). Moreover,
this phenotype is shared to a great extent with SCID patients that hold
mutations/defects in the common gamma chain or JAK3 genes (O’Shea et al., (2004).
JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol, 41:
727). JAK3-deficient mice are viable but display abnormal lymphopoiesis which leads
to a reduced thymus size (10-100 fold smaller than wild type). JAK3-deficient
peripheral T cells are unresponsive and have an activated/memory cell phenotype
(Baird et al., (1998). T cell development and tion in JAK3-deficient mice. J. Leuk.
Biol. 63: 669). The thymic defect in these mice strongly resembles that seen in IL-7 and
IL-7 receptor knockout mice, suggesting that the e of IL-7 signaling accounts for
this defect in JAK3 -/-mice (von Freeden-Jeffry et al., (1995). Lymphopenia in
Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7 as a non-redundant Cytokine. J Exp
Med, 181:1519; Peschon et al, (1994). Early lymphocyte expansion is severely
impaired in interleukin 7 receptor-deficient mice. J Exp Med, 180: 1955). These mice,
like SCID humans, have no NK cells, probably due to the e of IL-15 ing, a
survival factor for these cells. JAK3 ut mice, unlike SCID patients, show
deficient B cell lymphopoiesis while in human ts, B cells are present in circulation
but are not responsive leading to obulinemia a et al., (2004). JAK3 and
the pathogenesis of severe combined immunodeficiency. Mol Immunol, 41: 727). This
is explained by species-specific differences in IL-7 function in B and T cell development
in mice and humans. On the other hand, Grossman et al. (1999. Dysregulated
myelopoiesis in mice lacking JAK3. Blood, 94:932:939) have shown that the loss of
JAK3 in the T-cell compartment drives the expansion of the myeloid lineages leading to
dysregulated oiesis.
JAK2-deficient mice are embrionically lethal, due to the absence of definitive
erythropoiesis. Myeloid progenitors fail to respond to Epo, Tpo, IL-3 or GM-CSF, while
G-CSF and IL-6 signaling are not affected. JAK2 is not required for the generation,
amplification or functional differentiation of lymphoid progenitors (Parganas et al.,
(1998). JAK2 is essential for signaling h a variety of cytokine receptors. Cell,
93:385).
JAK1-deficient mice die perinatally due to a nursing . JAK1 binds exclusively to
the gp130 chain shared by the IL-6 cytokine family (i.e. LIF, CNTF, OSM, CT-1) and
along with JAK3, is an essential component of the receptors g the common
gamma chain, by binding to the non-shared receptor subunit. In this regard, JAK1-
deficient mice show similar hematopoiesis defects as JAK3-deficient mice. In addition,
they show defective responses to neurotrophic factors and to all interferons (class II
cytokine receptors) (Rodig et al., (1998). Disruption of the JAK1 gene demonstrates
obligatory and non-redundant roles of the JAKs in cytokine-induced ical
response. Cell, 93:373).
Finally, Tyk2-deficient mice show an impaired response to IL-12 and IL-23 and only
partially impaired to IFN-alpha (Karaghiosoff et al., (2000). Partial impairment of
ne responses in eficient mice. Immunity, 13:549; Shimoda et al., (2000).
Tyk2 plays a restricted role in IFNg signaling, gh it is required for ILmediated
T cell function. Immunity, 13:561). However, human Tyk2 deficiency demonstrates that
Tyk2 is involved in the signaling from IFN-α, IL-6, IL-10, IL-12 and IL-23 (Minegishi et
al., (2006). Human ne kinase 2 deficiency reveals its requisite roles in multiple
cytokine signals involved in innate and acquired immunity. Immunity, 25:745).
The role of JAK kinases in ucing the signal from a myriad of nes makes
them ial targets for the treatment of diseases in which cytokines have a
pathogenic role, such as dermatological diseases; respiratory diseases; allergic
diseases; inflammatory or autoimmune-mediated; function disorders and neurological
disorders; cardiovascular diseases; viral infection; metabolism/endocrine function
disorders; neurological disorders and pain; bone marrow and organ lant
rejection; myelo-dysplastic me; myeloproliferative disorders (MPDs); cancer and
hematologic malignancies, leukemia, lymphomas and solid tumors.
In view of the numerous conditions that are contemplated to benefit by treatment
involving modulation of the JAK pathway or of the JAK Kinases it is immediately
apparent that new compounds that modulate JAK pathways and use of these
nds should e substantial therapeutic benefits to a wide variety of
patients.
Some substituted pyrimidines as Janus kinase inhibitors were described in WO
2013/025628 and .
Provided herein are novel 2-(pyrazolopyridinyl)pyrimidine derivatives for use in the
ent of conditions in which targeting of the JAK pathway or inhibition of JAK
kinases can be therapeutically .
The compounds bed in the present invention are simultaneously potent JAK1,
JAK2 and JAK3 inhibitors, i.e. pan-JAK inhibitors.
SUMMARY OF THE INVENTION
Thus the present invention is directed to a 2-(pyrazolopyridinyl)pyrimidine derivative
which 2-(pyrazolopyridinyl)pyrimidine derivative is a compound of formula (I), or a
pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated
derivative thereof:
Formula (I)
wherein
• X represents –O- or –NR3- group,
• R1 and R2 are ndently selected from the group consisting of a hydrogen
atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or branched C1-4
alkoxy group and -CN group;
• R3 is selected from the group consisting of a hydrogen atom, a linear or
ed C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine
group;
• G1 is a –O-R6 group,
• Q is selected from the group consisting of:
wherein
o R4 is selected from the group consisting of a linear or branched C1-4 alkyl
group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, -
CO(CH2)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6-
membered heterocyclyl group containing at least one heteroatom
selected from O, S and N and a monocyclic 5- to 6- membered
heteroaryl group containing at least one heteroatom selected from O, S
and N, wherein the heterocyclyl and heteroaryl group independently are
unsubstituted or substituted with one or more substituents selected from
–(CH2)m-CN group and a C1-2 hydroxyalkyl group,
o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group;
o G2 ents a phenyl group, a pyrimidine group or a ne group,
wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or
substituted by one or more substituents selected from a halogen atom, a
linear or ed C1-4 alkyl group, a hydroxyl group, a –CN group,
• R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O-
R”’ group, a linear or branched (C1-6 )-(C1-6 alkyl) group and a linear or
branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more substituents selected from a
halogen atom, a hydroxyl group and –NR’R” group,
• R’ and R’’ independently represents a hydrogen atom, a linear or branched C1-3
alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched
C1-3 alkoxy group,
• R”’ represents a C1-2 alkyl group or a benzyl group, and
• m ndently has a value from 0 to 3.
Described is a 2-(pyrazolopyridinyl)pyrimidine derivative for use in the treatment of the
human or animal body, which 2-(pyrazolopyridinyl)pyrimidine tive is a
compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or e,
or stereoisomer or deuterated derivative thereof:
Formula (I)
wherein
• X represents –O- or –NR3- group,
• R1 and R2 are independently selected from the group consisting of a hydrogen
atom, a halogen atom, a linear or ed C1-4 alkyl, a linear or branched C1-4
alkoxy group and -CN group;
• R3 is selected from the group consisting of a en atom, a linear or
branched C1-4 alkyl group, a 1-3NR’R’’ group and a –(CH2)1pyrrolidine
group;
• G1 is selected from the group consisting of –CN group, -CO-Ra group, a –O-R6
group, a -(CHR7)m-NR’R’’ group, a phenyl group, a monocyclic C5-7 cycloalkyl
group, a clic 5- to 6- membered heteroaryl group containing at least one
heteroatom selected from O, S and N and a monocyclic 5- to 6- membered
heterocyclyl group containing at least one heteroatom selected from O, S and
N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are
unsubstituted or substituted by one or more substituents selected from a
halogen atom, a yl group, a linear or branched C1-4 alkyl group, a linear
or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a -
(CH2)0-2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra
represents a hydrogen atom, a hydroxyl group, a linear or branched C1-3 alkyl
group, a linear or branched C1-3 alkoxy group or an amino group,
• Q is selected from the group consisting of:
wherein
o R4 is selected from the group consisting of a linear or branched C1-4 alkyl
group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, -
CO(CH2)1CF3 group, a hiazole group, a monocyclic 4- to 6-
membered heterocyclyl group containing at least one heteroatom
ed from O, S and N and a monocyclic 5- to 6- membered
heteroaryl group ning at least one atom selected from O, S
and N, wherein the heterocyclyl and heteroaryl group independently are
tituted or substituted with one or more substituents selected from
–(CH2)m-CN group and a C1-2 hydroxyalkyl group,
o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group;
o G2 represents a phenyl group, a pyrimidine group or a pyridine group,
wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or
substituted by one or more substituents selected from a halogen atom, a
linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group,
• R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O-
R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or
branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more tuents selected from a
halogen atom, a yl group and –NR’R” group,
• R7 represents a hydrogen atom, a hydroxyl or a C1-2 alkyl group,
• R’ and R’’ ndently represents a hydrogen atom, a linear or branched C1-3
alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched
C1-3 alkoxy group,
• R”’ represents a C1-2 alkyl group or a benzyl group, and
• m independently has a value from 0 to 3,
wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not:
• 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a]
nylpyrimidinyl)amino]piperidinyl}oxopropanenitrile
• 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxopropanenitrile
• (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxetanyl)acetonitrile
• Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
• 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxoethanol
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
Also described is a 2-(pyrazolopyridinyl)pyrimidine tive, which 2-
(pyrazolopyridinyl)pyrimidine tive is a nd of formula (I), or a
pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated
derivative thereof:
Formula (I)
wherein
• X represents –O- or –NR3- group,
• R1 and R2 are independently selected from the group consisting of a hydrogen
atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or branched C1-4
alkoxy group and -CN group;
• R3 is selected from the group consisting of a hydrogen atom, a linear or
branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine
group;
• G1 is selected from the group ting of –CN group, -CO-Ra group, a –O-R6
group, a -(CHR7)m-NR’R’’ group, a phenyl group, a monocyclic C5-7 cycloalkyl
group, a monocyclic 5- to 6- membered aryl group containing at least one
heteroatom selected from O, S and N and a monocyclic 5- to 6- ed
heterocyclyl group containing at least one heteroatom selected from O, S and
N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are
unsubstituted or substituted by one or more substituents selected from a
halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear
or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a -
-2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra
represents a hydrogen atom, a hydroxyl group, a linear or branched C1-3 alkyl
group, a linear or branched C1-3 alkoxy group or an amino group,
• Q is selected from the group consisting of:
wherein
o R4 is selected from the group consisting of a linear or branched C1-4 alkyl
group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, -
)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6-
ed heterocyclyl group containing at least one heteroatom
selected from O, S and N and a clic 5- to 6- membered
heteroaryl group containing at least one heteroatom selected from O, S
and N, wherein the heterocyclyl and heteroaryl group ndently are
unsubstituted or substituted with one or more substituents selected from
–(CH2)m-CN group and a C1-2 hydroxyalkyl group,
o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group;
o G2 represents a phenyl group, a pyrimidine group or a pyridine group,
wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or
substituted by one or more substituents selected from a n atom, a
linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group,
• R6 is selected from the group ting of a hydrogen atom, -(CH2)(1-2)-CO-O-
R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or
branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more substituents selected from a
halogen atom, a hydroxyl group and –NR’R” group,
• R7 ents a en atom, a hydroxyl or a C1-2 alkyl group,
• R’ and R’’ independently represents a hydrogen atom, a linear or branched C1-3
alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched
C1-3 alkoxy group,
• R”’ represents a C1-2 alkyl group or a benzyl group, and
• m independently has a value from 0 to 3,
wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not:
• 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile
• 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
piperidinyl}oxopropanenitrile
• (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxetanyl)acetonitrile
• Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
• 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxoethanol
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
no}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxopropanenitrile
• 3-[(3R)({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a]
pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• )[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl}
lo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a]
pyridinyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile
• (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl)
pyrimidinyl)amino)piperidinyl)oxopropanenitrile
Further described are synthetic processes and intermediates, which are useful for
preparing said 2-(pyrazolopyridinyl)pyrimidine derivatives.
The invention is also directed to a azolopyridinyl)pyrimidine derivative of the
invention as described herein for use in the treatment of the human or animal body by
therapy.
The invention also provides a pharmaceutical composition comprising the 2-
(pyrazolopyridinyl)pyrimidine tives of the invention and a pharmaceuticallyacceptable
diluent or carrier.
The invention is also directed to the 2-(pyrazolopyridinyl)pyrimidine derivatives of the
invention as bed , for use in the treatment of a pathological condition or
disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular
wherein the pathological condition or disease is selected from a dermatological
disease, a respiratory disease, an allergic disease, an inflammatory or autoimmunemediated
disease, a function disorder, a neurological er, a cardiovascular
e, a viral infection, a lism/endocrine function disorder, a neurological
disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic
syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy,
leukemia, lymphoma and solid tumor. More in particular wherein the pathological
condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis,
eczema, c hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic
keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus,
cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome,
pyoderma gangrenosum, lichen planus, blistering es including but not limited to
pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia,
lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic
lateral sclerosis, systemic lupus matosis, autoimmune hemolytic anemia, type I
diabetes, , chronic obstructive ary disease , cystic fibrosis,
bronchiectasis, cough, idiopathic pulmonary is, sarcoidosis, allergic rhinitis,
inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic
conjunctivitis and keratoconjuntivitis sicca.
The invention is also directed to use of the 2-(pyrazolopyridinyl)pyrimidine
derivatives of the invention as described , in the manufacture of a medicament
for treatment of a pathological condition or disease susceptible to amelioration by
ton of Janus Kinases (JAK), in particular wherein the pathological condition or
disease is selected from a dermatological disease, a respiratory disease, an allergic
disease, an matory or autoimmune-mediated disease, a function disorder, a
neurological disorder, a cardiovascular disease, a viral infection, a
metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow
and organ transplant rejection, dysplastic syndrome, a myeloproliferative
disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid
tumor. More in particular wherein the pathological condition or disease is selected from
atopic itis, sis, contact dermatitis, eczema, c hand eczema, basal
cell carcinoma, squamous cell carcinoma, actinic keratosis, ma, vitiligo,
alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits,
dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma
gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus
vulgaris, bullous pemphigoid and molysis a, leukemia, mas and
solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis,
systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma,
chronic obstructive ary disease (COPD), cystic fibrosis, bronchiectasis, cough,
idiopathic ary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease,
ulcerative colitis, s disease, dry eye, uveitis, allergic conjunctivitis and
keratoconjuntivitis sicca.
Also described is a method of treatment of a pathological condition or disease
susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein
the pathological condition or disease is selected from a dermatological disease, a
respiratory disease, an allergic disease, an inflammatory or mune-mediated
e, a on disorder, a neurological disorder, a cardiovascular disease, a viral
infection, a metabolism/endocrine function disorder, a neurological disorder, pain,
bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a
myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia,
lymphoma and solid tumor. More in particular wherein the ogical condition or
disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema,
chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic
sis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus,
cutaneous vasculitits, dermatomyositis, cutaneous T-cell ma, Sézary syndrome,
pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to
gus vulgaris, bullous pemphigoid and epidermolysis bullosa, ia,
lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic
lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I
diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis,
bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis,
matory bowel disease, ulcerative colitis, s disease, dry eye, uveitis, ic
conjunctivitis and keratoconjuntivitis sicca.
Also described is a ation product sing (i) the 2-(pyrazolopyridin
yl)pyrimidine tives of the invention as described herein; and (ii) one or more
additional active substances.
DETAILED DESCRIPTION OF THE INVENTION
When describing the azolopyridinyl)pyrimidine derivatives, itions, and
methods of the invention, and ations described, the following terms have the
following meanings, unless otherwise indicated.
As used herein the term C1-C6 alkyl embraces linear or branched radicals having 1 to 6
carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, l, sec-butyl, tbutyl
, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1,1-
dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, lbutyl, 2-ethylbutyl, 1,1-
dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
2-methylpentyl, 3-methylpentyl and iso-hexyl radicals.
As used herein the term C1-C4 alkyl embraces linear or branched radicals having 1 to 4
carbon atoms. Analogously, the term C1-C3 alkyl embraces linear or branched radicals
having 1 to 3 carbon atoms and the term C1-C2 alkyl embraces linear or branched
ls having 1 to 2 carbon atoms.
As used herein, the term C1-C6 yalkyl es linear or branched alkyl radicals
having 1 to 6 carbon atoms, any one of which may be substituted with one or more
hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl,
hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl.
As used herein, the term C1-C3 hydroxyalkyl embraces linear or branched alkyl radicals
having 1 to 3 carbon atoms, any one of which may be substituted with one or more
hydroxyl radicals. es of such radicals include hydroxymethyl, hydroxyethyl or
hydroxypropyl.
As used herein, the term C1-C2 hydroxyalkyl embraces linear or ed alkyl radicals
having 1 to 2 carbon atoms, any one of which may be substituted with one or more
hydroxyl radicals. Examples of such radicals include hydroxymethyl or hydroxyethyl.
As used herein, the term C1-C6 alkoxy (or alkyloxy) embraces linear or branched oxycontaining
radicals each having alkyl portions of 1 to 6 carbon atoms. Examples of C1-
C6 alkoxy ls include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy,
t-butoxy, n-pentoxy and n-hexoxy.
As used herein, the term C1-C4 alkoxy (or alkyloxy) es linear or branched oxycontaining
radicals each having alkyl portions of 1 to 4 carbon atoms. Examples of C1-
C4 alkoxy radicals include methoxy, ethoxy, n-propoxy, oxy, xy, toxy
or t-butoxy.
As used herein, the term C1-C3 alkoxy (or alkyloxy) embraces linear or branched oxy-
containing radicals each having alkyl portions of 1 to 3 carbon atoms. Examples of C1-
C3 alkoxy ls include methoxy, ethoxy, n-propoxy and oxy.
As used herein, the term (C1-6 alkoxy)-(C1-6 alkyl) es linear or branched radicals
having 1 to 6 carbon atoms substituted with a C1-6 alkoxy group. Examples of (C1-6
alkoxy)-(C1-6 alkyl) e methoxy-methyl, ethoxy-methyl, y-ethyl, ethoxy-ethyl,
methoxy-propyl, propoxy-methyl, ethoxy-propyl, propoxy-ethyl, propoxy-propyl,
methoxy-butyl, ethoxy-butyl, methoxy-pentyl, ethoxy-pentyl and methoxy-hexyl.
As used herein, the term C5-7 lkyl embraces saturated monocyclic carbocyclic
radicals having from 5 to 7 carbon atoms. Examples of monocyclic cycloalkyl groups
include cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, the term 5- to 6-membered heteroaryl radical embraces typically a 5-
to 6- membered ring system sing at least one heteroaromatic ring and
containing at least one heteroatom selected from O, S and N.
Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl,
pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl or pyrrolyl.
As used herein, the term 4- to 6-membered heterocyclyl radical embraces typically a
non-aromatic, saturated or unsaturated C4-6 carbocyclic ring system in which one or
more, for example 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon
atoms are replaced by a heteroatom selected from N, O and S.
Examples of 4- to 6-membered heterocyclyl radicals include oxetanyl, azetidinyl,
piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl,
pyrazolinyl, pirazolidinyl, triazolyl, lyl, olyl, imidazolidinyl, 4,5-dihydrooxazolyl
, 1,3-dioxolone, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl,
tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl or 1,4-azathianyl.
As used herein, the term 5- to 6-membered heterocyclyl radical es typically a
non-aromatic, saturated or unsaturated C5-6 carbocyclic ring system in which one or
more, for example 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon
atoms are replaced by a heteroatom selected from N, O and S.
Examples of 5- to 6-membered cyclyl radicals include piperidyl, idyl,
pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl,
triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, 1,3-dioxolone,
ydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl,
tetrahydrothiopyranyl or 1,4-azathianyl.
As used herein, some of the atoms, radicals, moieties, chains and cycles present in the
general structures of the invention are stituted or substituted”. This means that
these atoms, radicals, moieties, chains and cycles can be either unsubstituted or
substituted in any position by one or more, for example 1, 2, 3 or 4, substituents,
whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties,
chains and cycles are replaced by chemically able atoms, radicals, moieties,
chains and .
As used herein, the term halogen atom embraces ne, fluorine, bromine and iodine
atoms. A halogen atom is typically a fluorine, chlorine or bromine atom. The term halo
when used as a prefix has the same meaning.
Compounds containing one or more chiral centre may be used in enantiomerically or
diastereoisomerically pure form, in the form of racemic mixtures and in the form of
mixtures enriched in one or more stereoisomer. The scope of the invention as
described and claimed encompasses the racemic forms of the compounds as well as
the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
tional ques for the preparation/isolation of individual enantiomers include
chiral synthesis from a suitable optically pure precursor or tion of the racemate
using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively,
the racemate (or a racemic precursor) may be reacted with a suitable optically active
compound, for example, an l, or, in the case where the compound contains an
acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The
resulting diastereomeric mixture may be separated by chromatography and/or
onal crystallization and one or both of the diastereoisomers converted to the
corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral
compounds of the invention (and chiral precursors thereof) may be obtained in
enantiomerically-enriched form using tography, typically HPLC, on an
asymmetric resin with a mobile phase consisting of a hydrocarbon, lly heptane or
hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to
% of an alkylamine, typically 0.1 % lamine. Concentration of the eluate affords
the enriched mixture. Stereoisomer conglomerates may be separated by conventional
techniques known to those d in the art. See, e.g. "Stereochemistry of Organic
Compounds" by Ernest L. ElieI (Wiley, New York, 1994).
As used , the term pharmaceutically acceptable salt refers to a salt prepared
from a base or acid which is acceptable for administration to a patient, such as a
mammal. Such salts can be derived from ceutically-acceptable inorganic or
organic bases and from pharmaceutically-acceptable inorganic or organic acids.
Pharmaceutically acceptable acids include both inorganic acids, for example
hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric
acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, ,
malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic,
methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid,
xinafoic (1-hydroxynaphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and
the like.
Salts d from pharmaceutically-acceptable inorganic bases include um,
um, m, copper, ferric, ferrous, lithium, magnesium, ic,
manganous, potassium, sodium, zinc and the like.
Salts derived from pharmaceutically-acceptable organic bases include salts of primary,
secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl
amines, cyclic amines, naturally-occurring amines and the like, such as arginine,
betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-
diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-
ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine, dine, polyamine
resins, procaine, purines, theobromine, triethylamine, hylamine, pylamine,
tromethamine and the like.
Other salts according to the invention are quaternary ammonium compounds wherein
an equivalent of an anion (X-) is associated with the positive charge of the N atom. X-
may be an anion of various mineral acids such as, for example, chloride, bromide,
, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for
example, acetate, maleate, te, citrate, oxalate, succinate, tartrate, malate,
mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
As used herein, an N-oxide is formed from the tertiary basic amines or imines present
in the molecule, using a convenient oxidising agent.
The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may exist in both
unsolvated and solvated forms. The term solvate is used herein to describe a
molecular complex comprising a compound of the invention and an amount of one or
more pharmaceutically acceptable t molecules. The term hydrate is employed
when said solvent is water. Examples of solvate forms include, but are not limited to,
compounds of the invention in association with water, acetone, dichloromethane, 2-
propanol, l, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid,
ethanolamine, or mixtures f.
It is specifically contemplated that in the t ion one t molecule can be
associated with one molecule of the compounds of the present invention, such as a
hydrate. Furthermore, it is specifically contemplated that in the present invention, more
than one solvent molecule may be ated with one molecule of the compounds of
the present invention, such as a dihydrate. Additionally, it is specifically contemplated
that in the present invention less than one t molecule may be associated with
one molecule of the compounds of the present invention, such as a hemihydrate.
Furthermore, solvates of the t invention are plated as solvates of
compounds of the present invention that retain the biological effectiveness of the nonsolvate
form of the compounds.
The invention also includes isotopically-labeled 2-(pyrazolopyridinyl)pyrimidine
derivatives of the invention, wherein one or more atoms is replaced by an atom having
the same atomic number, but an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of isotopes suitable
for inclusion in the nds of the invention include isotopes of hydrogen, such as
2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as
18F, iodine, such as 123I and 125I, en, such as 13N and 15N, oxygen, such as 15O,
17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Preferred isotopically-
labeled compounds include deuterated derivatives of the compounds of the invention.
As used herein, the term deuterated derivative embraces compounds of the invention
[Link]
http://en.wikipedia.org/wiki/Stable_isotope
[Link]
/en.wikipedia.org/wiki/Hydrogen
where in a ular position at least one hydrogen atom is replaced by ium.
Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural
abundance of 0.015 molar %.
Isotopically-labeled 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention can
generally be ed by conventional techniques known to those skilled in the art or
by processes analogous to those described herein, using an appropriate isotopicallylabeled
reagent in place of the non-labeled reagent otherwise ed.
gs of the 2-(pyrazolopyridinyl)pyrimidine derivatives described herein are also
within the scope of the invention. Thus certain derivatives of the 2-(pyrazolopyridin
yl)pyrimidine derivatives of the present ion, which derivatives may have little or
no pharmacological activity themselves, when administered into or onto the body may
be converted into compounds of the present invention having the desired activity, for
example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further
ation on the use of prodrugs may be found in Pro-drugs as Novel ry
Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible
Carriers in Drug Design, on Press, 1987 (ed. E. B. Roche, an
Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing
appropriate functionalities present in the compounds of the present invention with
certain moieties known to those skilled in the art as 'pro-moieties' as described, for
example, in Design of gs by H. Bundgaard (Elsevier, 1985).
In the case of 2-(pyrazolopyridinyl)pyrimidine derivatives that are solids, it is
understood by those skilled in the art that the inventive compounds and salts may exist
in different crystalline or polymorphic forms, or in an amorphous form, all of which are
intended to be within the scope of the present invention.
Typically, R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl
group, for example, a fluorine atom, a hydrogen atom or a methyl group. Preferably, R1
represents a fluorine atom.
Typically, R2 represents a hydrogen atom or a fluorine atom. Preferably, R2 represents
a hydrogen atom.
lly, X represents a –NR3- group. atively, X may represent -O-.
Typically, R3 represents a hydrogen atom.
Typically, Q represents Qa.
If R4 is a -CO-R’ group, then R’ is lly not H.
lly, R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group.
Preferably, R4 represents a –C(O)CH2OH group or a -C(O)CH2CN group.
Typically, Ra represents a hydroxyl group, a linear or branched C1-3 alkyl group, a linear
or branched C1-3 alkoxy group or an amino group.
Typically, G1 represents a –O-R6 group, a CN group or a monocyclic 5- to 6-membered
aryl group containing at least one heteroatom ed from O, S and N and
being unsubstituted or substituted by one or more substituents selected from a halogen
atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-2
hydroxyalkyl group or a linear or branched C1-4 alkoxy group. Preferably, G1 represents
a –O-R6 group or a monocyclic 5- to 6-membered heteroaryl group containing at least
one heteroatom selected from O, S and N and being unsubstituted or substituted by
one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl
group or a linear or ed C1-4 alkoxy group. For instance, G1 may represent an –
O-R6 group.
Typically, R6 represents a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group or a linear
or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more substituents selected from a halogen
atom and a hydroxyl group.
Typically, the 2-(pyrazolopyridinyl)pyrimidine derivative is not:
• 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile
• 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxopropanenitrile
• (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxetanyl)acetonitrile
• Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
• 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxoethanol
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• )[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
or a pharmaceutically acceptable salt, or solvate, or N-oxide, or isomer or
deuterated derivative thereof.
Preferably, the 2-(pyrazolopyridinyl)pyrimidine derivative is not:
• 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile
• 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxopropanenitrile
• (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxetanyl)acetonitrile
• Ethyl -[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
• 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxoethanol
• )({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxopropanenitrile
• 3-[(3R)({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a]
pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• ){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• )[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a]
pyridinyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile
• (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl)
pyrimidinyl)amino)piperidinyl)oxopropanenitrile
or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or
deuterated derivative thereof.
Preferably, the 2-(pyrazolopyridinyl)pyrimidine tive is not a compound of
formula (I), wherein
• X is NR3;
• R1 is Me or F;
• R2 is H;
• R3 is H or -CH2CH2N(CH3)2;
• G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, 4-hydroxymethyl-phenyl, 4-
formyl-phenyl or phenyl substituted with hydroxyl and –CH2NHCH3;
• Q is Qa;
• R4 is –C(O)CH2CN, -C(O)CH2OH, -C(O)OCH2CH3, or oxetanyl substituted with
–CH2CN.
Preferably, the 2-(pyrazolopyridinyl)pyrimidine derivative is not a compound of
formula (I), n
• X is NR3;
• R1 is Me or F;
• R2 is H;
• R3 is H or -CH2CH2N(CH3)2;
• G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, razinyl or phenyl,
which phenyl is substituted with one or more, typically one or two, substituents
independently selected from hydroxyl, fluoro, -CH2OH, -C(O)H and –
CH2NHCH3;
• Q is Qa;
• R4 is –C(O)CH2CN, -C(O)CH2OH, -C(O)OCH2CH3, or oxetanyl substituted with
Typically, the 2-(pyrazolopyridinyl)pyrimidine derivative is not a nd of a
(I), wherein
• X is NR3;
• R1 is Me or F;
• R2 is H;
• R3 is H or -CH2CH2N(CH3)2;
• G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, 4-hydroxymethyl-phenyl, 4-
formyl-phenyl or phenyl substituted with hydroxyl and –CH2NHCH3;
• Q is Qa;
• R4 is –C(O)CH2CN, -C(O)CH2OH, -C(O)OCH2CH3, or oxetanyl tuted with
–CH2CN
or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or
deuterated derivative thereof.
Typically, the 2-(pyrazolopyridinyl)pyrimidine derivative is not a compound of formula
(I), wherein
• X is NR3;
• R1 is Me or F;
• R2 is H;
• R3 is H or -CH2CH2N(CH3)2;
• G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, N-piperazinyl or phenyl,
which phenyl is substituted with one or more, typically one or two, substituents
independently selected from hydroxyl, fluoro, -CH2OH, -C(O)H and –
CH2NHCH3;
• Q is Qa;
• R4 is –C(O)CH2CN, H2OH, -C(O)OCH2CH3, or oxetanyl substituted with
–CH2CN;
or a pharmaceutically able salt, or solvate, or N-oxide, or stereoisomer or
deuterated derivative thereof.
It is particularly preferred that:
a. X represents -O-; or
b. X represents -NR3- and R3 is selected from:
i. a 1-3NR’R’’ group, wherein R’ and R’’ independently represents a
linear or branched C1-3 yalkyl group or a linear or branched C1-3
alkoxy group; or
ii. a ’R’’ group, wherein R’ and R’’ ndently represents a
hydrogen atom, a linear or branched C1-3 alkyl group, a linear or
branched C1-3 hydroxyalkyl group, a linear or branched C1-3 alkoxy
group; or
iii. a CH2-pyrollidine group; or
c. R1 is a linear or branched C1-4 alkoxy group or a -CN group; or
d. R2 is a halogen atom or a -CN group; or
e. G1 is selected from the group ting of –CN group, -CO-Ra group, a –O-R6
group, and a )m-NR’R’’ group; or
f. G1 is selected from a phenyl group, a monocyclic C5-7 cycloalkyl group, a
monocyclic 5- to 6- membered heteroaryl group containing at least one
heteroatom selected from O, S and N and a clic 5- to 6- membered
heterocyclyl group containing at least one heteroatom selected from O, S and
N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are
substituted by one or more substituents selected from a linear or branched C3
hydroxyalkyl group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra
represents a hydroxyl group, a linear or branched C1-3 alkyl group, a linear or
branched C1-3 alkoxy group or an amino group; or
g. Q is Qa and R4 is selected from the group consisting of a cyanothiazole group,
and a monocyclic 5- to 6- membered heteroaryl group containing at least one
heteroatom selected from O, S and N, wherein the heteroaryl group is
unsubstituted or substituted with one or more substituents selected from –
(CH2)m-CN group and a C1-2 hydroxyalkyl group; or
h. Q is Qc and R’ is a linear or branched C1-3 yalkyl group or a linear or
branched C1-3 alkoxy group.
In a preferred embodiment,
• R1 represents a hydrogen atom, a ne atom, a chlorine atom or a methyl
group, for example, a fluorine atom, a en atom or a methyl group,
preferably a fluorine atom;
• R2 represents a hydrogen atom or a fluorine atom, ably a hydrogen atom;
• X ents a –O- or –NR3- group , preferably a –NR3- group;
• R3 represents a en atom;
• Q represents Qa;
• R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; preferably
R4 represents a –C(O)CH2OH group or a -C(O)CH2CN group;
• G1 represents a –O-R6 group, a CN group or a monocyclic 5- to 6-membered
heteroaryl group containing at least one heteroatom selected from O, S and N
and being unsubstituted or substituted by one or more substituents selected
from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a
linear or branched C1-2 hydroxyalkyl group or a linear or branched C1-4 alkoxy
group, preferably G1 represents a –O-R6 group or a monocyclic 5- to 6-
membered heteroaryl group containing at least one heteroatom selected from
O, S and N and being unsubstituted or substituted by one or more substituents
selected from a halogen atom, a linear or branched C1-4 alkyl group or a linear
or branched C1-4 alkoxy group; and
• R6 represents a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group or a linear or
ed C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more substituents selected from a
halogen atom and a hydroxyl group.
In a more preferred embodiment,
• X ents –O- or –NR3- group,
• R1 and R2 are independently selected from the group consisting of a hydrogen
atom, a fluorine atom and a methyl group;
• R3 is selected from the group consisting of a hydrogen atom and a methyl
group;
• G1 is selected from the group consisting of –CN group, a –CONH2 group, a -
CO2Et group, a –CO2iPr group, a –O-R6 group, a CH2OH group, a
phenyl group, a pyridinyl group, a pyrazolyl group, a piperidinyl group, a
piperazinyl group, a morpholinyl group, wherein the phenyl, pyridinyl, pyrazolyl,
piperidinyl, piperazinyl and morpholinyl groups are unsubstituted or substituted
by one or more substituents selected from a hydroxyl group, a methyl group, a -
CH2OH group, a –CH2-C(OH)(CH3)2 group, a methoxy group, an amino group, a
–N(CH3)2 group, a –COOH group and a –CO2Et group;
• R4 is selected from the group consisting of a -CO(CH2)-OH group; 2)-
CN group, a pyrazinyl group and a pyrimidinyl group, n the pyrazinyl and
pyrimidinyl groups independently are unsubstituted or substituted with a CN
group or a –-CH2OH group;
• R5 represents a N group;
• G2 represents a pyrimidine group or a pyridine group, wherein the pyrimidine
and pyridine groups are unsubstituted or substituted by a fluorine atom; and
• R6 is selected from the group consisting of a hydrogen atom, a 2CH2Ph
group, a –(CH2)2OCH3 group, a –(CH2)2OCH2CH3 group, a –CH(CH3)CH2OCH3
group, a methyl group, an ethyl group, a butyl group, a –CH2CF3 group, a –
CH2CHF2 group, a CH(CH3)2 group, a –(CH2)2OH group, a –(CH2)2-3N(CH3)2
group, a -CH(CH3)-CH2OH group, a –CH2CH(OH)CH2OH group.
Particular individual compounds described herein include:
(Trans{[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}cyclohexyl)acetonitrile;
(Trans{[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}cyclohexyl)acetonitrile;
[(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]cyclohexyl}acetonitrile;
({6-[4-(dimethylamino)piperidinyl]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile;
(Trans{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}cyclohexyl)acetonitrile;
{Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]cyclohexyl}acetonitrile;
{Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]cyclohexyl}acetonitrile;
[Trans({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl}amino)cyclohexyl]acetonitrile;
[trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile;
[Trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile;
6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrazolo
[1,5-a]pyridinylpyrimidinamine;
2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]etanol;
(2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]propane-1,2-diol;
3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxopropanenitrile;
3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitril;
3-((3R){[6-(6-Aminopyridinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
){[5-fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
mino}piperidinyl)oxopropanenitrile;
3-((3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-{(3R)[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl](methyl)amino]piperidinyl}oxopropanenitrile;
1-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)piperidinol;
2-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
2-((3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol;
2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
Ethyl luoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)methylpiperidinecarboxylate;
2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin
ylpyrimidinyl]amino}piperidinyl)oxoethanol;
Ethyl [(3R)(cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-
a]pyridinylpyrimidinyl)piperidinecarboxylate;
1-(6-{[(3R)(Cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)piperidinecarboxylic acid;
2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(1H-pyrazolyl)pyrimidin
yl]amino}piperidinyl)oxoethanol;
1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)-1H-pyrazolyl]methylpropanol;
2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol;
2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
Ethyl 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)pyridinecarboxylate;
2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)oxy]propanol;
2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinol;
Benzyl [(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]acetate;
2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
Ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
midinecarboxylate;
-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarbonitrile;
-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarboxamide;
2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidin-
4-yl]amino}piperidinyl)oxoethanol;
2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
]piperidinyl}oxoethanol;
3-{(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxopropanenitrile;
-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrazinecarbonitrile;
(5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}pyrazinyl)methanol;
-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}pyrazinecarbonitrile;
2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrimidinecarbonitrile;
2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
(2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]propanol;
2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
(2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]propanol;
)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxoethanol;
3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxopropanenitrile;
2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]oxy}piperidinyl)oxoethanol;
3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]oxy}piperidinyl)oxopropanenitrile;
2-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxoethanol;
3-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
midinyl]oxy}piperidinyl)oxopropanenitrile;
2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxoethanol;
3-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile;
){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]oxy}piperidinyl)oxoethanol;
3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]oxy}piperidinyl)oxopropanenitrile;
3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile;
2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxoethanol;
1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)piperidinol;
3-((3R){[5-Fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile;
2-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl](methyl)amino]piperidinyl}oxoethanol;
3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile;
-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)pyridinecarboxylic acid;
2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-[(3R)({6-[6-(Dimethylamino)pyridinyl]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
2-{(3R)[(5-Fluoro-2'-methylpyrazolo[1,5-a]pyridinyl-4,5'-bipyrimidin
yl)amino]piperidinyl}oxoethanol;
2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
3-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile;
2-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile;
2-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
3-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
midinyl}amino)piperidinyl]oxopropanenitrile;
(2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)oxy]propanol;
5-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile;
Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinecarboxylate;
2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin
yl}oxoethanol;
3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin
yl}oxopropanenitrile;
){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
5-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrazinecarbonitrile;
-(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin
yl)pyridinol;
3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)(methyl)amino]piperidinyl}oxoethanol; or
a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated
derivative thereof.
Of outstanding interest are:
){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
no}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)oxy]propanol;
2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
ro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarbonitrile;
2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidin-
1-yl}oxoethanol;
3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile;
2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}-
thanol;
3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}-
3-oxopropanenitrile;
2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
5-(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin
yl)pyridinol;
3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile; or
a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer, or deuterated
derivative thereof.
GENERAL TIC PROCEDURES
The 2-(pyrazolopyridinyl)pyrimidine tives of the invention can be prepared
using the methods and procedures described herein, or using similar s and
procedures. It will be appreciated that where typical or preferred process conditions
(i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.)
are given; other process ions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular nts or solvent used, but
such conditions can be determined by one skilled in the art by routine optimization
procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting
groups may be ary to prevent certain functional groups from undergoing
red reactions. The choice of a le protecting group for a particular functional
group, as well as suitable conditions for protection and deprotection, are well known in
the art. For example, us protecting groups, and their introduction and removal
are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic
Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
Processes for ing compounds of the invention are provided as further
embodiments of the invention and are illustrated by the procedures below.
According to one embodiment of the present invention, compounds of general formula
(I) may be prepared by the following synthetic route as illustrated in Scheme 1:
Scheme 1
Treatment of dichloropyrimidines of formula (II) with amines or alcohols of formula (III)
in the presence of a base such as triethylamine or sodium hydrogencarbonate in a
solvent such as ol or ethanol at temperatures ranging from ambient
temperature to reflux gives rise to compounds of formula (IV).
In the particular case where G1 is an aryl or heteroaryl ring, nds of formula (I)
may be obtained from chloropyrimidines of formula (IV) by reaction with compounds of
formula (V), where Y is a boronic acid or a boronate ester, under Suzuki-Miyaura
reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457). Such
reactions may be catalysed by a suitable ium catalyst such as [1,1'-
phenylphosphino)ferrocene]palladium(II) dichloride romethane complex or
tetrakis(triphenylphosphine)palladium(0) in a solvent such as e, 1,4-dioxane or
1,2-dimethoxyethane in the presence of a base such as cesium carbonate or sodium
carbonate at temperatures ranging from 80 ºC to 110 ºC with or without the use of
microwave irradiation.
Boronic acids or boronates of formula (V) where G1 is an aryl or heteroaryl ring and Y is
a boronic acid or te ester may be commercially available or may be prepared
from the corresponding haloderivatives of formula (V), where Y is a bromine atom or a
chlorine atom, by treatment with an riate boron reagent such as
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) with a palladium catalyst such
as bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex
or bis(dibenzylideneacetone)palladium(0), in a solvent such as 1,4-dioxane or 1,2-
dimethoxyethane, with or without the presence of a ligand such as
lohexylphosphine, in the presence of a base such as potassium acetate at
temperatures g from 80-150 ºC with or without the use of microwave irradiation.
In another particular case where G1 is an heterocyclyl group attached to the pyrimidine
ring through a nitrogen atom, a –CN group, a (CHR7)m-NR’R’’, or a –O-R6 group,
compounds of formula (I) may be prepared by reaction of chloroderivatives of formula
(IV) with heterocyclic or linear amines, alcohols or cyanides of formula (V), where Y is
an hydrogen or metal atom, in the presence of a base such as sodium
hydrogencarbonate or N-ethyl-N-isopropylpropanamine without the use of a solvent
or in a t such as N,N’-dimethylacetamide or 1-methylpyrrolidinone at
temperatures ranging from 80-130 ºC with or without the use of microwave irradiation.
Compounds of a (II) may be prepared as illustrated in Scheme 2:
Scheme 2
Reaction of ethyl propiolate with N-aminopyridinium salts of formula (VII) in the
presence of a base, for example ium carbonate, in a solvent such as N,N’-
dimethylformamide at temperatures ranging from 0 ºC to ambient temperature,
furnishes esters of a (VIII). N-Aminopyridinium salts of formula (VII) may be
commercially available or may be prepared by reaction of the corresponding pyridines
of formula (VI) with O-(mesitylsulfonyl)hydroxylamine in a suitable t such as
dichloromethane at temperatures ranging from 0 ºC to ambient temperature. Treatment
of esters of formula (VIII) with a mixture of trimethylaluminum and ammonium chloride
in a solvent such as toluene at 80 ºC provides amidine intermediates of formula (IX).
Amidines of formula (IX) may be reacted with malonate esters of formula (X) to give
dihydroxypirimidines of formula (XI). Such reactions may be carried out in the presence
of a suitable base such as sodium ide in a t such as methanol at
temperatures ranging from 0 ºC to ambient temperature. Dihydroxypirimidines of
formula (XI) may be converted to dichloropyrimidines of formula (II) by treatment with a
suitable chlorinating agent, for example phosphorus(V) oxychloride, at temperatures
ranging from 25 ºC to reflux.
In the particular case where G1 is an aryl or heteroaryl ring, compounds of l
formula (I) may also be prepared by an alternative synthetic approach as shown in
Scheme 3:
Scheme 3
Treatment of trichloropyrimidines of formula (XII) with amines of formula (III) in the
presence of a base such as triethylamine or sodium hydrogencarbonate in a solvent
such as ethanol at -20 ºC gives rise to compounds of formula (XIII).
In the particular case where G1 is an aryl or aryl ring, compounds of formula
(XIV) may be ed from dichloropyrimidines of formula (XIII) by reaction with
nds of formula (V), where Y is a boronic acid or a boronate ester, under
-Miyaura reaction conditions. Such reactions may be catalysed by a suitable
palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such
as 1,2-dimethoxyethane in the presence of a base such as sodium carbonate at 80 ºC.
Reaction of chloropyrimidines of formula (XIV) with stannanes of formula (XV) in the
presence of a palladium catalyst such as tetrakis (triphenylphosphine)palladium(0) in a
solvent such as 1,4-dioxane at 100 ºC es compounds of formula (I).
In yet another particular case, compounds of formula (I), in which the residue at G1, or
Q contains an alcohol, phenol or carboxylic acid moiety functionalized with an
riate protecting group such as benzyl (Bn) or methoxy (OMe), may be
deprotected at the alcohol, phenol or carboxylic acid moiety under standard ions
e's Protective Groups in Organic sis, ISBN: 0471697540). In the
particular case of primary alcohols, the free alcohol moiety may then be oxidized under
standard conditions to give the corresponding aldehyde.
In yet r particular case, compounds of formula (I), in which the residue at G1, or
Q contains an amine moiety functionalized with an appropriate protecting group such
as tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), may be deprotected at the
amine moiety under standard conditions (Greene's Protective Groups in Organic
Synthesis, ISBN: 0471697540). The corresponding free amine may then be further
functionalized under standard conditions to give the corresponding amides,
carbamates and N-alkylated and N-arylated amines.
Starting nds are commercially available or may be obtained following the
conventional synthetic methods y known in the art.
The synthesis of the compounds of the invention and of the intermediates for use
therein are illustrated by the following Examples (1-63) (including Preparations 1-8) and
are given in order to provide a person skilled in the art with a sufficiently clear and
complete explanation of the present invention, but should not be considered as limiting
of the essential aspects of its subject, as set out in the preceding portions of this
description.
PREPARATIONS
PREPARATION 1
Pyrazolo[1,5-a]pyridinecarboximidamide
a) Ethyl pyrazolo[1,5-a]pyridinecarboxylate
ium carbonate (6.10 g, 44.14 mmol) was added to a stirred solution of 1-
aminopyridinium iodide (6.57 g, 29.59 mmol) in anhydrous N,N-dimethylformamide (44
mL) at 0 °C. Ethyl propiolate (3 mL, 29.7 mmol) was then added se and the
resulting mixture was stirred overnight at room temperature. The on mixture was
ioned between water and chloroform. The c phase was separated, washed
with water and brine, dried over sodium sulfate and the solvent was evaporated to
dryness to yield the title compound (5.51 g, 96%) as a red oil.
LRMS (m/z): 191 (M+1)+.
b) lo[1,5-a]pyridinecarboximidamide
A 2.0 M solution of trimethylaluminum in toluene (58.9 mL, 118.29 mmol) was added
se to a stirred suspension of ammonium de (5.90 g, 118.29 mmol) in
toluene (100 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 1
hour. A solution of ethyl pyrazolo[1,5-a]pyridinecarboxylate (Preparation 1a, 7.50 g,
39.43 mmol) in toluene (20 mL) was then added and the resulting mixture was stirred
overnight at 80 ºC. Additional 2.0 M solution of trimethylaluminum in toluene (58.9 mL,
118.29 mmol) and ammonium chloride (5.90 g, 118.29 mmol) in toluene (100 mL) were
added and the reaction e was stirred at 80 ºC for further 24h. After cooling to 0
ºC in an ice bath, methanol (40 mL) was added dropwise. The solid formed was filtered
and washed with methanol and the filtrate was evaporated to dryness. Purification of
the e by flash chromatography (dichloromethane to 7:3 dichloromethane/ethanol)
gave the title compound (4.72 g, 74%) as a yellow solid.
LRMS (m/z): 161 (M+1)+.
c) 5-Fluoropyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol
Pyrazolo[1,5-a]pyridinecarboximidamide (Preparation 1b, 4.75 g, 29.47 mmol) was
added nwise to a stirred solution of sodium (1.63 g, 71.02 mmol) in methanol
(120 mL) at 0 °C. l 2-fluoromalonate (7.0 mL, 44.20 mmol) was then added and
the reaction mixture was stirred from 0 ºC to room temperature overnight. The solvent
was evaporated to dryness to yield the title compound (7.25 g, 99%) as a solid that was
used in the next synthetic step without further purification.
LRMS (m/z): 247 (M+1) +.
1H-NMR (300 MHz, DMSO-d
6): 7.23 (t, 1H), 7.50 - 7.73 (m, 1H), 8.71 (d, 1H),
8.85 - 8.94 (m, 2H), 11.83 (bs, 1H), 12.70 (br.s., 1H).
d) 3-(4,6-Dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine
A mixture of ropyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol (Preparation 1c,
7.00 g, 28.43 mmol) and phosphorus(V) oxychloride (55 mL, 589 mmol) was d at
110 ºC for 24 hours. The solvent was then removed under reduced pressure and the
residue was partitioned between dichloromethane and water. The organic layer was
separated, washed with brine, dried over magnesium e and the solvent was
evaporated in vacuo. The crude product was purified by flash chromatography
(hexanes to dichloromethane) to yield the title compound (5.3 g, 65%) as a yellow
solid.
LRMS (m/z): 283 (M+1) +.
1H -NMR (300 MHz, CDCl
3): 7.00 (td, 1H), 7.44 (ddd, 1H), 8.62 (ddt, 2H), 8.74
(s, 1H).
PREPARATION 2
{Trans[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]
cyclohexyl}acetonitrile
A mixture of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation
1d, 0.30 g, 1.06 mmol), (transaminocyclohexyl)acetonitrile hydrochloride* (0.22 g,
1.27 mmol) and sodium hydrogencarbonate (0.39 g, 4.63 mmol) in ethanol (6 mL) was
heated at reflux overnight. The solvent was evaporated and the residue was partitioned
n water and ethyl acetate. The aqueous layer was extracted with ethyl acetate,
the combined organic layers were washed with brine, dried over magnesium e
and the solvent was evaporated in vacuo. The resulting crude was purified by flash
chromatography (gradient from hexanes to ethyl acetate) to yield the title compound
(0.30 g, 72%) as a solid.
*Prepared following the experimental procedure described in WO2011157397,
Preparation 50.
LRMS (m/z): 385 (M+1)+.
PREPARATION 3
(S)Chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl)(pyrazolo[1,5-a]pyridin
yl)pyrimidinamine
A mixture of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation
1d, 1.00 g, 3.53 mmol), (1S)(5-fluoropyridinyl)ethanamine dihydrochloride (0.85 g,
6.06 mmol) and sodium hydrogencarbonate (1.40 g, 16.66 mmol) in ethanol (20 mL)
was heated at reflux overnight. The t was evaporated and the residue was
crystallized from methanol to yield the title compound (1.25 g, 82%) as a solid.
LRMS (m/z): 387 (M+1)+.
PREPARATION 4
6-Chlorofluoro-N-[(1S)(5-fluoropyrimidinyl)ethyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinamine
ed as a solid (70%) from 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-
a]pyridine (Preparation 1d) and (1S)(5-fluoropyrimidinyl)ethanamine following the
experimental procedure as described in Preparation 3, followed by purification of the
crude product by flash chromatography ent from dichloromethane to
dichloromethane/methanol 95:5).
LRMS (m/z): 388 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.72 (d, 3H), 5.63 (m, 1H), 6.32 (m, 1H), 6.94 (t,
1H), 7.43 (m, 1H), 8.52 (m, 2H), 8.64 (d, 2H).
PREPARATION 5
Tert-butyl -[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinecarboxylate
rt-butyl 3-aminopiperidinecarboxylate (2.97 g, 14.83 mmol) was added to a
solution of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation
1d, 3.50 g, 12.36 mmol) and triethylamine (2.0 mL, 15.08 mmol) in ethanol (80 mL) and
the resulting mixture was stirred at 80 ºC for 48 hours. After cooling to room
temperature, the solvent was evaporated under reduced pressure and water was
added. The precipitate was filtered and dried in vacuo to give the title compound (5.60
g, 100%) as a white solid.
LRMS (m/z): 447 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.6 (s, 9H), 1.7 - 1.9 (m, 3H), 2.0 - 2.1 (m, 1H),
3.5 (bs, 4H), 4.3 (d, 1H), 5.2 (s, 1H), 6.9 (t, 1H), 7.3 - 7.4 (m, 1H), 8.5 (t, 2H),
8.3 (s, 1H).
PREPARATION 6
3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]
piperidinyl}oxopropanenitrile
a) 6-Chlorofluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin-
4-amine
4.0 M Hydrogen chloride solution in oxane (31.4 mL, 125.6 mmol) was added to a
on of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate (Preparation 5, 5.61 g, 12.55 mmol) in oxane
(150 mL) and the resulting mixture was stirred overnight at room temperature. The
precipitate formed was filtered and washed with 1,4-dioxane and diethyl ether and
dried in vacuo to give the hydrochloride salt of the title compound (5.50 g, 100%) as a
white solid.
LRMS (m/z): 347 .
1H-NMR (300 MHz, CD
3OD): 1.73 - 2.24 (m, 5H), 2.93 - 3.15 (m, 2H), 3.43 (t,
1H), 3.61 - 3.73 (m, 1H), 4.44 - 4.75 (m, 1H), 7.10 (td, 1H), 7.50 (ddd, 1H), 8.53
(d, 1H), 8.61 (dd, 2H).
b) 3-{(3R)[(6-Chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]
piperidinyl}oxopropanenitrile
-Dioxopyrrolidinyl)oxy]oxopropanenitrile (prepared as described in
BE875054(A1), 3.58 g, 19.66 mmol) was added to a solution of 6-chlorofluoro-N-
[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl-pyrimidinamine (Preparation 6a,
.5 g, 13.10 mmol) and triethylamine (9.1 mL, 65.7 mmol) in dichloromethane (10 mL).
The resulting mixture was stirred overnight at room temperature. Additional 3-[(2,5-
dioxopyrrolidinyl)oxy]oxopropanenitrile (0.80 g, 4.39 mmol) was added and the
reaction mixture was d at room temperature for further 5 hours. The resulting
mixture was partitioned between water and ethyl acetate, the organic layer was
separated and the aqueous phase was extracted twice with ethyl acetate. The
combined organic layers were washed with water, brine, dried over magnesium sulfate
and concentrated in vacuo. The resulting crude was purified by flash chromatography
(gradient from hexanes to ethyl acetate) to yield the title compound (0.37 g, 80%) as a
white solid.
LRMS (m/z): 414 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.71 - 2.02 (m, 4H), 2.20 (t, 1H), 3.34 - 3.51 (m,
2H), 3.62 - 3.71 (m, 1H), 3.92 (dd, 1H), 4.30 (bs, 1H), 4.60 (d, 1H), 5.03 (d, 1H),
6.91 (dt, 1H), 7.39 (ddd, 1H), 8.40 - 8.61 (m, 2H), 8.7 (s, 1H).
PREPARATION 7
(R)(3-((6-Chlorofluoro(pyrazolo[1,5-a]pyridinyl)pyrimidinyl)amino)
piperidinyl)hydroxyethanone
A e of 6-chlorofluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl
dinamine (Preparation 6a, 0.46 g, 1.10 mmol), 2-hydroxyacetic acid (0.10 g,
1.10 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
oxide hexafluorophosphate (0.54 g, 1.42 mmol) and triethylamine (0.53 mL, 3.82 mmol)
in methylformamide (2 mL) was d at room temperature for 18 hours. The
resulting mixture was partitioned between water and ethyl acetate, the organic layer
was separated and the aqueous phase was extracted twice with ethyl e. The
combined organic layers were washed with water, brine, dried over ium sulfate
and concentrated in vacuo. The resulting crude was purified by flash chromatography
(gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title
compound (0.37 g, 80%) as a white solid.
LRMS (m/z): 405 (M+1)+.
PREPARATION 8
Tert-butyl(3R)[(6-chloromethylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino] piperidinecarboxylate
a) 5-Methyl(pyrazolo[1,5-a]pyridinyl)pyrimidine-4,6-diol
Pyrazolo[1,5-a]pyridinecarboximidamide (Preparation 1b, 2.89 g, 18.05 mmol) and
diethyl methylmalonate (6.44 mL, 37.45 mmol) were added nwise to a solution of
sodium (1.24 g, 53.91 mmol) in methanol (14 mL) at 0 ºC and the resulting suspension
was stirred at room ature ght. The solvent was evaporated to dryness and
the residue was dissolved in water and acidified to pH=1 using a 6N hydrochloric acid
solution. The precipitate was filtered, washed with water and dried under vacuum to
yield the title compound (3.54 g, 81%) as a yellow solid.
LRMS (m/z): 243 (M+1)+.
1H-NMR (400 MHz, DMSO-d6): 1.79 (s, 3H), 7.10 - 7.14 (t, 1H), 7.52 - 7.56 (dd,
1H), 8.73 - 8.75 (d, 1H), 8.81 - 8.83 (d, 1H), 8.91 (s, 1H).
b) 3-(4,6-Dichloromethylpyrimidinyl)pyrazolo[1,5-a]pyridine
Obtained as a solid (30%) from yl(pyrazolo[1,5-a]pyridinyl)pyrimidine-4,6-
diol (Preparation 8a) and phosphorus(V) oxychloride following the experimental
procedure as described in Preparation 1b followed by purification of the crude product
by flash chromatography (hexanes/ ethyl acetate 1:4).
LRMS (m/z): 279 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 2.47 (s, 3H), 6.93 - 6.97 (t, 1H), 7.39 - 7.44 (dd, 1H),
8.53 - 8.56 (m, 1H), 8.71 (s, 1H).
c) (R)-Tert-butyl 3-((6-chloromethyl(pyrazolo[1,5-a]pyridinyl)pyrimidin
yl)amino)piperidinecarboxylate
A mixture of 3-(4,6-dichloromethylpyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation
8b, 1.11 g, 3.98 mmol), (R)-tert-butyl 3-aminopiperidinecarboxylate (0.93 g, 4.65
mmol) and diisopropylethylamine (1.04 mL, 5.97 mmol) in ethanol (12 mL) was stirred
68 hours at 80 ºC. N,N’-dimethylacetamide (9 mL) was then added and the reaction
mixture was stirred at 100 ºC for r 68 hours. Ethanol was evaporated and excess
of water was added. The precipitate was filtered, washed with water and dried to give
the title compound (1.49 g, 85%).
LRMS (m/z): 443 (M+1)+.
PREPARATION 9
Tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin
]piperidinecarboxylate
To a on of tert-butyl (3R)hydroxypiperidinecarboxylate (853 mg, 4.24 mmol)
in dioxane (50 mL) was added potassium tert-butoxide (476 mg, 4.24 mmol). The
mixture was stirred at room temperature for 15 minutes and then 3-(4,6-dichloro
fluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 1d, 1.00 g, 2.53 mmol) was
added. The mixture was stirred at room temperature for 3 hours and then at 50 ºC for 1
hour and then the t was removed. The residue was partitioned between water
and ethyl acetate. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were washed with water and
brine, dried over magnesium e and evaporated to dryness. The resulting crude
was purified by flash chromatography ent from hexane to 30% hexane/ethyl
acetate ) to yield the title compound (1.40 g, 89%) as a pale solid.
LRMS (m/z): 448 (M+1)+.
PREPARATION 10
Tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
a) 2-Pyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol
To an ice-bath cooled solution of sodium methoxide (prepared from 0.77 g of metal
sodium in 30 mL methanol were added pyrazolo[1,5-a]pyridinecarboximidamide
chlorohydrate (Preparation 1b, 1.68 g, 8.54 mmol) and diethyl malonate (3.16 mL, 20.8
mmol). The mixture was stirred at room ature overnight. Excess sodium
meythoxyde (0.200 g of sodium in 10 mL of ol) and diethyl te (1 mL,
9.75 mmol) were added and the e was stirred for an additional 24 hours. The
solvent was removed under reduced pressure and the residue was redissolved in water
(50 mL). After stirring for 30 minutes the solution was using a 2N hydrochloric acid
solution. The precipitate was filtered, washed with water and dried under vacuum to
yield the title compound (993 mg, 51%) as a pale solid.
LRMS (m/z): 229 (M+1)+.
b) 3-(4,6-Dichloropyrimidinyl)pyrazolo[1,5-a]pyridine
Obtained as a solid (69%) from 2-pyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol
(Preparation 10a) and orus(V) oxychloride following the experimental procedure
as described in Preparation 1d.
LRMS (m/z): 265 (M+1)+.
c) utyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
Tert-butyl (3R)aminopiperidinecarboxylate (716 mg, 3.58 mmol) was added to a
solution of 3-(4,6-dichloropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 10b, 790
mg, 2.98 mmol) and triethylamine (623 µL, 4.46 mmol) in ethanol (20 mL) and the
resulting mixture was stirred at reflux temperature for 64 hours. After g to room
temperature, the solvent was evaporated under d pressure. The residue was
redissolved in ethyl acetate and the solution was washed with water and brine, dried
over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude was
purified by flash chromatography (gradient from chloroform to 5% chloroform/methanol)
to yield the title compound (1.22 g, 95%) as a white solid.
LRMS (m/z): 430 (M+1)+.
EXAMPLE 1
(Trans{[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}cyclohexyl)acetonitrile
A suspension of {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin
no]cyclohexyl}acetonitrile (Preparation 2, 0.060 g, 0.16 mmol) and piperidinol
(0.063 g, 0.62 mmol) in N,N’-dimethylacetamide (0.3 mL) was stirred at 100 ºC for 3
hours. The reaction mixture was cooled to room temperature, poured into water and
extracted with ethyl acetate. The combined c layers were washed with water,
brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified
by flash tography (gradient from dichloromethane to dichloromethane /methanol
95:5) to yield the title compound (0.045 mg, 64%) as a yellow solid.
LRMS (m/z): 450 (M+1)+.
1H-NMR (300 MHz, DMSO-d
6): 1.18 - 1.50 (m, 6H), 1.57 - 1.72 (m, 1H), 1.78 -
1.93 (m, 4H), 1.97 - 2.09 (m, 2H), 3.11 - 3.28 (m, 2H), 3.62 - 3.78 (m, 1H), 3.86
- 3.98 (m, 1H), 3.98 - 4.15 (m, 2H), 4.72 (d, 1H), 6.64 - 6.74 (m, 1H), 6.94 - 7.06
(m, 1H), 7.36 - 7.47 (m, 1H), 8.40 (d, 1H), 8.46 (s, 1H), 8.75 (d, 1H).
EXAMPLE 2
(Trans{[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}cyclohexyl)acetonitrile
a)Tert-butyl[1-(6-{[trans(cyanomethyl)cyclohexyl]amino}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)piperidinyl]carbamate
A mixture of (S)chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl)(pyrazolo[1,5-
a]pyridinyl)pyrimidinamine (Preparation 2, 0.080 g, 0.21 mmol), tert-butyl
piperidinylcarbamate (0.060 g, 0.30 mmol) and sodium hydrogencarbonate (0.070 g,
0.83 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred overnight at 100 ºC. After
cooling to room temperature, water was added and the solid formed was ed and
dried in vacuo to yield the title compound (0.095 g, 79%).
LRMS (m/z): 551 (M+1)+.
b) {[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}cyclohexyl)acetonitrile
4.0 M Solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.60 mmol) was added to a
solution of tert-butyl [1-(6-{[trans(cyanomethyl)cyclohexyl]amino}fluoro
lo[1,5-a]pyridinylpyrimidinyl)piperidinyl]carbamate (Example 2a, 0.095 g,
0.17 mmol) and the resulting mixture was stirred at room temperature for 5 hours. The
solvent was evaporated to dryness and the residue was diluted with water. The pH was
adjusted to 9 by addition of 2N aqueous sodium hydroxide solution, extracted with
romethane (x3), the combined c layers were washed with brine, dried and
the solvent was evaporated to dryness. The resulting crude was purified by flash
chromatography (gradient from romethane to dichloromethane
/methanol/ammonia 100:8:1) to yield the title compound (0.029 g, 37%) as a beige
solid.
LRMS (m/z): 449 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.20 - 1.53 (m, 6H), 1.70 - 1.85 (m, 1H), 1.87 -
2.07 (m, 4H), 2.25 - 2.41 (m, 4H), 2.88 - 3.13 (m, 3H), 3.92 - 4.16 (m, 1H), 4.32
- 4.46 (m, 2H), 4.52 (dd, 1H), 6.79 - 6.87 (m, 1H), 7.22 - 7.32 (m, 1H), 8.40 -
8.52 (m, 2H), 8.55 (s, 1H).
EXAMPLE 3
{Trans[(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]cyclohexyl}acetonitrile
a)Tert-butyl4-(6-{[trans(cyanomethyl)cyclohexyl]amino}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)piperazinecarboxylate
Obtained as a solid (60%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and tert-butyl piperazine-
1-carboxylate following the mental procedure as described in Example 2a.
LRMS (m/z): 535 (M+1)+.
b){Trans[(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
cyclohexyl}acetonitrile
Obtained as a solid (47%) from tert-butyl 4-(6-{[trans(cyanomethyl)cyclohexyl]
amino}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)piperazinecarboxylate
(Example 3a) following the experimental ure as described in Example 2b.
LRMS (m/z): 435 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.17 - 1.49 (m, 5H), 1.92 - 2.08 (m, 2H), 2.25 -
2.39 (m, 4H), 2.94 - 3.11 (m, 4H), 3.65 - 3.77 (m, 4H), 3.95 - 4.12 (m, 1H), 4.53
(dd, 1H), 6.77 - 6.88 (m, 1H), 7.22 - 7.31 (m, 1H), 8.40 - 8.51 (m, 2H), 8.54 (s,
1H).
EXAMPLE 4
[Trans({6-[4-(dimethylamino)piperidinyl]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile
Obtained as a solid (33%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinyl
dinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and N,N-dimethyl piperidin-
4-amine following the experimental procedure as described in Example 2a followed by
purification of the crude product by flash chromatography (gradient from
dichloromethane to dichloromethane/methanol/ammonia 100:8:1).
LRMS (m/z): 477 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.17 - 1.46 (m, 4H), 1.60 - 1.81 (m, 2H), 1.90 -
2.09 (m, 4H), 2.27 - 2.40 (m, 4H), 2.34 (s, 6H), 2.40 - 2.54 (m, 1H), 2.96 (t, 2H),
3.95 - 4.19 (m, 1H), 4.53 (d, 3H), 6.75 - 6.90 (m, 1H), 7.23 - 7.33 (m, 1H), 8.41 -
8.52 (m, 2H), 8.55 (s, 1H).
EXAMPLE 5
{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}cyclohexyl)acetonitrile
Ethylene glycol (0.32 mL, 5.83 mmol) was added to a suspension of potassium tert-
de (0.043 g, 0.38 mmol) in 1,4-dioxane (0.5 mL) and the resulting mixture was
stirred at room temperature for 15 minutes. {Trans[(6-chlorofluoropyrazolo[1,5-
a]pyridinyl pyrimidinyl)amino]cyclohexyl}acetonitrile ration 2, 0.050 g, 0.13
mmol) was then added and the on e was stirred at 90 ºC overnight. After
cooling to room temperature, the reaction mixture was partitioned between water and
ethyl acetate. The organic layer was separated and the aqueous layer was extracted
with ethyl acetate. The combined c layers were washed with brine, dried over
magnesium e and evaporated to dryness. The resulting crude was purified by
flash chromatography (gradient from dichloromethane to dichloromethane/methanol
95:5) to yield the title compound (0.035 g, 65%) as a solid.
LRMS (m/z): 411 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.20 - 1.50 (m, 4H), 1.69 - 1.89 (m, 1H), 1.97 -
2.09 (m, 2H), 2.26 - 2.42 (m, 4H), 3.11 - 3.29 (m, 1H), 3.98 - 4.14 (m, 3H), 4.64
- 4.81 (m, 3H), 6.84 - 6.92 (m, 1H), 7.29 - 7.38 (m, 1H), 8.35 - 8.54 (m, 2H),
8.55 (s, 1H).
EXAMPLE 6
{Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]cyclohexyl}acetonitrile
ns[(6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclohexyl}acetonitrile
Obtained as a solid (51%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinyl
pyrimidinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and [(4R)-2,2-dimethyl-1,3-
dioxolanyl]methanol following the experimental procedure as described in Example
5.
LRMS (m/z): 481 (M+1)+.
b) {Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)amino]cyclohexyl}acetonitrile
To a solution of {trans[(6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro
pyrazolo [1,5-a]pyridinylpyrimidinyl)amino]cyclohexyl}acetonitrile (Example 6a,
0.051 g, 0.11 mmol) in tetrahydrofurane (1 mL), 1M hydrochloric acid solution (1 mL, 1
mmol) and the resulting solution was d at room temperature for 3 hours. The
solvent was evaporated to dryness, the pH of the resulting solution was adjusted to 8
by addition of saturated aqueous solution of sodium hydrogencarbonate, extracted with
ethyl acetate (x3), the combined organic layers were washed with brine, dried and the
t was evaporated in vacuo to yield the title compound (0.036 g, 76%) as a yellow
solid.
LRMS (m/z): 441 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.43 (m, 3H), 1.80 (m, 1H), 2.05 (m, 2H), 2.42 (m,
4H), 3.80 (m, 2H), 4.12 (m, 2H), 4.73 (d, 2H), 4.82 (d, 1H), 6.91 (m, 1H), 7.40
(dd, 1H), 8.44 (d, 1H), 8.55 (m, 2H).
EXAMPLE 7
{Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]cyclohexyl}acetonitrile
a){Trans[(6-{[(4S)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro
pyrazolo[1,5-a] pyridinylpyrimidinyl)amino]cyclohexyl}acetonitrile
Obtained as a solid (71%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinyl
pyrimidinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and 2,2-dimethyl-1,3-
anyl]methanol following the experimental procedure as described in Example
LRMS (m/z): 481 (M+1)+.
b){Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin-
3-yl pyrimidinyl)amino]cyclohexyl}acetonitrile
Obtained as a light yellow solid (70%) from {trans[(6-{[(4S)-2,2-dimethyl-1,3-
dioxolanyl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]cyclohexyl}acetonitrile (Example 7a) following the experimental procedure as
described in Example 6b.
LRMS (m/z): 441 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.35 (m, 4H), 1.78 (m, 1H), 2.02 (m, 2H), 2.31 (m,
2H), 2.36 (d, 2H), 2.48 (t, 1H), 3.75 (m, 3H), 4.07 (m, 2H), 4.63 (d, 2H), 4.75 (d,
1H), 6.87 (m, 1H), 7.33 (m, 1H), 8.41 (d, 1H), 8.51 (m, 2H).
EXAMPLE 8
[Trans({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile
ed as a light yellow solid (41%) from {trans[(6-{[(4R)-2,2-dimethyl-1,3-
dioxolanyl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclo
hexyl}acetonitrile (Preparation 2) and 2-aminoethanol following the experimental
procedure as described in Example 2a followed by purification of the crude product by
flash chromatography (gradient from dichloromethane to dichloromethane/methanol
95:5).
LRMS (m/z): 410 .
1H-NMR (300 MHz, CDCl3): 1.16 - 1.51 (m, 4H), 1.72 - 1.88 (m, 1H), 1.96 -
2.12 (m, 2H), 2.25 - 2.44 (m, 4H), 3.66 - 3.83 (m, 2H), 3.86 - 3.95 (m, 2H), 3.99
- 4.13 (m, 1H), 4.26 (br. s., 1H), 4.48 (d, 1H), 5.03 (br. s., 1H), 6.86 (t, 1H), 7.33
(d, 1H), 8.41 - 8.54 (m, 2H), 8.56 (s, 1H).
EXAMPLE 9
[trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile
Obtained as a light yellow solid (56%) from {trans[(6-{[(4R)-2,2-dimethyl-1,3-
dioxolanyl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclo
hexyl}acetonitrile (Preparation 2) and 2-(dimethylamino)ethanol ing the
experimental procedure as described in Example 5 followed by purification of the crude
product by flash chromatography (gradient from dichloromethane to
dichloromethane/methanol 95:5).
LRMS (m/z): 438 (M+1)+.
1H-NMR (300 MHz, : 1.16 - 1.52 (m, 3H), 1.62 - 1.86 (m, 5H), 1.94 -
2.13 (m, 2H), 2.23 - 2.50 (m, 7H), 2.87 (t, 2H), 3.80 - 4.21 (m, 1H), 4.66 (t, 2H),
6.81 - 6.96 (m, 1H), 7.26 - 7.39 (m, 2H), 8.43 - 8.65 (m, 2H).
EXAMPLE 10
[Trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile
ed as a white solid (42%) from {trans[(6-{[(4R)-2,2-dimethyl-1,3-dioxolan
yl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclohexyl}
acetonitrile (Preparation 2) and 3-(dimethylamino)propanol following the
experimental procedure as described in Example 5 followed by purification of the crude
product by flash tography ent from dichloromethane to
dichloromethane/methanol 95:5).
LRMS (m/z): 453 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.05 - 1.45 (m, 4H), 1.50 - 1.83 (m, 7H), 1.89 -
2.10 (m, 3H), 2.25 (s, 5H), 2.38 - 2.55 (m, 2H), 3.86 - 4.16 (m, 1H), 4.31 - 4.70
(m, 2H), 6.68 - 6.93 (m, 1H), 7.07 - 7.39 (m, 2H), 8.08 - 8.72 (m, 2H).
E 11
6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrazolo
[1,5-a]pyridinylpyrimidinamine
a)Tert-butyl[1-(5-fluoro{[(1S)(5-fluoropyridinyl)ethyl]amino}
pyrazolo[1,5-a] pyridineylpyrimidinyl)piperidinyl]carbamate
Obtained as a solid (60%) from (S)chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl)
(pyrazolo[1,5-a]pyridinyl)pyrimidinamine (Preparation 4) and tert-butyl piperidin
ylcarbamate ing the experimental procedure as described in Example 2a followed
by purification of the crude product by flash chromatography (gradient from
dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 551 (M+1)+.
b) 6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl]
pyrazolo [1,5-a]pyridinylpyrimidinamine
Obtained as a solid (68%) from utyl fluoro{[(1S)(5-fluoropyridinyl)
ethyl]amino}pyrazolo[1,5-a]pyridinylpyrimidinyl)piperidinyl]carbamate
(Example 11a) following the experimental procedure as described in Example 2b.
LRMS (m/z): 451 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.33 - 1.54 (m, 3H), 1.65 (s, 3H), 1.85 - 2.10 (m,
3H), 2.88 - 3.26 (m, 3H), 4.41 (d, 2H), 5.36 - 5.51 (m, 1H), 5.60 (d, 1H), 6.81 (t,
1H), 7.17 - 7.26 (m, 1H), 7.31 - 7.47 (m, 2H), 8.28 (d, 1H), 8.43 - 8.55 (m, 2H).
EXAMPLE 12
2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]ethanol
Obtained as a solid (26%) from 6-chlorofluoro-N-[(1S)(5-fluoropyrimidin
yl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Preparation 5) and ethylene
glycol following the experimental procedure as described in Example 5.
LRMS (m/z): 414 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.72 (d, 3H), 3.08 - 3.37 (m, 1H), 4.04 (d, 2H),
4.55 - 4.79 (m, 2H), 5.50 - 5.73 (m, 1H), 6.01 (d, 1H), 6.79 - 6.97 (m, 1H), 7.28 -
7.43 (m, 1H), 8.38 - 8.68 (m, 5H).
EXAMPLE 13
(2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]propane-1,2-diol
a)6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro-N-[(1S)(5-
fluoropyrimidinyl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidinamine
Obtained as a solid (77%) from 6-chlorofluoro-N-[(1S)(5-fluoropyrimidin
yl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Preparation 5) and ,2-
dimethyl-1,3-dioxolanyl)methanol following the experimental procedure as bed
in Example 5.
LRMS (m/z): 484 (M+1)+.
b)(2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]propane-1,2-diol
ed as a white solid (12%) from 6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}-
5-fluoro-N-[(1S)(5-fluoropyrimidinyl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidin
amine (Example 13a) following the experimental procedure as described in Example
LRMS (m/z): 444 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.72 (d, 3H), 3.56 - 3.92 (m, 2H), 4.15 (br. s., 1H),
4.65 (d, 2H), 5.49 - 5.77 (m, 1H), 6.00 - 6.26 (m, 1H), 6.88 (t, 1H), 7.35 (t, 1H),
8.26 - 8.77 (m, 5H).
EXAMPLE 14
3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
a)Tert-butyl(3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained as an orange solid (76%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinecarboxylate (Preparation
) and ethylene glycol following the experimental procedure as described in Example 5.
LRMS (m/z): 473 (M+1)+.
b)2-({5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl} oxy)ethanol
To a solution of tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-
a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 14a, 0.16 g, 0.34
mmol) in 1,4-dioxane (1 mL), 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.30
mL, 5.2 mmol) was added. The resulting mixture was stirred at room temperature for 5
hours and ated in vacuo to yield the ochloride salt of the title compound
(0.15 g, 93%) as a yellow solid.
LRMS (m/z): 373 (M+1)+.
c) 3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxopropanenitrile
Obtained as a light yellow solid (38%) from fluoro[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)ethanol (Example 15b) following the
experimental procedure as described in Preparation 7. The crude was ed by flash
tography (gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 440 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.71 - 2.08 (m, 3H), 2.15 - 2.32 (m, 1H), 2.67 -
2.85 (m, 1H), 2.97 - 3.15 (m, 1H), 3.26 - 3.52 (m, 3H), 3.55 - 3.74 (m, 2H), 3.78
- 3.99 (m, 1H), 4.00 - 4.13 (m, 1H), 4.19 - 4.36 (m, 2H), 4.59 - 4.73 (m, 3H),
4.76 - 4.91 (m, 1H), 6.80 - 7.01 (m, 1H), 7.33 - 7.48 (m, 1H), 8.29 - 8.66 (m,
3H).
EXAMPLE 15
3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxopropanenitrile
a)Tert-butyl(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino] piperidinecarboxylate
Metal sodium (0.058 g, 2.52 mmol) was added to butanol (7 mL) and the mixture
was stirred at room temperature until metal sodium was consumed. Tert-butyl (3R)
[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine
carboxylate (Preparation 5, 0.25 g, 0.56 mmol) was added, the reaction mixture was
stirred overnight at 90 ºC, then cooled to room ature and partitioned between
water and ethyl acetate. The organic layer was separated and the aqueous layer was
extracted twice with ethyl acetate, the combined organic layers were washed with
brine, dried and concentrated in vacuo. The resulting crude was purified by flash
chromatography (gradient from hexanes to dichloromethane) to yield the title
compound (0.174 g, 64%) as a solid.
LRMS (m/z): 485 (M+1)+.
toxyfluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin-
ed as a yellow solid dihydrochloride salt (100%) from tert-butyl (3R)[(6-
butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine
carboxylate le 15a) following the experimental procedure as described in
Example 14b.
LRMS (m/z): 385 (M+1)+.
c)3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]
piperidinyl}oxopropanenitrile
Obtained as a light yellow solid (58%) from xyfluoro-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 15b) ing the experimental
procedure as described in Preparation 7b. The crude was purified by flash
chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 452 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 0.96 - 1.10 (m, 3 H), 1.26 (s, 2 H), 1.47 - 1.69 (m,
2 H), 1.69 - 2.01 (m, 4 H), 2.11 - 2.30 (m, 1 H), 2.93 (d, 1 H), 3.22 - 3.47 (m, 2
H), 3.52 - 3.73 (m, 1 H), 3.78 - 4.02 (m, 1 H), 4.15 - 4.31 (m, 1 H), 4.45 - 4.60
(m, 2 H), 4.63 - 4.82 (m, 1 H), 6.82 - 6.98 (m, 1 H), 7.30 - 7.42 (m, 1 H), 8.33 -
8.70 (m, 3 H).
EXAMPLE 16
3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
a) Tert-butyl (3R)-3)fluoropyrazolo[1,5-a]pyri-{[6-(2-ethoxyethoxy din
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained as a colourless oil (81%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinecarboxylate (Preparation
5) and 2-ethoxyethanol following the experimental procedure as described in Example
LRMS (m/z): 501 (M+1)+.
b)6-(2-Ethoxyethoxy)fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained as a light yellow solid (100%) from tert-butyl (3R)-3)fluoropyrazolo[1,5-
a]pyri-{[6-(2-ethoxyethoxydinylpyrimidinyl]amino}piperidinecarboxylate
(Example 16a) ing the experimental ure as described in Example 15b.
LRMS (m/z): 401 (M+1)+.
c)3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl] amino}piperidinyl)oxopropanenitrile
Obtained as a light yellow solid (60%) from 6-(2-ethoxyethoxy)fluoro-N-[(3R)-
piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 16b) ing
the experimental procedure as described in Preparation 7b. The crude was purified by
flash tography (gradient from dichloromethane to dichloromethane/methanol
95:5).
LRMS (m/z): 468 (M+1)+.
1H-NMR (300 MHz, CDCl3): 0.73 - 1.01 (m, 1H), 1.14 - 1.36 (m, 4H), 1.69 -
2.08 (m, 3H), 2.13 - 2.30 (m, 1H), 2.93 (d, 1H), 3.19 - 3.47 (m, 2H), 3.54 - 3.74
(m, 3H), 3.77 - 4.02 (m, 2H), 4.12 - 4.32 (m, 1H), 4.59 - 4.87 (m, 3H), 6.79 -
6.98 (m, 1H), 7.29 - 7.43 (m, 1H), 8.33 - 8.68 (m, 3H).
E 17
3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
A Schlenk tube was charged with from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile (Preparation 7b,
0.35 g, 0.85 mmol), 4-hydroxymethylphenylboronic acid (0.19 g, 1.28 mmol), 2.0 M
aqueous sodium carbonate solution (0.64 mL, 1.28 mmol) and 1,2-dimethoxyethane (4
mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with
argon and then tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.09 mmol) was
added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube
was sealed and the mixture was stirred and heated at 80 ºC overnight. The solvent was
removed and the residue was purified by flash chromatography (gradient from hexanes
to hexanes/ethyl e 1:9) to yield the title compound (0.32 g, 77%) as a white solid.
LRMS (m/z): 486 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.71 - 1.90 (m, 2H), 2.10-2.35 (m, 2H), 3.21 - 3.54
(m, 4H), 3.63 - 3.70 (m, 1H), 3.91 (dd, 1H), 4.30 (br.s., 2H), 4.62 (dd, 1H), 4.81
(t, 2H), 5.10 (bs, 1H), 6.94 (dt, 1H), 7.33 - 7.45 (m, 1H), 7.53 - 7.62 (m, 2H),
8.10 (d, 2H), 8.54 - 8.26 (m, 2H), 8.70 (s, 1H).
EXAMPLE 18
3-((3R){[6-(6-Aminopyridinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxopropanenitrile
Obtained as a solid (44%) from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]piperidinyl}oxopropanenitrile (Preparation 6b) and 5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinamine following the experimental
procedure as described in Example 18 followed by purification of the crude t by
flash chromatography (gradient from dichloromethane to dichloromethane/methanol
95:5).
LRMS (m/z): 472 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.70 - 2.07 (m, 3H), 2.16 - 2.30 (m, 1H), 3.33 -
3.54 (m, 4H), 3.84 - 4.04 (m, 1H), 4.23 - 4.41 (m, 1H), 4.74 (d, 2H), 4.96 - 5.15
(m, 1H), 6.57 - 6.69 (m, 1H), 6.78 - 6.96 (m, 1H), 7.32 - 7.44 (m, 1H), 8.26 (d,
1H), 8.48 - 8.59 (m, 2H), 8.65 (d, 1H), 8.93 (dd, 1H).
EXAMPLE 19
3-((3R){[5-fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
Obtained as a solid (42%) from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin
midinyl)amino]piperidinyl}oxopropanenitrile (Preparation 6b) and (6-
methoxypyridinyl)boronic acid following the experimental procedure as described in
Example 18 followed by cation of the crude product by flash tography
(gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 487 (M+1)+.
1H-NMR (400 MHz, CDCl3): 1.68 - 2.08 (m, 3H), 2.18 - 2.33 (m, 1H), 3.13 -
3.52 (m, 4H), 3.57 - 3.72 (m, 1H), 3.87 - 3.99 (m, 1H), 4.05 (s, 3H), 4.27 - 4.44
(m, 1H), 5.09 (d, 1H), 6.85 - 6.97 (m, 2H), 7.34 - 7.44 (m, 1H), 8.38 (dd, 1H),
8.49 - 8.60 (m, 2H), 8.67 (d, 1H), 8.98 - 9.06 (m, 1H).
EXAMPLE 20
3-((3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
a)tert-Butyl(3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl] amino}piperidinecarboxylate
To a solution of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]piperidinecarboxylate (1.0 g, 2.24 mmol), (2-methylpyridin
yl)boronic acid (0.46g , 3.36 mmol) and 0.18 g (0.22 mmol) of [1,1′-
Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with romethane
in dioxane (50 mL) was added a 2M aqueous solution of cesium ate (3.36 mL).
The resulting mixture was stirred at 90 ºC under nitrogen atmosphere overnight, then
cooled to room temperature, filtered h Celite®, the solvent was removed and the
residue was purified first by flash chromatography oromethane to
dichloromethane/methanol 90:10) and then by reverse phase chromatography (C-18
silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium
formate buffered] 0% to 100%) to yield the title compound (0.827 g, 73%) as a light
yellow solid.
LRMS (m/z): 504 (M+1)+.
b)5-Fluoro(2-methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-
a]pyridinylpyrimidinamine
To a solution of tert-butyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-
a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 20a, 0.087 g, 0.17
mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.5 mL) and the
resulting mixture was stirred at room temperature overnight. The volatiles were
evaporated under reduced pressure and the residue was partitioned between water
and dichloromethane. The aqueous layer was ted and the pH was adjusted with
diluted solution of sodium ide until it reached basic pH. The product was
ted with dichloromethane (x3) and the combined organic layers were washed
with brine, dried over magnesium sulfate and evaporated to dryness to yield the title
compound (0.064 g, 92%) as a light yellow solid.
LRMS (m/z): 404 (M+1)+.
c)3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
Obtained as a light yellow solid (66%) from ro(2-methylpyridinyl)-N-[(3R)-
piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine le 20b) following
the mental procedure as described in Preparation 6b. The crude was purified by
flash tography (gradient from romethane to romethane/methanol
90:10).
LRMS (m/z): 471 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.80 – 2.31 (m, 5H), 2.68 – 2.85 (m, 3H), 3.20 –
4.61 (m, 7H), 5.14 – 5.35 (m, 1H), 6.85 – 6.98 (m, 1H), 7.35 – 7.45 (m, 1H),
7.82 – 8.04 (m, 2H), 8.43 – 8.77 (m, 4H).
EXAMPLE 21
)[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl](methyl)amino]piperidinyl}oxopropanenitrile
-butyl(3R)[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl](methyl)amino]piperidinecarboxylate
To a solution of tert-butyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-
a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 20a, 0.218 g, 0.43
mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% dispersion in
mineral oil, 0.034 g, 1.42 mmol). The resulting suspension was stirred at room
temperature for 15 min. and then methyl iodide (0.040 mL, 0.64 mmol) were added.
The mixture was stirred for 2 hours and then it was partitioned between water and ethyl
acetate. The organic layer was separated and washed with water and brine, dried over
magnesium sulfate, filtered and the solvents were removed under reduced pressure to
give 196 mg (88% yield) of the title compound as a light yellow solid.
LRMS (m/z): 518 (M+1)+.
b)5-Fluoro-N-methyl(2-methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo
[1,5-a] pyridinylpyrimidinamine
Obtained as a light yellow solid (94%) from tert-butyl (3R)[[5-fluoro(2-
methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidinyl](methyl)amino]piperidine-
1-carboxylate (Example 21a) following the experimental procedure as described in
Example 20b.
LRMS (m/z): 418 (M+1)+.
c)3-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinyl
pyrimidinyl](methyl)amino]piperidinyl}oxopropanenitrile
Obtained as a pale white solid (56%) from 5-fluoro-N-methyl(2-methylpyridinyl)-N-
[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 21b)
following the experimental procedure as described in Example 20c. The crude was
purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 418 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.65 – 2.27 (m, 6H), 2.79 – 3.06 (m, 4H), 3.10 –
3.65 (m, 6H), 3.73 – 3.91 (m, 1H), 4.46 – 4.92 (m, 2H), 6.86 – 7.04 (m, 1H),
7.30 – 7.51 (m, 1H), 7.98 – 8.26 (m, 2H), 8.40 (d, 1H), 8.50 – 8.75 (m, 3H).
EXAMPLE 22
luoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)piperidinol
A suspension of )[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.060 g, 0.15 mmol) and piperidin-
4-ol (0.060 g, 0.59 mmol) in N,N’-dimethylacetamide (0.3 mL) was d at 110 ºC for
2 hours. The reaction mixture was cooled to room temperature, poured into water and
extracted with ethyl acetate. The combined organic layers were washed with water,
brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified
by flash chromatography (gradient from romethane to dichloromethane /methanol
95:5) to yield the title compound (0.046 mg, 62%) as a yellow solid.
LRMS (m/z): 470 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.66 - 1.95 (m, 4H), 1.97 - 2.09 (m, 2H), 2.11 -
2.28 (m, 1H), 2.98 - 3.35 (m, 3H), 3.41 - 3.59 (m, 2H), 3.64 - 3.81 (m, 1H), 3.84
- 4.06 (m, 3H), 4.16 - 4.32 (m, 5H), 4.54 - 4.71 (m, 1H), 6.75 - 6.93 (m, 1H),
7.17 - 7.37 (m, 1H), 8.39 (d, 2H), 8.44 - 8.53 (m, 1H), 8.58 (d, 1H).
EXAMPLE 23
2-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxoethanol
Obtained as a yellow solid (54%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-
a]pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and
dinylmethanol ing the experimental procedure as described in Example
LRMS (m/z): 484 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.30 - 1.51 (m, 3H), 1.68 - 1.95 (m, 6H), 2.05 -
2.24 (m, 1H), 2.93 - 3.29 (m, 4H), 3.36 - 3.61 (m, 4H), 3.62 - 3.80 (m, 1H), 3.83
- 4.07 (m, 1H), 4.14 - 4.29 (m, 2H), 4.51 (d, 2H), 4.58 - 4.71 (m, 1H), 6.75 - 6.95
(m, 1H), 7.20 - 7.33 (m, 1H), 8.37 - 8.52 (m, 2H), 8.53 - 8.64 (m, 1H).
E 24
2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol
Obtained as a solid (28%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 2-amino ethanol
following the mental procedure as bed in Example 22.
LRMS (m/z): 431 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.67 - 1.80 (m, 2H), 1.78 - 1.93 (m, 1H), 2.08 -
2.26 (m, 1H), 2.99 - 3.31 (m, 1H), 3.34 - 3.58 (m, 2H), 3.59 - 3.83 (m, 3H), 3.84
- 4.06 (m, 3H), 4.09 - 4.32 (m, 3H), 4.47 - 4.72 (m, 2H), 4.97 - 5.17 (m, 1H),
6.77 - 6.94 (m, 1H), 7.28 - 7.36 (m, 1H), 8.29 - 8.62 (m, 3H).
EXAMPLE 25
2-((3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol
Obtained as a beige solid (61%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 1-
methylpiperazine following the experimental procedure as described in Example 22.
LRMS (m/z): 469 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.26 - 1.38 (m, 1H), 1.71 - 1.96 (m, 3H), 2.10 -
2.24 (m, 1H), 2.36 (s, 3H), 2.48 - 2.58 (m, 3H), 2.93 - 3.31 (m, 2H), 3.35 - 3.55
(m, 1H), 3.62 - 3.84 (m, 5H), 3.86 - 4.06 (m, 2H), 4.13 - 4.29 (m, 2H), 4.53 -
4.71 (m, 1H), 6.76 - 6.90 (m, 1H), 7.22 - 7.35 (m, 1H), 8.30 - 8.64 (m, 3H).
EXAMPLE 26
2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
a)Tert-butyl(3R)[(5-methylmorpholinylpyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]piperidinecarboxylate
A mixture of tert-butyl (3R)[(6-chloromethylpyrazolo[1,5-a]pyridinylpyrimidin-
mino]piperidinecarboxylate (Preparation 8c) and morfoline was heated for 48
hours at 100ºC. The reaction e was cooled to room temperature and poured into
water. The resulting precipitate was filtered off, washed with water and dried under
vacuum to yield the title compound (0.13 g, 59%) as a yellow solid.
LRMS (m/z): 494 (M+1)+.
thylmorpholinyl-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained as a yellow solid dihydrochloride salt (100%) from tert-butyl (3R)[(5-
methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine
carboxylate (Example 26a) following the experimental procedure as described in
Example 14b.
LRMS (m/z): 394 (M+1)+.
c)2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
Obtained as a solid (43%) from ylmorpholinyl-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 26b) following the experimental
procedure as described in Preparation 7. The crude was purified by flash
chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 452 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.67 - 1.93 (m, 4H), 2.00 (s, 3H), 2.09 - 2.30 (m,
1H), 3.08 - 3.44 (m, 5H), 3.44 - 4.02 (m, 7H), 4.11 - 4.61 (m, 4H), 6.70 - 6.98
(m, 1H), 7.15 - 7.42 (m, 1H), 8.33 - 8.78 (m, 3H).
E 27
2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol
a) Tert-butyl -{[6-(2-methoxyethoxy)methylpyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained as a colourless oil (65%) from (3R)[(6-chloromethylpyrazolo[1,5-
a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 9c) and 2-
methoxyethanol following the experimental procedure as described in Example 5.
LRMS (m/z): 483 (M+1)+.
b) Methoxyethoxy)methyl-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained as a yellowish solid dihydrochloride salt (98%) from tert-butyl (3R){[6-(2-
methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine-
1-carboxylate (Example 27a) following the experimental procedure as described in
Example 15b.
LRMS (m/z): 383 (M+1)+.
c)2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol
Obtained as a white solid (23%) from methoxyethoxy)methyl-N-[(3R)-piperidinyl]-
2-pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 27b) following the
experimental procedure as described in Preparation 7. The crude was purified by flash
chromatography (gradient from romethane to dichloromethane/methanol 95:5).
LRMS (m/z): 441 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 0.78 - 1.21 (m, 2H), 1.68 - 1.89 (m, 3H), 1.96 (s,
3H), 2.09 - 2.27 (m, 1H), 3.06 - 3.28 (m, 1H), 3.34 - 3.58 (m, 4H), 3.63 - 4.01
(m, 4H), 4.09 - 4.44 (m, 3H), 4.53 - 4.71 (m, 2H), 6.75 - 6.96 (m, 1H), 7.21 -
7.35 (m, 1H), 8.40 - 8.77 (m, 3H).
EXAMPLE 28
Ethyl 1-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)methylpiperidinecarboxylate
Obtained as a deep yellow solid (58%) from 2-{(3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol
(Preparation 7) and ethyl ylpiperidinecarboxylate following the experimental
procedure as described in Example 2a followed by cation of the crude product by
flash chromatography ent from dichloromethane to dichloromethane/methanol
95:5).
LRMS (m/z): 540 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.14 - 1.39 (m, 5H), 1.49 - 1.67 (m, 6H), 1.68 -
1.98 (m, 4H), 2.13 - 2.38 (m, 2H), 3.06 - 3.63 (m, 3H), 3.62 - 4.08 (m, 3H), 4.08
- 4.36 (m, 4H), 4.50 - 4.80 (m, 1H), 6.77 - 6.95 (m, 1H), 6.78 - 6.97 (m, 1H),
7.26 - 7.38 (m, 1H), 8.28 - 8.60 (m, 3H).
EXAMPLE 29
2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin
ylpyrimidinyl]amino}piperidinyl)oxoethanol
a) 1-Aminomethylpyridinium 2,4,6-trimethylbenzenesulfonate
A solution of O-(mesitylsulfonyl)hydroxylamine (23.11 g, 107.4 mmol) in
dichloromethane (272 mL) was added dropwise to a cooled (0 ºC) solution of 4-
methylpyridine (10.0 g, 107.4 mmol) in dichloromethane (136 mL) and the resulting
mixture was stirred for 2 hours at room temperature. The solvent was partially
evaporated and diethyl ether was added to precipitate an oil. The reaction mixture was
cooled to 0 ºC and the solvents were decanted. The oil was dried under vacuum to
yield the title compound (33.11 g, 99%).
LRMS (m/z): 109 (M)+.
1H-NMR (300 MHz, CDCl
3): 2.22 (s, 3H), 2.42 (s, 3H), 2.61 (s, 6H), 6.80 (s, 2H),
7.26 - 7.39 (d, 2H), 8.84 - 8.86 (d, 2H).
b) Ethyl 5-methylpyrazolo[1,5-a]pyridinecarboxylate
Obtained as a solid (54%) from 1-aminomethylpyridinium 2,4,6-trimethylbenzene
sulfonate (Example 29a) and ethyl propiolate following the experimental procedure as
bed in Preparation 1a ed by purification of the crude t by flash
chromatography (hexanes/ethyl e).
LRMS (m/z): 205 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.38 - 1.42 (t, 3H), 2.46 (s, 3H), 4.34 - 4.40 (q, 2H),
6.75 - 6.77 (d, 1H), 7.92 (s, 1H), 8.33 (s, 1H), 8.37 - 8.39 (d, 1H).
c) 5-Methylpyrazolo[1,5-a]pyridinecarboximidamide
2.0 M Trimethylaluminium solution in toluene (62 mL, 124 mmol) was added se
to a cooled (0 ºC) suspension of ammonium chloride (6.18 g, 115.6 mmol) in toluene
(133 mL) and the resulting mixture was stirred until no more gas was formed. A
solution of ethyl ylpyrazolo[1,5-a]pyridinecarboxylate (Example 29b, 7.87 g,
38.53 mmol) in toluene (25 mL) was then added dropwise and the reaction mixture was
stirred overnight at 80 ºC. Additional ammonium chloride (6.18 g, 115.6 mmol) and 2.0
M trimethylaluminium solution in toluene (62 mL, 124 mmol) were added and the
suspension was d overnight at 80 ºC and a weekend at room temperature. The
reaction mixture was cooled at 0 ºC and methanol (30 mL) was added dropwise. The
suspension was ed over diatomaceous earth (Celite©) and the solid was washed
with methanol. The organic phases were ed, solvents were partially evaporated
(up to 100 mL of solution) and dichloromethane (100 mL) was added. The solid formed
was filtered and the solvents were ated to dryness. Purification of the residue by
flash chromatography (dichloromethane/methanol) gave the title nd (6.7 g,
98%).
LRMS (m/z): 175 (M+1)+.
1H-NMR (300 MHz, DMSO-d
6): 2.50 (s, 3H), 7.08 - 7.10 (d, 1H), 7.88 (s, 1H),
8.65 (s, 1H), 8.81 - 8.83 (d, 1H), 8.97 (bs, 3H).
d) ro(5-methylpyrazolo[1,5-a]pyridinyl)pyrimidine-4,6-diol
Obtained as a yellow solid (80%) from 5-methylpyrazolo[1,5-a]pyridine
carboximidamide (Example 29c) and diethyl 2-fluoromalonate ing the
experimental procedure as bed in Preparation 4a.
LRMS (m/z): 261(M+1)+.
1H-NMR (400 MHz, DMSO-d
6): 2.50 (s, 3H), 6.99 - 7.01 (d, 1H), 8.47 (s, 1H), 8.71
- 8.73 (d, 1H), 8.82 (s, 1H), 12.59 (bs, 1H).
e) 3-(4,6-Dichlorofluoropyrimidinyl)methylpyrazolo[1,5-a]pyridine
A mixture of 5-fluoro(5-methylpyrazolo[1,5-a]pyridinyl)pyrimidine-4,6-diol
(Example 29d, 1.19 g, 4.57 mmol) and phosphorus(V) oxychloride (9.3 mL, 99.6 mmol)
was stirred at 110 ºC for 75 minutes. The solvent was removed under reduced
pressure and water was added. The precipitate was filtered, washed with water and
dried under vacuum to yield the title compound (1.08 g, 79%) as a yellow solid.
LRMS (m/z): 297 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 2.51 (s, 3H), 6.78 - 6.80 (d, 1H), 8.23 (s, 1H), 8.41 -
8.43 (d, 1H), 8.62 (s, 1H).
f)Tert-butyl(3R){[6-chlorofluoro(5-methylpyrazolo[1,5-a]pyridin
yl)pyrimidinyl]amino}piperidinecarboxylate
Obtained as a pink solid (93%) from 3-(4,6-dichlorofluoropyrimidinyl)
methylpyrazolo[1,5-a]pyridine (Example 29e) and (R)-tert-butyl 3-aminopiperidine
carboxylate following the experimental procedure described in Preparation 5.
LRMS (m/z): 460 (M+1)+.
g)Tert-butyl(3R){[5-fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin-
4-ylpyrimidinyl]amino}piperidinecarboxylate
Obtained as a solid (47%) from tert-butyl (3R){[6-chlorofluoro(5-
methylpyrazolo[1,5-a]pyridinyl)pyrimidinyl]amino}piperidinecarboxylate
(Example 29f) and morfoline following the experimental ure described in
e 32a followed by purification by flash chromatography ent from hexanes
to ethyl acetate).
LRMS (m/z): 512 (M+1)+.
h)5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholinyl-N-[(3R)-
piperidinyl] pyrimidinamine
Obtained as a solid (85%) from tert-butyl (3R){[5-fluoro(5-methylpyrazolo[1,5-
a]pyridinyl)morpholinylpyrimidinyl]amino}piperidinecarboxylate (Example
29g) following the experimental procedure as described in Example 15b.
LRMS (m/z): 412 (M+1)+.
i)2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin
ylpyrimidin-yl] amino}piperidinyl)oxoethanol
Obtained as a deep yellow solid (40%) from 5-fluoro(5-methylpyrazolo[1,5-a]pyridin-
3-yl)morpholinyl-N-[(3R)-piperidinyl]pyrimidinamine (Example 29h) following
the experimental procedure as described in Preparation 7. The crude was purified by
flash chromatography (gradient from hexanes to ethyl acetate).
LRMS (m/z): 470 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.66 - 1.81 (m, 2H), 1.80 - 1.99 (m, 1H), 2.09 -
2.27 (m, 1H), 2.41 (s, 3H), 3.09 - 3.29 (m, 2H), 3.32 - 3.58 (m, 1H), 3.65 - 3.79
(m, 5H), 3.81 - 3.90 (m, 4H), 3.92 - 4.04 (m, 1H), 4.11 - 4.34 (m, 2H), 4.47 -
4.75 (m, 1H), 6.60 - 6.75 (m, 1H), 8.07 - 8.62 (m, 3H).
E 30
Ethyl 1-(6-{[(3R)(cyanoacetyl)piperidinyl]amino}fluoropyrazolo
[1,5-a]pyridinylpyrimidinyl)piperidinecarboxylate
Obtained as a solid (48%) from )[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino] piperidinyl}oxopropanenitrile (Preparation 7b) and ethyl
piperidinecarboxylate following the experimental procedure as bed in Example
2a followed by cation of the crude product by flash chromatography (gradient from
dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 535 (M+1) +.
1H-NMR (300 MHz, CDCl3): 1.29 (t, 3H), 1.66 - 2.12 (m, 7H), 2.10 - 2.28 (m,
1H), 2.50 - 2.72 (m, 1H), 3.01 - 3.27 (m, 3H), 3.31 - 3.69 (m, 4H), 3.75 - 3.92
(m, 1H), 4.07 - 4.29 (m, 2H), 4.33 - 4.46 (m, 2H), 4.47 - 4.77 (m, 1H), 6.75 -
6.95 (m, 1 H), 7.32 (d, 1 H), 8.25 - 8.59 (m, 3 H).
EXAMPLE 31
1-(6-{[(3R)(Cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)piperidinecarboxylic acid
To a solution of ethyl 1-(6-{[(3R)(cyanoacetyl)piperidinyl]amino}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)piperidinecarboxylate (Example 30, 0.046 g,
0.08 mmol) in a mixture of tetrahydrofuran and water (1:1) (1.4 mL), lithium hydroxide
monohydrate (0.014 g, 0.34 mmol) was added and the mixture was stirred at room
ature for 2 hours. The solvent was evaporated in vacuo, water was added and
the pH of the s solution was adjusted to 3 by addition of 0.5 N hloric acid.
The aqueous solution was extracted with dichloromethane (x3), the combined organic
layers were washed with brine, dried over magnesium sulfate and evaporated to
dryness to yield the title nd (0.019 g, 40%) as a brown solid.
LRMS (m/z): 507 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.63 - 2.25 (m, 6H), 2.55 - 2.81 (m, 1H), 3.07 -
3.31 (m, 3H), 3.30 - 3.67 (m, 4H), 3.70 - 3.93 (m, 2H), 4.12 - 4.30 (m, 1H), 4.32
- 4.47 (m, 2H), 4.47 - 4.86 (m, 1H), 6.76 - 7.00 (m, 1H), 7.29 - 7.45 (m, 1H),
8.27 - 8.66 (m, 3H).
EXAMPLE 32
2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(1H-pyrazolyl)pyrimidin
yl]amino}piperidinyl)oxoethanol
A Schlenk tube was charged with 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7, 0.047 g,
0.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.034 g, 0.18
mmol), 2M aqueous on of potassium triphosphate (0.17 mL, 0.35 mmol) and 1,4-
e (0.5 mL). The Schlenk tube was subjected to three cycles of evacuationbackfilling
with argon and then [1,1'-bis(diphenylphosphino) ferrocene]palladium(II)
dichloride complex with dichloromethane (0.01 g, 0.01 mmol) was added. After three
further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and
the mixture was stirred overnight at 90 ºC. The reaction mixture was cooled to room
temperature and more 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
(0.034 g, 0.18 mmol) and 1,1'-bis(diphenylphosphino) ferrocene]palladium(II)
dichloride complex with dichloromethane (0.01 g, 0.01 mmol) were added. After three
cycles of evacuation-backfilling, the e was stirred at 90ºC for 6 hours. The
mixture was cooled to room temperature, filtered through Celite®, the solvent was
removed and the residue was ed by flash chromatography (dichloromethane to
dichloromethane/methanol 95:5) to yield the title compound (0.018 g, 35%) as a light
yellow solid.
LRMS (m/z): 437 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.47 - 1.76 (m, 2H), 2.11 - 2.33 (m, 1H), 3.10 -
3.31 (m, 1H), 3.37 - 3.55 (m, 1H), 3.68 - 3.82 (m, 4H), 3.91 - 4.10 (m, 1H), 4.19
- 4.30 (m, 2H), 4.29 - 4.71 (m, 1H), 4.92 - 5.08 (m, 1H), 6.82 - 6.99 (m, 1H),
7.30 - 7.42 (m, 1H), 8.33 (br. s., 2H), 8.49 - 8.62 (m, 2H), 8.69 (d, 1H).
EXAMPLE 33
1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)-1H-pyrazolyl]methylpropanol
a)2-Methyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazol
yl]propanol
A microwave r was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole (0.50 g, 2.58 mmol), 2,2-dimethyloxirane (0.57 mL, 6.44 mmol), cesium
carbonate (1.25 g, 3.84 mmol) and acetonitrile (5 mL). The reaction mixture was
subjected to microwave irradiation for 1 hour at 130 ºC. The solid was filtered, washed
with dichloromethane and the filtrate and gs were concentrated in vacuo to yield
the title compound (0.28 g, 42%) as an oil.
b)1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinyl pyrimidinyl)-1H-pyrazolyl]methylpropanol
Obtained as a solid (57%) from )[(6-chlorofluoropyrazolo[1,5-a]pyridin
midinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 2-methyl[4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl]propanol (Example
33a) following the experimental procedure as described in Example 32.
LRMS (m/z): 509 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.23 (s, 6H), 1.70 - 1.98 (m, 3H), 2.13 - 2.31 (m,
1H), 3.10 - 3.32 (m, 1H), 3.38 - 3.58 (m, 1H), 3.67 - 3.83 (m, 2H), 3.89 - 4.09
(m, 2H), 4.19 (d, 2H), 4.23 - 4.39 (m, 2H), 4.55 - 4.77 (m, 1H), 4.98 (t, 1H), 6.82
- 6.95 (m, 1H), 7.11 - 7.44 (m, 1H), 7.44 - 7.66 (m, 1H), 8.14 (s, 1H), 8.26 (d,
1H), 8.46 - 8.60 (m, 1H), 8.67 (d, 1H).
EXAMPLE 34
2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol
A Schlenk tube was charged with 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol ration 8, 0.080 g,
0.20 mmol), (2-methylpyridinyl)boronic acid (0.041 g, 0.30 mmol), 2M aqueous
solution of cesium carbonate (0.29 mL), 0.59 mmol) and 1,4-dioxane (1 mL). The
Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and
then bis(diphenylphosphino) ferrocene]palladium(II) dichloride complex with
dichloromethane (0.01 g, 0.01 mmol) was added. After three further cycles of
evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was
stirred overnight at 90 ºC. The mixture was cooled to room temperature, filtered
through Celite®, the solvent was removed and the residue was purified by flash
chromatography (dichloromethane to dichloromethane/methanol 95:5) to yield the title
compound (0.036 g, 39%) as a light orange solid.
LRMS (m/z): 462 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.73 - 2.02 (m, 3H), 2.12 - 2.33 (m, 1H), 2.70 (s,
3H), 3.12 - 3.30 (m, 1H), 3.37 - 3.61 (m, 2H), 3.69 - 3.85 (m, 1H), 3.95 - 4.13
(m, 1H), 4.20 - 4.43 (m, 2H), 4.66 (dd, 1H), 5.16 (t, 1H), 6.85 - 6.98 (m, 1H),
7.31 - 7.44 (m, 1H), 7.80 (d, 1H), 7.87 (br. s., 1H), 8.47 - 8.61 (m, 2H), 8.63 -
8.80 (m, 2H).
EXAMPLE 35
2-((3R){[5-Fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol
Obtained as a light yellow solid (58%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-
a] pyridin yrimidinyl)amino]piperidinyl}oxoethanol ration 7) and (6-
ypyridinyl)boronic acid following the experimental procedure as bed in
Example 17 followed by purification by flash chromatography (gradient from
dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 478 (M+1)+.
1H-NMR (300 MHz, CDCl3): 0.74 - 0.97 (m, 2H), 1.00 - 1.34 (m, 1H), 1.70 -
2.03 (m, 3H), 2.13 - 2.33 (m, 1H), 3.11 - 3.31 (m, 1H), 3.34 - 3.51 (m, 1H), 3.51
- 3.85 (m, 1H), 4.05 (s, 3H), 4.13 - 4.43 (m, 2H), 4.70 (dd, 1H), 5.07 (t, 1H), 6.74
- 7.07 (m, 2H), 7.29 - 7.56 (m, 1H), 8.28 - 8.83 (m, 3H), 9.01 (s, 1H).
EXAMPLE 36
2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol
Obtained as a light yellow solid (61%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-
a] n ylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and (6-
methylpyridinyl)boronic acid ing the experimental procedure as described in
Example 17 followed by purification by flash tography (gradient from
dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 462 (M+1)+.
1H-NMR (300 MHz, CDCl3): 0.70 - 1.37 (m, 1H), 1.55 - 2.07 (m, 1H), 2.10 -
2.32 (m, 1H), 2.49 (s, 1H), 2.67 (s, 3H), 3.03 - 3.32 (m, 2H), 3.37 - 3.56 (m, 1H),
3.90 - 4.13 (m, 1H), 4.19 - 4.40 (m, 3H), 4.68 (dd, 1H), 5.03 - 5.25 (m, 1H), 6.76
- 7.21 (m, 1H), 7.29 - 7.42 (m, 2H), 8.28 - 8.40 (m, 1H), 8.50 - 8.81 (m, 3H),
9.28 (s, 1H).
EXAMPLE 37
2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol
a) 4-Bromo[(tetrahydro-2H-pyranyloxy)methyl]pyridine
To a solution of (4-bromopyridinyl)metanol (0.30 g, 1.60 mmol) in dichloromethane
(8 mL) and tetrahydrofuran (4 mL), pyridinium para-toluenesulfonate (0.080 g, 0.32
mmol) and 3,4-dihydro-2H-pyran (0.32 mL, 3.51 mmol) were added. The reaction
mixture was d at for 3.5 hours at 50ºC and for 60 hours at room temperature. The
solvent was evaporated in vacuo and the residue was purified by flash chromatography
(gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title
compound (0.33 g, 76%) as a colorless oil.
LRMS (m/z): 272, 274 (M+1, M+3)+.
1H-NMR (300 MHz, CDCl3): 1.46 - 1.65 (m, 2H), 1.69 - 1.83 (m, 2H), 1.83 -
2.02 (m, 2H), 3.51 - 3.65 (m, 1H), 3.81 - 3.96 (m, 1H), 4.62 (d, 1H), 4.78 (t, 1H),
4.89 (d, 1H), 7.37 (d, 1H), 7.67 (s, 1H), 8.37 (d, 1H).
b) 2-[(Tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine
A Schlenk tube was charged with 4-bromo[(tetrahydro-2H-pyran
yloxy)methyl]pyridine (Example 37a, 0.32 g, 1.18 mmol), 4,4,4',4',5,5,5',5'-octamethyl-
2,2'-bi-1,3,2-dioxa borolane (0.45 g, 1.76 mmol), potassium acetate (0.35 g, 3.53
mmol) and oxane (6 mL). The Schlenk tube was subjected to three cycles of
evacuation-backfilling with argon and then bis (diphenylphosphino) ferrocene]
palladium(II) dichloride (0.058 g, 0.07 mmol) was added. After three further cycles of
evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was
stirred and heated at 80 ºC overnight. The mixture was , filtered through
diatomaceous earth (Celite®) and the t was concentrated to dryness to yield the
title compound as a black oil (0.35 g, 93%).
LRMS (m/z): 238 (M+1)+.
c) )[(5-Fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H-pyran
yloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinyl}oxoethanol
Obtained as na Orange oil (59%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 2-
[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyridine (Example 37b) following the experimental procedure as described in
Example 40.
LRMS (m/z): 562 (M+1)+.
d) 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxoethanol
To a solution of 2-{(3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H-
pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinyl}oxoethanol
(Example 37c, 0.055 g, 0.10 mmol) in tetrahydrofuran (0.3 mL), 1N hydrochloric acid
(0.30 mL, 0.30 mmol) was added. The reaction mixture was stirred at room
temperature for 4.5 hours, the solvent was concentrated in vacuo and saturated
sodium bicarbonate aqueous solution was added until the pH was adjusted to 8. The
mixture was extracted with ethyl acetate (x3), the combined organic layers were
washed with brine, dried over magnesium e and the solvent was evaporated to
dryness. The crude was ed by preparative HPLC (gradient from water to
methanol) to yield the title compound (0.022 g, 47%) as a yellow solid.
LRMS (m/z): 478 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.82 - 2.03 (m, 3H), 2.15 - 2.33 (m, 2H), 3.26 (dd,
2H), 3.35 - 3.58 (m, 1H), 3.94 - 4.13 (m, 1H), 4.20 - 4.46 (m, 2H), 4.65 (d, 1H),
4.91 (s, 2H), 5.11 - 5.27 (m, 1H), 6.92 (q, 1H), 7.31 - 7.45 (m, 1H), 7.85 - 8.03
(m, 2H), 8.43 - 8.61 (m, 2H), 8.61 - 8.84 (m, 2H).
EXAMPLE 38
Ethyl 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)pyridinecarboxylate
a) Ethyl 5-(6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)pyridinecarboxylate
Obtained as a light yellow solid (72%) from utyl 3-[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5,
0.300 g, 0.67 mmol) and ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine-
2-carboxylate (0.600 g, 2.17 mmol) following the experimental procedure as bed
in Example 20a. The crude product was purified by flash chromatography es to
hexanes/ethyl acetate 20:80).
LRMS (m/z): 562 (M+1)+.
b) Ethyl luoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin
midinyl}pyridinecarboxylate
Obtained as a light yellow solid (89%) from ethyl 5-(6-{[(3R)(tertbutoxycarbonyl
)piperidinyl]amino}fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)pyridinecarboxylate (Example 38a) following the experimental procedure as
described in Example 20b.
LRMS (m/z): 462 (M+1)+.
c) 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)pyridinecarboxylate
Obtained as a light yellow solid (72%) from ethyl 5-{5-fluoro[(3R)-piperidin
ylamino]pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinecarboxylate (Example
38b) following the experimental procedure as described in Preparation 7. The crude
was purified by flash chromatography (gradient from hexanes to ethyl acetate and then
to ethyl acetate/ethanol 70:30).
LRMS (m/z): 520 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.44 – 1.53 (m, 3H), 1.69 – 2.29 (m, 4H), 3.11 –
3.53 (m, 3H), 3.69 – 4.41 (m, 5H), 4.47 – 4.59 (m, 2H), 5.09 – 5.29 (m, 1H),
6.82 – 6.97 (m, 1H), 7.29 – 7.41 (m, 1H), 8.22 – 8.35 (m, 1H), 8.45 – 8.81 (m,
4H), 9.53 (s, 1H).
EXAMPLE 39
2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
a) Tert-butyl (3R){[5-fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
2-Methoxyethanol (0.11 mL, 1.45 mmol) was added to a suspension of sodium hydride
(60% dispersion in mineral oil, 0.10 g, 1.13 mmol) in tetrahydrofurane (1.5 mL) and the
mixture was stirred at room temperature for 1 hour. Tert-butyl (3R)[(6-chloro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate
(Preparation 5, 0.10 g, 0.22 mmol) was then added and the reaction mixture was
stirred under reflux overnight. The reaction mixture was cooled to room temperature
and partitioned between water and ethyl acetate. The c layer was separated and
the aqueous layer was extracted with ethyl acetate. The combined c layers were
washed with brine, dried over magnesium sulfate and concentrated in vacuo. The
ing crude was purified by flash chromatography ent from dichloromethane
to dichloromethane/methanol 90:10) to yield the title compound (0.067 g, 60%) as a
solid.
LRMS (m/z): 487 (M+1)+.
b) 5-Fluoro(2-methoxyethoxy)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinamine
Obtained as a solid dihydrochloride salt (100%) from 5-fluoro(2-methoxyethoxy)-N-
[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 39a)
following the mental procedure as bed in Example 14b.
LRMS (m/z): 387 (M+1)+.
c)2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol
Obtained as an off-white solid (47%) from 5-fluoro(2-methoxyethoxy)-N-[(3R)-
piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 39b) following
the experimental procedure as described in Preparation 7 followed by purification by
flash chromatography (gradient from dichloromethane to dichloromethane/methanol
95:5).
LRMS (m/z): 445 (M+1)+.
1H-NMR (300 MHz, : 1.69 - 2.01 (m, 4H), 2.12 - 2.30 (m, 1H), 2.91 -
3.23 (m, 1H), 3.31 - 3.44 (m, 1H), 3.48 (s, 3H), 3.54 (t, 1H), 3.68 - 3.78 (m, 1H),
3.80 - 3.90 (m, 2H), 3.96 - 4.08 (m, 1H), 4.14 - 4.32 (m, 2H), 4.62 - 4.84 (m,
3H), 6.78 - 6.96 (m, 1H), 7.29 - 7.39 (m, 1H), 8.33 - 8.54 (m, 2H), 8.60 (d, 1H).
EXAMPLE 40
2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
no}piperidinyl)oxoethanol
a) Tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin
midinyl]amino}piperidinecarboxylate
Ethylene glycol (0.5 mL, 8.94 mmol) was added to a suspension of potassium tert-
de (0.08 g, 0.67 mmol) in 1,4-dioxane (0.7 mL) and the resulting mixture was
stirred at room temperature for 15 minutes. Tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5,
0.10 g, 0.22 mmol) was then added and the reaction mixture was d at 90 ºC
overnight. After cooling to room temperature, the on mixture was partitioned
between water and ethyl acetate. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate. The combined organic layers were washed with
brine, dried over magnesium sulfate and ated to dryness. The resulting crude
was purified by flash chromatography (gradient from dichloromethane to
dichloromethane/methanol 95:5) to yield the title compound (0.081 g, 77%) as a solid.
LRMS (m/z): 473 (M+1)+.
b) Tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained as a solid dihydrochloride salt (100%) from tert-butyl (3R){[5-fluoro(2-
hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine
carboxylate (Example 40a) following the mental procedure as described in
Example 14b.
LRMS (m/z): 373 (M+1)+.
c)2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol
Obtained as a solid (46%) from tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)
pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 40b)
following the experimental procedure described in Preparation 7 followed by
purification by flash chromatography (gradient from dichloromethane to
dichloromethane/methanol 95:5).
LRMS (m/z): 431 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.67 - 1.81 (m, 1H), 1.82 - 1.99 (m, 1H), 2.09 -
2.29 (m, 1H), 2.97 - 3.26 (m, 2H), 3.33 - 3.58 (m, 2H), 3.66 - 3.81 (m, 1H), 3.92
- 4.10 (m, 3H), 4.13 - 4.35 (m, 3H), 4.61 - 4.87 (m, 4H), 6.83 - 6.95 (m, 1H),
7.30 - 7.38 (m, 1H), 8.41 (dd, 1H), 8.51 (d, 1H), 8.59 (d, 1H).
EXAMPLE 41
3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
midinyl)oxy]propanol
a)Tert-butyl(3R){[5-fluoro(3-hydroxypropoxy)pyrazolo[1,5-a]pyridinyl
pyrimidinyl]amino}piperidinecarboxylate
Obtained as an orange oil (78%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5)
and propane-1,3-diol following the experimental procedure as described in Example 5.
LRMS (m/z): 487 (M+1)+.
b)3-({5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl}oxy)propanol
Obtained as a yellow solid dihydrochloride salt (97%) from tert-butyl (3R){[5-fluoro
roxypropoxy)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine
ylate le 41a) following the experimental ure as described in
Example 14b.
LRMS (m/z): 387 (M+1)+.
c)3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]propanol
Obtained as a white solid (52%) from 3-({5-fluoro[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)propanol (Example 41b) following the
experimental procedure as described in Preparation 7 followed by purification by flash
chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 445 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.64 - 1.79 (m, 2H), 1.78 - 1.94 (m, 1H), 1.95 -
2.59 (m, 3H), 2.87 - 3.26 (m, 2H), 3.29 - 3.57 (m, 2H), 3.59 - 3.89 (m, 2H), 3.88
- 4.06 (m, 1H), 4.08 - 4.32 (m, 2H), 4.54 - 4.87 (m, 3H), 6.73 - 6.95 (m, 1H),
7.27 - 7.40 (m, 1H), 8.22 - 8.73 (m, 4H).
EXAMPLE 42
2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
a)Tert-butyl(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
Metal sodium (0.039 g, 1.69 mmol) was added to methanol (5 mL) and the mixture was
stirred at room temperature until metal sodium was consumed. Tert-butyl (3R)[(6-
chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine
carboxylate (Preparation 5, 0.300 g, 0.67 mmol) was added, the reaction mixture was
stirred overnight at reflux under nitrogen atmosphere, then cooled to room temperature,
the solvent was d under d pressure and the residue was ioned
between water and ethyl acetate. The organic layer was separated and washed with
brine, dried and concentrated in vacuo to yield 0.297 g (100% yield) of the title
compound, which was used without further purification in the next synthetic step.
LRMS (m/z): 443 (M+1)+.
uoromethoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl
pyrimidinamine
Obtained as a pale white solid (100%) from tert-butyl (3R)[(5-fluoromethoxy
lo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Example 42a)
ing the experimental procedure as described in Example 20b.
LRMS (m/z): 343 (M+1)+.
c)2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
Obtained as a white solid (80%) from 5-fluoromethoxy-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 42b) following the experimental
procedure as described in Preparation 7. The crude was purified by flash
chromatography (gradient from dichloromethane to dichloromethane/methanol 93:7).
LRMS (m/z): 401 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.64 – 2.28 (m, 4H), 2.93 – 3.79 (m, 5H), 3.90 –
4.31 (m, 5H), 4.59 – 4.79 (m, 1H), 6.80 – 6.93 (m, 1H), 7.27 – 7.36 (m, 1H),
8.33 – 8.74 (m, 3H).
EXAMPLE 43
-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinol
a)5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidinol
A sion of 2-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)amino]piperidinyl}oxoethanol (Example 42c, 0.086 g, 0.21 mmol) in a 4M
solution of hydrochloric acid in dioxane (6 mL) was heated at 80 ºC in a sealed tube
overnight. Then the mixture was allowed to cool to room temperature and the volatiles
were removed under reduced pressure to give 0.078 g (100% yield) of the title
compound as its hydrochloric salt.
LRMS (m/z): 329 (M+1)+.
b)5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinol
Obtained as a white solid (100%) from ro[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinol (Example 43a) following the experimental
procedure as bed in Preparation 7. The crude was ed by reverse phase
chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as s
[0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 387 (M+1)+.
EXAMPLE 44
Benzyl[(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]
pyridinylpyrimidinyl)oxy]acetate
To a solution of 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinol (Example 43b, 0.062 g, 0.16 mmol) in N,N-
dimethylformamide (5 mL) was added silver (I) carbonate (0.530 g, 1.92 mmol) and
benzyl 2-bromoacetate (0.220 g, 0.96 mmol) and the e was stirred at room
temperature for 24 hours. Then it was diluted with water and the resulting suspension
was extracted with ethyl acetate. The organic layer was washed with water and brine,
dried over ium sulfate, filtered and the solvents were evaporated in vacuo. The
crude product was ed first by flash chromatography (gradient from
dichloromethane to dichloromethane/methanol 90:10) and then by reverse phase
chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents
[0.1% v/v ammonium formate buffered] 0% to 100%) to give 0.045 g (53% yield) of the
title compound as a white solid.
LRMS (m/z): 535 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.67 – 1.81 (m, 2H), 1.82 – 1.97 (m, 1H), 2.12 –
2.27 (m, 1H), 2.95 – 4.31 (m, 8H), 4.68 – 4.88 (m, 2H), 5.05 (s, 2H), 5.22 (s,
2H), 6.76 – 6.88 (m, 1H), 7.11 – 7.36 (m, 5H), 8.19 – 8.37 (m, 1H), 8.42 – 8.59
(m, 2H).
EXAMPLE 45
2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
a)Tert-butyl(3R)[(6-ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
Obtained as an oil (63%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-
a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and ethanol
following the experimental procedure as described in Example 15a.
LRMS (m/z): 457 (M+1)+.
b) 6-Ethoxyfluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin-
4-amine
Obtained as a solid dihydrochloride salt (100%) from utyl (3R)[(6-ethoxy
fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate
(Example 45a) following the experimental ure as described in Example 14b.
LRMS (m/z): 357 (M+1)+.
c)2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
ed as a white solid (42%) from xyfluoro-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 45b) following the experimental
procedure described in Preparation 7 followed by purification by flash chromatography
(gradient from romethane to dichloromethane/methanol 95:5).
LRMS (m/z): 415 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.43 - 1.56 (m, 3H), 1.75 (br. s., 2H), 1.90 (br. s.,
1H), 2.21 (br. s., 1H), 2.91 - 3.28 (m, 2H), 3.31 - 3.64 (m, 2H), 3.73 (d, 1H), 4.02
(d, 1H), 4.15 - 4.36 (m, 2H), 4.50 - 4.86 (m, 3H), 6.89 (q, 1H), 7.33 (br. s., 1H),
8.34 - 8.61 (m, 3H).
EXAMPLE 46
Ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinecarboxylate
a)Tert-butyl(3R)[(6-cyanofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinecarboxylate
A solution of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)amino]piperidinecarboxylate (Preparation 5, 0.892 g, 2.00 mmol),
ylstannanecarbonitrile (1.26 g, 3.99 mmol), is(triphenylphosphine)palladium
(0) (0.923 g, 0.80 mmol) and bis(tri-tert-butylphosphine)palladium (0) (0.408 g, 0.80
mmol) in dioxane (20 mL) was heated in a sealed tube under en atmosphere
overnight. Then the reaction mixture was allowed to cool to room temperature, diluted
with dichloromethane and filtered through Celite®. The filtered solution was washed
with water and brine, dried over magnesium sulfate, filtered and the solvents were
removed under reduced pressure. The crude product was purified by flash
chromatography es/ethyl acetate from 0% to 100%) to yield 1.04 g of a
semisolid that contained mostly the title compound.
LRMS (m/z): 438 (M+1)+.
b)6-{[(3R)(Tert-butoxycarbonyl)piperidinyl]amino}fluoropyrazolo[1,5-
a]pyridinylpyrimidinecarboxylic acid
The product obtained in Example 46a was dissolved in 2-propanol (4 mL) an 2M
aqueous on of sodium hydroxide (15 mL) and heated for 35 s at 80 ºC
under microwave irradiation. Then the reaction mixture was partitioned between
dichloromethane and water and the layers were separated. The s layer was
acidified with hloric acid 2M and extracted with dichloromethane/methanol (98:2)
several times. The combined organic solution was dried over ium sulfate,
filtered and the solvents were removed. The crude product was purified by reverse
phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as
eluents [0.1% v/v ammonia in both eluent systems] 0% to 100%) to give 0.193 g (21%
yield in two steps) of the title compound as a white solid.
LRMS (m/z): 456 (M+1)+.
c)Ethylfluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinyl
pyrimidine carboxylate
A solution of R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinecarboxylic acid (Example 46b, 0.299 g, 0.66
mmol) and concentrated sulfuric acid (0.174 mL, 3.3 mmol) in ethanol (8 mL) was
heated to 100 ºC overnight. Then the volatiles were removed under reduced pressure
and the residue was partitioned between water and dichloromethane. The aqueous
layer was separated and the pH was adjusted to 8 by slow addition of a diluted solution
of sodium hydroxide and it was extracted with dichloromethane. The organic solution
was washed with brine, dried over magnesium sulfate, filtered and the solvent was
removed under d pressure to give 0.101 g of the title compound (30% yield).
LRMS (m/z): 385 (M+1)+.
lfluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]
pyridinylpyrimidinecarboxylate
Obtained as a light yellow solid (24%) from 5-fluoro[(3R)-piperidinylamino]
lo[1,5-a]pyridinylpyrimidinol (Example 46c) following the experimental
procedure as described in ation 7. The crude was purified first by flash
chromatography (dichloromethane/methanol from 0% to 15%) and then by e
phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as
eluents [0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 443 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.37 – 1.53 (m, 3H), 1.62 – 1.96 (m, 4H), 3.07 –
3.83 (m, 3H), 3.97 – 4.10 (m, 1H), 4.17 – 4.73 (m, 5H), 5.20 (d, J = 7.6 Hz, 1H),
6.82 – 6.95 (m, 1H), 7.29 – 7.42 (m, 1H), 8.47 – 8.76 (m, 3H).
EXAMPLE 47
-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarbonitrile
a)5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidine
carbonitrile
A solution of tert-butyl (3R)[(6-cyanofluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)amino]piperidinecarboxylate (Example 46a, 0.150 g, 0.34 mmol) and
trated sulfuric acid (0.091 mL, 1.7 mmol) in l (6 mL) was heated to 100
ºC overnight. Then the volatiles were removed under reduced pressure and the residue
was partitioned between water and dichloromethane. The aqueous layer was
separated and the pH was adjusted to 8 by slow addition of aqueous solution of sodium
hydrogencarbonate and it was extracted with dichloromethane. The c solution
was washed with brine, dried over ium sulfate, filtered and the solvent was
removed under reduced pressure to give 0.083 g of the title compound as a deep
yellow solid (63% yield).
LRMS (m/z): 338 (M+1)+.
b)5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarbonitrile
Obtained as a yellow solid (38%) from 5-fluoro[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinecarbonitrile (Example 47a) following the
experimental procedure as bed in ation 7. The crude was purified by
reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 396 (M+1)+.
1H-NMR (400 MHz, DMSO-d
6): 1.44 – 1.90 (m, 3H), 1.93 – 2.12 (m, 1H), 2.56
– 3.09 (m, 3H), 3.58 – 3.87 (m, 1H), 3.91 – 4.29 (m, 3H), 4.50 – 4.75 (m, 1H),
7.07 (s, 1H), 7.40 – 7.58 (m, 1H), 8.19 – 8.40 (m, 2H), 8.58 – 8.69 (m, 1H), 8.79
(s, 1H).
EXAMPLE 48
5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarboxamide
To a on of ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinecarboxylate (Example 46d, 23 mg, 0.052 mmol) in a mixture
of tetrahydrofurane (2 mL) and water (0.5 mL) were added a few drops of concentrated
ammonia. The resulting solution was stirred overnight at room temperature and then
partitioned between water and dichloromethane. The organic layer was separated and
washed with water and brine, dried over magnesium sulfate, ed and the solvent
was removed to give 0.008 g (37% yield) of the title compound as a pale solid.
LRMS (m/z): 414 (M+1)+.
EXAMPLE 49
){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-
trifluoroethoxy)pyrimidinyl]amino}piperidinyl)oxoethanol
a)Tert-butyl(3R){[5-fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)
pyrimidinyl]amino}piperidinecarboxylate
Obtained as an white solid (92%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5)
and 2,2,2-trifluoroethanol following the experimental procedure described in Example
LRMS (m/z): 511 (M+1)+.
b)5-Fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl(2,2,2-
trifluoroethoxy) pyrimidinamine
Obtained as a solid ochloride salt (100%) from tert-butyl (3R){[5-fluoro
pyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidinyl]amino}piperidine
carboxylate (Example 49a) following the experimental procedure described in e
14b.
LRMS (m/z): 411 (M+1)+.
c)2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)
pyrimidinyl]amino}piperidinyl)oxoethanol
Obtained as a white solid (32%) from 5-fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-
a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidinamine (Example 49b) following the
experimental procedure described in Preparation 7 followed by cation by flash
chromatography (gradient from romethane to dichloromethane/methanol 95:5).
LRMS (m/z): 469 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.69 - 1.85 (m, 2H), 1.86 - 2.04 (m, 1H), 2.12 -
2.38 (m, 1H), 2.92 - 3.26 (m, 2H), 3.28 - 3.65 (m, 2H), 3.68 - 3.83 (m, 1H), 3.95
- 4.15 (m, 1H), 4.15 - 4.36 (m, 2H), 4.69 - 5.08 (m, 3H), 6.85 - 7.00 (m, 1H),
7.32 - 7.45 (m, 1H), 8.33 (d, 1H), 8.43 (d, 1H), 8.49 - 8.61 (m, 1H).
EXAMPLE 50
2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol
a)Tert-butyl-(3R){[6-(2,2-difluoroethoxy)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained as a beige solid (99%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5)
and 2,2-difluoroethanol following the experimental procedure described in Example 5.
LRMS (m/z): 493 (M+1)+.
b)6-(2,2-Difluoroethoxy)fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinamine
Obtained as a solid dihydrochloride salt (100%) from tert-butyl (3R){[6-(2,2-
difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine
carboxylate (Example 50a) following the experimental procedure as bed in
Example 14b.
LRMS (m/z): 393 (M+1)+.
c)2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinyl
dinyl]amino}piperidinyl)oxoethanol
Obtained as a white solid (40%) from 6-(2,2-difluoroethoxy)fluoro-N-[(3R)-piperidin-
3-yl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 50b) following the
experimental procedure described in Preparation 7 ed by purification by flash
chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 451 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.64 - 1.85 (m, 2H), 1.84 - 2.05 (m, 1H), 2.12 -
2.35 (m, 1H), 2.94 - 3.29 (m, 2H), 3.29 - 3.61 (m, 2H), 3.66 - 3.79 (m, 1H), 3.93
- 4.10 (m, 1H), 4.16 - 4.37 (m, 2H), 4.58 - 4.96 (m, 3H), 6.24 (t, 1H), 6.84 - 7.00
(m, 1H), 7.32 - 7.45 (m, 1H), 8.35 (d, 1H), 8.44 (d, 1H), 8.50 - 8.61 (m, 1H).
EXAMPLE 51
2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
a)Tert-butyl-(3R)[(5-fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)amino]piperidinecarboxylate
Obtained as an orange oil (92%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5)
and isopropanol following the mental procedure described in Example 15a.
LRMS (m/z): 471 (M+1)+.
b)5-Fluoroisopropoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained as a solid dihydrochloride salt (86%) from tert-butyl (3R)[(5-fluoro
isopropoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate
(Example 51a) following the experimental procedure bed in Example 14b.
LRMS (m/z): 371 (M+1)+.
c) 2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
Obtained as a light yellow solid (29%) from 5-fluoroisopropoxy-N-[(3R)-piperidin
yl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 51b) ing the
experimental procedure bed in Preparation 7 followed by purification by flash
chromatography (gradient from dichloromethane to methanol 95:5).
LRMS (m/z): 429 (M+1)+.
1H-NMR (300 MHz, CDCl
3): 1.47 (d, 6H), 1.65 - 1.80 (m, 2H), 1.82 - 1.94 (m,
1H), 2.09 - 2.28 (m, 1H), 2.87 - 3.25 (m, 2H), 3.25 - 3.57 (m, 2H), 3.67 - 3.79
(m, 1H), 3.93 - 4.08 (m, 1H), 4.11 - 4.30 (m, 2H), 4.61 - 4.85 (m, 1H), 5.42 -
.64 (m, 1H), 6.74 - 6.95 (m, 1H), 7.28-7.33 (m, 1H), 8.28 - 8.58 (m, 3H).
EXAMPLE 52
2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxoethanol
a) 3-(4-Chlorofluoromorpholinylpyrimidinyl)pyrazolo[1,5-a]pyridine
To a solution of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine
(Preparation 1d, 0.500 g, 1.77 mmol) in a mixture of ethanol (20 mL) and
ydrofurane (10 mL) were added morpholine (0.183 mL, 2.11 mmol) and
triethylamine (0.295 mL, 2.12 mmol). The resulting mixture was stirred for 3 hours and
then the les were removed under reduced pressure. The residue was partitioned
between water and dichloromethane, the organic layer was ted and washed with
water, diluted hydrochloric acid and brine, dried over magnesium sulfate, filtered and
the t was removed to give 0.575 g (98% yield) of the title compound as a pale
solid.
LRMS (m/z): 334 (M+1)+.
b)Tert-butyl-(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridin
ylpyrimidinyl)oxy]piperidinecarboxylate
To a solution of tert-butyl (3R)hydroxypiperidinecarboxylate (0.975 g, 4.84 mmol)
in dioxane (10 mL) was added potassium tert-butoxide (0.370 g, 3.30 mmol). It was
stirred at room temperature for 15 s and then 3-(4-chlorofluoromorpholin
ylpyrimidinyl)pyrazolo[1,5-a]pyridine (Example 52a, 0.275 g, 0.82 mmol) were
added. The resulting mixture was heated to 90 ºC overnight and then it was allowed to
cool to room temperature and diluted with ethyl acetate, washed with water (x3) and
brine, dried over magnesium sulfate, filtered and the ts were removed. The
crude product was purified first by flash chromatography (dichloromethane to
dichloromethane/methanol 94:6) and then by reverse phase chromatography (C-18
silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium
formate buffered] 0% to 100%) to yield the title compound (0.362 g, 88% yield) as a
white solid.
LRMS (m/z): 499 (M+1)+.
c)3-{5-Fluoromorpholinyl[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo
[1,5-a]pyridine
Obtained as a pale white solid (95%) from tert-butyl (3R)[(5-fluoromorpholinyl-
zolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate le 52b)
following the experimental procedure as described in Example 20b.
LRMS (m/z): 399 .
d)2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxoethanol
Obtained as a white solid (74%) from 3-{5-fluoromorpholinyl[(3R)-piperidin
yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 52c) following the experimental
procedure as bed in Preparation 7. The crude was purified by reverse phase
chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents
[0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 457 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.70 – 2.27 (m, 4H), 3.18 – 3.76 (m, 4H), 3.76 –
3.92 (m, 7H), 3.94 – 4.33 (m, 2H), 5.20 – 5.35 (m, 1H), 6.81 – 6.93 (m, 1H),
7.27 – 7.36 (m, 1H), 8.26 – 8.40 (m, 1H), 8.47 – 8.63 (m, 2H).
EXAMPLE 53
3-{(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxopropanenitrile
Obtained as a white solid (80%) from 3-{5-fluoromorpholinyl[(3R)-piperidin
pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 52c, 0.135 mg, 0.34 mmol)
following the experimental ure as described in Preparation 6b. The crude was
purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 466 (M+1)+.
1H-NMR (400 MHz, CDCl
3): 1.63 – 2.33 (m, 4H), 3.12 – 3.29 (m, 1H), 3.41 –
3.71 (m, 4H), 3.82 (m, 8H), 4.02 – 4.25 (m, 1H), 5.25 – 5.40 (m, 1H), 6.82 –
6.94 (m, 1H), 7.29 – 7.38 (m, 1H), 8.27 – 8.39 (m, 1H), 8.46 – 8.60 (m, 2H).
EXAMPLE 54
-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrazinecarbonitrile
A mixture of ((5-fluoro(piperidinylamino)(pyrazolo[1,5-a]pyridin
yl)pyrimidinyl)oxy)ethanol dihydrochloride (Example 40b, 0.050 g, 0.13 mmol), 2-
chlorocyanopyrazine (0.025 g, 0.18 mmol) and triethylamine (0.056 mL, 0.4 mmol) in
N,N-dimethylformamide (1.0 mL) was heated in a microwave at 120 °C for 2 hours.
The reaction mixture was cooled to ambient temperature and ethyl acetate (10 mL)
was added. The solution was washed with water (10 mL) and brine (20 mL). The
organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and
concentrated under d pressure. The residue was taken up in dichloromethane (5
mL), the suspension was filtered and dried in vacuo to give the title compound (0.012
g, 19%) as a solid.
LRMS (m/z): 476 (M+1)+.
1H-NMR (300 MHz, DMSO-d
6): 1.50 - 1.98 (m, 4H), 2.00 - 2.17 (m, 1H), 3.02
(dd, 2H), 3.68 - 3.87 (m, 2H), 4.14 (br. s., 1H), 4.42 (d, 1H), 4.50 (d, 2H), 4.75
(br. s., 1H), 4.93 (d, 1H), 6.94 - 7.10 (m, 1H), 7.30 (dd, 2H), 8.32 (d, 1H), 8.46
(d, 1H), 8.58 (s, 1H), 8.80 (d, 1H).
EXAMPLE 55
(5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
no]piperidinyl}pyrazinyl)methanol
A e of (R)fluoromethoxy-N-(piperidinyl)(pyrazolo[1,5-a]pyridin
yl)pyrimidinamine dihydrochloride (Example 42b, 0.040 g, 0.12 mmol), (5-
pyrazinyl)methanol (0.017 g, 0.12 mmol) and diethylisopropylamine (0.061
mL, 0.35 mmol) in N-Methylpyrrolidone (1.0 mL) was heated in a microwave at 120
°C for 19 hours. The on mixture was cooled to ambient temperature and ethyl
acetate (10 mL) was added. The solution was washed with water (10 mL) and brine (20
mL). The organic layer was separated, dried over anhydrous magnesium sulfate,
filtered, and concentrated under reduced pressure. Purification of the residue by flash
chromatography (dichloromethane to 95:5 dichloromethane/ethanol) gave the title
compound (0.007 mg, 13%) as a solid.
LRMS (m/z): 446 (M+1)+.
1H-NMR (300 MHz, CDCl3): 1.52 - 2.02 (m, 3H), 2.12 - 2.27 (m, 1H), 3.16 -
3.51 (m, 2H), 4.01 (dd, 1H), 4.15 (s, 3H), 4.25 - 4.40 (m, 1H), 4.45 (dd, 1H),
4.70 (s, 2H), 4.95 (d, 1H), 6.75 - 6.95 (m, 1H), 7.13 - 7.26 (m, 1H), 8.12 (s, 1H),
8.21 (s, 1H), 8.39 - 8.56 (m, 2H), 8.64 (s, 1H).
E 56
-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}pyrazinecarbonitrile
A mixture of (R)fluoromethoxy-N-(piperidinyl)(pyrazolo[1,5-a]pyridin
yl)pyrimidinamine dihydrochloride (Example 42b, 0.054 g, 0.13 mmol), 2-chloro
cyanopyrazine (0.054 g, 0.38 mmol) and potassium carbonate (0.090 g, 0.65 mmol) in
N,N-dimethylformamide (1.0 mL) was heated in a microwave at 120 °C for 1 hours.
The on mixture was cooled to ambient temperature and ethyl acetate (10 mL)
was added. The on was washed with water (10 mL) and brine (20 mL). The
organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was taken up in dichloromethane (5
mL), the suspension was filtered and dried in vacuo to give the title compound (0.012
g, 19%) as a pale yellow solid.
LRMS (m/z): 446 (M+1)+.
1H-NMR (300 MHz, DMSO-d
6): 1.61 - 1.96 (m, 4H), 2.02 - 2.16 (m, 1H), 2.98 -
3.22 (m, 2H), 4.07 (s, 3H), 4.10 - 4.24 (m, 1H), 4.42 (d, 1H), 4.74 (br. s., 1H),
7.04 (d, 1H), 7.30 (dd, 2H), 8.37 (d, 1H), 8.47 (d, 1H), 8.60 (s, 1H), 8.81 (d, 1H).
EXAMPLE 57
2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
no}piperidinyl)pyrimidinecarbonitrile
A mixture of (R)((5-fluoro(piperidinylamino)(pyrazolo[1,5-a]pyridin
yl)pyrimidinyl)oxy)ethanol dihydrochloride le 40b, 0.060 g, 0.16 mmol), 2-
chloropyrimidinecarbonitrile (0.033 g, 0.24 mmol) and triethylamine (0.070 mL, 0.50
mmol) in N,N-dimethylformamide (1.0 mL) was heated in a microwave at 120 °C for 2
hours. The reaction mixture was cooled to ambient temperature and ethyl acetate (10
mL) was added. The solution was washed with water (10 mL) and brine (20 mL). The
organic layer was separated, dried over ous magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was taken up in dichloromethane (7
mL), the suspension was filtered and dried in vacuo to give the title compound (0.025
g, 33%) as a solid.
LRMS (m/z): 476 (M+1)+.
1H-NMR (300 MHz, DMSO-d6): 1.44 - 1.96 (m, 4H), 2.00 - 2.22 (m, 1H), 2.84
- 3.15 (m, 2H), 3.67 - 3.85 (m, 2H), 4.06 (d, 1H), 4.50 (d, 2H), 4.68 (d, 1H), 4.93
(d, 1H) 5.07 (dd, 1H), 6.94 - 7.09 (m, 1H), 7.22 - 7.38 (m, 2H), 8.33 (d, 1H), 8.63
(s, 1H), 8.80 (d, 2H).
E 58
2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin-
rimidinyl}amino)piperidinyl]oxoethanol
a) Tert-butyl (3R)({5-fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-
a]pyridinylpyrimidinyl}amino)piperidinecarboxylate
Obtained as an oil (72%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-
a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and (2S)
methoxypropanol following the experimental procedure described in Example 15a.
LRMS (m/z): 501 (M+1)+.
b) 5-Fluoro[(1S)methoxymethylethoxy]-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine
Obtained as a solid dihydrochloride salt (98%) from tert-butyl (3R)({5-fluoro[(1S)-
2-methoxymethylethoxy]pyrazolo[1,5-a]pyridinylpyrimidin
yl}amino)piperidinecarboxylate (Example 58a) following the experimental procedure
described in Example 14b.
LRMS (m/z): 401 (M+1)+.
c) 2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]
pyridinylpyrimidinyl}amino)piperidinyl]oxoethanol
ed as a white solid (24%) from 5-fluoro[(1S)methoxymethylethoxy]-
N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine ochloride
salt (Example 58b) following the experimental procedure described in Preparation 7
followed by purification by flash chromatography (gradient from dichloromethane to
dichloromethane/methanol 95:5).
LRMS (m/z): 459 (M+1)+.
1H NMR (300 MHz, CDCl
3): δ 1.24 – 1.33 (m, 3H), 1.45 – 1.52 (m, 3H), 1.69 –
1.81 (m, 2H), 1.90 (s, 1H), 2.15 – 2.28 (m, 1H), 2.92 – 3.23 (m, 2H), 3.26 – 3.40
(m, 1H), 3.46 (s, 3H), 3.52 – 3.81 (m, 2H), 3.96 – 4.12 (m, 1H), 4.18 – 4.31 (m,
1H), 4.65 – 4.83 (m, 1H), 5.52 – 5.67 (m, 1H), 6.81 – 6.98 (m, 1H), 7.30 – 7.37
(m, 1H), 8.30 – 8.70 (m, 3H).
EXAMPLE 59
(2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]propanol
To a 0 ºC cooled on of 2-[(3R)({5-fluoro[(1S)methoxymethylethoxy]
pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)piperidinyl]oxoethanol (Example
58c, 0.053 g, 0.12 mmol) in dichloromethane (1 mL), a 1M solution of boron tribromide
in dichloromethane (0.24 mL, 0.24 mmol) was added. The mixture was stirred at 0ºC
for 1.5 hours and concentrated to dryness. A mixture of ol and 7N ammonia in
ol (1:1) (2 mL) was added and the resulting suspension was concentrated to
dryness. The crude was ed by preparative HPLC (gradient from water to
methanol) to yield the pure title compound (0.021 g, 41%) as a white solid.
LRMS (m/z): 445 (M+1)+.
1H NMR (300 MHz, CDCl
3): δ 1.23 – 1.33 (m, 2H), 1.42 – 1.51 (m, 3H), 1.70 –
2.30 (m, 4H), 2.95 – 3.24 (m, 2H), 3.30 – 4.12 (m, 4H), 4.23 (d, 1H), 4.77 (m,
1H), 5.48 (m, 1H), 6.89 (m, 1H), 7.27 – 7.41 (m, 3H), 8.26 – 8.68 (m, 3H).
EXAMPLE 60
2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxoethanol
a) Tert-butyl (3R)({5-fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-
a]pyridinylpyrimidinyl}amino)piperidinecarboxylate
Obtained as a colorless oil (72%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5)
and (2R)methoxypropanol ing the experimental procedure described in
Example 15a.
LRMS (m/z): 501 (M+1)+.
b) 5-Fluoro[(1R)methoxymethylethoxy]-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine
Obtained as a yellow oil (100%) from tert-butyl (3R)({5-fluoro[(1R)methoxy
methylethoxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)piperidine
carboxylate (Example 60a) following the experimental procedure described in Example
20b.
LRMS (m/z): 401 (M+1)+.
c) 2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-
a]pyridinylpyrimidinyl}amino)piperidinyl]oxoethanol
ed as a white solid (46%) from 5-fluoro[(1R)methoxymethylethoxy]-
N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 60b)
following the experimental procedure described in Preparation 7 ed by
purification by reverse phase chromatography (C-18 silica from ®,
water/methanol as eluents 0% to 100%).
LRMS (m/z): 459 (M+1)+.
1H NMR (400 MHz, CDCl
3): δ 1.36 – 1.50 (m, 3H), 1.71 (m, 2H), 1.82 – 1.94 (m,
1H), 2.17 (s, 1H), 2.92 – 3.39 (m, 3H), 3.43 (s, 3H), 3.48 – 3.61 (m, 2H), 3.67 –
3.76 (m, 2H), 3.95 – 4.05 (m, 1H), 4.16 – 4.25 (m, 2H), 4.66 – 4.77 (m, 1H),
.47 – 5.63 (m, 1H), 6.76 – 6.91 (m, 1H), 7.26 – 7.36 (m, 1H), 8.31 – 8.66 (m,
3H).
EXAMPLE 61
(2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]propanol
Obtained as a white solid (90%) from 2-[(3R)({5-fluoro[(1R)methoxy
methylethoxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)piperidinyl]
oxoethanol (Example 60c) following the experimental ure described in Example
LRMS (m/z): 445 (M+1)+.
1H NMR (400 MHz, CDCl3): δ 1.45 (dd, 3H), 1.68 – 1.79 (m, 2H), 1.85 – 1.92
(m, 1H), 2.16 – 2.24 (m, 1H), 2.83 – 3.22 (m, 3H), 3.35 – 3.56 (m, 2H), 3.66 –
3.76 (m, 1H), 3.83 – 3.89 (m, 2H), 3.99 (dd, 4.2 Hz, 1H), 4.14 – 4.27 (m, 2H),
4.66 – 4.81 (m, 1H), 5.41 – 5.52 (m, 1H), 6.82 – 6.92 (m, 1H), 7.27 – 7.37 (m,
1H), 8.29 – 8.63 (m, 3H).
EXAMPLE 62
2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
Obtained as a yellow solid (18%) from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]
pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile (Preparation 7b)
following the experimental procedure described in Example 17 followed by purification
by flash chromatography ent from dichloromethane to dichloromethane/methanol
95:5).
LRMS (m/z): 448 (M+1)+.
1H NMR (400 MHz, : δ 1.69 – 2.01 (m, 3H), 2.21 (d, 1H), 3.13 – 3.51 (m,
4H), 3.77 (d, 1H), 3.92 – 4.08 (m, 1H), 4.19 – 4.40 (m, 3H), 4.66 (d, 1H), 5.13
(s, 1H), 6.80 – 6.95 (m, 1H), 7.29 – 7.41 (m, 1H), 7.41 – 7.56 (m, 1H), 8.38 –
8.82 (m, 5H), 9.37 (s, 1H).
E 63
2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxoethanol
a) Tert-butyl (3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinecarboxylate
Metal sodium (0.031 g, 1.34 mmol) was added to methanol (8 mL) and the mixture was
stirred at room temperature until metal sodium was consumed. Tert-butyl (3R)[(6-
chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate
(Preparation 9, 0.300 g, 0.67 mmol) was added, the reaction mixture was stirred
overnight at room temperature. The solid that had formed was filtered and the clean
solution was concentrated in vacuo to yield 0.297 g (100% yield) of the title compound,
which was used without further purification in the next synthetic step.
LRMS (m/z): 444 (M+1)+.
b) 3-{5-Fluoromethoxy[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo[1,5-
a]pyridine
Obtained as a pale white solid (55%) from utyl (3R)[(5-fluoromethoxy
pyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate (Example 63a)
following the experimental ure as bed in Example 20b.
LRMS (m/z): 344 (M+1)+.
c) 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxoethanol
Obtained as a white solid (38%) from luoromethoxy[(3R)-piperidin
yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 63b) following the experimental
procedure as described in Preparation 7. The crude was purified first by flash
chromatography (dichloromethane to 95:5 dichloromethane/methanol) and then by
reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 402 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.89 - 2.33 (m, 4H), 3.16 - 3.69 (m, 4H), 3.77 -
4.44 (m, 6H), 5.29 (dt, 1H), 6.82 - 6.99 (m, 1H), 7.29 - 7.43 (m, 1H), 8.35 -
8.47 (m, 1H), 8.49 – 8.68 (m, 2H).
EXAMPLE 64
3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxopropanenitrile
Obtained as a white solid (43%) from 3-{5-fluoromethoxy[(3R)-piperidin
yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 63b) following the experimental
procedure as described in Preparation 6b. The crude was purified first by flash
tography (gradient from dichloromethane to dichloromethane/methanol 85:15)
and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).
LRMS (m/z): 411 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.72 – 2.29 (m, 4H), 3.28 – 3.64 (m, 4H), 3.64 –
3.89 (m, 2H), 4.17 (d, 3H), 5.27 – 5.43 (m, 1H), 6.85 – 6.98 (m, 1H), 7.32 – 7.45
(m, 1H), 8.33 – 8.48 (m, 1H), 8.48 – 8.66 (m, 2H).
EXAMPLE 65
2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]oxy}piperidinyl)oxoethanol
a) Tert-butyl -{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinecarboxylate
A mixture of utyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.250 g, 0.56 mmol) and cesium
de (0.42 g, 2.77 mmol) in dimethyl sulfoxide (10 mL) was stirred at 80 ºC for 2
hours. Then it was allowed to cool to room temperature and ethylene glycol (0.310 mL,
.56 mmol) was added. The solution was stirred at 80 ºC for one hour and at room
temperature for 16 hours, then it was partitioned between water and ethyl acetate. The
organic layer was separated and washed with water and brine, dried over magnesium
sulfate, ed and the solvents were removed in vacuo. The crude was ed by
flash chromatography (gradient from dichloromethane to romethane/methanol
95:5) to give the title nd (87% yield) as a white solid
LRMS (m/z): 474 (M+1)+.
b) 2-({5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin
yl}oxy)ethanol
To a solution of tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-
a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 65a, 0.229 g, 0.48
mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.37 mL) and the
resulting mixture was stirred at room temperature for 2 hours. The volatiles were
evaporated under reduced pressure and the residue was treated with a saturated
aqueous solution of sodium bicarbonate (30 mL) and stirred vigorously for 1 hour. Then
the product was extracted with dichloromethane (x3) and the combined organic layers
were washed with brine, dried over magnesium sulfate and evaporated to dryness to
yield the title compound (0.174 g, 96%) as a white solid.
LRMS (m/z): 374 (M+1)+.
c) 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxoethanol
A mixture of 2-({5-fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)ethanol le 65b, 0.087 g, 0.23 mmol), 2-hydroxyacetic acid
(0.021 g, 0.28 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-
b]pyridiniumoxide hexafluorophosphate (0.106 g, 1.20 mmol) and triethylamine
(0.097 mL, 0.70 mmol) in N,N-dimethylformamide (2 mL) was stirred at room
ature for 64 hours. The resulting mixture was partitioned between s
saturated solution of sodium bicarbonate and ethyl e, the organic layer was
separated and the aqueous phase was extracted twice with ethyl acetate. The
combined organic layers were washed with water, brine, dried over magnesium sulfate
and concentrated in vacuo. The res ulting crude was purified by flash chromatography
ent from dichloromethane to dichloromethane/methanol 92:8) to yield the title
compound (0.048 g, 48%) as a white solid.
LRMS (m/z): 432 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.92 – 2.33 (m, 4H), 3.17 – 3.75 (m, 4H), 3.81 –
4.40 (m, 5H), 4.61 – 4.73 (m, 2H), 5.23 – 5.37 (m, 1H), 6.84 – 6.97 (m, 1H),
7.29 – 7.42 (m, 1H), 8.35 (dd, 1H), 8.46 – 8.66 (m, 2H).
EXAMPLE 66 3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile
3-[(2,5-Dioxopyrrolidinyl)oxy]oxopropanenitrile (prepared as described in
BE875054(A1), 0.051 g, 0.28 mmol) was added to a solution of 2-({5-fluoro[(3R)-
piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)ethanol (Example 65b,
0.087 g, 0.23 mmol) and triethylamine (0.065 mL, 0.47 mmol) in dichloromethane (3
mL). The resulting mixture was stirred at room temperature for 68 hours. A saturated
aqueous solution of sodium bicarbonate (20 mL) was added and the mixture was
stirred vigorously for 30 minutes. Then methylene chloride was added, the organic
layer was separated and the s phase was ted twice with more methylene
chloride. The combined organic layers were washed with water, brine, dried over
ium sulfate and concentrated in vacuo. The resulting crude was purified first by
flash chromatography (gradient from dichloromethane to dichloromethane/methanol
92:8) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as s [0.1% v/v ammonium formate buffered] 0% to 100%)
to yield the title compound (0.049 g, 48%) as a white solid.
LRMS (m/z): 441 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.85 – 2.31 (m, 4H), 3.19 – 3.92 (m, 5H), 3.95 –
4.18 (m, 3H), 4.63 – 4.74 (m, 2H), 5.26 – 5.44 (m, 1H), 6.85 – 6.98 (m, 1H),
7.33 – 7.45 (m, 1H), 8.28 – 8.43 (m, 1H), 8.48 – 8.64 (m, 2H).
EXAMPLE 67
2-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxoethanol
a) Tert-butyl (3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin-
rimidinyl]oxy}piperidinecarboxylate
A mixture of utyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.250 g, 0.56 mmol) and 1-
piperazine (0.224 g, 2.23 mmol) in tetrahydrofurane (2 mL) was stirred at reflux
temperature overnight. Then the reaction e was partitioned between water and
ethyl acetate, the organic layer was separated and the aqueous phase was extracted
twice with ethyl acetate. The combined organic layers were washed with water, brine,
dried over magnesium sulfate and concentrated in vacuo to yield the title compound
(0.285 g, 100%) as an oil.
LRMS (m/z): 512 (M+1)+.
b) 3-{5-Fluoro(4-methylpiperazinyl)[(3R)-piperidinyloxy]pyrimidin
yl}pyrazolo[1,5-a]pyridine
To a solution of tert-butyl (3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-
a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 67a, 0.285 g, 0.56
mmol) in dioxane (3 mL) was added a 4 M solution of hydrochloric acid (2.6 mL) and
the resulting mixture was stirred at room temperature for 2 hours. The volatiles were
evaporated under reduced pressure to give the title compound as a dichlorohydrate
(0.270 g, 100%) as a brownish solid.
LRMS (m/z): 412 (M+1)+.
c) ){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxoethanol
A mixture of 2-hydroxyacetic acid (0.040 g, 0.53 mmol) and 1-
[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridiniumoxide
hexafluorophosphate (0.220 g, 0.58 mmol) in N,N-dimethylformamide (1.5 mL) was
stirred at room temperature for 30 s. A solution of 3-{5-fluoro(4-
methylpiperazinyl)[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine
dichlorohydrate salt (Example 67b, 0.198 g, 0.48 mmol) and triethylamine (0.335 mL,
2.4 mmol) in N,N-dimethylformamide (1.5 mL) was added and the resulting mixture
was stirred at room temperature overnight. Then water was added and the t was
ted with methylene chloride (x3). The ed c layers were washed with
water, brine, dried over magnesium e and concentrated in vacuo. The resulting
crude was purified by reverse phase chromatography (C-18 silica from Waters®,
water/1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title compound
(0.062 g, 27%) as a white solid.
LRMS (m/z): 470 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.90 – 2.26 (m, 4H), 2.27 – 2.52 (m, 3H), 2.66 (s,
4H), 3.12 – 4.38 (m, 11H), 5.28 (s, 1H), 6.81 – 6.96 (m, 1H), 7.28 – 7.38 (m,
1H), 8.34 (dd, 1H), 8.45 – 8.62 (m, 2H).
EXAMPLE 68
3-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile
3-[(2,5-Dioxopyrrolidinyl)oxy]oxopropanenitrile (prepared as bed in
BE875054(A1), 0.175 g, 0.96 mmol) was added to a solution of 3-{5-fluoro(4-
methylpiperazinyl)[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine
dichlorohydrate salt (Example 67b, 0.198 g, 0.48 mmol) and triethylamine (0.335 mL,
2.41 mmol) in romethane (25 mL). The ing mixture was stirred overnight at
room temperature and then it was diluted with methylene chloride. The solution was
washed with water, brine, dried over magnesium sulfate and concentrated in vacuo.
The resulting crude was purified by reverse phase chromatography (C-18 silica from
Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title
compound (0.018 g, 8%) as a white solid.
LRMS (m/z): 479 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.85 – 2.31 (m, 4H), 2.47 (d, 7H), 3.09 – 3.96 (m,
9H), 4.01 – 4.27 (m, 1H), 5.31 (s, 1H), 6.75 – 6.98 (m, 1H), 7.29 – 7.42 (m, 1H),
8.20 – 8.42 (m, 1H), 8.42 – 8.63 (m, 2H).
EXAMPLE 69
2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
midinyl}oxy)piperidinyl]oxoethanol
a) Tert-butyl (3R)({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}oxy)piperidinecarboxylate
A solution of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.250 g, 0.56 mmol) and 2-
aminoethanol (0.340 g, 5.58 mmol) in dioxane (2 mL) was stirred at reflux temperature
ght. Then the reaction mixture was partitioned between water and ethyl acetate,
the organic layer was separated and the s phase was extracted twice with ethyl
acetate. The combined organic layers were washed with water, brine, dried over
magnesium sulfate and trated in vacuo to yield the title compound (0.264 g,
100%) as an oil.
LRMS (m/z): 473 (M+1)+.
b) 2-({5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin
yl}amino)ethanol
Prepared from tert-butyl (3R)({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-
a]pyridinylpyrimidinyl}oxy)piperidinecarboxylate (Example 69a, 0.263 g, 0.56
mmol) following the experimental procedure as described in Example 67b to give the
title compound (100% yield) as the dichlorohydrate salt.
LRMS (m/z): 373 (M+1)+.
c) 2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxoethanol
ed from fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)ethanol dichlorohydrate salt (Example 69b, 0.156 g, 0.42 mmol)
following the experimental ure as described in Example 67c. The crude product
was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents 0% to 100%) to yield the title compound (0.072 g,
39%) as a white solid.
LRMS (m/z): 431 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.89 – 2.27 (m, 4H), 3.17 – 4.01 (m, 9H), 4.01 –
4.39 (m, 2H), 5.21 – 5.40 (m, 2H), 6.81 – 6.95 (m, 1H), 7.28 – 7.38 (m, 1H),
8.30 – 8.44 (m, 1H), 8.45 – 8.66 (m, 2H).
EXAMPLE 70
3-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile
ed as a light yellow solid (42%) from fluoro[(3R)-piperidinyloxy]
pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)ethanol dichlorohydrate salt (Example
69b) following the experimental procedure as bed in Preparation 6b. The crude
product was purified by reverse phase chromatography (C-18 silica from Waters®,
water/1:1 acetonitrile-methanol as eluents 0% to 100%).
LRMS (m/z): 440 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.86 – 2.34 (m, 4H), 3.14 – 4.23 (m, 11H), 5.20 –
.47 (m, 2H), 6.77 – 6.98 (m, 1H), 7.26 – 7.43 (m, 1H), 8.27 – 8.46 (m, 1H),
8.46 – 8.65 (m, 2H).
EXAMPLE 71
2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxoethanol
a) utyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinecarboxylate
Obtained as a light yellow solid (95%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate (Preparation 9,
0.300 g, 0.67 mmol) and (2-methylpyridinyl)boronic acid following the experimental
procedure as described in Example 34 followed by purification by flash
chromatography (gradient from dichloromethane to dichloromethane/methanol 85:15).
LRMS (m/z): 505 (M+1)+.
b) 3-{5-Fluoro(2-methylpyridinyl)[(3R)-piperidinyloxy]pyrimidin
yl}pyrazolo[1,5-a]pyridine
Prepared from tert-butyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-
a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 71a, 0.326 g, 0.65
mmol) following the experimental procedure as described in Example 67b to give the
title compound (100% yield) as the rohydrate salt.
LRMS (m/z): 405 (M+1)+.
c) 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxoethanol
Prepared from luoro(2-methylpyridinyl)[(3R)-piperidinyloxy]pyrimidin
yl}pyrazolo[1,5-a]pyridine dichlorohydrate salt (Example 71b, 0.179 g, 0.44 mmol)
following the mental procedure as described in Example 67c. The crude product
was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents 0% to 100%) followed by stirring in a mixture of
methanol (5 mL), water (1 mL) and a few drops of a 2 M solution of sodium hydroxide
for 3 hours. Then the t was extracted with methylene chloride (x3) and the
organic solution washed with water and brine, dried over magnesium e, filtered
and the ts removed in vacuo to yield the pure title compound (0.082 g, 40%) as a
white solid.
LRMS (m/z): 463 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.93 – 2.34 (m, 4H), 2.74 (s, 3H), 3.21 – 4.46 (m,
7H), 5.43 (s, 1H), 6.86 – 7.01 (m, 1H), 7.31 – 7.49 (m, 1H), 7.80 – 8.00 (m, 2H),
8.48 (t, 1H), 8.53 – 8.60 (m, 1H), 8.61 – 8.77 (m, 2H).
EXAMPLE 72
3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile
Obtained as a light yellow solid (49%) from 3-{5-fluoro(2-methylpyridinyl)[(3R)-
dinyloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine dichlorohydrate salt le
71b) following the experimental procedure as described in Preparation 6b. The crude
t was purified by flash chromatography (gradient from dichloromethane to
dichloromethane/methanol 85:15).
LRMS (m/z): 472 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.89 – 2.42 (m, 4H), 2.73 (s, 3H), 3.21 – 4.30 (m,
6H), 5.49 (s, 1H), 6.84 – 7.04 (m, 1H), 7.41 (s, 1H), 7.77 – 8.00 (m, 2H), 8.42 –
8.52 (m, 1H), 8.52 – 8.60 (m, 1H), 8.60 – 8.80 (m, 2H).
EXAMPLE 73
3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile
a) Tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H-
pyranyloxy)methyl]pyridinyl}pyrimidinyl)oxy]piperidinecarboxylate
ed as a pale solid (90%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate (Preparation 9, 0.150 g, 0.34
mmol) and 2-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine (Example 37b) following the experimental procedure as
described in Example 20a followed by cation by flash chromatography (gradient
from hexane to hexane/ethyl acetate 30:70).
LRMS (m/z): 606 (M+1)+.
b) (4-{5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin
yl}pyridinyl)methanol
To a solution of tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2-
[(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidinyl)oxy]piperidine
carboxylate (Example 73a, 0.182 g, 0.30 mmol) in tetrahydrofurane (2 mL) was added
2 M hydrochloric acid (0.45 mL). The resulting solution was d at 60 ºC for 5 hours
and at room temperature for 16 hours. Then it was diluted with water, basified with 2 M
sodium hydroxide solution and extracted with methylene chloride (x3). The combined
organic layer was washed with brine, dried over magnesium e, filtered and the
solvent was removed to yield the title compound (0.126 g, 100%) as a pale solid.
LRMS (m/z): 421 (M+1)+.
c) 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile
Obtained as a white solid (34%) from (4-{5-fluoro[(3R)-piperidinyloxy]
lo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 73b) following
the experimental procedure as described in Preparation 6b. The crude was purified by
flash chromatography (dichloromethane to 90:10 dichloromethane/methanol).
LRMS (m/z): 488 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.92 – 2.38 (m, 3H), 3.02 – 4.37 (m, 7H), 4.92 (s,
2H), 5.34 – 5.57 (m, 1H), 6.86 – 7.05 (m, 1H), 7.33 – 7.51 (m, 1H), 7.97 (s, 1H),
8.00 (s, 1H), 8.44 – 8.53 (m, 1H), 8.53 – 8.61 (m, 1H), 8.62 – 8.75 (m, 1H), 8.75
– 8.84 (m, 1H).
E 74
2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxoethanol
Obtained as a light yellow solid (58%) from (4-{5-Fluoro[(3R)-piperidinyloxy]
pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 73b) following
the experimental procedure as described in Preparation 7. The crude product was
purified by flash chromatography (gradient from dichloromethane to
dichloromethane/methanol 90:10).
LRMS (m/z): 479 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.78 – 2.43 (m, 4H), 3.24 – 4.24 (m, 7H), 4.94 (s,
2H), 5.42 – 5.57 (m, 1H), 6.89 – 7.03 (m, 1H), 7.37 – 7.49 (m, 1H), 7.90 – 8.12
(m, 2H), 8.40 – 8.51 (m, 1H), 8.57 (t, 1H), 8.62 – 8.73 (m, 1H), 8.78 (t, 1H).
EXAMPLE 75
1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)piperidinol
a) Tert-butyl (3R){[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl]oxy}piperidinecarboxylate
A mixture of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.300 g, 0.67 mmol) and piperidinol
(0.271 g, 2.68 mmol) in dimethylacetamide (2 mL) was stirred at 110 ºC for 1 hour.
Then the on e was partitioned between water and ethyl acetate, the organic
layer was ted and the s phase was extracted twice with ethyl acetate.
The ed organic layers were washed with water, brine, dried over magnesium
sulfate and concentrated in vacuo to yield the title compound (0.332 g, 100%) as an oil.
LRMS (m/z): 513 (M+1)+.
b) luoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin
yl}piperidinol
Prepared from tert-butyl (3R){[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-
a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 75a, 0.332 g, 0.65
mmol) following the experimental procedure as described in Example 67b to give the
title nd (100% yield) as the dichlorohydrate salt.
LRMS (m/z): 413 (M+1)+.
c) 1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin
midinyl)piperidinol
Prepared from 1-{5-fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin
midinyl}piperidinol dichlorohydrate salt le 75b, 0.133 g, 0.32 mmol)
following the experimental procedure as described in Example 67c. The crude product
was purified by flash chromatography (gradient from 100% dichloromethane to 100%
ol) to yield the pure title compound (0.106 g, 70%) as a white solid.
LRMS (m/z): 471 (M+1)+.
1H-NMR (400 MHz, DMSO-d6): δ 1.07 – 2.15 (m, 10H), 2.91 – 3.11 (m, 2H),
3.53 – 4.34 (m, 6H), 4.38 – 4.63 (m, 1H), 4.78 (s, 1H), 5.00 – 5.36 (m, 1H), 6.91
– 7.12 (m, 1H), 7.34 – 7.60 (m, 1H), 8.23 – 8.42 (m, 1H), 8.48 – 8.66 (m, 1H),
8.69 – 8.86 (m, 1H).
EXAMPLE 76
3-((3R){[5-Fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile
Obtained as a white solid (62%) from 1-{5-Fluoro[(3R)-piperidinyloxy]
pyrazolo[1,5-a]pyridinylpyrimidinyl}piperidinol dichlorohydrate (Example 75b)
following the experimental procedure as described in Preparation 6b. The crude was
purified first by flash chromatography (dichloromethane to 90:10
dichloromethane/methanol) and then by reverse phase chromatography (C-18 silica
from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate
buffered] 0% to 100%).
LRMS (m/z): 488 (M+1)+.
1H-NMR (400 MHz, CDCl3): δ 1.62 – 2.35 (m, 8H), 3.12 – 4.33 (m, 12H), 5.31
(s, 1H), 6.79 – 6.96 (m, 1H), 7.28 – 7.39 (m, 1H), 8.27 – 8.44 (m, 1H), 8.45 –
8.61 (m, 2H).
E 77
2-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl](methyl)amino]piperidinyl}oxoethanol
A mixture of 2-hydroxyacetic acid (0.016 g, 0.21 mmol) and 1-
[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridiniumoxide
hexafluorophosphate (0.082 g, 0.22 mmol) in N,N-dimethylformamide (2 mL) was
stirred at room temperature for 15 s. 5-fluoro-N-methyl(2-methylpyridinyl)-
N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 21b,
0.075 g, 0.18 mmol) and triethylamine (0.150 mL, 1.1 mmol) were added and the
resulting mixture was d at room temperature for 2 hours. Then water (50 mL) and
a 2 M sodium hydroxide aqueous solution (5 mL) were added and the resulting solution
was d for 30 minutes. Then the product was extracted with ethyl acetate (x3), the
combined organic layers were washed with water, brine, dried over magnesium sulfate
and concentrated in vacuo. The crude product was purified by flash chromatography
(dichloromethane to 92:8 dichloromethane/methanol) to yield the title compound
(0.055 g, 64%) as a white solid.
LRMS (m/z): 476 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.62 – 2.25 (m, 4H), 2.50 – 3.34 (m, 8H), 3.41 –
3.78 (m, 2H), 4.03 – 4.35 (m, 2H), 4.41 – 4.61 (m, 1H), 4.61 – 5.03 (m, 1H),
6.80 – 6.95 (m, 1H), 7.31 (q, 1H), 7.73 – 7.98 (m, 2H), 8.45 (d, 1H), 8.49 – 8.59
(m, 1H), 8.59 – 8.74 (m, 2H).
EXAMPLE 78
3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
a) Tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H-
pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinecarboxylate
ed as a pale solid (90%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-
a]pyridinylpyrimidinyl) amino]piperidinecarboxylate (Preparation 5, 0.250 g,
0.56 mmol) and 2-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)pyridine (Example 37b, 0.268 g, 0.84 mmol) following the
mental procedure as described in Example 20a.
LRMS (m/z): 605 (M+1)+.
b) (4-{5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}pyridinyl)methanol
Obtained as a white solid (99%) from tert-butyl (3R)[(5-fluoropyrazolo[1,5-
a]pyridinyl{2-[(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidin
yl)amino]piperidinecarboxylate (Example 78a) following the experimental ure
as described in Example 73b.
LRMS (m/z): 420 (M+1)+.
c) 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
Obtained as a white solid (31%) from (4-{5-fluoro[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 78b) following
the experimental procedure as described in Preparation 6b. The crude was purified by
flash tography (dichloromethane to 92:8 dichloromethane/methanol).
LRMS (m/z): 487 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.74 – 2.33 (m, 4H), 3.18 – 4.60 (m, 8H), 4.82 –
4.98 (m, 2H), 5.19 (s, 1H), 6.77 – 7.05 (m, 1H), 7.39 (s, 1H), 7.79 – 8.07 (m,
2H), 8.36 – 8.86 (m, 4H).
EXAMPLE 79
5-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
midinyl)pyridinecarboxylic acid
To a solution of ethyl luoro{[(3R)glycoloylpiperidinyl]amino}
pyrazolo[1,5-a]pyridinylpyrimidinyl)pyridinecarboxylate (Example 38c, 0.120 g,
0.23 mmol) in a mixture of tetrahydrofurane (3 mL) and water (3 mL) was added a 2 M
aqueous solution of sodium hydroxide (0.580 mL) and the resulting solution was stirred
at room temperature overnight. Then the reaction mixture was diluted with water and
acidified to pH = 5 and directly injected for purification by reverse phase
chromatography (C-18 silica from Waters®, water/1:1 itrile-methanol as s
[0.1% v/v ammonium formate buffered] 0% to 100%) to yield the title compound (0.039
g, 34%) as a white solid.
LRMS (m/z): 492 (M+1)+.
EXAMPLE 80
2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
Obtained as a dark yellow solid (79%) from 3-{(3R)[(6-chlorofluoro
lo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile
(Preparation 7b) following the experimental procedure bed in Example 20a.
LRMS (m/z): 448 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.67 – 2.04 (m, 3H), 2.11 – 2.29 (m, 1H), 3.10 –
3.34 (m, 2H), 3.39 – 3.56 (m, 2H), 3.64 – 3.83 (m, 1H), 3.95 – 4.12 (m, 1H),
4.32 (d, 1H), 4.58 – 4.76 (m, 1H), 5.08 – 5.22 (m, 1H), 6.85 – 6.94 (m, 1H), 7.30
– 7.42 (m, 1H), 8.00 (d, 2H), 8.53 (dt 2H), 8.61 – 8.84 (m, 3H).
EXAMPLE 81
2-[(3R)({6-[6-(Dimethylamino)pyridinyl]fluoropyrazolo[1,5-a]pyridin
midinyl}amino)piperidinyl]oxoethanol
Obtained from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.098 g, 0.24 mmol) and N,N-
dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinamine (prepared as
described in Example 37b from 5-bromo-N,N-dimethylpyridinamine) following the
experimental procedure as described in Example 20a. The crude product was purified
first by flash chromatography (dichloromethane to dichloromethane/methanol 98:2) and
then by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents [0.1% v/v ammonium e buffered] 0% to 100%)
to yield the title compound (0.040 g, 34%) as a white solid.
LRMS (m/z): 491 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.67 – 2.38 (m, 4H), 3.06 – 3.29 (m, 6H), 3.33 –
5.09 (m, 9H), 6.53 – 6.71 (m, 1H), 6.79 – 6.97 (m, 1H), 7.28 – 7.39 (m, 1H),
8.28 (d, 1H), 8.45 – 8.79 (m, 3H), 9.04 (s, 1H).
EXAMPLE 82
2-{(3R)[(5-Fluoro-2'-methylpyrazolo[1,5-a]pyridinyl-4,5'-bipyrimidin
yl)amino]piperidinyl}oxoethanol
Obtained from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.098 g, 0.24 mmol) and 2-
methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrimidine (prepared as
bed in Example 37b from 5-bromomethylpyrimidine) following the
experimental procedure as described in Example 20a. The crude product was purified
first by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) and
then by e phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%)
to yield the title compound (0.049 g, 44%) as a white solid.
LRMS (m/z): 463 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.68 – 2.40 (m, 4H), 2.85 (s, 3H), 3.09 – 4.75 (m,
8H), 5.06 – 5.31 (m, 1H), 6.79 – 6.98 (m, 1H), 7.26 – 7.42 (m, 1H), 8.32 – 8.86
(m, 3H), 9.39 (s, 2H).
EXAMPLE 83
2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
a) Tert-butyl (3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridin
midinyl]oxy}piperidinecarboxylate
Obtained as a colorless solid (63%) from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5)
and 2-ethoxyethanol following the experimental procedure described in Example 15a.
LRMS (m/z): 501 (M+1)+.
b) 3-{4-(2-Ethoxyethoxy)fluoro[(3R)-piperidinyloxy]pyrimidin
yl}pyrazolo[1,5-a]pyridine
Obtained as an oil (100%) from tert-butyl (3R){[6-(2-ethoxyethoxy)fluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 83a)
following the experimental procedure bed in e 20b.
LRMS (m/z): 401 (M+1)+.
c) ){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol
Obtained as a white solid (51%) from 2-ethoxyethoxy)fluoro[(3R)-piperidin-
3-yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 83b) following the experimental
procedure described in Preparation 7 followed by purification by reverse phase
chromatography (C-18 silica from Waters®, water/methanol as eluents 0% to 100%).
LRMS (m/z): 459 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.20 – 1.29 (m, 3H), 1.65 – 1.94 (m, 3H), 2.17 (s,
1H), 2.92 – 3.20 (m, 2H), 3.29 – 3.66 (m, 3H), 3.66 – 3.78 (m, 1H), 3.81 – 3.90
(m, 2H), 3.95 – 4.04 (m, 1H), 4.14 – 4.32 (m, 2H), 4.60 – 4.78 (m, 3H), 6.85 (q,
1H), 7.26 – 7.36 (m, 1H), 8.28 – 8.70 (m, 3H).
EXAMPLE 84
2-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol
a) utyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{6-[(tetrahydro-2H-
pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinecarboxylate
Obtained from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl) amino]piperidinecarboxylate (Preparation 5, 0.250 g, 0.56 mmol)
and 2-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridine (prepared as described in Example 37a and 37b from (5-bromopyrimidin-
2-yl)methanol) following the experimental procedure as described in Example 20a. The
crude t was ed by flash tography (hexane to hexane/ethyl acetate
:80) to yield the title compound (0.237 g, 70%) as a white solid.
LRMS (m/z): 605 (M+1)+.
b) Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}pyridinyl)methanol
Obtained as a white solid (100%) from tert-butyl (3R)[(5-fluoropyrazolo[1,5-
a]pyridinyl{6-[(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidin
yl)amino]piperidinecarboxylate (Example 84a) following the experimental procedure
as described in Example 73b.
LRMS (m/z): 420 (M+1)+.
c) 2-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxoethanol
Prepared from (5-{5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}pyridinyl)methanol (Example 84b, 0.065 g, 0.16 mmol) following the
experimental ure as described in Example 67c. The crude product was ed
first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-
methanol as eluents 0% to 100%) and then by preparative HPLC (gradient from water
to methanol) to yield the pure title compound (0.005 g, 7%) as a white solid.
LRMS (m/z): 478 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.68 – 2.30 (m, 3H), 2.98 – 4.95 (m, 11H), 5.01 –
5.23 (m, 1H), 6.82 – 6.98 (m, 1H), 7.29 – 7.57 (m, 2H), 8.39 – 8.60 (m, 2H),
8.60 – 8.80 (m, 1H), 9.32 (s, 1H).
EXAMPLE 85
3-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
Obtained as a pale solid (23%) from (5-{5-fluoro[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 84b, 0.023 g,
0.06 mmol) following the experimental procedure as bed in Preparation 6b. The
crude was purified by flash tography (dichloromethane to 90:10
dichloromethane/methanol).
LRMS (m/z): 487 .
1H-NMR (400 MHz, CDCl
3): δ 2.13 – 2.40 (m, 2H), 3.08 – 4.97 (m, 9H), 6.77 –
7.02 (m, 1H), 7.31 – 7.43 (m, 1H), 7.43 – 7.58 (m, 1H), 8.34 – 8.83 (m, 3H),
9.25 (d, 1H).
EXAMPLE 86
2-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol
Obtained from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.098 g, 0.24 mmol) and 2,6-
dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine (prepared as described
in Example 37b from 4-bromo-2,6-dimethylpyridine) following the experimental
procedure as described in Example 20a. The crude product was purified first by flash
chromatography oromethane to dichloromethane/methanol 98:2) and then by
reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents [0.1% v/v ammonium e buffered] 0% to 100%) to yield the
title compound (0.014 g, 12%) as a white solid.
LRMS (m/z): 476 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.76 – 2.32 (m, 4H), 2.65 (s, 6H), 2.96 – 5.39 (m,
9H), 6.76 – 6.99 (m, 1H), 7.35 (q, 1H), 7.64 (d, 2H), 8.41 – 8.61 (m, 2H),
8.70 (m, 1H).
EXAMPLE 87
3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
a) Tert-butyl (3R){[6-(2,6-dimethylpyridinyl)fluoropyrazolo[1,5-
a]pyridinylpyrimidinyl]amino}piperidinecarboxylate
Obtained from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl) amino]piperidinecarboxylate (Preparation 5, 0.300 g, 0.67 mmol)
and 2,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine red as
described in Example 37b from o-2,6-dimethylpyridine) following the
experimental procedure as described in Example 20a. The crude product was purified
by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents 0% to 100%) to yield the title compound (0.149 g, 43%) as a white
solid.
LRMS (m/z): 519 (M+1)+.
b) 6-(2,6-Dimethylpyridinyl)fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-
a]pyridinylpyrimidinamine
To a solution of tert-butyl (3R){[6-(2,6-dimethylpyridinyl)fluoropyrazolo[1,5-
a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 87a, 0.149 g, 0.29
mmol) in dioxane (2 mL) was added a 4 M solution of hydrochloric acid in dioxane (1.5
mL). The reaction mixture was stirred at room temperature for 1 hour and then the
volatiles were removed under reduced pressure to give 0.141 g (100% yield) of the title
compound as a dichlorohydrate salt.
LRMS (m/z): 418 .
c) 3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
Obtained as a light yellow solid (77%) from 6-(2,6-Dimethylpyridinyl)fluoro-N-
[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine le 87b)
following the mental ure as described in Preparation 6b. The crude
product was purified by flash chromatography (dichloromethane to
romethane/methanol 90:10).
LRMS (m/z): 485 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.74 – 2.33 (m, 4H), 2.67 (s, 6H), 2.99 – 5.28 (m,
8H), 6.80 – 7.03 (m, 1H), 7.31 – 7.47 (m, 1H), 7.58 – 7.76 (m, 2H), 8.39 – 8.60
(m, 2H), 8.60 – 8.78 (m, 1H).
EXAMPLE 88
)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol
a) Tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{5-[(tetrahydro-2H-
pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinecarboxylate
Obtained from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl) amino]piperidinecarboxylate ration 5, 0.335 g, 0.56 mmol)
and 3-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridine (prepared as described in Example 37a and 37b from (5-bromopyridin
yl)methanol) following the experimental procedure as described in Example 20a. The
crude product was purified by flash chromatography (hexane to hexane/ethyl acetate
:80) to yield the title compound (0.335 g, 99%) as a white solid.
LRMS (m/z): 605 (M+1)+.
b) (5-{5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}pyridinyl)methanol
To a solution of tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{5-
[(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidine
carboxylate (Example 88a, 0.335 g, 0.56 mmol) in tetrahydrofuran (2 mL), 1N
hydrochloric acid (1.70 mL) was added. The on mixture was d at room
temperature for 1 hour and then at 60 ºC for 3 hours, then water (15 mL) and a 2M
solution of sodium hydroxide (1 mL) were added. The product was extracted with
dichloromethane (x3), the combined organic layers were washed with brine, dried over
magnesium sulfate and the solvent was evaporated to dryness to yield the title
nd (0.209 g, 90%) as a pale solid.
LRMS (m/z): 420 (M+1)+.
c) 2-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxoethanol
Prepared from Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}pyridinyl)methanol (Example 88b, 0.104 g, 0.25 mmol) following the
experimental procedure as described in Example 67c. The crude t was treated
with a mixture of methanol (15 mL), water (15 mL) and a few drops of a 2 M on of
sodium hydroxide for 1 hour and then purified by flash chromatography
(dichloromethane to 85:15 dichloromethane/methanol) to yield the title compound
(0.041 g, 35%) as a white solid.
LRMS (m/z): 478 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.58 – 2.32 (m, 5H), 3.04 – 4.43 (m, 7H), 4.55 –
4.70 (m, 1H), 4.79 (s, 2H), 6.77 – 6.97 (m, 1H), 7.27 – 7.39 (m, 1H), 8.38 – 8.53
(m, 2H), 8.53 – 8.73 (m, 3H), 9.17 (s, 1H).
EXAMPLE 89
3-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
Obtained as a light yellow solid (51%) from (5-{5-fluoro[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 88b) following
the experimental procedure as described in Preparation 6b. The crude product was
ed by flash chromatography (dichloromethane to dichloromethane/methanol
90:10).
LRMS (m/z): 487 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.61 – 2.29 (m, 4H), 2.99 – 4.18 (m, 6H), 4.17 –
4.36 (m, 1H), 4.46 – 4.63 (m, 1H), 4.80 (s, 2H), 6.79 – 6.97 (m, 1H), 7.30 – 7.44
(m, 1H), 8.28 – 8.54 (m, 2H), 8.54 – 8.76 (m, 2H), 9.06 – 9.28 (m, 1H).
EXAMPLE 90
(2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]propanol
a) Tert-butyl -[(5-fluoro{[(2S)hydroxypropyl]oxy}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate
Obtained as a (1.8:1) mixture of the title compound and tert-butyl (3R)({5-fluoro
[(1S)hydroxymethylethoxy]pyrazolo[1,5-a]pyridinylpyrimidin
)piperidinecarboxylate from tert-butyl (3R)[(6-chlorofluoro
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5)
and (2S)methoxypropanol following the experimental procedure described in
Example 15a.
LRMS (m/z): 488 (M+1)+.
b) (2S)({5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)propanol
Obtained as a (2:1) mixture of the title compound and (2S)({5-fluoro[(3R)-
piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)propanol (71%)
from the mixture obtained in Example 90a, following the experimental procedure
described in Example 20a.
LRMS (m/z): 388 (M+1)+.
c) (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]propanol
Obtained as a white solid (16%) from the mixture obtained in Example 90b, following
the experimental procedure described in Preparation 7 followed by purification by
reverse phase chromatography (C-18 silica from Waters®, water/methanol as eluents
0% to 100%).
LRMS (m/z): 445 (M+1)+.
1H NMR (400 MHz, CDCl
3): δ 1.29 – 1.39 (m, 3H), 1.66 – 1.96 (m, 3H), 2.13 –
2.25 (m, 1H), 2.98 – 3.79 (m, 5H), 3.93 – 4.81 (m, 7H), 6.82 – 6.94 (m, 1H),
7.28 – 7.39 (m, 1H), 8.32 – 8.47 (m, 1H), 8.61 (s, 2H).
EXAMPLE 91
-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile
Obtained as a pale yellow solid (47%) from 5-fluoro[(1R)methoxy
methylethoxy]-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine
le 60b) following the experimental ure bed in Example 54 followed
by purification by flash chromatography (gradient from hexane to ethyl acetate).
LRMS (m/z): 504 .
1H NMR (300 MHz, DMSO-d6): δ 1.31 – 1.39 (m, 3H), 1.54 – 2.16 (m, 5H), 2.91
– 3.21 (m, 3H), 3.48 – 3.73 (m, 2H), 4.74 (s, 5H), 5.54 (td, 1H), 6.94 – 7.07 (m,
1H), 7.20 – 7.37 (m, 2H), 8.23 – 8.35 (m, 1H), 8.39 – 8.49 (m, 1H), 8.56 (s, 1H),
8.75 – 8.83 (m, 1H).
E 92
Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinecarboxylate
a) Isopropyl 6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinecarboxylate
A mixture of 6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro
pyrazolo[1,5-a]pyridinylpyrimidinecarboxylic acid (Example 46b, 0.093 g, 0.18
mmol), cesium carbonate (0.115 g, 0.35 mmol) and propane (0.027 mL, 1.50
mmol) in N,N-dimethylformamide (2.5 mL) was d at 60 ºC for 1 hour. Then the
reaction mixture was partitioned between water and ethyl e and the organic layer
was washed with brine, dried over magnesium sulfate, filtered and the solvents were
evaporated in vacuo. The product w as purified by flash chromatography
(dichloromethane to dichloromethane/methanol 95:5) to give the title compound (0.085
g, 90%) as an oil.
LRMS (m/z): 499 (M+1)+.
b) Isopropyl 5-fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin
ylpyrimidinecarboxylate
To a solution of isopropyl 6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro-
2-pyrazolo[1,5-a]pyridinylpyrimidinecarboxylate (Example 92a, 0.085 g, 0.17
mmol) in dichloromethane (3 mL), trifluoroacetic acid (0.302 mL) was added. The
mixture was stirred at room temperature for 30 minutes, the volatiles were removed in
vacuo and the residue was redissolved in water. The pH was adjusted to 9 with a
saturated sodium bicarbonate solution and the product was extracted with
dichloromethane (x3). The combined organic layer was washed with brine, dried over
magnesium sulfate, filtered and the solvents were ated in vacuo to give the title
nd (0.068 g, 100%) as an oil.
LRMS (m/z): 399 (M+1)+.
c) Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinecarboxylate
Prepared from isopropyl 5-fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinecarboxylate (Example 92b, 0.068 g, 0.17 mmol) following the
mental procedure as described in Example 67c. The crude product was purified
by flash chromatography (dichloromethane to 95:5 dichloromethane/methanol) to yield
the title compound (0.015 g, 19%) as a pale yellow solid.
LRMS (m/z): 457 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.37 – 1.47 (m, 6H), 1.69 – 2.27 (m, 4H), 3.09 –
4.67 (m, 8H), 5.19 (s, 1H), 5.28 – 5.45 (m, 1H), 6.82 – 6.92 (m, 1H), 7.29 – 7.41
(m, 1H), 8.46 – 8.55 (m, 1H), 8.55 – 8.78 (m, 2H).
EXAMPLE 93
2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin
no]piperidinyl}oxoethanol
a) utyl (3R)[(6-methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin-
4-yl)amino]piperidinecarboxylate
Obtained as an oil (31%) from (R)-tert-butyl 3-((6-chloromethyl(pyrazolo[1,5-
a]pyridinyl)pyrimidinyl)amino)piperidinecarboxylate (Preparation 8c) following
the experimental procedure bed in e 42c.
LRMS (m/z): 439 (M+1)+.
b) 6-Methoxymethyl-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained as a solid dihydrochloride salt (99%) from tert-butyl (3R)[(6-methoxy
methylpyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate
(Example 93a) following the experimental procedure described in Example 14b.
LRMS (m/z): 339 (M+1)+.
c) 2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol
Obtained as a white solid (41%) from 6-methoxymethyl-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 93b) following the experimental
procedure described in Example 67c followed by purification by reverse phase
chromatography (C-18 silica from Waters®, water/methanol as eluents 0% to 100%).
LRMS (m/z): 396 (M+1)+.
1H NMR (400 MHz, CDCl
3): δ 1.59 – 1.86 (m, 6H), 2.06 – 2.15 (m, 1H), 3.02 –
3.93 (m, 6H), 4.01 (d, 3H), 4.09 – 4.35 (m, 3H), 6.75 – 6.86 (m, 1H), 7.21 (s,
1H), 8.39 – 8.72 (m, 3H).
EXAMPLE 94
2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin-
1-yl}oxoethanol
a) Tert-butyl (3R)[(6-methoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
Obtained as a white solid (74%) from tert-butyl (3R)[(6-chloropyrazolo[1,5-
a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 10c, 0.300 g,
0.70 mmol) following the experimental procedure as described in Example 42a. Excess
solution of sodium methoxide in methanol was added until the on was completed.
LRMS (m/z): 425 (M+1)+.
b) 6-Methoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin
amine
Obtained as a pale white solid (80%) from tert-butyl (3R)[(6-methoxypyrazolo[1,5-
a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Example 94a) following the
experimental procedure as described in Example 20b.
LRMS (m/z): 343 (M+1)+.
c) 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidin
no]piperidinyl}oxoethanol
Obtained as a white solid (80%) from 6-methoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-
a]pyridinylpyrimidinamine (Example 94b) following the experimental procedure as
described in Preparation 7. The crude was purified by flash chromatography (gradient
from dichloromethane to dichloromethane/methanol 91:9).
LRMS (m/z): 383 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.65 – 2.23 (m, 4H), 3.01 – 3.18 (m, 1H), 3.31 –
3.92 (m, 4H), 3.92 – 4.10 (m, 3H), 4.10 – 4.93 (m, 3H), 5.43 – 5.64 (m, 1H),
6.77 – 6.94 (m, 1H), 7.28 – 7.42 (m, 1H), 8.39 – 8.60 (m, 2H), 8.60 – 8.78 (m,
1H).
EXAMPLE 95
3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin-
3-oxopropanenitrile
Obtained as a white solid (93%) from 6-methoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-
dinylpyrimidinamine (Example 94b) following the experimental procedure as
described in Preparation 6b. The crude was purified by flash tography (gradient
from dichloromethane to dichloromethane/methanol 80:20).
LRMS (m/z): 383 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.66 – 2.25 (m, 4H), 3.23 – 3.91 (m, 5H), 3.93 –
4.15 (m, 3H), 4.18 – 4.86 (m, 2H), 5.57 (d, 1H), 6.88 (dt, 1H), 7.28 – 7.42 (m,
1H), 8.46 – 8.59 (m, 2H), 8.59 – 8.75 (m, 1H).
EXAMPLE 96
2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
a) Tert-butyl (3R){[6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinecarboxylate
A solution of 2-methoxyethanol (0.55 mL, 7.0 mmol) and potassium tert-butanol (0.236
g, 2.1 mmol) in dioxane (3 mL) was stirred at room temperature for 30 minutes. Then
tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine-
1-carboxylate (Preparation 10c, 0.300 g, 0.70 mmol) was added and the reaction
mixture was stirred under reflux overnight. The reaction mixture was cooled to room
temperature and ioned n water and ethyl acetate. The c layer was
separated and the aqueous layer was extracted with ethyl acetate. The combined
c layers were washed with brine, dried over ium e and concentrated
in vacuo. The resulting crude was purified by flash chromatography (gradient from
dichloromethane to dichloromethane/methanol 95:5) to yield the title nd (0.188
g, 57%) as a solid.
LRMS (m/z): 469 (M+1)+.
b) 6-(2-Methoxyethoxy)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained as a pale white solid (86%) from tert-butyl (3R){[6-(2-methoxyethoxy)
pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 96a)
following the experimental procedure as described in Example 20b.
LRMS (m/z): 369 (M+1)+.
c) 2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
Obtained as a white solid (20%) from 6-(2-methoxyethoxy)-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 96b) following the experimental
procedure as described in Preparation 6b. The crude was purified first by reverse
phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as
eluents 0% to 100%), then by flash chromatography (dichloromethane to
dichloromethane/methanol 85:15) and finally by preparative HPLC (gradient from water
to methanol).
LRMS (m/z): 427 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.63 – 2.25 (m, 4H), 3.01 – 3.25 (m, 2H), 3.25 –
4.30 (m, 9H), 4.37 – 4.81 (m, 3H), 5.47 – 5.70 (m, 1H), 6.79 – 6.96 (m, 1H),
7.27 – 7.37 (m, 1H), 8.40 – 8.57 (m, 2H), 8.57 – 8.71 (m, 1H).
EXAMPLE 97
3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
Obtained as a white solid (25%) from 6-(2-methoxyethoxy)-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 96b) following the experimental
ure as described in Preparation 6b. The crude was purified first by flash
chromatography (dichloromethane to dichloromethane/methanol 85:15), then by
reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents 0% to 100%) and finally by preparative HPLC (gradient from water
to methanol).
LRMS (m/z): 436 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.64 – 2.25 (m, 4H), 2.87 – 4.17 (m, 11H), 4.34 –
4.81 (m, 3H), 5.53 – 5.67 (m, 1H), 7.28 – 7.40 (m, 1H), 8.41 – 8.58 (m, 2H),
8.58 – 8.70 (m, 1H)
EXAMPLE 98
2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
no}piperidinyl)oxoethanol
a) utyl (3R){[6-(2-methoxypyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate (Preparation 10c, 0.300 g, 0.70 mmol) ing the
mental procedure as described in Example 20a. The crude product was purified
by reverse phase tography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents 0% to 100%) to yield the title compound (0.153 g, 38%) as a white
solid.
LRMS (m/z): 502 (M+1)+.
b) ethoxypyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained as a pale white solid (57%) from tert-butyl (3R){[6-(2-methoxypyridinyl)-
2-pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example
98a) following the experimental procedure as bed in Example 20b.
LRMS (m/z): 402 .
c) 2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
Obtained as a white solid (29%) from 6-(2-methoxypyridinyl)-N-[(3R)-piperidinyl]-
2-pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 98b) ing the
experimental procedure as described in Preparation 7. The crude was purified first by
flash chromatography (gradient from dichloromethane to dichloromethane/methanol
91:9), then by reverse phase tography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents 0% to 100%) and finally by preparative HPLC
(gradient from water to methanol).
LRMS (m/z): 460 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.65 – 2.32 (m, 4H), 3.08 – 3.90 (m, 5H), 4.02 (s,
3H), 4.09 – 5.03 (m, 3H), 6.57 (m, 1H), 6.90 (m, 1H), 7.31 – 7.48 (m, 2H), 7.53
(m, 1H), 8.31 (d, 1H), 8.54 (t, 1H), 8.63 (dd, 1H), 8.75 (m, 1H).
EXAMPLE 99
2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
a) Tert-butyl (3R){[6-(6-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate (Preparation 10c, 0.300 g, 0.70 mmol) following the
experimental ure as described in Example 20a. The crude product was purified
first by flash chromatography (gradient from dichloromethane to
dichloromethane/methanol 85:15) and then by reverse phase chromatography (C-18
silica from Waters®, 1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the
title compound (0.128 g, 41%) as a white solid.
LRMS (m/z): 486 (M+1)+.
b) 6-(6-Methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
Obtained from tert-butyl -{[6-(6-methylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate (Example 99a) ing the
experimental procedure as described in Example 67b to give the title compound (93%
yield) as the dichlorohydrate salt.
LRMS (m/z): 386 .
c) 2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
no}piperidinyl)oxoethanol
Prepared from 6-(6-methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinamine dichlorohydrate salt (Example 99b, 0.085 g, 0.18 mmol) following
the experimental procedure as described in Example 67c. The crude product was
ed first by flash chromatography (dichloromethane to 85:15
dichloromethane/methanol) and then by reverse phase chromatography (C-18 silica
from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title
compound (0.082 g, 50%) as a pale solid.
LRMS (m/z): 444 (M+1)+.
1H-NMR (400 MHz, DMSO-d6): δ 1.38 – 2.10 (m, 4H), 2.55 (s, 3H), 2.60 – 3.15
(m, 2H), 3.57 – 4.80 (m, 4H), 6.67 – 6.89 (m, 1H), 7.04 (s, 1H), 7.27 – 7.58 (m,
2H), 8.18 – 9.30 (m, 4H).
EXAMPLE 100
3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
Obtained as a white solid (48%) from 6-(6-methylpyridinyl)-N-[(3R)-piperidinyl]
pyrazolo[1,5-a]pyridinylpyrimidinamine dichlorohydrate salt (Example 99b)
following the experimental procedure as described in Preparation 6b. The crude was
ed first by flash chromatography (dichloromethane to dichloromethane/methanol
85:15) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents 0% to 100%).
LRMS (m/z): 453 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.68 – 2.30 (m, 4H), 2.65 (s, 3H), 3.06 – 3.93 (m,
5H), 4.03 – 4.55 (m, 2H), 4.81 – 5.04 (m, 1H), 6.48 – 6.69 (m, 1H), 6.80 – 7.02
(m, 1H), 7.28 – 7.44 (m, 2H), 8.29 (d, 1H), 8.47 – 8.82 (m, 3H), 9.23 (s, 1H).
EXAMPLE 101
2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
a) Tert-butyl -{[6-(2,6-dimethylpyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate ration 10c, 0.276 g, 0.64 mmol) following the
experimental procedure as described in Example 20a. The crude product was purified
by flash chromatography (gradient from dichloromethane to romethane/methanol
85:15) to yield the title compound as a white solid.
LRMS (m/z): 500 (M+1)+.
b) 6-(2,6-Dimethylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinamine
ed as a solid dihydrochloride salt (52%) from utyl (3R){[6-(2,6-
dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine
carboxylate (Example 101a) following the experimental procedure described in
Example 14b.
LRMS (m/z): 400 (M+1)+.
c) 2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol
Obtained as a white solid (55%) from 6-(2,6-dimethylpyridinyl)-N-[(3R)-piperidin-
3-yl]pyrazolo[1,5-a]pyridinylpyrimidinamine dihydrochloride salt (Example
101b) following the experimental procedure described in Preparation 7. The crude was
ed first by flash chromatography (dichloromethane to dichloromethane/methanol
85:15) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents 0% to 100%).
LRMS (m/z): 458 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.65 – 2.29 (m, 4H), 2.65 (s, 6H), 3.01 – 5.07 (m,
9H), 6.43 – 6.73 (m, 1H), 6.77 – 7.06 (m, 1H), 7.31 – 7.46 (m, 1H), 7.52 – 7.75
(m, 2H), 8.45 – 8.86 (m, 3H).
EXAMPLE 102
3-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
Obtained as a white solid (54%) from 6-(2,6-dimethylpyridinyl)-N-[(3R)-piperidin
yl]pyrazolo[1,5-a]pyridinylpyrimidinamine dihydrochloride salt (Example 101b)
following the experimental ure as described in Preparation 6b. The crude was
purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1
acetonitrile-methanol as eluents 0% to 100%) and then by flash tography
(chloroform to chloroform/methanol 95:5).
LRMS (m/z): 467 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.69 – 2.30 (m, 4H), 2.65 (s, 6H), 3.19 – 4.53 (m,
7H), 4.76 – 5.12 (m, 1H), 6.63 (d, 1H), 6.82 – 7.03 (m, 1H), 7.32 – 7.49 (m, 1H),
7.56 – 7.71 (m, 2H), 8.45 – 8.70 (m, 2H), 8.70 – 8.85 (m, 1H).
EXAMPLE 103
3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
a) utyl (3R){[6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinecarboxylate
To a solution of potassium tert-butoxide (0.523 g, 4.7 mmol) in dioxane (3 mL),
ethylene glycol (2 mL) was added and the resulting solution was stirred at room
temperature for 30 minutes. Then tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)amino]piperidinecarboxylate ration 10c, 0.400 g, 0.93
mmol) was added and the mixture was heated at 85 ºC ght. Excess ts
were added and the mixture was heated at reflux until the starting material was
consumed. The reaction mixture was partitioned between water and ethyl acetate and
the organic layer was washed with water and brine, dried over magnesium sulfate,
filtered and evaporated under reduced pressure. The crude product was purified by
reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents 0% to 100%) to yield the title compound (0.324 g, 76%) as a
yellowish oil.
LRMS (m/z): 455 (M+1)+.
b) 2-({6-[(3R)-Piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin
yl}oxy)ethanol
Obtained as a solid ochloride salt (100%) from tert-butyl (3R){[6-(2-
hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine
carboxylate (Example 103a) following the experimental procedure described in
Example 14b.
LRMS (m/z): 355 (M+1)+.
c) 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
Obtained as a pale solid (61%) from [(3R)-piperidinylamino]pyrazolo[1,5-
a]pyridinylpyrimidinyl}oxy)ethanol dihydrochloride salt (Example 103b) following
the mental procedure as bed in ation 6b. The crude was purified by
flash chromatography (dichloromethane to dichloromethane/methanol 85:15).
LRMS (m/z): 422 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.67 – 2.23 (m, 4H), 2.91 – 4.18 (m, 10H), 4.36 –
4.92 (m, 3H), 5.62 (s, 1H), 6.77 – 6.99 (m, 1H), 7.28 – 7.44 (m, 1H), 8.41 – 8.57
(m, 2H), 8.57 – 8.68 (m, 1H).
EXAMPLE 104
-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrazinecarbonitrile
A suspension of 2-({6-[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl}oxy)ethanol dihydrochloride salt (Example 103b, 0.292 g, 0.82 mmol), 5-
chloropyrazinecarbonitrile (0.126 g, 0.91 mmol) and potassium carbonate (0.182 g,
1.32 mmol) in N,N-dimethylformamide (8 mL) was heated at 120 ºC for 1 hour under
microwave irradiation. The reaction mixture was partitioned between water and ethyl
acetate and the organic layer was washed with water and brine, dried over magnesium
sulfate, filtered and evaporated under d pressure. The crude product was
purified first by flash chromatography (100% hexane to 100% ethyl acetate) and then
by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol
as eluents 0% to 100%) to yield the title compound (0.068 g, 18%) as a solid.
LRMS (m/z): 458 (M+1)+.
1H-NMR (400 MHz, CDCl
3): δ 1.65 – 2.30 (m, 4H), 3.10 – 3.52 (m, 3H), 3.87 –
4.15 (m, 4H), 4.44 – 4.68 (m, 3H), 4.78 (s, 1H), 5.60 (s, 1H), 6.77 – 6.96 (m,
1H), 7.19 – 7.25 (m, 1H), 8.11 – 8.21 (m, 1H), 8.34 (d, 1H), 8.40 – 8.48 (m, 1H),
8.48 – 8.56 (m, 1H), 8.64 (s, 1H).
EXAMPLE 105
-(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
midinyl)pyridinol
a) Tert-butyl (3R){[6-(5-hydroxypyridinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinecarboxylate
Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate (Preparation 10c, 0.400 g, 0.93 mmol) following the
experimental procedure as described in Example 20a. The crude product was used
without further purification in the next step.
LRMS (m/z): 488 (M+1)+.
b) 5-{6-[(3R)-Piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin
yl}pyridinol
Obtained as a solid dihydrochloride salt from tert-butyl (3R){[6-(5-hydroxypyridin
yl)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (crude
product obtained in Example 105a) following the experimental procedure described in
Example 14b.
LRMS (m/z): 388 (M+1)+.
c) 5-(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)pyridinol
Obtained as a white solid (0.031 g, 27%) from 5-{6-[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinol dihydrochloride salt (Example
105b) following the mental procedure described in Preparation 7. The crude was
purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1
itrile-methanol as s 0% to 100%) and then by ative HPLC (gradient
from water to ol).
LRMS (m/z): 446 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) δ 1.45 – 2.15 (m, 4H), 2.60 – 3.21 (m, 3H), 3.49
– 4.81 (m, 6H), 6.76 (s, 1H), 7.04 (s, 1H), 7.33 – 7.62 (m, 2H), 7.82 (s, 1H), 8.14
– 8.35 (m, 1H), 8.49 – 8.94 (m, 3H), 10.19 (s, 1H).
EXAMPLE 106
3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
Obtained as a pale solid (0.030 g, 26%) from 5-{6-[(3R)-piperidinylamino]
pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinol dihydrochloride salt (Example
105b) following the experimental procedure as described in Preparation 6b. The crude
was purified by preparative HPLC (gradient from water to methanol).
LRMS (m/z): 455 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) δ 1.38 – 1.83 (m, 4H), 2.59 – 3.19 (m, 5H), 3.45
– 4.43 (m, 4H), 6.66 – 6.94 (m, 1H), 6.95 – 7.19 (m, 1H), 7.31 – 7.68 (m, 2H),
7.82 (s, 1H), 8.23 (s, 1H), 8.45 – 8.94 (m, 3H), 10.19 (s, 1H).
EXAMPLE 107
2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)(methyl)amino]piperidinyl}oxoethanol
PHARMACOLOGICAL ACTIVITY
In vitro JAK kinase Assays
Compounds were ed for their ability to inhibit JAK1, JAK2 and JAK3 using the
assays as indicated below.
The catalytic domains of human JAK1 (aa 54), JAK2 (aa 826-1132), JAK3 (aa
795-1124) and Tyk2 (aa 871-1187) were expressed as inal GST-fusion proteins
using a baculovirus expression system and were purchased from Carna Biosciences.
The enzymatic activity was d using as substrate a biotinylated peptide, poly
(GT)-Biotin (CisBio). The e concentration in the reactions was 60 nM for JAK1,
20 nM for JAK2, 140 nM for JAK3 and 50 nM for Tyk2. The degree of phosphorylation
was detected by TR-FRET (time-resolved fluorescence energy transfer).
IC50s of compounds were measured for each kinase in a reaction mixture containing
the enzyme, ATP and the peptide in 8 mM MOPS (pH 7.0), 10 mM MgCl2, 0.05% βmercaptoethanol
, 0.45 mg/ml BSA. The ATP concentration in the reactions was 3 µM
for JAK1, 0.2 µM for JAK2, 0.6 µM for JAK3 and 1.8 µM for Tyk2. The enzymatic
reactions took place for 30 minutes at room temperature. Then, the reactions were
d with 20 µL of quench detection buffer (50 mM HEPES, 0.5 M KF, EDTA 0.25
M, 0.1% (w/v) BSA, pH 7.5) ning 0.115 µg/mL of anti-phosphoTyr (PT66)-
Cryptate (CisBio) and a variable concentration of SA-XL665 (CisBio) to keep the SA-B
ratio constant. Incubate for 3 h and read on Victor 2V spectrofluorometer (PerkinElmer)
set to read fluorescence resonance energy transfer.
Some of the acronyms used above have the following meaning:
AA: aminoacids
GST: glutathione-S-transferase
MOPS: 3-(N-morpholino)propane sulfonic acid
BSA: bovine serum n
ATP: adenosine tri-phosphate
EDTA: nediaminetetraacetic acid
HEPES: 4-(2-hydroxyethyl)piperazineethanesulfonic acid
SA-XL665: Streptavidin (biotin-binding tetrameric protein isolated from Streptomyces
avidinii) XL665
Table 1 depicts IC50 values for certain exemplary compounds described herein.
Table 1
Example No. IC50 JAK3 IC50 JAK2 IC50 JAK1
(nM) (nM) (nM)
1 3 0.5 12
2 4 1 82
3 4 0.8 150
4 4 1 220
2 0.5 9
6 3 0.7 15
7 2 0.5 10
8 10 0.7 16
9 3 0.7 85
0.7 0.5 32
11 3 1 40
12 4 0.5 4
13 4 1 4
14 1 0.5 1
2 1 13
16 1 0.7 4
e No. IC50 JAK3 IC50 JAK2 IC50 JAK1
(nM) (nM) (nM)
17 1 0.6 2
18 2 0.6 1
19 2 0.3 2
1 0.5 1
21 11 1 6
22 4 0.7 7
23 5 1 8
24 6 1 17
2 0.6 22
26 30 4 26
27 3 0.7 19
28 3 0.8 5
29 10 4 27
2 0.6 4
31 2 0.4 1
32 4 0.6 2
33 2 0.6 6
34 4 0.2 2
2 2 7
36 2 0.5 2
37 7 1 2
38 6 2 4
39 3 0.8 11
40 2 0.8 4
41 3 1 8
42 1 1 13
43 1 0.7 4
44 140 74 970
45 3 1 4
46 4 3 10
47 12 4 10
48 5 2 13
49 14 10 35
e No. IC50 JAK3 IC50 JAK2 IC50 JAK1
(nM) (nM) (nM)
50 9 3 15
51 3 2 36
52 11 1 11
53 3 0.5 2
54 2 2 7
55 33 12 170
56 8 7 43
57 2 2 19
58 7 2 66
59 4 3 29
60 16 7 110
61 8 10 58
62 7 1 4
63 9 3 127
64 4 3 28
65 9 2 38
66 4 0.3 10
67 23 5 139
68 6 1 48
69 11 3 37
70 8 3 28
71 26 2 35
72 6 1 6
73 27 2 13
74 4 1 3
75 26 4 29
76 5 1 9
77 23 2 3
e No. IC50 JAK3 IC50 JAK2 IC50 JAK1
(nM) (nM) (nM)
78 1 0.5 2
79 6 1 2
80 4 1 2
81 2 1 3
82 8 2 9
83 4 2 32
84 5 1 2
85 4 1 1
86 1 3 1
87 3 1 10
88 4 1 14
89 3 1 5
90 4 1 14
91 5 2 114
92 4 1 12
93 6 3 23
94 7 1 7
95 7 3 3
96 2 1 6
97 1 1 2
98 5 2 3
99 7 9 2
100 2 2 0.5
101 1 1 2
102 5 2 1
Example No. IC50 JAK3 IC50 JAK2 IC50 JAK1
(nM) (nM) (nM)
103 1 1 1
104 1 3 4
105 5 5 2
106 1 1 1
It can be seen from Table 1 that the compounds of formula (I) are potent inhibitors of
JAK1, JAK2 and JAK3 kinases. red compounds of the invention possess an IC50
value for the inhibition of JAK1, JAK2 and JAK3 kinases (determined as defined above)
of less than 1 µM (1000 nM), preferably of less than 0.5 µM (500 nM), more preferably
of less than 0.2 µM (200 nM) for each Janus Kinase.
The compounds of this invention have been shown to display an improved profile in the
Ames genotoxicity screen.
The invention is also directed to a nd of the invention as bed herein for
use in the treatment of the human or animal body by therapy. Compounds of the
invention intended for pharmaceutical use may be administered as crystalline or
amorphous products, or mixtures thereof. They may be obtained, for example, as solid
plugs, powders, or films by s such as precipitation, crystallization, freeze drying,
spray drying, or evaporative drying. Microwave or radio frequency drying may be used
for this purpose.
COMBINATIONS
The 2-(pyrazolopyridinyl)pyrimidine derivatives of the present invention may also be
combined with other active compounds in the treatment of a pathological condition or
e susceptible to amelioration by inhibition of Janus Kinases.
The combinations described can optionally se one or more additional active
substances which are known to be useful in the treatment of dermatological diseases,
a respiratory diseases, allergic diseases, inflammatory or mune-mediated
es, function disorders, neurological disorders, cardiovascular diseases, viral
infections, lism/endocrine function disorders, neurological disorders, pain, bone
marrow and organ transplant rejections, myelo-dysplastic syndromes,
myeloproliferative disorder (MPDs), cancer, hematologic malignancies, leukemia,
lymphoma and solid tumors; more in particular n the pathological ion or
disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema,
chronic hand eczema, basal cell oma, squamous cell carcinoma, c
keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus,
cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome,
pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to
pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia,
lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic
lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I
diabetes, asthma, chronic obstructive ary disease (COPD), cystic fibrosis,
iectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis,
inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic
conjunctivitis and keratoconjuntivitis sicca, such as
a) Corticoids and glucocorticoids, such as beclomethasone, betamethasone,
betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate,
fluticasone nate, hydrocortisone, methylprednisolone, sone furoate,
prednicarbate, prednisolone or prednisone;
b) ofolate reductase inhibitors, such as methotrexate or pralatrexate;
c) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide,
teriflunomide or ASLAN-003 or LAS186323;
d) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine;
e) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine;
f) Calcineurin inhibitors, such as cyclosporine A, imus, pimecrolimus or
voclosporin;
g) e-monophosphate dehydrogenase (IMPDH) inhibitors, such as
mycophenolate mophetyl, rin or mizoribine;
h) c acid , such as dimethyl fumarate;
i) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol;
j) Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin;
k) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal dies, such
as infliximab, adalimumab, certolizumab pegol or golimumab;
l) Soluble Tumor necrosis -alpha (TNF-alpha) receptors such as etanercept
or CC-11050;
m) Anti-Interleukin 6 Receptor ) antibody, such as zumab, sarilumab,
SA-237 or ALX-0061;
n) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R)
antibody, such as ustekinumab;
o) nterleukin 17 Receptor (IL-17R) antibody, such as umab;
p) Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab,
uzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab;
q) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab;
r) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab;
s) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab;
t) Anti-Interleukin 4 or ) / Interleukin 13 or (IL-13R) antibody,
such as dupilumab;
u) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or
bimekizumab;
v) Anti-Interleukin 1 Receptor (IL-1R) antibody
w) Anti-Inmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab;
x) -cell activating factor (BAFF), such as belimumab or atacicept;
y) Anti-CD19 (B lymphocyte protein) onal antibody, such as blinatumomab,
MEDI-551 or MOR-208;
z) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or ;
aa) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant,
orvepitant, tradipitant or serlopitant;
bb) Dihydropteroate synthase tors, such as dapsone or sulfadoxine;
cc) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine,
desloratadine, hazine, mizolastine or cetirizine;
dd) nyl riene (CysLT) receptor antagonists, such as montelukast,
zafirlukast, tipelukast, masilukast;
ee) Chemoattractant receptor homologous molecule expressed on TH2 cells
(CRTH2) inhibitors, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipripant;
ff) Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or
sodium hypochlorite water-baths.
The compounds of formula (I) and the combinations described may be used in the
treatment of dermatological diseases, a respiratory es, ic diseases,
inflammatory or autoimmune-mediated diseases, function disorders, neurological
disorders, cardiovascular diseases, viral infections, metabolism/endocrine function
disorders, neurological disorders, pain, bone marrow and organ transplant rejections,
myelo-dysplastic syndromes, myeloproliferative disorder (MPDs), cancer, logic
malignancies, ia, lymphoma and solid tumors; more in particular wherein the
pathological condition or disease is selected from atopic dermatitis, psoriasis, contact
dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell
carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus
erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma,
Sézary syndrome, ma gangrenosum, lichen planus, ring diseases
ing but not limited to pemphigus vulgaris, bullous goid and epidermolysis
bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis,
amyotrophic lateral sclerosis, systemic lupus matosis, autoimmune hemolytic
anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic
fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic
is, inflammatory bowel e, ulcerative colitis, Crohn’s disease, dry eye, uveitis,
allergic ctivitis and keratoconjuntivitis sicca; ably in the treatment of atopic
dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and
vitiligo.
In a preferred embodiment the compounds of formula (I) and the combinations
bed may be used in the treatment of dermatological diseases.
The active compounds in the combination product may be administered together in the
same pharmaceutical ition or in different compositions intended for separate,
simultaneous, concomitant or sequential administration by the same or a different
route.
It is plated that all active agents would be administered at the same time, or
very close in time. Alternatively, one or two actives could be administered in the
morning and the other (s) later in the day. Or in another scenario, one or two actives
could be administered twice daily and the other (s) once daily, either at the same time
as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and
more preferably all, of the actives would be administered together at the same time.
Preferably, at least two, and more preferably all actives would be administered as an
admixture.
Also described is a combination product of the 2-(pyrazolopyridinyl)pyrimidine
tives of the invention together with one or more other therapeutic agents for use
in the treatment of a pathological condition or disease tible to amelioration by
inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or
disease is ed from atopic dermatitis, psoriasis, contact itis, eczema,
chronic hand eczema, basal cell carcinoma, squamous cell oma, actinic
keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus,
cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome,
pyoderma gangrenosum, lichen planus, blistering diseases ing but not limited to
pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia,
lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic
lateral sclerosis, systemic lupus erythematosis, autoimmune tic anemia, type I
diabetes, , chronic obstructive pulmonary disease (COPD), cystic fibrosis,
bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic is,
inflammatory bowel disease, ulcerative colitis, Crohn’s e, dry eye, uveitis, allergic
conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic
itis, psoriasis, chronic hand , cutaneous lupus, alopecia areata and
vitiligo.
The invention also encompasses the use of a combination of the compounds of the
invention er with one or more other therapeutic agents for the manufacture of a
formulation or medicament for treating these diseases.
Also described is a method of treatment of a pathological condition or disease
susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein
the pathological condition or disease is selected from atopic dermatitis, psoriasis,
contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell
carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus
erythematosus, ous vasculitits, dermatomyositis, cutaneous T-cell ma,
Sézary syndrome, ma nosum, lichen planus, blistering diseases
including but not limited to gus vulgaris, bullous pemphigoid and epidermolysis
bullosa, leukemia, mas and solid tumors, rheumatoid arthritis, multiple sclerosis,
amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic
, type I diabetes, asthma, chronic obstructive pulmonary disease , cystic
fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic
rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis,
allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic
dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and
vitiligo, comprising administering a therapeutically effective amount of a combination of
the 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention together with one or
more other therapeutic agents.
The active compounds in the combinations described may be administered by any
suitable route, depending on the nature of the er to be treated, e.g. orally (as
syrups, tablets, capsules, lozenges, lled-release preparations, fast-dissolving
preparations, etc); topically (as creams, ointments, s, nasal sprays or aerosols,
etc) or by injection (subcutaneous, intradermic, intramuscular, enous, etc).
The active compounds in the combination, i.e. the 2-(pyrazolopyridinyl)pyrimidine
derivatives of the invention, and the other optional active compounds may be
administered together in the same pharmaceutical composition or in different
itions intended for separate, simultaneous, concomitant or sequential
administration by the same or a different route.
One execution described consists of a kit of parts comprising a 2-(pyrazolopyridin
yl)pyrimidine derivative of the invention together with instructions for aneous,
concurrent, separate or sequential use in combination with another active compound
useful in the treatment of atopic dermatitis, psoriasis, contact dermatitis, eczema,
chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic
keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus,
cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome,
pyoderma gangrenosum, lichen planus, ring es ing but not limited to
pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia,
lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic
lateral sis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I
diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis,
bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, ic rhinitis,
inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic
conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic
dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and
Another ion described consists of a package comprising a azolopyridin
yl)pyrimidine tive of the invention and another active compound useful in the
treatment of atopic dermatitis, psoriasis, t dermatitis, eczema, chronic hand
eczema, basal cell carcinoma, squamous cell carcinoma, c keratosis, melanoma,
vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits,
omyositis, ous T-cell lymphoma, Sézary syndrome, pyoderma
gangrenosum, lichen planus, blistering diseases including but not d to gus
vulgaris, bullous pemphigoid and epidermolysis a, leukemia, lymphomas and
solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis,
systemic lupus erythematosis, autoimmune hemolytic , type I diabetes, asthma,
chronic obstructive ary disease (COPD), cystic fibrosis, bronchiectasis, cough,
idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease,
tive colitis, Crohn’s e, dry eye, uveitis, allergic conjunctivitis and
keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis,
chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo.
PHARMACEUTICAL COMPOSITIONS
Pharmaceutical compositions ing to the present invention comprise the 2-
(pyrazolopyridinyl)pyrimidine derivatives of the invention in association with a
pharmaceutically acceptable diluent or carrier.
As used herein, the term pharmaceutical composition refers to a mixture of one or
more of the 2-(pyrazolopyridinyl)pyrimidine derivatives described herein, or
physiologically/pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers,
deuterated derivatives thereof or prodrugs thereof, with other chemical ents,
such as physiologically / pharmaceutically acceptable carriers and excipients. The
purpose of a ceutical ition is to facilitate administration of a compound
to an organism.
As used herein, a physiologically/pharmaceutically able diluent or r refers
to a r or diluent that does not cause significant irritation to an organism and does
not abrogate the biological activity and properties of the administered compound.
Further described are pharmaceutical compositions comprising the 2-(pyrazolopyridin-
3-yl)pyrimidine derivatives of the invention in association with a pharmaceutically
acceptable diluent or carrier together with one or more other therapeutic agents for use
in the treatment of a pathological condition or disease susceptible to amelioration by
inhibiton of Janus Kinases (JAK), such as the ones previously described.
The invention is also directed to pharmaceutical compositions of the ion for use
in the treatment of a pathological condition or disease susceptible to amelioration by
inhibiton of Janus Kinases (JAK), in particular atopic dermatitis, psoriasis, t
itis, eczema, c hand eczema, basal cell carcinoma, squamous cell
carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus
erythematosus, cutaneous itits, dermatomyositis, cutaneous T-cell lymphoma,
Sézary me, pyoderma gangrenosum, lichen planus, blistering diseases
including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis
a, leukemia, mas and solid tumors, rheumatoid arthritis, multiple sclerosis,
amyotrophic lateral sclerosis, ic lupus erythematosis, autoimmune hemolytic
anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic
fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic
rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis,
allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic
dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and
vitiligo.
Also described is the use of a pharmaceutical ition of the invention for the
manufacture of a medicament for treating these diseases.
Also described is a method of treatment of a pathological condition or disease
susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein
the pathological condition or disease is selected from atopic dermatitis, psoriasis,
contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell
carcinoma, actinic keratosis, melanoma, vitiligo, alopecia , cutaneous lupus
erythematosus, cutaneous vasculitits, dermatomyositis, ous T-cell lymphoma,
Sézary me, pyoderma gangrenosum, lichen planus, blistering diseases
including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis
bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sis,
amyotrophic lateral sclerosis, systemic lupus erythematosis, mune hemolytic
anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic
fibrosis, bronchiectasis, cough, idiopathic ary fibrosis, sarcoidosis, allergic
rhinitis, inflammatory bowel e, ulcerative colitis, Crohn’s disease, dry eye, uveitis,
allergic conjunctivitis and keratoconjuntivitis sicca; ably in the treatment of atopic
dermatitis, sis, chronic hand eczema, cutaneous lupus, alopecia areata and
vitiligo, comprising administering a therapeutically ive amount of a pharmaceutical
composition of the invention.
The present invention also provides pharmaceutical compositions which comprise, as
an active ingredient, at least a 2-(pyrazolopyridinyl)pyrimidine derivative which is a
compound of formula (I) or a ceutically acceptable salt, or solvate, or N-oxide,
or stereoisomer or ated derivative f in ation with a pharmaceutically
acceptable excipient such as a carrier or diluent. Preferably the compositions are made
up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable
administration. The compounds of the present invention show physicochemical
properties (such as solubility water and in a range of ilic and hydrophilic solvents,
melting point and stability), which make them specially suitable for topical
administration.
In a preferred embodiment, the compositions are made up in a form suitable for topical
administration.
Pharmaceutical compositions suitable for the ry of 2-(pyrazolopyridin
yl)pyrimidine derivatives of the invention and methods for their preparation will be
readily apparent to those skilled in the art. Such compositions and methods for their
preparation can be found, for example, in Remington: The Science and Practice of
Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.
i) l stration
The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may be administered
topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations
for this purpose include gels, hydrogels, s, solutions, creams, ointments, dusting
powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers,
bandages and microemulsions. Other means of topical administration e delivery
by oporation, iontophoresis, phonophoresis, sonophoresis and microneedle or
needle-free injection.
ations for topical administration may be formulated to be immediate and/or
modified release. Modified e formulations e delayed-, sustained-, pulsed-,
controlled-, targeted and programmed e.
ii) Oral Administration
The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may be administered
orally (peroral administration; per os (latin)). Oral administration involve swallowing, so
that the compound is absorbed from the gut and delivered to the liver via the portal
circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (GI)
tract.
Compositions for oral administration may take the form of tablets, retard tablets,
sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder
inhalation, or liquid preparations, such as es, solutions, elixirs, syrups or
suspensions, all containing the compound of the invention; such preparations may be
made by methods well-known in the art. The active ingredient may also be presented
as a bolus, electuary or paste.
iii) Oral mucosal administration
The 2-(pyrazolopyridinyl)pyrimidine tives of the invention can also be
administered via the oral l. Within the oral mucosal cavity, delivery of drugs is
classified into three categories: (a) sublingual delivery, which is systemic delivery of
drugs through the mucosal membranes lining the floor of the mouth, (b) buccal
delivery, which is drug administration through the mucosal membranes lining the
cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral
cavity.
Pharmaceutical products to be administered via the oral l can be designed
using hesive, quick dissolve tablets and solid lozenge formulations, which are
formulated with one or more mucoadhesive (bioadhesive) polymers and/or oral
mucosal permeation ers.
iv) Inhaled administration
The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention can also be
administered by inhalation, typically in the form of a dry powder from a dry powder
inhaler or as an l spray from a pressurized container, pump, spray, er
(preferably an atomizer using electrohydrodynamics to produce a fine mist), or
nebulizer, with or t the use of a suitable lant.
v) Nasal mucosal administration
The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may also be
administered via the nasal mucosal.
Typical compositions for nasal mucosa administration are typically applied by a
metering, atomizing spray pump and are in the form of a solution or suspension in an
inert e such as water optionally in combination with conventional excipients such
as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.
vi) Parenteral Administration
The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may also be
administered directly into the blood stream, into , or into an internal organ.
Suitable means for parenteral administration include intravenous, intraarterial,
intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, ranial,
intramuscular and subcutaneous. Suitable devices for parenteral administration include
needle (including eedle) injectors, needle-free injectors and infusion ques.
Parenteral formulations are typically aqueous solutions which may contain excipients
such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9),
but, for some applications, they may be more suitably formulated as a sterile eous
solution or as a dried form to be used in conjunction with a suitable vehicle
such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by
lyophilization, may y be accomplished using standard pharmaceutical techniques
well known to those skilled in the art. The solubility of compounds of the invention used
in the preparation of parenteral solutions may be increased by the use of appropriate
ation techniques, such as the incorporation of solubility-enhancing agents.
vii) /lntravaginal Administration
2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may be administered
rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
Cocoa butter is a traditional suppository base, but various atives may be used as
appropriate. Formulations for /vaginal administration may be formulated to be
immediate and/or modified release. Modified release formulations include delayed-,
ned-, -, controlled-, targeted and programmed release.
viii) Ocular Administration
2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may also be administered
directly to the eye or ear, typically in the form of drops of a micronized suspension or
solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular
and aural administration include nts, biodegradable {e.g. able gel
sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and
particulate or vesicular systems, such as niosomes or liposomes. Such formulations
may also be delivered by iontophoresis.
Formulations for /aural stration may be ated to be immediate and/or
modified release. Modified release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted, or programmed release.
The amount of the active 2-(pyrazolopyridinyl)pyrimidine derivative administered will
be dependent on the subject being d, the severity of the disorder or condition, the
rate of administration, the disposition of the compound and the discretion of the
prescribing physician. However, an effective dosage is typically in the range of 0.01-
3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of
a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered
in one or more treatments, preferably from 1 to 4 treatments, per day.
Preferably, the the pharmaceutical compositions of the invention are made up in a form
suitable for oral or topical administration, being ularly preferred topical
administration.
The amount of each active which is ed to achieve a therapeutic effect will, of
course, vary with the particular active, the route of administration, the subject under
treatment, and the particular er or disease being treated.
The following preparations forms are cited as formulation es:
Formulation Examples
Formulation Example 1 (Oral suspension)
Ingredient Amount
Active Compound 3 mg
Citric acid 0,5 g
Sodium chloride 2,0 g
Methyl paraben 0,1 g
Granulated sugar 25 g
Sorbitol (70% solution) 11 g
Veegum K 1,0 g
Flavoring 0,02 g
Dye 0,5 mg
Distilled water q.s. to 100 mL
Formulation Example 2 (Hard gelatine capsule for oral administration)
Ingredient Amount
Active Compound 1 mg
Lactose 150 mg
Magnesium stearate 3 mg
Formulation e 3 (O/W emulsion)
Ingredient Amount
Active compound 1%
Cetyl alcohol 3%
Stearyl alcohol 4%
yl monostearate 4%
Sorbitan monostearate 0.8%
Sorbitan monostearate POE 0.8%
Liquid vaseline 5%
Methylparaben 0.18%
Propylparaben 0.02%
Glycerine 15%
Purified water csp. 100%
ation Example 4 (O/W emulsion)
Ingredient Amount
Active compound 1%
ic/Carpic ceride 5%
Cetyl alcohol 7%
Gliceryl monostearate 3.5%
Sorbitan monostearate 0.8%
Sorbitan monostearate POE 0.7%
White petrolatum 10%
Stearoxytrimethysilane 5%
EDTA 0.1%
Methylparaben 0.18%
Propylparaben 0.02%
Glycerine 20%
Purified water csp. 100%
Formulation Example 5 (O/W emulsion)
Ingredient Amount
Active compound 1%
Octyldodecanol 5%
Cetyl alcohol 4%
Gliceryl monostearate 6%
Ceteareth-12 1.5%
Ceteareth-20 1.5%
an monostearate POE 0.7%
White petrolatum 3%
Dimethicole 1.5%
Benzyl alcohol 2%
Glycerine 20%
Propilenglycol 10%
Purified water csp. 100%
Modifications, which do not affect, alter, change or modify the essential aspects of the
2-(pyrazolopyridinyl)pyrimidine derivatives, combinations or pharmaceutical
compositions described, are ed within the scope of the present invention.
142 142
The following numbered paragraphs define particular aspects of the present invention:
1. A 2-(pyrazolopyridinyl)pyrimidine derivative for use in the treatment of the human
or animal body, which 2-(pyrazolopyridinyl)pyrimidine derivative is a compound of
formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or
stereoisomer or ated derivative thereof:
Formula (I)
wherein
• X represents –O- or –NR3- group,
• R1 and R2 are independently ed from the group consisting of a hydrogen
atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or branched C1-4
alkoxy group and -CN group;
• R3 is selected from the group consisting of a hydrogen atom, a linear or
branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine
group;
• G1 is selected from the group consisting of –CN group, -CO-Ra group, a –O-R6
group, a -(CHR7)m-NR’R’’ group, a phenyl group, a clic C5-7 cycloalkyl
group, a monocyclic 5- to 6- membered heteroaryl group containing at least one
heteroatom ed from O, S and N and a monocyclic 5- to 6- membered
cyclyl group containing at least one heteroatom selected from O, S and
N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are
unsubstituted or substituted by one or more substituents selected from a
halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear
or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a -
(CH2)0-2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra
represents a en atom, a yl group, a linear or branched C1-3 alkyl
group, a linear or ed C1-3 alkoxy group or an amino group,
• Q is selected from the group consisting of:
wherein
o R4 is selected from the group consisting of a linear or branched C1-4 alkyl
group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, -
CO(CH2)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6-
membered heterocyclyl group containing at least one heteroatom
selected from O, S and N and a monocyclic 5- to 6- membered
heteroaryl group containing at least one heteroatom selected from O, S
and N, wherein the heterocyclyl and heteroaryl group independently are
unsubstituted or substituted with one or more substituents selected from
–(CH2)m-CN group and a C1-2 yalkyl group,
o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group;
o G2 represents a phenyl group, a pyrimidine group or a pyridine group,
wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or
substituted by one or more substituents selected from a n atom, a
linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group,
• R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O-
R”’ group, a linear or ed (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or
branched C1-6 alkyl group wherein said linear or ed C1-6 alkyl group is
unsubstituted or substituted with one or more substituents ed from a
halogen atom, a hydroxyl group and –NR’R” group,
• R7 represents a hydrogen atom, a hydroxyl or a C1-2 alkyl group,
• R’ and R’’ independently represents a hydrogen atom, a linear or ed C1-3
alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched
C1-3 alkoxy group,
• R”’ represents a C1-2 alkyl group or a benzyl group, and
• m independently has a value from 0 to 3,
wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not:
• 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a]
nylpyrimidinyl)amino]piperidinyl}oxopropanenitrile
• 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxopropanenitrile
• (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxetanyl)acetonitrile
• Ethyl -[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
• 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxoethanol
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile or
• 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile.
2. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 1
wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not:
• )[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxopropanenitrile
• 3-[(3R)({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a]
pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a]
pyridinyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile
• (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl)
pyrimidinyl)amino)piperidinyl)oxopropanenitrile
3. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraphs 1 or 2
wherein R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl
group, preferably a fluorine atom, a hydrogen atom or a methyl group.
4. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any one of the
ing paragraphs wherein R2 represents a hydrogen atom or a ne atom,
preferably a en atom.
. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any preceding
paragraph wherein X represents a –O- or –NR3- group.
6. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 5
wherein R3 represents a hydrogen atom.
7. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any preceding
paragraph wherein Q represents Qa.
8. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraph 7
n R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; preferably
R4 represents a –C(O)CH2OH group or a -C(O)CH2CN group.
9. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any preceding
paragraph wherein G1 ents a –O-R6 group, a CN group or a monocyclic 5- to 6-
membered heteroaryl group containing at least one heteroatom selected from O, S and
N and being unsubstituted or substituted by one or more substituents selected from a
halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or
ed C1-2 hydroxyalkyl group or a linear or branched C1-4 alkoxy group.
. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 9
wherein R6 represents a linear or branched (C1-6 )-(C1-6 alkyl) group or a linear or
branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more substituents selected from a halogen
atom and a hydroxyl group.
11. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraph 1
wherein
• R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl
group, preferably a fluorine atom, a hydrogen atom or a methyl group;
• R2 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom;
• X represents a –O- or –NR3- group;
• R3 ents a hydrogen atom;
• Q represents Qa;
• R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; preferably
R4 ents a –C(O)CH2OH group or a -C(O)CH2CN group;
• G1 represents a –O-R6 group, a CN group or a monocyclic 5- to 6-membered
heteroaryl group containing at least one heteroatom selected from O, S and N
and being unsubstituted or substituted by one or more substituents selected
from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a
linear or branched C1-2 hydroxyalkyl group or a linear or branched C1-4 alkoxy
group; and
• R6 represents a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group or a linear or
branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more tuents selected from a
halogen atom and a hydroxyl group.
12. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 1
wherein
• X represents –O- or –NR3- group,
• R1 and R2 are independently ed from the group consisting of a en
atom, a fluorine atom and a methyl group;
• R3 is selected from the group consisting of a hydrogen atom and a methyl
group;
• G1 is ed from the group consisting of –CN group, a –CONH2 group, a -
CO2Et group, a –CO2iPr group, a –O-R6 group, a –NHCH2CH2OH group, a
phenyl group, a pyridinyl group, a pyrazolyl group, a piperidinyl group, a
piperazinyl group, a morpholinyl group, wherein the phenyl, pyridinyl, pyrazolyl,
piperidinyl, piperazinyl and morpholinyl groups are unsubstituted or substituted
by one or more substituents selected from a hydroxyl group, a methyl group, a -
CH2OH group, a –CH2-C(OH)(CH3)2 group, a methoxy group, an amino group, a
)2 group, a –COOH group and a –CO2Et group;
• R4 is selected from the group consisting of a -CO(CH2)-OH group; 2)-
CN group, a pyrazinyl group and a pyrimidinyl group, wherein the pyrazinyl and
pyrimidinyl groups independently are unsubstituted or substituted with a CN
group or a –-CH2OH group;
• R5 represents a N group;
• G2 represents a pyrimidine group or a pyridine group, wherein the pyrimidine
and pyridine groups are tituted or substituted by a fluorine atom; and
• R6 is selected from the group consisting of a hydrogen atom, a -CH2CO2CH2Ph
group, a –(CH2)2OCH3 group, a –(CH2)2OCH2CH3 group, a 3)CH2OCH3
group, a methyl group, an ethyl group, a butyl group, a –CH2CF3 group, a –
CH2CHF2 group, a CH(CH3)2 group, a –(CH2)2OH group, a –(CH2)2-3N(CH3)2
group, a -CH(CH3)-CH2OH group, a –CH2CH(OH)CH2OH group.
13. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraph 1
which is one of
(Trans{[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}cyclohexyl)acetonitrile;
(Trans{[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}cyclohexyl)acetonitrile;
{Trans[(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]cyclohexyl}acetonitrile;
[Trans({6-[4-(dimethylamino)piperidinyl]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile;
(Trans{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
no}cyclohexyl)acetonitrile;
{Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]cyclohexyl}acetonitrile;
{Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)amino]cyclohexyl}acetonitrile;
[Trans({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl}amino)cyclohexyl]acetonitrile;
[trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile;
[Trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)cyclohexyl]acetonitrile;
6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrazolo
[1,5-a]pyridinylpyrimidinamine;
2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]etanol;
(2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-
a]pyridinylpyrimidinyl)oxy]propane-1,2-diol;
3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxopropanenitrile;
3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitril;
3-((3R){[6-(6-Aminopyridinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-((3R){[5-fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxopropanenitrile;
3-((3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-{(3R)[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl](methyl)amino]piperidinyl}oxopropanenitrile;
1-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)piperidinol;
2-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
2-((3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol;
2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
no]piperidinyl}oxoethanol;
2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
Ethyl 1-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)methylpiperidinecarboxylate;
2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin
ylpyrimidinyl]amino}piperidinyl)oxoethanol;
Ethyl 1-(6-{[(3R)(cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-
a]pyridinylpyrimidinyl)piperidinecarboxylate;
1-(6-{[(3R)(Cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl)piperidinecarboxylic acid;
2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(1H-pyrazolyl)pyrimidin
yl]amino}piperidinyl)oxoethanol;
1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)-1H-pyrazolyl]methylpropanol;
2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin
midinyl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxoethanol;
2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
Ethyl 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)pyridinecarboxylate;
2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)oxy]propanol;
2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]
piperidinyl}oxoethanol;
ro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinol;
Benzyl [(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]acetate;
)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
Ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarboxylate;
-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarbonitrile;
-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinecarboxamide;
2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidin-
4-yl]amino}piperidinyl)oxoethanol;
2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
]piperidinyl}oxoethanol;
3-{(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxopropanenitrile;
5-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrazinecarbonitrile;
(5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
no]piperidinyl}pyrazinyl)methanol;
-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}pyrazinecarbonitrile;
2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrimidinecarbonitrile;
2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
(2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]propanol;
2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
(2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl)oxy]propanol;
2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
]piperidinyl}oxoethanol;
3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin
yl)oxy]piperidinyl}oxopropanenitrile;
2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]oxy}piperidinyl)oxoethanol;
3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]oxy}piperidinyl)oxopropanenitrile;
2-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxoethanol;
3-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile;
2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxoethanol;
3-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile;
2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]oxy}piperidinyl)oxoethanol;
3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
xy}piperidinyl)oxopropanenitrile;
3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile;
2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}oxy)piperidinyl]oxoethanol;
1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin
midinyl)piperidinol;
){[5-Fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile;
2-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin-
4-yl](methyl)amino]piperidinyl}oxoethanol;
3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile;
-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)pyridinecarboxylic acid;
2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-[(3R)({6-[6-(Dimethylamino)pyridinyl]fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
2-{(3R)[(5-Fluoro-2'-methylpyrazolo[1,5-a]pyridinyl-4,5'-bipyrimidin
yl)amino]piperidinyl}oxoethanol;
2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
2-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
3-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile;
2-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile;
2-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxoethanol;
3-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile;
(2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin
ylpyrimidinyl)oxy]propanol;
)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile;
Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin-
3-ylpyrimidinecarboxylate;
)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinyl}oxoethanol;
2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin
yl}oxoethanol;
3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin
yl}oxopropanenitrile;
2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
no}piperidinyl)oxoethanol;
2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxoethanol;
3-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)pyrazinecarbonitrile;
-(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin
yl)pyridinol;
3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile;
2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)(methyl)amino]piperidinyl}oxoethanol; or
a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated
tive f.
14. A 2-(pyrazolopyridinyl)pyrimidine derivative as d in any one of paragraphs
1 to 13, for use in the treatment of a pathological condition or disease susceptible to
amelioration by inhibition of Janus Kinases.
. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any one of
paragraphs 1 to 14, wherein the treatment is of a pathological condition or disease
selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand
eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma,
vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits,
omyositis, ous T-cell lymphoma, Sézary syndrome, pyoderma
gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus
vulgaris, bullous pemphigoid and epidermolysis bullosa, ia, lymphomas and
solid tumors, rheumatoid arthritis, multiple sis, amyotrophic lateral sclerosis,
ic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma,
chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough,
thic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease,
ulcerative colitis, Crohn’s disease, dry eye, uveitis, ic conjunctivitis and
keratoconjuntivitis sicca; preferably from atopic dermatitis, psoriasis, chronic hand
eczema, ous lupus, alopecia areata and vitiligo.
16. A pharmaceutical composition comprising a 2-(pyrazolopyridinyl)pyrimidine
derivative as defined in any one of paragraphs 1 to 13 in association with a
pharmaceutically acceptable diluent or carrier.
17. Use of a 2-(pyrazolopyridinyl)pyrimidine tive as defined in any one of
paragraphs 1 to 13, for the manufacture of a medicament for the treatment of a
pathological condition or disease as defined in aph 14 or 15.
18. A method for treating a subject afflicted with a ogical condition or disease as
defined in paragraph 14 or 15, which comprises administering to said subject a
therapeutically effective amount of a 2-(pyrazolopyridinyl)pyrimidine derivative as
d in any one of paragraphs 1 to 13, or a ceutical composition as defined
in aph 16.
19. A combination t sing (i) at least one 2-(pyrazolopyridinyl)pyrimidine
derivative as defined in any one of paragraphs 1 to 13, and (ii) one or more active
ingredients selected from:
gg) Corticoids and glucocorticoids, such as beclomethasone, betamethasone,
betamethasone dipropionate, nide, dexamethasone, fluticasone furoate,
fluticasone propionate, hydrocortisone, methylprednisolone, sone furoate,
prednicarbate, prednisolone or prednisone;
hh) Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate;
ii) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide,
teriflunomide or ASLAN-003 or LAS186323;
jj) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine;
kk) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine;
ll) Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or
voclosporin;
mm) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as
enolate mophetyl, ribavirin or mizoribine;
nn) Fumaric acid esters, such as dimethyl fumarate;
oo) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol;
pp) Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin;
qq) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) onal antibodies, such
as infliximab, adalimumab, certolizumab pegol or golimumab;
rr) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept
or CC-11050;
ss) Anti-Interleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab,
SA-237 or ALX-0061;
tt) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor R)
antibody, such as numab;
uu) Anti-Interleukin 17 Receptor (IL-17R) antibody, such as brodalumab;
vv) Anti-CD20 (B lymphocyte protein) antibody, such as mab, ofatumumab,
uzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab;
ww) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab;
xx) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab;
yy) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab;
zz) Anti-Interleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody,
such as dupilumab;
aaa) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, umab or
bimekizumab;
bbb) Anti-Interleukin 1 or (IL-1R) antibody
ccc) Anti-Inmunoglobuline E (IgE) antibody, such as omalizumab or umab;
ddd) Anti-B-cell activating factor (BAFF), such as belimumab or atacicept;
eee) Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab,
MEDI-551 or MOR-208;
fff) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or ;
ggg) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant,
orvepitant, tradipitant or serlopitant;
hhh) Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine;
iii) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine,
desloratadine, promethazine, mizolastine or cetirizine;
jjj) Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast,
ukast, tipelukast, kast;
kkk) Chemoattractant receptor homologous molecule expressed on TH2 cells
(CRTH2) inhibitors, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or ipant;
lll) Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or
sodium hypochlorite water-baths.
. A 2-(pyrazolopyridinyl)pyrimidine tive, which 2-(pyrazolopyridin
yl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically acceptable
salt, or solvate, or N-oxide, or stereoisomer or ated derivative thereof:
Formula (I)
wherein
• X represents –O- or –NR3- group,
• R1 and R2 are independently selected from the group consisting of a hydrogen
atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or ed C1-4
alkoxy group and -CN group;
• R3 is selected from the group consisting of a hydrogen atom, a linear or
branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine
group;
• G1 is selected from the group consisting of –CN group, -CO-Ra group, a –O-R6
group, a -(CHR7)m-NR’R’’ group, a phenyl group, a monocyclic C5-7 cycloalkyl
group, a monocyclic 5- to 6- membered heteroaryl group containing at least one
heteroatom selected from O, S and N and a monocyclic 5- to 6- membered
heterocyclyl group containing at least one heteroatom selected from O, S and
N, wherein the phenyl, cycloalkyl, heteroaryl and cyclyl groups are
unsubstituted or substituted by one or more substituents selected from a
halogen atom, a yl group, a linear or branched C1-4 alkyl group, a linear
or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a -
(CH2)0-2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra
represents a en atom, a yl group, a linear or branched C1-3 alkyl
group, a linear or branched C1-3 alkoxy group or an amino group,
• Q is selected from the group consisting of:
wherein
o R4 is selected from the group consisting of a linear or branched C1-4 alkyl
group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, -
)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6-
ed heterocyclyl group containing at least one heteroatom
selected from O, S and N and a monocyclic 5- to 6- membered
heteroaryl group containing at least one atom selected from O, S
and N, wherein the heterocyclyl and heteroaryl group independently are
unsubstituted or substituted with one or more substituents selected from
–(CH2)m-CN group and a C1-2 hydroxyalkyl group,
o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group;
o G2 represents a phenyl group, a pyrimidine group or a pyridine group,
wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or
substituted by one or more substituents ed from a n atom, a
linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group,
• R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O-
R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or
branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is
unsubstituted or substituted with one or more substituents selected from a
halogen atom, a hydroxyl group and –NR’R” group,
• R7 represents a hydrogen atom, a yl or a C1-2 alkyl group,
• R’ and R’’ independently represents a hydrogen atom, a linear or ed C1-3
alkyl group, a linear or ed C1-3 hydroxyalkyl group, a linear or branched
C1-3 alkoxy group,
• R”’ represents a C1-2 alkyl group or a benzyl group, and
• m independently has a value from 0 to 3,
wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not:
• 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a]
nylpyrimidinyl)amino]piperidinyl}oxopropanenitrile
• 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxopropanenitrile
• (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl) amino]piperidinyl}oxetanyl)acetonitrile
• Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin
yl)amino]piperidinecarboxylate
• 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxoethanol
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin-
3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl)
amino]piperidinyl}oxopropanenitrile
• )({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin-
4-yl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a]
pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin
ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile
• 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin
ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile
• 3-((3R){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin
yl]amino}piperidinyl)oxopropanenitrile
• 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl}
pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}
oxopropanenitrile
• (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a]
nyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile
• (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl)
dinyl)amino)piperidinyl)oxopropanenitrile
21. A 2-(pyrazolopyridinyl)pyrimidine derivative according to paragraph 20, which 2-
(pyrazolopyridinyl)pyrimidine derivative is a compound of formula (I), or a
pharmaceutically acceptable salt, or solvate, or e, or stereoisomer or deuterated
derivative thereof, as defined in any one of paragraphs 3 to 13.
Claims (26)
1. A 2-(pyrazolopyridinyl)pyrimidine derivative, which 2-(pyrazolopyridin yl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically able 5 salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof: Formula (I) wherein 10 • X represents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or ed C1-4 alkoxy group and -CN group; • R3 is selected from the group consisting of a hydrogen atom, a linear or 15 branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a 1pyrrolidine group; • G1 is a –O-R6 group, • Q is selected from the group consisting of: 20 n o R4 is selected from the group consisting of a linear or branched C1-4 alkyl group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, - CO(CH2)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6- membered heterocyclyl group containing at least one heteroatom 25 selected from O, S and N and a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N, n the heterocyclyl and heteroaryl group independently are unsubstituted or substituted with one or more substituents selected from –(CH2)m-CN group and a C1-2 hydroxyalkyl group, o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group; o G2 represents a phenyl group, a pyrimidine group or a pyridine group, 5 wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents selected from a n atom, a linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group, • R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O- R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or 10 branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group and –NR’R” group, • R’ and R’’ independently represents a hydrogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched 15 C1-3 alkoxy group, • R”’ represents a C1-2 alkyl group or a benzyl group, and • m independently has a value from 0 to 3.
2. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 wherein R1 20 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group,
3. A azolopyridinyl)pyrimidine derivative according to claim 2, wherein R1 ents a fluorine atom, a hydrogen atom or a methyl group. 25
4. A 2-(pyrazolopyridinyl)pyrimidine derivative according to any one of the preceding claims wherein R2 represents a hydrogen atom or a fluorine atom,
5. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 4, wherein R2 represents a hydrogen atom.
6. A 2-(pyrazolopyridinyl)pyrimidine derivative according to any one of the preceding claims wherein X represents a –O- or –NR3- group.
7. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 6 n R3 35 represents a hydrogen atom.
8. A 2-(pyrazolopyridinyl)pyrimidine derivative according to any one of the preceding claims wherein Q represents Qa.
9. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 8 wherein R4 5 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group
10. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 9, n R4 represents a –C(O)-CH2OH group or a –C(O)CH2CN group. 10
11. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 wherein • R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, • R2 represents a hydrogen atom or a fluorine atom ; • X represents a –O- or –NR3- group; 15 • R3 ents a hydrogen atom; • Q represents Qa; • R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; • G1 represents a –O-R6 group; and • R6 represents a linear or branched (C1-6 )-(C1-6 alkyl) group or a linear or 20 branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents ed from a halogen atom and a hydroxyl group.
12. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 11, wherein 25 • R1 represents a fluorine atom, a hydrogen atom or a methyl group. • R2 represents a hydrogen atom • R4 represents a –C(O)CH2OH group or a –C(O)CH2CN group.
13. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 wherein 30 • X ents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a en atom, a fluorine atom and a methyl group; • R3 is selected from the group consisting of a hydrogen atom and a methyl group; 35 • G1 is a –O-R6 group; • R4 is selected from the group consisting of a -CO(CH2)-OH group; -CO(CH2)-CN group, a nyl group and a pyrimidinyl group, wherein the pyrazinyl and pyrimidinyl groups independently are unsubstituted or substituted with a CN group or a –-CH2OH group; 5 • R5 represents a –CH2-CN group; • G2 represents a pyrimidine group or a pyridine group, wherein the pyrimidine and ne groups are unsubstituted or substituted by a fluorine atom; and • R6 is selected from the group consisting of a hydrogen atom, a -CH2CO2CH2Ph group, a –(CH2)2OCH3 group, a 2OCH2CH3 group, a –CH(CH3)CH2OCH3 10 group, a methyl group, an ethyl group, a butyl group, a –CH2CF3 group, a – CH2CHF2 group, a )2 group, a –(CH2)2OH group, a –(CH2)2-3N(CH3)2 group, a -CH(CH3)-CH2OH group, a –CH2CH(OH)CH2OH group.
14. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 which is one of (Trans{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin 15 yl]amino}cyclohexyl)acetonitrile; {Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; {Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; 20 [trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; [Trans({6-[2-(dimethylamino)propoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; 2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-a]pyridin- 25 3-ylpyrimidinyl)oxy]ethanol; (2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propane-1,2-diol; 3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxopropanenitrile; 30 3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxopropanenitrile; 3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin 35 yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 5 3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; )[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino] dinyl}oxoethanol; 5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin 10 ylpyrimidinol; Benzyl [(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]acetate; 2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 15 2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin 20 no]piperidinyl}oxoethanol; 5-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; (5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinyl)methanol; 25 5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinecarbonitrile; 2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrimidinecarbonitrile; 2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin 30 ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; 2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin 35 ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxoethanol; 3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile; 5 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin 10 yl]amino}piperidinyl)oxoethanol; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; 5-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile; 15 2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin yl}oxoethanol; 3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin 20 yl}oxopropanenitrile; 2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxopropanenitrile; 25 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 5-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; or a pharmaceutically acceptable salt, N-oxide, e, isomer or deuterated 30 derivative thereof.
15. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 1, which is 3-[(5- Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)oxy]propanol, or a pharmaceutically acceptable salt, N-oxide, solvate, 35 stereoisomer or deuterated derivative thereof.
16. A 2 -(pyrazolopyridinyl)pyrimidine tive according to claim 1, which is 2- {(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin no]piperidinyl}oxoethanol, or a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated derivative thereof.
17. A 2 -(pyrazolopyridinyl)pyrimidine derivative according to claim 1, which is 3- ((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxopropanenitrile, or a pharmaceutically acceptable salt, N- oxide, solvate, stereoisomer or deuterated derivative thereof.
18. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1, which is 3- ((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile, or a pharmaceutically acceptable salt, N- oxide, solvate, stereoisomer or ated derivative f.
19. A 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 18, for use in the treatment of the human or animal body.
20. A 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 20 18, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Janus Kinases.
21. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to claim 20, wherein the treatment is of a pathological condition or disease selected from atopic 25 itis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo.
22. A pharmaceutical composition sing a 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 18, in association with a 30 pharmaceutically acceptable diluent or carrier.
23. Use of a 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 18, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claim 20 or 21.
24. A 2-(pyrazolopyridinyl)pyrimidine tive, which 2-(pyrazolopyridin yl)pyrimidine derivative is a compound of formula (I) as claimed in any one of claims 1 to 21, substantially as herein described with reference to any example thereof. 5
25. A pharmaceutical composition as claimed in claim 22, substantially as herein described with reference to any example f.
26. A use as claimed in claim 23, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15382305 | 2015-06-11 | ||
EP15382305.9 | 2015-06-11 | ||
PCT/EP2016/063391 WO2016198663A1 (en) | 2015-06-11 | 2016-06-10 | 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as jak inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ737314A NZ737314A (en) | 2021-02-26 |
NZ737314B2 true NZ737314B2 (en) | 2021-05-27 |
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