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ZA200505935B - Pyrazolopyridine derivatives - Google Patents

Pyrazolopyridine derivatives Download PDF

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Publication number
ZA200505935B
ZA200505935B ZA200505935A ZA200505935A ZA200505935B ZA 200505935 B ZA200505935 B ZA 200505935B ZA 200505935 A ZA200505935 A ZA 200505935A ZA 200505935 A ZA200505935 A ZA 200505935A ZA 200505935 B ZA200505935 B ZA 200505935B
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ZA
South Africa
Prior art keywords
pyrazolo
fluorophenyl
pyridyl
bis
pyridine
Prior art date
Application number
ZA200505935A
Inventor
Carmen Almansa Rosales
Marina Virgili Bernado
Original Assignee
Uriach Y Compania S A J
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Publication of ZA200505935B publication Critical patent/ZA200505935B/en

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Description

Pyrazolopyridine derivatives
Field of the invention 3 The present invention relates to a new series of pyrazolopyridine derivatives, a process to prepare them, pharmaceutical compositions containing . 5 these compounds and their application in medicine. :
Background of the invention
Kinases are proteins involved in different cellular responses to external signals. In the Nineties, a new family of kinases called MAPK (mitogen-activated protein kinases) was discovered. MAPK activate their substrates by phosphorylation in serine and threonine residues.
MAPK are activated by other kinases in response to a wide range of signals including growth factors, pro-inflammatory cytokines, UV radiation, endotoxins and osmotic stress. Once they are activated, MAPK activate by phosphorylation other kinases or proteins, such as transcription factors, which, ultimately, induce an increase or a decrease in expression of a specific gene or group of genes.
The MAPK family includes kinases such as p38, ERK (exfracellular- regulated protein kinase) and JNK (C-Jun N-terminal kinase).
Kinase p38 plays a crucial role in cellular response to stress and in the activation pathway in the synthesis of numerous cytokines, especially tumor necrosis factor (TNF-q), interleukin-i (IL-1), interleukin-6 (IL-6) and interleukin-3 (IL-8).
IL-1 and TNF-a are produced by macrophages and monocytes and are involved in the mediation of immunoregulation processes and other physiopathological conditions. For example, elevated levels of TNF-a are associated with inflammatory and autoimmune diseases and with processes that trigger the degradation of connective and bone tissue such as rheumatoid arthritis, osteoarthritis, diabetes, inflammatory bowel disease and sepsis. , Thus, p38 kinase inhibitors could be useful to treat or prevent diseases mediated by cytokines such as IL-1 and TNF-a, as mentioned previously. g 30 On the other hand, it has also been found that p38 inhibitors inhibit other pro-inflammatory proteins such as IL-6, IL-8, interferon-y and GM-CSF (granulocyte-macrophage colony-stimulating factor). Moreover, in recent studies it has been found that p38 inhibitors not only block cytokine synthesis but also the
) cascade of signals that these induce, such as induction of the cyclooxygenase-2 enzyme (COX-2). . Description of the invention
One aspect of the present invention relates to the new compounds of . 5 general formula l
R __A NR
QC]
R2
R3 R* wherein:
A represents N or NO”;
R' represents phenyl or Het optionally substituted with one or mere substituents selected from R? and R®;
R? represents Het optionally substituted with one or more substituents selected from R? and R?; 18
R® represents H, Cy optionally substituted with one or more substituents selected from R? and R®, or R® represents Ci.salkyl optionally substituted with one or more substituents selected from R® and Cy*, wherein Cy* can be optionally substituted with one or more substituents selected from RP and R%;
R? represents H, R® halogen, -OR*, -OCOR? -OSO2R? -OCONR®R?, -NO,, © -CN, -COR¥, -CO;R?, -CONR¥R?, -NR¥R?, -NR¥COR?¥, -NR¥CONR’R?, -NR¥CO,R?, -NRTS0O,R?, -SR?, -SOR?, -SO,R? or -SO,NR*R¥;
R®can be placed on any of the 2 N of the pyrazole ring of formula | and represents
Hor R',
each R? independently represents Cy.salkyl, Cz.salkenyl, Ca.galkynyl or Cy, wherein the groups Cqsalkyl, Casalkenyl or Caoealkynyl can be optionally substituted with - one or more substituents selected from R® and Cy*, and wherein any of the groups
Cy or Cy* can be optionally substituted with one or more substituents selected ‘ 5 from RP? and RS each R? independently represents H or R% each RY independently represents halogen, -OR®, -OCORS, -OSO:R® -OCONRR®, -NO, -CN, -COR®, -CO;R®, -CONRR%, -CONR“NR’R’, ‘NR°R®, -NRSCOR®, -NR°CONR°R’, -NR°CO.R’, -NR°SO:R’, -SR°, -SOR®, -SO,R®. -SONRCR®, -C(NRY)NR°R®, -C(NSONR°R®)NR°R?, -C(NOR®)R®, _C(NNR®R®)R?, -NR°C(NR®)NR°R® or -NR*C(NCN)NR°R®; each R%independently represents Cq.salkyl, Co.salkenyl, Caealkynyl or Cy, wherein all these groups can be optionally substituted with one or more substituents RY; each R® independently represents H or R%; each RY independently represents halogen, RS, -OR?, -OCOR®, -0SQ:R®,
LOCONR®R®, -NO, -CN, -COR®, -CO.R®, -CONR’RY, -CONR’NR°R®,
NRER®, -NRCOR?, -NR*CONR®R®, -NR*CO;R®, -NR*SO;R®, -SR®, -SOR®, _SO,R®, -SONR®RY, -C(NR¥)NR®R®, -C(NSO.NR®R)NR®R®, -C(NOR®)R®, -C(NNR®R®)R?, -NR®C(NR®)NR®R®, -NR®C(NCN)NR'R® or Cy optionally substituted with one or more substituents selected from halogen, Re, -OR®, _OCOR®, -OSO,R®, -OCONR®R®, -NOz, -CN, -COR®, -CO:R°, -CONR°RY, _CONR®NR®R?, -NR®RY, -NR°COR®, -NR°CONR®R®, -NR°CO;R®, ) NR¥SO,R®, -SR®, -SOR®, -SOR®°, -SO.NR°R%, -C(NR*)NR°R®, -C(NSONRER¥INRR?, -C(NOR®)R®, -C(NNR®R®)R®, -NR®C(NR*)NR°R® and . 30 -NRYC(NCN)NR®R®; each R® independently represents Cs.galkyl or haloC1.ealkyl;
: each R® independently represents H or R%, : R' represents C1.salkyl, Ca.galkenyl, Casalkynyl or Cy, wherein the groups Ci.alkyl,
Casalkenyl or C,salkynyl can be optionally substituted with one or more . 5 substituents selected from R% and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from R® and
R?; each RY independently represents halogen, -OR¥, -OCOR? -OSOR? -OCONR®R®*, -NO;, -CN, -COR?, -CO,R¥, -CONR*R?¥, -CONR*NR'R? -NR*R?¥, -NR¥COR?¥, -NR¥CONR?R?¥, -NR¥CO,R?, -NR*SO.R?, -SR*, -SOR?, -SO,R?, -SO.NR?R¥, -C(NR*)NR*R?, -C(NSO.NR?R¥)NR¥R*, -C(NOR*)R?, -C(NNR¥R¥)R?, -NR*C(NR¥)NR®R¥ or -NR¥*C(NCN)NR*R;
Het in the above definitions represents pyridine, pyrazine, pyrimidine, pyridazine, 2(1H)-pyridone, 2(1H)-pyrazinone, 2(1H)-pyrimidinone or 2(1H)-pyridazinone;
Cy or Cy* in the above definitions represent a partially unsaturated, saturated or aromatic 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring, which optionally coniains from 1 to 4 heteroatoms selected from M, S and O, which can optionally contain 1 or 2 oxo groups when the ring is saturated or partially unsaturated, and wherein said ring or rings can be bonded to the rest of the molecule through a carbon or a nitrogen atom.
The present invention also relates to the addition salts of the compounds of the invention as well as their solvates and prodrugs. A prodrug is defined as any precursor of a compound of formula | that can be transformed in vivo into a compound of formula 1. ] Some compounds of formula | can have chiral centres that can give rise to various stereoisomers. The present invention relates to each of these : 30 stereoisomers and also mixtures thereof. Moreover, some of the compounds of the present invention can show cis/trans isomers. The present invention relates to each of the geometric isomers and mixtures thereof.
The compounds of formula t are selective p38 kinase inhibitors.
Thus, another aspect of this invention relates to the pharmaceutical compositions which comprise an effective amount of a compound of formula [ or a . pharmaceutically acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable excipients. . 5 Another aspect of the present invention relates to the use of a compound of formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the - manufacture of a medicament for the treatment or prevention of diseases mediated by p38.
Another aspect of the present invention relates to the use of a compound of formula | or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cytokines.
Another aspect of the present invention relates to the use of a compound of formula | or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by TNF-a, IL-1, IL-6 and/or IL-8.
Another aspect of the present invention relates to the use of a compound of formula | or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2. :
Another aspect of the present invention relates to the use of a compound of formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of diseases mediated by p38.
Another aspect of the present invention relates to the use of a compound of formula | or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of diseases mediated by cytokines. : 30 Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of diseases mediated by TNF-a, IL-1, IL-6 and/or IL-8.
Another aspect of the present invention relates to the use of a compound of formula | or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of a disease selected from immune, autoimmune and 3 inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and : 5 processes associated with the induction of cyclooxygenase-2. ~ Another aspect of the present invention relates to a method of treating or preventing diseases mediated by p38 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula | or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another aspect of the present invention relates to a method of treating or preventing diseases mediated by cytokines in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula | or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another aspect of the present invention relates to a method of treating or preventing diseases mediated by TNF-a, IL-1, IL-6 and/or IL-8 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable sali, solvate or prodrug thereof.
Another aspect of the present invention relates to a method of treating or preventing a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula | or a pharmaceutically acceptable salt, solvate i or prodrug thereof.
Another aspect of the present invention relates to a process for the : 30 preparation of a compound of formula I, which comprises: (a) reacting a ketone of formula IV
. Y*
R?
Iv . wherein R! and R? have the meaning described above, with an aminopyrazole of formula V and an aldehyde of formula Vi
RS : /
HoN N, " N 3. y R*-CHO
R4 \' vi wherein R®, R* and R® have the meaning described above; or (b) when in a compound of formula I, RS represents H and R® has the same meaning as R', reacting a ketone of formula IV or an enolate of formula VI 1 1
R? R?
AY, Vii wherein R! and R? have the meaning described above, with an aminopyrazole of formula ¥a
HoN H 2 N
N
J
R4
Va wherein R* has the meaning described above; or (c) when in a compound of formula | R* represents NH, treating a compound of formula XIX w Rr!
Na Cl
RZ NF CN
R3
XIX wherein R!, R? and R® have the meaning described above, with a hydrazine of formula Villa
NH,—NHR®
Villa wherein R® has the meaning described above; or ' (d) converting, in one or a plurality of steps, a compound of formula | into another compound of formula I; and (e) if desired, after the previous steps, reacting a compound of formula | with a base or an acid to give the corresponding salt.
In the previous definitions, the term Cy.ealkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 6 carbon atoms.
Examples include among others the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.
A haloC4salkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Cy.salkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or ido), which can be the same or different. Examples include, among others, trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluorcethyl, 2-bromoethyl, 2-icdoethyl, 2,2, 2-trifluoroethvl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2.2 3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5- fluoropentyl and 6-fluorohexyl.
The term Cagalkenyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 2 to 6 carbon atoms and that also contains one or more double bonds. Examples include, among others, the groups ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3- butadienyl, 1-pentenyl, 2-pentenyl, 3-penteny, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
The term Cacalkynyl, as a group or part of a group, means a straight or , branched alkyl chain which contains from 2 to 6 carbon atoms and that also contains one or more triple bonds. Examples include the groups ethynyl, 1- - propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5- ~ hexynyl.
An oxo group means a carbonyl group (-CO-).
A halogen radical means fluoro, chloro, bromo or iodo.
Het in the definitions of R! and R?> means pyridine, pyrazine, pyrimidine, . pyridazine, 2(1H)-pyridone, 2(1H)-pyrazinone, 2(1H)-pyrimidinone or 2(1H)- pyridazinone. As mentioned previously, these groups can be optionally substituted ) 5 with one or more substituents selected from R® and RP, which can be placed on any available position of the Het group, and can be bonded to the rest of the molecule via any available carbon or nitrogen atom.
The term Cy or Cy*, as a group or part of a group, means a 3- to 7- membered monocyclic carbocyclic group or an 8- to 12-membered bicyclic carbocyclic group which can be partially unsaturated, saturated or aromatic and which can optionally contain from 1 to 4 heteratoms selected from N, S and O.
When the Cy or Cy* group is saturated or partially unsaturated, it can optionally contain 1 or 2 oxo groups. The Cy or Cy* ring or rings can be substituted as mentioned in the definition of general formula |, these substituents being placed on any available position, and can be bonded to the rest of the molecule through any available carbon or nitrogen atom. Examples of Cy or Cy” groups include, among others, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, aziridine, oxirane, oxetane, imidazolidine, isothiazolidine, isoxazolidine, oxazolidine, pyrazolidine, pyrrolidine, thiazolidine, dioxane, morpholine, piperazine, piperidine, pyran, fetrahydropyran, azepine, oxazine, oxazoline, pyrroline, thiazoline, pyrazoline, imidazoline, isoxazoline, isothiazoline, phenyl, naphthyl, 1,2,4-oxadiazole, 1,2 4-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, furan, imidazole, isoxazole, isothiazole, oxazole, pyrazole, pyrrole, thiazole, thiophene, 1,2,3-triazole, 1,2,4-triazole, pyrazine, pyridazine, pyridine, pyrimidine, benzimidazole, benzofuran, benzothiazole, benzothiophene, imidazopyrazine, imidazopyridazine, imidazopyridine, imidazopyrimidine, indazole, indole, isoindole, isoquinoline, tetrahydroisoquinoline, naphthyridine, pyrazolopyrazine, . pyrazolopyridine, pyrazolopyrimidine, purine, quinazoline, quinoline, quinoxaline, cyclobutanone, - cyclopentanone, cyclohexanone, cycloheptanone, pyrrolidin-2- . 30 one, piperidin-2-one, piperidin-4-one, 2(1H)-pyridone, 2(1H)-pyrazinone, 2(1H)- pyrimidinone, 2(1H)-pyridazinone and phthalimide.
The term heteroaryl, as a group or part of a group, means an aromatic 5- or 6-membered monocyclic or 8- to 12-membered bicyclic ring which contains from 1 to 4 heteroatoms selected from N, S and O and which can be optionally substituted as disclosed whenever this term is used, wherein said substituents can - be placed on any available position. The heteroaryl group can be bonded to the rest of the molecule through any available carbon or nitrogen atom. Examples of ‘ 5 heteroaryl groups include among others 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,34 oxadiazole, 1,3,4-thiadiazole, furan, imidazole, isoxazole, isothiazole, oxazole, pyrazole, pyrrole, thiazole, thiophene, 1,2,3-triazole, 1,2,4-triazole, pyrazine, pyridazine, pyridine, pyrimidine, benzimidazole, benzofuran, benzothiazole, benzothiophene, = imidazopyrazine, imidazopyridazine, imidazopyridine, 10 imidazopyrimidine, indazole, indole, isoindole, isoquinoline, naphthiridine, pyrazolopyrazine, pyrazolopyridine, pyrazolopyrimidine, purine, quinazoline, quinoline and quinoxaline.
In the previous definitions of Het, heteroaryl, Cy and Cy*, the term is meant to be the radical derived from the corresponding cycle.
In the previous definitions of heteroaryl, Cy and Cy*, when the specified examples refer to a bicycle in general terms, all possible dispositions of the atoms are included. For example, the term pyrazolopyridine is to be understood as including groups such as 1H-pyrazolo[3,4-blpyridine, pyrazolo[1,5-a]pyridine, 1H- pyrazolo[3,4-c]pyridine, 1H-pyrazolo[4,3-c]pyridine and 1H-pyrazolo[4,3-b]pyridine; the term imidazopyrazing is io be understood as including groups such as 1H- oo imidazo[4,5-b]pyrazine, imidazo[1,2-alpyrazine and imidazo[1,5-a]pyrazine and the term pyrazolopyrimidine is to be understood as including groups such as 1H- pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[4,3-d]pyrimidine, pyrazolo[1,5-alpyrimidine and pyrazolo[1,5-c]pyrimidine.
The expression "optionally substituted with one or more” means that a group can be substituted with one or more, preferably with 1, 2, 3 or 4 substituents, provided that this group has 1, 2, 3 or 4 positions susceptible of . being substituted.
In the previous definitions, when it is mentioned that R® can be placed on ‘ 30 any one of the 2N of the pyrazole ring this means that R® can be placed on the N at position 1 of the ring or on the N at position 2. Thus, the compounds of formula include the following two types of compounds:
6 of oo RL 6 N - SN yo 2 SGP
R? A 3 R2 4 3 . R3 R* R3 R*
An embodiment of the invention are those compounds of formula | as defined above wherein A represents N. . 5 Another embodiment of the invention are the compounds of formula wherein A represents N and R® can be placed on any of the 2 N of the pyrazole ring of formula | and represents H or R%.
Another embodiment of the invention are the compounds of formula wherein when R® and R® both represent H and R? represents Het optionally substituted with one or more substituents selected from halogen, -CN, -CF3, -OH,
NO, -ORE, -NR®R®, -OCF3, Cysalkyl, Casalkenyl, Coalkynyl and Cy, wherein Cy can be optionally substituted with one or more substituents selected from R® and
R®, and wherein R® represents Cq.galkyl, then R* is not -NR¥COR?, -NHCONHR? or-NHCO:R®.
Another embodiment of the invention are the compounds of formula wherein when R® and RS both represent H, then R* is not -NR*COR?, -NHCONHR? or-NHCO,R®.
Another embodiment of the invention are the compounds of formula wherein A represents N; R* represents H, R®, halogen, -OR?¥, -OCOR?, -OSO:R?, -OCONR®R®, -NO., -CN, -COR¥, -CO:R®, -CONR*R¥, -NR?R¥, -NR¥SO;R?, _SR¥, -SOR?, -SO,R? or -SO:NR?R?; and R°® can be placed on any of the 2 N of the pyrazole ring of formula l and represents H or R2
Another embodiment of the invention are the compounds of formula wherein R' represents pyridine or phenyl, wherein all these groups can be ’ 25 optionally substituted with one or more substituents selected from R® and R®.
Another embodiment of the invention are the compounds of formula wherein R' represents phenyl optionally substituted with one or more substituents selected from R? and R®.
Another embodiment of the invention are the compounds of formula wherein R' represents phenyl optionally substituted with one or more substituents ; selected from halogen, -OR®, -NO,, -CN, -CONRCR®, -NR°R® and Ci.salkyl optionally substituted with one or more substituents selected from halogen, -OR", © 5 -COR®-NR°R® and -NR°COR®.
Another embodiment of the invention are the compounds of formula wherein R! represents phenyl optionally substituted with one or more substituents selected from halogen and haloC1.galkyl.
Another embodiment of the invention are the compounds of formula wherein R? represents pyridine or pyrimidine, wherein all these groups can be optionally substituted with one or more substituents selected from R? and RP.
Another embodiment of the invention are the compounds of formula wherein R? represents 4-pyridine or 4-pyrimidine, wherein all these groups can be optionally substituted with one or more substituents selected from R? and RP.
Another embodiment of the invention are the compounds of formula wherein R? represents 4-pyridine or 4-pyrimidine, wherein all these groups can be optionally substituted with one or more substituents selected from halogen, -OR®, -NR°RC, -SR® and -SO2R°.
Another embodiment of the invention are the compounds of formula I wherein R? represents 4-pyridine.
Another embodiment of the invention are the compounds of formula wherein R? represents 4-pyrimidine substituted with -NR°R®, wherein in R*: each R® independently represents H or RS; each R° independently represents Cq.salkyl optionally substituted with one or more substituents selected from Cy and -OR®; and each R? independently represents H or R®.
Another embodiment of the invention are the compounds of formula I . wherein R® represents H or Cy optionally substituted with one or more substituents selected from R®and R®. , 30 Another embodiment of the invention are the compounds of formula wherein R® represents H, heteroaryl or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from R® and R°.
’ Another embodiment of the invention are the compounds of formula wherein R® represents heteroaryl or phenyl, wherein all these groups can be . optionally substituted with one or more substituents selected from R? and RP.
Another embodiment of the invention are the compounds of formula wherein R® represents monocyclic heteroaryl or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from halogen, -NO,, -OR®, C,.salkyl and Cy, wherein Cigalkyl can be optionally substituted with one or more substituents selected from R® and Cy*, and any of the groups Cy or
Cy* can be optionally substituted with one or more substituents selected from R® and R®
Another embodiment of the invention are the compounds of formula wherein R® represents monocyclic heteroaryl or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from halogen, -NO,, ORE, C1.salkyl, haloCy.ealkyl and Cy; and wherein in R*: each R® independently represents H or RS; each R® independently represents Ci.galkyl optionally substituted with one or more substituents RY; and each RY independently represents Cy.
Another embodiment of the invention are the compounds of formula I wherein B® represents H, R% halogen, -OR?, -CN, -CONR*R?, -NR®R* or -NR¥COR™.
Another embodiment of the invention are the compounds of formula wherein R* represents H.
Another embodiment of the invention are the compounds of formula wherein R® represents H or R® represents R" and is placed on the N at position 2 of the pyrazole ring.
Another embodiment of the invention are the compounds of formula . wherein R® represents R and is placed on the N at position 2 of the pyrazole ring.
Another embodiment of the invention are the compounds of formula : 30 wherein Rf represents Ci.salkyl, Co.salkenyl or Cy, wherein the groups Ci.salkyl or
C.salkenyl can be optionally substituted with one or more substituents selected from RS and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from R? and R®.
: Another embodiment of the invention are the compounds of formula wherein Rf represents Cy.galkyl, Cosalkenyl or Cy, wherein the groups Ci.galkyl or - Casalkenyl can be optionally substituted with one or more substituents selected from R® and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from R® and R®, wherein each
RY independently represents halogen, -OR*, -COR?, -CO,R¥, -CONR?R?, ‘NR*R?, -NR¥COR?, -NR*CONR?R?, -NR¥SO,R?, -SR?, -SOR? or -SO.R*.
Another embodiment of the invention are the compounds of formula wherein R' represents Cisalkyl, Cgalkenyl or Cy, wherein the groups Cygalkyl or Casalkenyl can be optionally substituted with one or more substituents selected from R® and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from RY and R? wherein in R": each RY independently represents -OR®, -COR®, -CONR®R? -NR*R?, -NRTCOR?, -NR¥CONR?R?, -NR¥SO,R?, -SOR? or -SO:R; each R* independently represents H or R% each R? independently represents Cy or Cigalkyl, wherein Cisalkyl can be optionally substituted with one or more substituents selected from R® and Cy*, and any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from RP and RY, each R? independently represents -OR®, -NR°R®, -CN, -COR®, -8R® or -SORS; each R¢ independently represents H or R®, each R® independently represents Ci.¢alkyl or Cy, wherein all these groups can be optionally substituted with one or more R°.
Another embodiment of the invention are the compounds of formula wherein R® is placed on the N at position 2 of the pyrazole ring and represents R, wherein Rf represents Cigalkyl optionally substituted with one or more substituents selected from -OR?, -COR®, -CONR®R*, -NR’R*, -NR®COR? _NR¥CONR?R?* -NR¥SO,R* and Cy* optionally substituted with one or more : 30 substituents selected from R? wherein in R": each R? independently represents H or R?; each R? independently represents Cy or Cigalkyl, wherein Ci.galkyl can be optionally substituted with one or more substituents selected from R” and Cy*, and any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from R® and R®; . each R® independently represents -OR®, -NR°R®, -CN, -COR®, -SR°® or -SOR"; each R® independently represents H or R®; ©. 5 each R®independently represents Cq.salkyl or Cy, wherein all these groups can be optionally substituted with one or more RY; and each RY independently represents -OR®.
Another embodiment of the invention are the compounds of formula wherein R® represents H or R® represents R® and is placed on the N at position 2 of the pyrazole ring.
Another embodiment of the invention are the compounds of formula wherein R® represents R? and is placed on the N at position 2 of the pyrazole ring.
Another embodiment of the invention are the compounds of formula wherein R® in R® represents Cqsalkyl, Cogalkenyl or Cy, wherein the groups
Cjsalkyl or Cosalkenyl can be optionally substituted with one or more substituents selected from R® and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from R? and R®.
Another embodiment of the invention are the compounds of formula wherein R? in R® represents Cisalkyl, Czsalkenyl or Cy, wherein the groups Cyealkyl or Cogalkenyl can be optionally substituted with one or more substituents selected from RY and Cy*, and wherein any of the groups Cy or Cy® can be optionally substituted with one or more substituents selected from R® and R°, wherein each RP in R® independently represents halogen, -OR®, -COR®, -COzR®, _CONR®RE, -NR°R®, -NRCCOR®, -NRECONRCR®, -NR°SO:R’, -SR°, -SOR® or -SO.R°.
Another embodiment of the invention are the compounds of formula wherein R? in R® represents Cygalkyl, Cosalkenyl or Cy, wherein the groups } C1.salkyl or Ca.salkenyl can be optionally substituted with one or more substituents selected from R? and Cy*, and wherein any of the groups Cy or Cy* can be : 30 optionally substituted with one or more substituents selected from R® and RC, wherein in R: each R® independently represents -OR®, -COR?, -CONR’R?, -NR°R®, -NR°COR®, -NRSCONRCR®, -NR*SO,R®, -SOR® or -SOR°;

Claims (1)

  1. CLAIMS :
    : 1.- A compound of general formula : 1 5 R A N, R : QI R2 R3 R4 l wherein: A represents N or N*O'; R' represents phenyl or Het optionally substituted with one or more substituents selected from R® and R”; R? represents Het optionally substituted with one or more substituents selected from R? and R®; i5 RR? represents H, Cy optionally substituted with one or more substituents selected from R? and RY, or R® represents Csalkyl optionally substituted with one or more substituents selected from R® and Cy*, wherein Cy* can be optionally substituted with one or more substituents selected from R® and R%; R* represents H, R? halogen, -OR¥, -OCOR?, -OSO;R®, -OCONR’R®, -NO;, CN, -COR?, -CO,R¥, -CONR®R®, -NR®R¥, -NRYCOR®, -NR’CONR’R?, “NR¥CO,R?, -NR¥SO,R?, -SR?, -SOR?, -S0,R? or -SO0,NR*R*; R5 can be placed on any of the 2 N of the pyrazole ring of formula I and represents HorR, each R?independently represents Ci.salkyl, Ca¢alkenyl, Cz.galkynyl or Cy, wherein the groups Cr.ealkyl, Ca.calkenyl or Casalkynyl can be optionally substituted with one or more substituents selected from R® and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected : from R® and RS; "5 each R? independently represents H or R?; each R® independently represents halogen, -OR®, -OCOR® -OSO:R’ .OCONR°R®, -NO,, -CN, -COR®, -CO,R®, -CONR°R®, -CONR’NR°RC, -NRSR®, -NRECOR®, -NRECONRCR®, -NR°CO;R®, -NR°SO,R®, -SR®, -SOR’, -SO,R°, -SONRSR®, -C(NR®)NRCR®, -C(NSO:NR°R®)NR°R®, -C(NOR®)R’, -C(NNRSR%)R?, -NREC(NR*)NR°R® or -NREC(NCN)NRR®; each R®independently represents Ci.salkyl, Casalkenyl, Cz salkynyl or Cy, wherein all these groups can be optionally substituted with one or more substituents RY;
    each R® independently represents H or R®; each RY independently represents halogen, R°, -OR®¥, -OCOR®, -OSO:R®, -OCONR®R®, -NO,, -CN, -COR®, -CO,R®, -CONR®R®, -CONR*NR°R?, -NRER®, -NRECOR®, -NRECONRERY, -NRTCO:R®, -NR¥SO.R®, -3R, -SOR®, .SO,R®, -SONRRY, -C(NREINR®R®, -C(NSO:NRR®)NRR®, -C(NOR*)R®, -C(NNR®RE)R?, -NR¥C(NR®)NR®R®, -NR®C(NCN)NR*R® or Cy optionally substituted with one or more substituents selected from halogen, R° -OR®?, .OCOR®, -OSO,R¢, -OCONR®R®, -NO;, -CN, -COR®, -CO,R®, -CONR°R?, _CONRYNRSR®, -NR®R®, -NRYCOR®, -NR®CONRPR®, -NR®CO.R®, _NR®SO,R®, -SR®, -SOR®, -SO,R°, -SO.NR*R®, -C(NR®)NR°R?, _C(NSO-NR?R®)NR®R?, -C(NOR®)R®, -C(NNR®R®)R?, -NR®C(NR*)NR°R® and -NR¥C(NCN)NR®R®; : 30 each R® independently represents Cq.galkyl or haloC.galkyl; each RY independently represents H or R®;
    Rf represents Cygalkyl, Ca.salkenyl, Ca.salkynyl or Cy, wherein the groups Cigalkyl, Cagalkenyl or Coasalkynyl can be optionally substituted with one or more : substituents selected from R? and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from RS and RY each R° independently represents halogen, -OR?, -OCOR? -OSO:R% _OCONR®R®, -NO,, -CN, -COR®, -CO;R*, -CONR®R®, -CONR*NR’R?, NRZR®, -NR*COR?, -NR*CONR?R¥, -NR¥CO,R?, -NR¥S0O,R?, -SR*, -SOR®, -SO,R?, -SO.NR®R¥, -C(NR*)NR®R¥, -C(NSONR*R*)NR*R?, -C(NOR*)R?, -C(NNR?R¥)R?, -NR¥C(NR¥)NR*R? or -NR*C(NCN)NR*R?; Het in the above definitions represents pyridine, pyrazine, pyrimidine, pyridazine, 2(1H)-pyridone, 2(1H)-pyrazinone, 2(1H)-pyrimidinone or 2(1H)-pyridazinone; Cy or Cy* in the above definitions represent a partially unsaturated, saturated or aromatic 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring, which optionally contains from 1 to 4 heteroatoms selected from N, S and O, which can optionally contain 1 or 2 oxo groups when the ring is saturated or partially unsaturated, and wherein said ring or rings can be bonded to the rest of the molecule through a carbon or a nitrogen atom; and the salts, solvates and prodrugs thereof.
    2.- A compound according to claim 1 wherein A represents N.
    3.- A compound according to claim 2 wherein R% can be placed on any of the 2 N of the pyrazole ring of formula I and represents H or Re.
    4.- A compound according to any of claims 1 to 3 with the proviso that when R3 and R°® both represent H and R? represents Het optionally substituted with one or more substituents selected from halogen, -CN, -CF, -OH, -NO,, -OR®, -NR°R®, -OCF3, Ciealkyl, Caogalkenyl, Cosalkynyl and Cy, wherein Cy can be optionally substituted with one or more substituents selected from RP and R®, and wherein R® represents Ci.salkyl, then R* is not -NR¥*COR?, -NHCONHR® or -NHCO,R®,
    5.- A compound according to any of claims 1 to 4 wherein R' represents pyridine - or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from R? and R®.
    6.- A compound according to claim 5 wherein R' represents phenyl optionally substituted with one or more substituents selected from R® and R".
    7.- A compound according to claim 6 wherein R' represents phenyl optionally substituted with one or more substituents selected from halogen, -OR%, -NO,, -CN, -CONRCR®, -NR°R® and Cisalky! optionally substituted with one or more substituents selected from halogen, -OR®, -COR®, -NR°R® and -NR°COR®.
    8.- A compound according to claim 7 wherein R' represents phenyl optionally substituted with one or more substituents selected from halogen and haloC4.salkyl.
    9.- A compound according to any of claims 1 to 8 wherein R? represents pyridine or pyrimidine, wherein all these groups can be optionally substituted with one or more substituents selected from R® and RP.
    10.- A compound according to claim 9 wherein R? represents 4-pyridine or 4- pyrimidine, wherein all these groups can be optionally substituted with one or more substituents selected from R? and R”.
    11.- A compound according to claim 10 wherein R? represents 4-pyridine or 4- pyrimidine, wherein all these groups can be optionally substituted with one or 50 more substituents selected from halogen, -OR®, -MR°R®, -SR® and -SO2R".
    12.- A compound according to claim 11 wherein R? represents 4-pyridine.
    13.- A compound according to claim 11 wherein R? represents 4-pyrimidine substituted with -NR°R®, wherein in R?: each R® independently represents H or RS each R® independently represents Cy.salkyl optionally substituted with one or more substituents selected from Cy and -OR®; and each R® independently represents H or R®. . 14.- A compound according to any of claims 1 to 13 wherein R® represents H or Cy optionally substituted with one or more substituents selected from R® and R.
    15.- A compound according to claim 14 wherein R® represents H, heteroaryl or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from R? and R®, and wherein heteroaryl represents an aromatic 5- or 6-membered monocyclic or 8- to 12-membered bicyclic ring, which contains from 1 to 4 heteroatoms selected from N, S and O and which can be bonded to the rest of the molecule through a carbon or a nitrogen atom. : 16.- A compound according to claim 15 wherein R® represents heteroaryl or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from R® and R®.
    17.- A compound according to claim 16 wherein R® represents monocyclic heteroaryl or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from halogen, -NO;, -OR®, Cisalkyl and Cy, wherein Cigalkyl can be optionally substituted with one or more substituents selected from R® and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or more substituents selected from R® and R®.
    18.- A compound according to claim 17 wherein R® represents monocyclic heteroaryl or phenyl, wherein all these groups can be optionally substituted with one or more substituents selected from halogen, -NO,, -OR?, Cisalkyl, haloCs. 16 galkyl and Cy, and wherein in R>: each R® independently represents H or RS; each R® independently represents Ci.galkyl optionally substituted with one or more substituents RY; and each RY independently represents Cy. :
    12.- A compound according to any of claims 1 to 18 wherein R* represents H, R¢, halogen, -OR?, -CN, -CONR?R?, -NR*R? or -NR*COR?"
    20.- A compound according to claim 19 wherein R* represents H.
    21.- A compound according to any of claims 1 to 20 wherein R® represents H or R® represents R* and is placed on the N at position 2 of the pyrazole ring.
    22.- A compound according to claim 21 wherein RS represents R®.
    23.- A compound according to claim 21 or 22 wherein R® in R® represents
    Cs.salkyl, Ca.alkenyl or Cy, wherein the groups Cisalkyl or Caealkenyl can be optionally substituted with one or more substituents selected from R® and Cy*, and wherein any of the groups Cy or Cy* can be optionally substituted with one or : 30 more substituents selected from R? and RC.
    24.- A compound according to claim 23 wherein each R® in R® independently represents halogen, -OR®, -COR®, -CO;R%, -CONR°R®, -NR°R®, -NR°COR® -NRYCONRCR®, -NR°SO,R?, -SR¢, -SOR® or -SOR°.
    25.- A compound according to claim 24 wherein in R>: each RP independently represents -OR®, -COR®, -CONRCR®, -NR°R®, -NR*COR®, : -NR®CONR®R?, -NR®SO,R®, -SOR® or -SO,R°; each R® independently represents H or RY; "5 each R®%independently represents Cy or Cysalkyl, wherein all these groups can be optionally substituted with one or more substituents selected from RY; each RY independently represents R®, -OR®, -NR°R®, -CN, -COR®, -SR®, -SOR® or Cy.
    26.- A compound according to claim 22 wherein R® in R® represents Ci.alkyl optionally substituted with one or more substituents selected from. -OR®, -COR®, -CONRCR®, -NR°R®, -NR°COR®, -NR°CONRCR?, -NR*SO,R® and Cy* optionally substituted with one or more substituents selected from R® wherein in R®; each R® independently represents H or RS; each R® independently represents Cy or Cygalkyl, wherein all these groups can be optionally substituted with one or more substituents selected from RY; each RY independently represents -OR®, -NR®R®, -CN, -COR®, -SR®, -SOR® or Cy; each R® independently represents H or R®; and each R® independently represents Cqalkyl.
    27.- A compound according io claim 1 selected from: 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 4 6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 5-(4-pyridyl)-4,6-bis[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b] pyridine; 3-methyl-4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-blpyridine; 2-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 1-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine;
    4.6-bis(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolof3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; : 30 4,6-bis(4-fluorophenyl)-2,3-dimethyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-1,3-dimethyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 2-[2-[1-(tert-butoxycarbonyl)piperidin-4-yljethyl]-4,6-bis(4-fluorophenyf)-5-(4- pyridyl)pyrazolo[3,4-b]pyridine;
    1-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethy!]-4,6-bis(4-fluorophenyl)-5-(4- pyridyl)pyrazolo[3,4-b]pyridine;
    : 2-[1-(tert-butoxycarbonyl)piperidin-4-yl}-4,6-bis(4-fluorophenyl)-3-methyl-5-(4- pyridyl)pyrazolo[3,4-b]pyridine;
    1-[1-(tert-butoxycarbonyl)piperidin-4-yl}-4,6-bis(4-fluorophenyl)-3-methyl-5-(4- pyridyl)pyrazolo[3,4-blpyridine; 2-(3-chloropropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo(3,4-blpyridine; 1-(3-chioropropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridy!)pyrazolo[3,4-b]pyridin-2-yljpropan-1-ol;
    3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-ylJpropan-1-ol; 2-[1-(tert-butoxycarbonyl)piperidin-4-yl}-4,6-bis (4-fluorophenyl)-5-(4- pyridyl)pyrazolo[3,4-b]pyridine; 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4- pyridyl)pyrazolo[3,4-b]pyridine;
    2-methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 1-methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]- pyrazolo[3,4-blpyridine; 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yllethanol;
    4,6-bis(4-lucrophenyl)-2-(4-methylsulfanylbenzyl)-5-(4-pyridvl)pyrazolo[3,4- blpyridine; 4,6-bis(4-fluoropheny!)-1-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4- blpyridine; 2-[1-(tert-butoxycarbonyl)piperidin-4-ylimethyl]-4,6-bis(4-fluorophenyl)-5-(4-
    pyridyl)pyrazolo[3,4-b]pyridine;
    1-[1 -(tert-butoxycarbonyl)piperidin-4-ylmethyt]-4,6-bis(4-fluorophenyl)-5-(4- pyridyl)pyrazolo[3,4-blpyridine; 4,6-bis(4-fluorophenyl)-2-[2-(morpholin-4-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4- blpyridine;
    : 30 4,6-bis(4-fluorophenyl)-1-[2-(morpholin-4-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4- blpyridine; ethyl 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yljacetate; ethyl 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yllacetate;
    ethyl 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propionate; ethyl 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1 -yllpropionate;
    : 4,6-bis(4-fluorophenyl)-2-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; : 4,6-bis(4-fluorophenyl)-1-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine;
    4,6-bis(4-fluorophenyl)-2-(4-piperidylmethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-1 -(4-piperidyimethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(6-chloropyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine;
    4 ,6-bis(4-fluorophenyl)-3-methyl-2-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridine; 4,6-bis(4-fluorophenyl)-3-methyl-1 ~(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-
    blpyridine; 4 6-bis(4-fluorophenyl)-2-[2-(4-piperidyl)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyrid in-2-yljacetic acid; 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-ylacetic acid;
    3-{4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-blpyridin-2-yljpropionic acid, 3-[4,8-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1 -yllpropionic acid; 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-1 -(morpholin-4- yh)ethanone; 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-blpyridin-1-yllacetamide;
    2-]4,8-bis(4-flucro phenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1 -yl}-1-(morpholin-4- yhethanone; 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl}-1 -(morpholin-4- yl)propan-1-one; 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3 4-b]pyridin-1-yl]-N-
    propylpropionamide; 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1 -yl]-1-(morpholin-4- yl)propan-1-one; 4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolof3,4- b]pyridine;
    - 30 4 6-bis(4-fluorophenyl)-1-(4-methylsuifanylphenyl)-5-(4-pyridyl)pyrazolo[3 4-
    b)pyridine; 4 6-bis(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridine;
    4,6-bis(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)pyrazolo[3,4- blpyridine; : : 4,6-bis(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-5-(4-pyridyl)pyrazolo[3,4- blpyridine; 4,6-bis(4-fluorophenyl)-2-(4-methylsulfinylbenzyl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridine;
    4.6-bis(4-fluorophenyl)-2-(4-methyisulfonylbenzyl)-5-(4-pyridyl)pyrazolo(3 A- blpyridine; 4,6-bis(4-fluorophenyl)-1 ~(4-methylsulfinylbenzyl)-5-(4-pyridyl)pyrazolo[3,4- blpyridine; 4 ,6-bis(4-fluorophenyl)-1 -(4-methylsulfonylbenzyl)-5-(4-pyridyl)pyrazolo{3,4- blpyridine; 3-chloro-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine; 3-bromo-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine-3-carbonitrile; 3-bromo-4,6-bis(4-fluorophenyl)-1 -methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide; 3-aminomethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluoro-3-nitrophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine; 3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine; 3-amino-6-(4-fluorophenyl)-1 -methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4-[6-(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridin-4-yljphenol;
    2.(2,2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-blpyridine; 1-(2 2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyrid ine; 4,6-bis(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine-3-carbonitrile; 3-bromo-6-(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine; 6-fluorophenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; N-methyl-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-pyrazolo[3,4-b] pyridin-2- yllpropyllamine; [4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yllmethanol; 2-[4,6-bis(4-fluorophenyl )-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-N,N- dimethylacetamide;
    2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yI}-N,N- dimethylacetamide; 4,6-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)ethyl]-5-(4-pyridyl)pyrazolo[3,4- blpyridine; 4,6-bis(4-fluorophenyl)-1-[2-(2-methoxyethoxy)ethyl]-5-(4-pyridyl)pyrazolo[3,4- b]pyridine; 4,6-bis(4-fluorophenyl)-2-[3-(morpholin-4-yl)propyl]-5-(4-pyridy!)pyrazolo[3,4- blpyridine; 4,6-bis(6-chloropyridin-3-yl)-2-methyl-5-(4-pyridyl )pyrazolo[3,4-b]pyridine; 4,6-bis(6-chloropyridin-3-yl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(6-chloropyridin-3-yl)-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b] pyridine;
    4.6-bis(6-methylpyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-2-(2-phtalimidoethyt)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl}-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yllethanol; 6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-bjpyridine; 4,6-bis(4-fluorophenyl)-2-(3-phtalimidopropyl)-5-(4-pyridyl)pyrazolo[3,4-blpyridine; 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yllacetaldehyde; 2-(3-aminopropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; N-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-blpyridin-3-ylmethyl]-1- (ter-butoxycarbonyl)piperidine-4-carboxamide; N-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridin-3-ylmethyl]-1H- piperidine-4-carboxamide; 2-(3-benzyloxypropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 1-(3-benzyloxypropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-blpyridine; N, N-diethyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyllamine; N, N-diethyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1- yijethyllamine; : 30 4 6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-(3-pyridylmethyf)pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1-pyridin-3-yimethylpyrazolo[3,4-b]pyridine; N, N-dimethy!-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-pyrazolo[3,4-b]pyridin-2- yllpropyllJamine;
    N,N-dimethyl-[3-[4,6-bis(4-fluorophenyl)-5~(4-pyridyl)-pyrazolo[3,4-b]pyridin-1- yl]propyllamine; : 1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yllethyl]piperidin- 4-ol;
    ’ 5 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl}-2- hydroxypropan-1-ol; 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yi]-2- hydroxypropan-1-ol; 4,6-bis(4-fluorophenyl)-5-(4-pyridyl )-2-(4-pyridylmethyl)pyrazolo[3,4-b]pyridine;
    10 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1 ~(4-pyridylmethyl)pyrazolo[3,4-b]pyridine; N-(tert-butoxycarbonyl)-[1 -[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4- blpyridin-2-yl]propyl]piperidin-4-ylJamine;
    2-1 -(tert-butoxycarbonyl)piperidin-4-yl]-6-(4-fluorophenyl)-5-(4- pyridyl)pyrazolo[3,4-b]pyridine;
    11 -(tert-butoxycarbonyl)piperidin-4-yl]-6-(4-fluorophenyl)-5-(4- pyridyl)pyrazolo[3.4-b]pyridine; 3-methyl-4,6-bis(6-methylpyridin-3-yl)-5-(4-pyridyi)-1 H-pyrazolo[3,4-b]pyridine; 1 -[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yi}- propyl]piperidin-4-one;
    N-(teri-butoxycarbonyl)-[i-[2-[4,6-bis(4-flucrophenyl)-5-(4-pyridyl)pyrazolo[3,4- h)pyridin-2-yl]ethyl]piperidin-4-yllamine;
    N-methyl-{1 -[2-[4 ,6-bis(4-fluorophenyl)-5-(4-pyridyl)-pyrazolo[3,4-b]pyridin-2- yllethyl]piperidin-4-ylJamine; 1 -[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3 ,4-blpyridin-2-
    yllpropyllpiperidin-4-yllamine;
    2-1 -[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- ylJethyl]piperidin-4-yljethanol;
    [1 -[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-blpyridin-2- yllethyl]piperidin-4-yljamine;
    : 30 6-(4-fluorophenyl)-2-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-1 -(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 3-amino-5-[2-(methylsulfa nyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl}-1H- pyrazolo[3,4-b]pyridine;
    2-[3-[1-(4-tert-butoxycarbonyl)piperazin-1-yl]propyl]-4,6-bis(4-flucrophenyl)-5-(4- pyridyl)pyrazolo[3,4-b]pyridine; } 4,6-bis(4-fluorophenyl)-2-[3-(1-piperazin-1-yl)propyl}-5-(4-pyridyl)pyrazolo[3,4- blpyridine; : 5 5-[2-(methylsuifanyl)pyrimidin-4-yi]-6-[3-(trifluoromethyl)phenyl}-1H-pyrazolo[3,4- blpyridine; 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4- b)pyridine; (1S)-N-(1-phenylethyl)-[4-[6-[3-(trifluoromethyl)phenyl]-1 H-pyrazolo[3,4-b]pyridin- 5-yl]pyrimidin-2-ylJamine; 1-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllpropyl]piperidin-4-of; 2-[1-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yljpropyl]piperidin-4-yllethanal, 4,6-bis(d4-fluorophenyl)-3-(4-piperidyl)-5-(4-pyridyl}-1H-pyrazolo[3,4-bjpyridine; 6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile; 2-[2-[[1-(tert-butoxycarbonyl)piperidin-4-ylJamino}ethyl]-4,6-bis(4-fluorophenyl)-5- (4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-2-[2-[(4-piperidyl)amino]ethyl]-5-(4-pyridyl)pyrazolo[3,4- blpyridine; N-(2-methoxyethyl)-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin- 2-yllethyllamine; 1-[4-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yljethyl]piperazin-1-yfjethanone; 3-[4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan-1-ol, 3-[4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propan-1-ol; 2-ethyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 1-ethyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4,6-diphenyl-2-(2-phtalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine;
    . 30 2-(2-aminoethyl)-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 2-allyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 1-allyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine;
    1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin- 4-one;
    . 3-aminomethyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 3-amino-6-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; ’ 5 3-[N-[2-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyllJamino]propan-1-ol; N-ethyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyt)pyrazolo[3,4-b]pyridin-2- yllethyl]lamine; 2-[N-[2-]4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyllamino]ethanol; N-[(2-pyridyl)methyl]-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin- 2-yllethyllamine; N-{(2-thienyl)methyi]-[2-[4,6-bis (4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin- 2-yllethyllamine; 1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- vilethyl]piperidine-4-carboxamide; 4,6-bis(4-fluorophenyl)-2-[2-(pyrrolidin-1-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4- blpyridine; (3R)-1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b}pyridin-2- vllethyllpyrrolidin-3-ol; 2-[N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yljethyl]-N- methylamino]ethanol;
    4.,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-[2-(1,2,3 4-tetrahydroisoquinolin-2- yhethyllpyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-2-[2-(4-phenylpiperazin-1-yl)ethyl]-5-(4- pyridyl)pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-2-[2-[4-(1-piperidyl)piperidin-1-yl]ethyl]}-5-(4- pyridyl)pyrazolo[3,4-b]pyridine; : 3-[N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-N- : 30 methylamino]propiononitrile; N-methyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyllJamine;
    2-[2-{4-(tert-butoxycarbonyl)piperazin-1-yllethyl]-4,6-bis(4-fluorophenyl)-5-(4- pyridyl)pyrazolo[3,4-b]pyridine; } 4,6-bis(4-fluorophenyl)-2-[2-(piperazin-1-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4- blpyridine; : 5S 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-vinylpyrazolo[3,4-b]pyridine; 2-[N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yllethyl]-N-(2- hydroxyethyl)aminojethanol; N-cyclopropyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyllJamine;
    N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyilacetamide; N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-n'- isopropylurea;
    N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-bjpyridin-2-
    vylethyllmethanesulfonamide; 6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-4-(1H-imidazol-4-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 4-(5-bromothien-2-yl)-6-(4-fluorophenvl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine;
    4,6-bis(d-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4- blpyridine; 5-(2-chloropyridin-4-yl)-4,6-bis(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 4-(6-chloropyridin-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine;
    4-(3,4-dichlorophenyl)-1-ethyl-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4- blpyridine; 6-(4-fluorophenyl)-4-(1-methylpiperidin-4-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4- blpyridine; 3-amino-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-
    : 30 b]pyridine; 6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine; 4 6-diphenyl-5-(4-pyridyl)-2-[2-(tetrahyd ropyran-2-yloxy)ethyl]pyrazolo[3,4- b]pyridine;
    6-(4-fluorophenyl)-4-(2-furyl)-2-methyl-5-(4-pyridyt)pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-2-methyl-4-(1-methyl-1H-imidazol-4-yl)-5-(4- } pyridyl)pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-2-[2-(tetrahydropyran-2- : 5 yloxy)ethyllpyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-2-[3-(tetrahydropyran-2- yloxy)propyli]pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-2-[3-(tetrahydropyran-2- yloxy)propyl]pyrazolo[3,4-b]pyridine; 4-(5-bromothien-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4- blpyridine; 6-(4-fluorophenyl)-2-methyl-5-(2-methylsulfanylpyrimidin-4-yl)pyrazolo[3,4- blpyridine; 5-(2-chloropyridin-4-yl)-4,6-bis(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl)-2-[3-(tetrahydropyran-2- yloxy)propyl]pyrazolo[3,4-blpyridine; 4-(6-chloropyridin-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-2-[3-(tetrahydropyran-2- yloxy)propyllpyrazolo[3,4-b]pyridine; 4-(6-chloropyridin-3-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4- bipyridine; 5-(2-methylsulfanylpyrimidin-4-yl)-2-[3-(tetrahydropyran-2-yloxy)propyl]-6-(3- trifluoromethylphenyl)pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-4-[5-(3-pyridyl)thien-2-yllpyrazolo[3,4- blpyridine; 2-[4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-bpyridin-2-yl]ethanol; 3-[5-(2-methylsulfanylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)pyrazolo[3,4- b]pyridin-2-yl]propan-1-ol; 2-[6-(4-fluorophenyl)-5-(2-methyisulfanylpyrimidin-4-yl)pyrazolo[3,4-b]pyridin-2- yllethanol,
    . 30 3-[6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)pyrazolo[3,4-b]pyridin-2- ylJpropan-1-ol; 3-[4,6-bis(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)pyrazolo[3,4-b]pyridin- 2-yllpropan-1-ol;
    3-[6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllpropan-1-ol; 3-[4-(6-chloropyridin-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllpropan-1-ol; ’ 5 6-(4-fluorophenyl)-2-methyl-5-(2-methylsulfonylpyrimidin-4-yl)pyrazolo[3,4- b)pyridine; 3-[5-(2-methylsulfonylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)pyrazolo[3,4- b]pyridin-2-yl]propan-1-ol; 2-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)pyrazolo[3,4-b]pyridin-2- yllethanol; 3-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)pyrazolo{3,4-b]pyridin-2- yllpropan-1-ol; 3-[4,6-bis(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)pyrazolo[3,4-b]pyridin- 2-yl]propan-1-ol, N-cyclopropylmethyl-[4-[6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5- yllpyrimidin-2-ylJamine; (1S)-3-[5-[2-(1-phenylethylamino)pyrimidin-4-y{]-6-(3- trifluoromethylphenyl)pyrazolo[3,4-b]pyridin-2-ylJpropan-1-ol; N-cyclopropylmethyl-[4-[6-(4-fl uorophenyl)-2-methyl-pyrazolo[3,4-b]pyridin-5- vyllpyrimidin-2-yllamine; 2-[56-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-6-(4-fluorophenyl)pyrazolof3,4- b)pyridin-2-yl]ethanol; 3-[5-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-6-(4-fluorophenyl)pyrazolo[3,4- blpyridin-2-ylJpropan-1-ol; 3-[5-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-4,6-bis(4- fluorophenyl)pyrazolo[3,4-b]pyridin-2-yljpropan-1-ol; 4-[4-[4,6-bis(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridin-5-yllpyridin-2- ylamino]benzenesulfonamide; 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyrid in-3-ol;
    . 30 6-(4-fluorophenyl)-4-(3H-imidazol-4-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-4-(1H-pyrazol-3-yl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridine; 3-[6-(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-b]pyridin-4-ylJphenol; 4-cyclopropyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo[3,4-blpyridine;
    © 152 6-(4-fluorophenyl)-4-(5-methyifuran-2-yl}-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 4-(5-bromofuran-2-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine;
    . 4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4- blpyridine; ) 5 4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H- - pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-4-propyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b}pyridine; 4-(3-benzyloxyphenyl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 5-(2-chloropyridin-4-yl)-6-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine; 4-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-4-yljbutan-1-ol; 4-benzyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine; 4,6-bis(4-fluorophenyl)-5-pyrimidin-4-yl-1H-pyrazolo[3,4-b]pyridine; [(2S)-2-[4,6-bis(4-fluorophenyi)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyllpyrrolidine-2-carboxamide; 2-[2-(4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl)ethylamino]ethanol; 6-(4-fluorophenyl)-2-methyl-4-(3-pyridyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-3-methyl-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4- b]pyridine; 3-amino-5-(2-methylsulfanylpyrimidin-4-yl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine; 5-(2-methylsulfanylpyrimidin-4-yl)-6-phenyl-1 H-pyrazolo[3,4-b]pyridine; 6-(4-fluorophenyl)-4-methyl-5-(2-methylsulfanylpyrimidin-4-yl)-1 H-pyrazolo[3,4- blpyridine; 5-(2-methoxypyrimidin-4-yl)-6-(3-triftuoromethylphenyl)-1H-pyrazolo[3,4-b]pyridine; N-[2-[4,6-(diphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyllacetamide; N-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yl]propyllacetamide; N-[2-(4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl)ethyl}-N-(2- hydroxyethyl)acetamide; ) 30 N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yiJethyl]propionamide; N-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yl]propyllmethanesulfonamide;
    5-(2-aminopyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridine; N-[5-(2-methylsulfanylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4- blpyridin-3-yljacetamide; N-cyclopropylmethyl-[4-[3-benzyloxycarbonylamino-6-(3-trifluoromethylphenyl)- : 5 1H-pyrazolo[3,4-b}pyridin-5-yl]pyrimidin-2-ylJamine; N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl}-2- hydroxyacetamide; N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethyl]piperidine-4-carboxamide; N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yljethyl}-2- (methylamino)acetamide; N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yllethyl]-2-(2- hydroxyethylamino)acetamide; N-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- vllethvllnicotinamide; 4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4- b]pyridine; 6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-y1)-2-methylpyrazolof3,4- blpyridine; G-(4-fluorophenyl)-2,4-dimethyl-5-(4-pyridvl)oyrazolo[3,4-b] pyridine; 4-(4-benzvloxyphenyl)-6-(4-fluorophenyl)-2-methyl-5-(2-methylsulfanylpyrimidin-4- yl)pyrazolo[3,4-b]pyridine; 2-(1-benzylpyrrolidin-2-ylmethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridine; 4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-2-methyl-5-pyrimidin-4-ylpyrazolo[3,4- bipyridine; 6-(4-fluorophenyl)-2-methyl-4-(5-methylfuran-2-yl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridine; 4-(5-bromofuran-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-
    . 30 blpyridine; 6-(4-fluorophenyl)-2-methyl-4-propyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine; 4-(3-benzyloxyphenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4- b]pyridine;
    6-(4-fluorophenyl)-2-methyl-4-(2-phenylethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine;
    : 5-(2-chloropyridin-4-yl)-6-(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine;
    ] 4-benzyl-6-(4-fluorophenyl)-2-methyl-5-(4-pyrid yl)pyrazolo[3,4-b]pyridine; 4-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-4-yljbutan-1-ol;
    : 5 4-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-4-ylJphenol; N-[6-(4-fluorophenyl)-5-(2-methyisulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin- 3-yllacetamide; N-[5-[2-[(cyclopropylmethyl}amino]pyrimidin-4-yI}-6-(4-fluorophenyl)-1H- pyrazolo[3,4-b]pyridin-3-ylJacetamide;
    3-[6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl}propan-1- ol; 2-[4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yllethanol; 3-[4-(4-benzyloxyphenyl)-6-(4-fluoropheny!)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-
    yllpropan-1-ol; 3-[6-(4-fluorophenyl)-4-(5-methylfuran-2-yl)-5-(4-pyridyl )pyrazolo[3,4-b]pyridin-2- yl}propan-1-ol; 3-[4-cyclopropyl-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan- 1-ol;
    3-[4-(5-bromothien-2-yl)-6-(4-flucrophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2- yl}propan-1-ol; 3-[6-(4-fluorophenyl)-4-propyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan-1-ol; 3-[4,6-bis(4-fluorophenyl)-5-pyrimidin-4-ylpyrazolo[3,4-b]pyridin-2-yl]propan-1-ol; 3-[4-(3-benzyloxyphenyl)-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-
    yllpropan-1-ol; 3-[4-benzyl-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yljpropan-1-ol; (1S)-N-(1-phenylethyl)-[4-[6-(4-fluorophenyl)-3-methyl-1 H-pyrazolo[3,4-b]pyridin-5- yl]pyrimidin-2-ylJamine; N-cyclopropylmethy!-[4-[6-(4-fluorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-
    } 30 yllpyrimidin-2-yllJamine; 1-[4-[6-(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- ylamino]propan-2-ol;
    N-cyclopropylmethyl-[4-[6-phenyl-1 H-pyrazolo[3,4-b] pyridin-5-yl]pyrimidin-2- yllamine; -
    } 2-[4-[6-(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- ylamino]propan-1-ol;
    : 5 4-[4-[6-(4-fluorophenyl)-2-methyl-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- ylamino]butan-1-ol; (1S)-N-(1-phenylethyl)-{4-[6-phenyl-1H-pyrazolo[3,4-bjpyridin-5-yl]pyrimidin-2- yllamine; N-(3-methoxypropyl)-[4-[6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-5-
    yllpyrimidin-2-ylJamine; 3-(4-[6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- ylamino]propan-1-ol; 3-[4-[6-(4-flucrophenyl)-2-(3-hydroxypropyl)pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- ylamino]propan-1-ol;
    N-ethyl-[4-[6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- ylJamine; N-benzyl-[4-[6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- yllamine; 4-[5-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl}-6-(4-fluorophenyl)-2-
    methylpyrazolo[3,4-b]pyridin-4-yilphenol; 4-[6-(4-fluorophenyl)-2-(3-hydroxypropyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-4- yllphenol; 4-[6-(4-fluorophenyl)-2-methyl-5-pyrimidin-4-ylpyrazolo(3,4-b]pyridin-4-yl]phenol;
    3-[6-(4-fluorophenyl)-2-(3-hydroxypropyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-4-
    yllphenol; 3-[6-(4-fluorophenyt)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-4-yllphenol;
    4 ,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-(pyrrolidin-2-ylmethyl)pyrazolo[3,4- b]pyridine; 4-[4-[6-(4-fluorophenyl)-2-methylpyrazolo[3,4-blpyridin-5-yl]pyridin-2-
    ylamino]benzenesulfonamide; N-[5-[2-[(cyclopropylmethyl)amino]pyrimidin-4-yl]-6-(4-fluorophenyl)-1H- pyrazolo[3,4-b]pyridin-3-ylJacetamide 7-oxide; and N-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-3-yljisonicotinamide;
    or a salt, solvate or prodrug thereof.
    28.- Process for preparing a compound of formula | according to claim 1, which ] comprises: (a) reacting a ketone of formula IV . "Y’ R2 v wherein R' and R? have the same meaning as in claim 1, with an aminopyrazole of formula V and an aldehyde of formula VI RS / HoN N,
    N 3. y R°-CHO R4 \'4 vi wherein R?, R* and R® have the same meaning as in claim 1; or (b) when in a compound of formula I, R® represents H and R® has the same meaning as R’, reacting a ketone of formula IV or an enolate of formula VII 1 1 Yr ys 1 R? R2 J] Iv Vil wherein R' and R? have the same meaning as in claim 1, with an aminopyrazole of formula Va.
    HN. H B Y R4 Va wherein R* has the same meaning as in claim 1; or (c) when in a compound of formula | R* represents NH, treating a compound of formula XIX
    RL _Ng _Cl
    © . J CN
    R3 . XIX wherein R', R? and R® have the same meaning as in claim 1, with a hydrazine of formula Villa NH,—NHRS Villa wherein R® has the same meaning as in claim 1; or (d) converting, in one or a plurality of steps, a compound of formula | into another compound of formula I; and (e) if desired, after the previous steps, reacting a compound of formula | with a base or an acid to give the corresponding salt.
    29.- A pharmaceutical composition which comprises an effective amount of a compound of formula | according to any of claims 1 to 27 or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable excipients.
    30.- Use of a compound of formula | according to any of claims 1 to 27 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by p38.
    31.- Use of a compound of formula | according to any of claims 1 to 27 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cytokines.
    32.- Use of a compound of formula 1 according to any of claims 1 to 27 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by TNF-a, IL- 1, IL-6 and/or IL-8.
    33.- Use of a compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable sait, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious
    PCT/EP2004/001974 diseases, bone resorption diseases, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.
    34. A substance or composition for use in a method for the treatment or prevention of diseases mediated by p38, said substance or composition comprising a compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and said method comprising administering said substance of composition.
    35. A substance or composition for use in a method for the treatment or prevention of diseases mediated by cytokines, said substance or composition comprising a compound of formula | according to any of claims 1 to 27 or a pharmaceutically acceptabie salt, soivate or prodrug thereof, and said method comprising administering said substance or composition.
    36. A substance or composition for use in a method for the treatment or prevention of diseases mediated by TNF-a, IL-1, IL-6 and/or IL-8, said substance or composition comprising a compound of formula | according to any of claims 1 to 27 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and said method comprising administering said substance or composition.
    37. A substance or composition for use in a method for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption diseases, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2, said substance or composition comprising a compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and said method comprising administering said substance or composition.
    38. A compound according to any one of claims 1 to 27, substantially as herein described and illustrated. AMENDED SHEET i
    PCT/EP2004/001974
    39. A process according to claim 28, substantially as herein described and illustrated.
    40. A composition according to claim 29, substantially as herein described and illustrated.
    41. Use according to any one of claims 30 to 33, substantially as herein described and illustrated.
    42. A substance or composition for use in a method of treatment or prevention according to any one of claims 34 to 37, substantially as herein described and illustrated.
    43. A new compound, a new process for preparing a compound, a new composition, a new use of a compound as claimed in any one of claims 1 to 27, or a substance or composition for a new use in a method of treatment or prevention, substantially as herein described. AMENDED SHEET f
ZA200505935A 2003-02-27 2006-02-15 Pyrazolopyridine derivatives ZA200505935B (en)

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