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WO2015118434A1 - Dérivés de pyrazolo[1,5-a]pyrimidine, en tant qu'inhibiteurs de la kinase jak-2 - Google Patents

Dérivés de pyrazolo[1,5-a]pyrimidine, en tant qu'inhibiteurs de la kinase jak-2 Download PDF

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Publication number
WO2015118434A1
WO2015118434A1 PCT/IB2015/050715 IB2015050715W WO2015118434A1 WO 2015118434 A1 WO2015118434 A1 WO 2015118434A1 IB 2015050715 W IB2015050715 W IB 2015050715W WO 2015118434 A1 WO2015118434 A1 WO 2015118434A1
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methyl
amine
pyrimidin
pyrazolo
pyrazol
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Inventor
Michal MROCZKIEWICZ
Joanna LIPNER
Pawel GUNERKA
Krzysztof DUBIEL
Maciej Wieczorek
Daria ZDZALIK
Aleksandra Stanczak
Monika Lamparska-Przybysz
Bartosz STYPIK
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Celon Pharma SA
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Celon Pharma SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel pyrazolo[l,5-a]pyrimidine compounds, exhibiting the ability of tyrosine kinase JAK-2 inhibition, pharmaceutical compositions containing them and their use as a medicament.
  • the compounds can find the use in particular in the treatment of myeloproliferative, cancer, and inflammatory diseases.
  • Tyrosine kinases JAKl, JAK2, JAK3 and TYK2 from JAK family are involved in intracellular signal transduction in the JAK-STAT signaling pathway and play pivotal role in the activation of STAT proteins and initiation of transcription.
  • Activation of JAK kinases is considered one of the factors of cancer cells proliferation.
  • the activity of transcriptional factor STAT in a cell depends on the level of its phosphorylation. Increase of phosphorylation level leads to pathological myeloproliferative disorders and leukemias.
  • Phosphorylation level of transcriptional factor STAT in a cell depends on the activity of JAK2 kinase - inhibition of JAK2 kinase results in reduction of STAT phosphorylation and its transcriptional activity.
  • JAK2 kinase is also activated in the range of solid tumors and leukemias. Therefore, JAK2 kinase inhibitors block specific signaling pathway that can lead to excessive cell proliferation and development of cancer and can find use in the treatment of myeloproliferative and cancer diseases.
  • JAK-STAT pathway is an important element in the development and progress of inflammatory diseases such as rheumatoid arthritis, psoriasis or asthma.
  • Stimulation of JAK kinases in T lymphocytes by proinflammatory cytokines leads to the activation of STAT factor.
  • JAK2 inhibitors by blocking phosphorylation of STAT factor, may inhibit differentiation of T lymphocytes population and development of inflammation and therefore find use in the treatment of diseases of inflammatory origin.
  • JAK2 inhibitors the compounds of the general formula as below
  • Substituent R 5 in the position 7 of the pyrazolo[l,5-a]pyrimidine core can represent H, alkyl, halogen, -O-alkyl or aryl.
  • Ri a encompasses amine group
  • R 3 encompasses lower alkyl
  • R 5 encompasses lower alkyl, and any of them can be substituted with any, however not closer defined, substituent.
  • Virtually all specific disclosed subgroups and examples of the compounds have substituted amide group in the position 5 or 6 (substituents Ri a and R 2a ).
  • the present invention relates to the compound of the general formula (I)
  • - Q represents a 6-membered heteroaromatic ring containing 2 N atoms and Ri is hydrogen atom, or
  • - Q represents a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of N and S, one substituent Ri is attached at C or N atom of said Q ring and Ri is selected from the group consisting of Cl-C4-alkyl and C3-C4-cycloalkyl;
  • R 2 represents - R7 a R7b or -CH 2 - R 8a R 8 b;
  • R 3 represents Cl-C4-alkyl
  • R 4 represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;
  • R 5 and 5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;
  • heteroalicyclic ring contains 1 or 2 heteromoieties selected from the group consisting of N, O and -S(0) 2 - and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl-C4-alkyl;
  • R 8a and R 8 b independently represent hydrogen atom, Cl-C4-alkoxy-Cl-C4-alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S02-Cl-C4-alkyl; or R 8a and R 8 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring wherein said heteroalicyclic ring contains 1 or 2 heteromoieties selected from the group consisting of N, O and -S(0) 2 - and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -
  • the invention encompasses single optically active enantiomers of such compounds of formula (I) or (IA) as well as their enantiomeric mixtures, including in particular substantially equimolar enantiomeric mixtures of the opposite enantiomers, especially racemic mixtures. It should be understood that any of subgroups and embodiments of the compound of the invention defined herein below relates both to the formula (I) and formula (IA).
  • a first subgroup of the compounds of the invention are the compounds wherein:
  • - Q represents a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of N and S, and one substituent Ri is attached at C or N atom of said Q ring;
  • - Ri is selected from the group consisting of Cl-C4-alkyl and C3-C4-cycloalkyl;
  • R 2 represents - R7 a R7b or -CH 2 - R 8a R 8 b;
  • R 3 represents Cl-C4-alkyl
  • R 4 represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;
  • R 5 and 5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;
  • R 7a and R 7 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl-C4-alkyl;
  • R 8a and R 8 b independently represent hydrogen atom, Cl-C4-alkoxy-Cl-C4-alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl-C4-alkyl; or R 8a and R 8 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl
  • a second subgroup of the compounds of the invention are the compounds wherein:
  • - Q represents a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of N and S, and one substituent Ri is attached at C or N atom of said Q ring;
  • - Ri is selected from the group consisting of Cl-C4-alkyl and C3-C4-cycloalkyl;
  • - R 2 represents - R7 a R7b or -CH 2 - R8 a R8b;
  • R 3 represents Cl-C4-alkyl
  • R 4 represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;
  • R 5 and 5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;
  • heteroalicyclic ring contains 1 or 2 heteromoieties selected from the group consisting of N, O and -S(0) 2 - and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl-C4-alkyl;
  • R 8a and R 8 b independently represent hydrogen atom, Cl-C4-alkoxy-Cl-C4-alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -C1-C4- alkyl; or R 8a and R 8 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring wherein said heteroalicyclic ring contains 1 or 2 heteromoieties selected from the group consisting of N, O and -S(0) 2 - and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and
  • a third subgroup of the compounds of the invention are the compounds wherein:
  • - Q represents a 6-membered heteroaromatic ring containing 2 N atoms and Ri is hydrogen atom, or
  • - Q represents a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of N and S, one substituent Ri is attached at C or N atom of said Q ring and Ri is selected from the group consisting of Cl-C4-alkyl and C3-C4-cycloalkyl;
  • - R 2 represents - R7 a R7b or -CH 2 - R8 a R8b;
  • R 3 represents Cl-C4-alkyl
  • R 4 represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;
  • R 5 and R5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;
  • R 7a and R 7 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring, wherein said heteroalicyclic ring contains one -S(0) 2 - heteromoiety and is unsubstituted;
  • R 8a and R 8 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring wherein said heteroalicyclic ring contains one -S(0) 2 - heteromoiety and is unsubstituted; optically active enantiomers and enantiomeric mixtures thereof, and pharmaceutically acceptable salts thereof.
  • - Q represents a 6-membered heteroaromatic ring containing 2 N atoms and Ri is hydrogen atom;
  • - R 2 represents - R7 a R7b or -CH 2 - R 8a R 8 b;
  • R 3 represents Cl-C4-alkyl
  • R 4 represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;
  • R5 and R5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;
  • R 7a and R 7 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl-C4-alkyl;
  • R 8a and R 8 b independently represent hydrogen atom, Cl-C4-alkoxy-Cl-C4-alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -C1-C4- alkyl; or R 8a and R 8 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl
  • - Q represents a 6-membered heteroaromatic ring containing 2 N atoms and Ri is hydrogen atom;
  • R 2 represents - R 7a R 7 b or -CH 2 - R 8a R 8 b; - R.3 represents Cl-C4-alkyl;
  • R 4 represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;
  • R5 and R5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;
  • heteroalicyclic ring contains 1 or 2 heteromoieties selected from the group consisting of N, O and -S(0) 2 - and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl-C4-alkyl;
  • R 8a and R 8 b independently represent hydrogen atom, Cl-C4-alkoxy-Cl-C4-alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -C1-C4- alkyl; or R 8a and R 8 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring wherein said heteroalicyclic ring contains 1 or 2 heteromoieties selected from the group consisting of N, O and -S(0) 2 - and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and
  • - Q represents a 6-membered heteroaromatic ring containing 2 N atoms and Ri is hydrogen atom;
  • R 2 represents - R 7a R 7 b or -CH 2 - R 8a R 8 b;
  • - R3 represents Cl-C4-alkyl
  • - R.4 represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;
  • R 5 and 5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;
  • R 7a and R 7 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring, wherein said heteroalicyclic ring contains one -S(0) 2 - heteromoiety and is unsubstituted;
  • R 8a and R 8 b together with nitrogen atom to which they are attached form a 6- membered heteroalicyclic ring wherein said heteroalicyclic ring contains one -S(0) 2 - heteromoiety and is unsubstituted; optically active enantiomers and enantiomeric mixtures thereof, and pharmaceutically acceptable salts thereof.
  • heteroaromatic ring designated in formula (I) by symbol Q is attached to the bridging moiety - H- linking Q with pyrazolo[l,5-a]- pyrimidine core through carbon atom of said heteroaromatic Q ring.
  • Q represents a 6- membered heteroaromatic ring containing 2 N atoms, especially pyrazine ring, such as pyrazin-2-yl, and Ri is hydrogen atom.
  • Q represents a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of N and S, and one substituent Ri is attached at C or N atom of said Q ring.
  • Ri is Cl-C4-alkyl, which can be a straight or branched chain alkyl and encompasses methyl, ethyl, ⁇ -propyl, z ' so-propyl, 3 ⁇ 4-butyl, sec- butyl and tert-butyl.
  • Ri is methyl.
  • Ri is cycloalkyl C3-C4 and encompasses cyclopropyl and cyclobutyl.
  • Ri is cyclopropyl.
  • Q represents lH-pyrazole or ⁇ H- imidazole ring. In one preferred group of the compounds of the invention Q represents lH-pyrazole or IH- imidazole ring and Ri is methyl.
  • Q represents lH-pyrazole or lH-imidazole ring and R 5 and 5 both are hydrogen atoms.
  • Q represents lH-pyrazole or lH-imidazole ring and R3 is methyl.
  • Q represents lH-pyrazole or lH-imidazole ring
  • Ri is methyl
  • R5 and R5 both are hydrogen atoms and R3 is methyl.
  • Q represents lH-pyrazole ring
  • this can be lH-pyrazol-3-yl, lH-pyrazol-4-yl or ⁇ H- pyrazol-5-il, especially lH-pyrazol-3-yl.
  • Q represents lH-imidazole ring
  • this can be lH-imidazol-4-yl, lH-imidazol-5-yl or lH-imidazol-2-yl, especially lH-imidazol-4-yl.
  • Q represents thiazole ring, including thiazol-2-yl, thiazol-4-yl and thiazol-5-il, especially thiazol-2-yl.
  • R5 and R5 are both hydrogen atoms.
  • one of R5 and R5 is hydrogen atom and the other is Cl-C4-alkyl
  • Cl-C4-alkyl includes methyl, ethyl, zz-propyl, z ' o-propyl, n- butyl, sec-butyl and tert-butyl, especially methyl.
  • R 3 is Cl-C4-alkyl, which can be a straight or branched chain alkyl and encompasses methyl, ethyl, zz-propyl, z ' so-propyl, zz-butyl, sec-butyl and tert-butyl.
  • R 3 is methyl or ethyl, especially methyl.
  • R 4 is phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxy.
  • Halogen encompasses fluorine, chlorine and bromine atoms, especially fluorine and chlorine atoms
  • Cl-C4-alkoxyl encompasses straight or branched chain alkyl groups, including methoxyl, ethoxyl, zz-propoxyl, iso- propoxyl, zz-butoxyl, sec-butoxyl and tert-butoxyl, preferably methoxyl.
  • R 4 is phenyl substituted with one fluorine atom, two fluorine aroms or one fluorine and one chlorine atoms.
  • R 4 is a 5- or 6-membered heteroaryl, which includes 1 or 2 heteroatoms selected from the group consisting of N and S, and R 4 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluorom ethyl, hydroxyl and Cl-C4-alkoxyl.
  • Halogen encompasses fluorine, chlorine and bromine atoms, especially fluorine and chlorine atoms
  • Cl-C4-alkoxyl encompasses straight or branched chain alkyl groups, including methoxyl, ethoxyl, n- propoxyl, zso-propoxyl, «-butoxyl, sec-butoxyl and tert-butoxyl, preferably methoxyl.
  • R4 when said R4 is a 5- or 6-membered heteroaryl, when substituted, is substituted at its C atom.
  • the 5- or 6-membered heteroaryl which includes 1 or 2 heteroatoms selected from the group consisting of N and S encompasses 5-membered heteroaryl groups such as for example pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, and 6- membered heteroaryl groups such as for example pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • R 4 is pyridinyl, especially pyridinyl substituted with fluorine atom, or thiazolyl.
  • R 2 is - R7 a R7b, wherein R 7a and R 7 b together with nitrogen atom to which they are attached form a 6-membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteromoieties selected from the group consisting of N, O and -S(0) 2 - and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S0 2 -Cl-C4-alkyl.
  • one of said 1 or 2 heteromoieties is said nitrogen atom to which R 7a and R 7 b are attached.
  • second of said 1 or 2 heteromoieties is in the position 4 of the heteroalicyclic ring with respect to the nitrogen atom to which R 7a and R 7 b are attached.
  • C1-C4 alkyl encompasses groups such as discussed above for R 4 , preferably methyl.
  • R 7a and R 7 b together with nitrogen atom to which they are attached form morpholine, piperidine or piperazine ring, which are unsubstituted or substituted with methyl or -S0 2 -CH 3 .
  • R 7a and R 7 b together with nitrogen atom to which they are attached form unsubstituted 1, 1-dioxothiomorpholine ring.
  • R 2 is -CH 2 - Rs a R8b.
  • R 8a and R 8 b together with nitrogen atom to which they are attached form a 6-membered heteroalicyclic ring which includes 1 or 2 ring heteroatoms selected from the group consisting of N and O, and said heteroalicyclic ring is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S02-Cl-C4-alkyl, preferably morpholine, piped dine or piperazine ring, unsubstituted or substituted with methyl or -SO2-CH3.
  • one of said 1 or 2 heteroatoms is said nitrogen atom to which R 8a and R 8 b are attached.
  • second of said 1 or 2 heteroatoms is in the position 4 of the heteroalicyclic ring with respect to the nitrogen atom to which R 8a and R 8 b are attached.
  • R 8a and R 8 b independently represent hydrogen atom, C1-C4- alkoxy-Cl-C4-alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, wherein said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S02-Cl-C4-alkyl.
  • Cl-C4-alkyl can be a straight or branched chain alkyl, preferably straight chain, especially
  • said heteroalicyclic ring is morpholine, piperidine or piperazine ring, unsubstituted or substituted with methyl or -SO2-CH3.
  • one of R 8a and R 8 b is hydrogen atom
  • the second is Cl-C4-alkoxy-Cl-C4- alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring
  • said heteroalicyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N and O and is unsubstituted or substituted at C or N atom(s) with one or two substituents selected from the group consisting of Cl-C4-alkyl and -S02-Cl-C4-alkyl, preferably Cl- C4-alkoxy-Cl-C4-alkyl or Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, especially morpholine, piperidine or piperazine ring, unsubstituted or substituted with methyl or -SO2-CH3.
  • R 8a and R 8 b when one of R 8a and R 8 b is Cl-C4-alkyl substituted with a 6-membered heteroalicyclic ring, then said 6-membered heteroalicyclic ring may be attached to Cl-C4-alkyl through its C or N atom as linking atom.
  • one of its heteroatoms is in the position 4 with respect to said linking atom.
  • said 6-membered heteroalicyclic ring is attached to Cl-C4-alkyl through its N atom, and the second of its heteroatoms, if present, is in the position 4 with respect to said linking N atom.
  • novel pyrazolo[l,5-a]pyrimidine compounds of the invention exhibit potent ability of selective kinase JAK2 inhibition and advantageous pharmacokinetic properties.
  • the object of the invention is therefore the compound of formula (I) as defined above for use as a medicament.
  • the object of the invention is also a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient the compound of formula (I) as defined above, in admixture with pharmaceutically acceptable auxiliary substance(s).
  • JAK2 inhibitors the compounds of formula (I) as defined above can be useful in the treatment of proliferative disorders, cancer diseases and diseases of inflammatory origin.
  • the object of the invention is therefore the compound of formula (I) as defined above for use in a method of treating proliferative disorders, cancer diseases and diseases of inflammatory origin.
  • the object of the invention is also the use of the compound of formula (I) as defined above for the preparation of a medicament for treating proliferative disorders, cancer diseases and diseases of inflammatory origin.
  • the object of the invention is also a method of treating proliferative disorders, cancer diseases and diseases of inflammatory origin in a mammal, including human, which comprises administering of a therapeutically effective amount of the compound of formula (I) as defined above or the pharmaceutical composition comprising the compound of formula (I) as defined above.
  • Specific embodiment of the invention are the compounds selected from the group consisting of the compounds presented hereinbelow in Examples 1 to 99 and their pharmaceutically acceptable salts.
  • Yet another embodiment of the invention are the compounds selected from the group consisting of the compounds presented hereinbelow in Examples 77-84 and 89-90 and their pharmaceutically acceptable salts.
  • the compound of the formula (I) of the invention may contain chiral center other than that at the carbon atom carrying substituents R 5 and R 6 , and such a compound can exist in the form of optical isomers and their mixtures. Such optical isomers and their mixtures at different ratios, including equimolar or substantially equimolar racemic mixtures, are also covered by the scope of the invention.
  • Salts of the compounds of the formula (I) according to the invention comprise salts with inorganic or organic acids.
  • Preferred are pharmaceutically acceptable salts.
  • Inorganic and organic acids that are able to form pharmaceutically acceptable salts with the compounds having basic nitrogen atom and methods of their preparation are well known in the art.
  • Salts with inorganic acids may in particular comprise salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids.
  • Salts with organic acids may in particular comprise salts of methanesulphonic, ethanesulphonic, toluenesulphonic, benzenesulphonic, naphthalene- sulphonic, acetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • the compounds of the invention of the general formula (I) can be obtained by reacting corresponding chloroderivative of the general formula (II) with corresponding aminoheteroaryl compound of the general formula (III), as shown in the Scheme 1 below:
  • reaction of compound (II) and compound (III) to obtain the compound (I) can be carried out under Buchwald-Hartwig coupling conditions, in a solvent, in the presence of a palladium catalyst, phosphine ligand and an inorganic or organic base.
  • Aprotic solvents such as benzene, toluene, xylenes, tetrahydrofuran, dioxane, dimethoxyethane or diethoxyethane, or aprotic solvents, such as butanol, water or a mixture of said solvents, can be used in the reaction.
  • the amount of aminoheteroaryl (III) is from 1 to 3 molar equivalents per one equivalent of the compound of formula (II).
  • Palladium catalyst can be tris(dibenzylidene- acetone)dipalladium(O) (preferred), bis(dibenzylideneacetone)palladium(0), palladium(II) acetate or l,l'-bis(diphenylphosphine)ferrocene.
  • the amount of palladium catalyst is from 0.05 to 0.10 molar equivalents per one equivalent of the compound of formula (II).
  • Suitable phosphine ligands are Xantphos - 4,5-bis(diphenylphosphine)-9,9- dimethylxanthene or BINAP - 2,2'-bis(diphenylphosphine)-l, l'-binaphthyl.
  • the amount of phosphine ligand is from 0.10 to 0.20 molar equivalents per one equivalent of the compound of formula (II).
  • sodium hydroxide lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or potassium tert-butanolate can be used in the amount from 1.00 to 1.5 molar equivalents per one equivalent of the compound of formula (II).
  • the reaction is carried out in strictly anaerobic conditions under inert gas atmosphere such as argon or nitrogen. The reaction is carried at the temperature 80 to 120 °C.
  • Protecting group (PG) for protection of pyrrole nitrogen atom can be a typical protecting group such as tert-butyl (t-Bu), tert-butoxycarbonyl (Boc-), benzyl (Bn-), para- methoxybenzyl (Pmb-) or dimethoxybenzyl (Dmb-).
  • Protecting groups are introduced according to the well-known in the literature methods of protection of nitrogen functional groups, such as introduction of tert-butoxycarbonyl group in the reaction with tert-butoxycarbonyl anhydride (Boc 2 0), introduction of benzyl group in the reaction with halogenide such as benzyl chloride (Bn-Cl) or bromide (Bn-Br), introduction of para-methoxybenzyl group in the reaction with para-methoxybenzyl halogenide such as para-methoxybenzyl chloride (Pmb-Cl) or bromide (Pmb-Br), introduction of dimethoxybenzyl group, for example 2,4-dimethoxybenzyl group, in the reaction with dimethoxybenzyl halogenide, such as dimethoxybenzyl chloride (Dmb-Cl) or bromide (Dmb-Br), for example 2,4-dimethoxybenzyl chloride or bromide.
  • PG lH-pyrazolyl group
  • preferred group (PG) protecting pyrrole nitrogen atom is tert-butyl group.
  • Protecting group (t-Bu-) can be introduced at the step of synthesis of pyrazole ring.
  • l-tert-butyl-3-methyl-lH-pyrazol-5-amine (VII) is obtained in accordance with the procedure described in Org. Process. Res. Rev. 2012, 16, 70-81 in the reaction of tert-butylhydrazine hydrochloride (V) and 3-aminobut-2-enenitrile (VI) in the presence of sodium hydroxide aqueous solution, as shown in the Scheme 3 below.
  • V tert-butylhydrazine hydrochloride
  • VI 3-aminobut-2-enenitrile
  • V VI tert-Butyl group can be removed by the reaction with trifluoroacetic acid with the addition of water. It is possible, although not necessary, to use solvent such as dichloromethane or chloroform. Preferably, the mixture trifluoroacetic acid - water at the volume ratio from 1 : 1 to 1 : 5 and from 15 to 40 molar equivalents of trifluoroacetic acid per one equivalent of the compound of formula (VII) can be used.
  • the reaction is carried out at the temperature from room temperature to 120 °C. It is preferred to perform the reaction at the temperature from the range 80 to 100 °C.
  • tert-Butoxycarbonyl group can be removed by the reaction with acetic, trifluoroacetic, hydrochloric or sulphuric acid, with or without the addition of water.
  • Benzyl, para- methoxybenzyl and dimethoxybenzyl groups can be removed by the reaction with trifluoroacetic acid with or without the addition of water, as described above, or by hydrogenolysis reaction catalyzed with palladium on active carbon.
  • aminoheteroaryles of the formula (III) can be obtained from commercially available corresponding nitro derivatives by reduction of nitro group to amino group under reductive conditions, such as hydrogenolysis catalyzed with palladium on active carbon, tin(I) chloride (SnCb) in acidic environment or iron in acidic environment.
  • reductive conditions such as hydrogenolysis catalyzed with palladium on active carbon, tin(I) chloride (SnCb) in acidic environment or iron in acidic environment.
  • the compounds of the general formula (II) are obtained according to two general methods, depending on the kind of R 2 group in the general formula (II).
  • R 2 represents - R7aR7b
  • the compounds of the general formula (II) can be represented by the general formula (IX).
  • R 2 represents -CH 2 - RsaR8b
  • the compounds of the general formula (II) can be represented by the general formula (X).
  • Suitable lH-pyrazol-5-amine (XI) with suitable malonic acid ester pyrazolo[l,5-a]pyrimidin-5,7-dioles of the general formula (XII) are obtained.
  • the reaction is carried out in a protic organic solvent, such as methanol, ethanol or propanol, preferably ethanol, under basic conditions at reflux temperature.
  • Metal alkoxylate preferably sodium ethanolate, is used as a base, in a pure form or generated from metallic sodium and ethanol.
  • the base is used in the amount of from 2 to 2.5 molar equivalents per one equivalent of the compound of formula (XI).
  • Malonic acid ester is methyl or ethyl ester, in the amount from 1.5 to 3 molar equivalents per one equivalent of the compound of formula (XI).
  • the compound of the general formula (XII) is converted into compound of the formula (XIII) in the reaction of nucleophilic substitution of hydroxyl groups with chlorine, by means of a chlorinating agent such as phosphorus (V) oxychloride or thionyl chloride, without a solvent or in an aprotic organic solvent, such as chloroform, dichloromethane or acetonitrile.
  • Chlorinating agent is used in the amount of 2 to 30 molar equivalents per one equivalent of the compound of formula (XII), preferably above 10.
  • the reaction is carried out at the temperature from the range 80 to 120 °C or at reflux temperature.
  • the compound of the general formula (XIII) is converted into compound of the general formula (IX) in the reaction with suitable amine H- R7 a R7b, wherein R 7a and R 7 b are as defined above for the formula (I).
  • Amine H- R 7a R 7 b is used in the amount from 1 to 2 molar equivalents per one equivalent of the compound of formula (XVII).
  • the reaction is carried out in the presence of an inorganic base, such as for example metal carbonate, such as sodium, potassium or cesium carbonate, or an organic base, such as jak triethylamine or pyridine.
  • Preferred base is sodium carbonate.
  • the base is used in the amount of 1 to 5 molar equivalents per one equivalent of the compound of formula (XVII).
  • the reaction is carried out in an aprotic organic solvent, such as acetonitrile, dioxane or tetrahydrofuran, preferably acetonitrile.
  • an aprotic organic solvent such as acetonitrile, dioxane or tetrahydrofuran, preferably acetonitrile.
  • the reaction is carried out at the temperature in the range from 20 to 50 °C.
  • Suitable lH-pyrazol-5-amine (XI) is reacted with a suitable compound of the general formula (XIV), wherein R9 represents alkyl such as methyl, ethyl, propyl, preferably ethyl, to obtain bicyclic compound of the general formula (XV).
  • Compound (XIV) is used in the amount from 1 to 1.5 molar equivalents per one equivalent of the compound of formula (XI).
  • the reaction is carried out in a solvent, such as methanol or ethanol, preferably ethanol, at the reflux temperature. After cooling the reaction mixture, the product precipitates in the form of a white solid, and then is filtered and washed with the solvent.
  • TBMS- tert-Butyl dimethyl silyl group
  • TBMS- tert-Butyl dimethyl silyl group
  • tetrabutylamonium fluoride used as a solution in an organic solvent, such as tetrahydrofuran, dioxane, diethyl ether, dimethylformamide or methanol, preferably ethanol.
  • Tetrabutylamonium fluoride is used in the amount of 2 to 5 molar equivalents per one equivalent of the compound of formula (XV).
  • the compound of the general formula (XVI) thus obtained, after evaporation of the solvent, is without further purification converted in the subsequent step into compound of the general formula (XVII) by chlorination.
  • the chlorination reaction is carried out using chlorinating agent such as phosphorus (V) oxychloride or thionyl chloride, without solvent or in an aprotic organic solvent, such as chloroform, dichloromethane or acetonitrile.
  • Chlorinating agent is used in the amount of 2 to 30 molar equivalents per one equivalent of the compound of formula (XII), preferably above 10.
  • the reaction is carried out at the temperature from the range 80 to 120 °C or at the reflux temperature.
  • the compound of the general formula (XVII) is converted to the compound of the general formula (X) by reaction with corresponding amine H- R 8a R 8 b, wherein R 8a and R 8 b are as defined above for the formula (I).
  • Amine H- R 8a R 8 b is used in the amount from 1 to 2 molar equivalents per one equivalent of the compound of formula (XVII).
  • the reaction is carried out in the presence of an organic base, such as triethylamine or pyridine.
  • the base is used in the amount of from 1 to 5 molar equivalents per one equivalent of the compound of formula (XVII).
  • the reaction is carried out in an organic aprotic solvent, such as acetonitrile, dioxane or tetrahydrofuran, preferably acetonitrile.
  • organic aprotic solvent such as acetonitrile, dioxane or tetrahydrofuran, preferably acetonitrile.
  • the reaction is carried out at the temperature in the range from 20 to 50 °C.
  • the compound of the general formula (XIV) can be obtained from propargyl alcohol in accordance with the following Scheme 6.
  • Propargyl alcohol (XVIII) is reacted with tert-butyldimethylsilyl chloride (XIX) to obtain tert-butyldimethylsilyl ether (XX).
  • tert-Butyldimethylsilyl chloride (XIX) is used in the amount from 1 to 1.2 molar equivalents per one equivalent of propargyl alcohol (XVIII).
  • the reaction is carried out with the addition of imidazole in the amount of 2 molar equivalents per one equivalent of propargyl alcohol (XVIII).
  • the reaction is carried out in an anhydrous organic solvent, such as dichloromethane or chloroform.
  • Alkyl chloroformate is used in the amount from 1 to 2 molar equivalents per one equivalent of the compound of formula (XX).
  • the reaction is carried out in an anhydrous organic solvent, such as tetrahydrofuran, diethyl ether, preferably tetrahydrofuran, in the presence of a base such as «-butyllithium, tert-butyllithium, sec-butyllithium, z ' so-propyllithium, preferably «-butyllithium used as a hexane solution.
  • a base such as «-butyllithium, tert-butyllithium, sec-butyllithium, z ' so-propyllithium, preferably «-butyllithium used as a hexane solution.
  • the base is used in the amount from 1 to 1.2 molar equivalents per one equivalent of the compound (XX).
  • the reaction is carried out at -78°C, and then at room temperature.
  • Propargyl halogenide (XXI), such as propargyl chloride or bromide, is reacted with amine H- R8aR8b, wherein R 8a and R 8 b are as defined above for the formula (I), to obtain corresponding compound of the general formula (XXII).
  • the reaction is carried out in the presence of an organic base, such as metal carbonate, such as sodium, potassium or cesium carbonate, preferably sodium carbonate, in an alcoholic solvent such as methanol or ethanol.
  • Amine H- R 8a R 8 b is used in the amount of 1 to 1.2 molar equivalents per one equivalent of propargyl halogenide (XXI).
  • Compound (XXII) is converted to compound
  • Alkyl chloroformate is used in the amount from 1 to 2 molar equivalents per one equivalent of the compound of formula (XXII).
  • the reaction is carried out in an anhydrous aprotic organic solvent, such as tetrahydrofuran, diethyl ether, preferably tetrahydrofuran, in the presence of a base such as ⁇ -butyllithium, tert-butyllithium, sec-butyllithium or z ' so-propyllithium, preferably n- butyllithium, used as a hexane solution.
  • the base is used in the amount from 1 to 1.2 molar equivalents per one equivalent of the compound (XX).
  • the reaction is carried out at -78 °C and then at room temperature.
  • lH-Pyrazol-5-amine (XI) is reacted with the compound of the formula (XXIII) to obtain a bicyclic compound of the formula (XXIV).
  • the compound of the formula (XXIII) is used in the amount from 1 to 1.5 molar equivalents per one equivalent of the compound of formula (XI).
  • the reaction is carried out in an alcoholic solvent, such as methanol or ethanol, at the reflux of the solvent.
  • the compound of the general formula (XXIV) is converted to the compound of the general formula (X) in the reaction with a chlorinating agent, such as phosphorus (V) oxychloride or thionyl chloride, without a solvent or in an aprotic organic solvent, such as chloroform, dichloromethane or acetonitrile.
  • a chlorinating agent such as phosphorus (V) oxychloride or thionyl chloride
  • Chlorinating agent is used in the amount from 1 to 15 molar equivalents per one equivalent of the compound of formula
  • Suitable carbonyl compound of the general formula (XXV) such as aldehyde (Rio represents hydrogen atom) or ketone (Rio represents Cl-C4-alkyl) is converted into alkene of the general formula (XXVI) under conditions of the Horner- Wadswoth-Emmons reaction or Wittig reaction.
  • the reaction is carried out between carbonyl compound (XXV) and dialkyl cyanomethylphosphonate such as dimethyl cyanomethylphosphonate or diethyl cyanomethylphosphonate.
  • Dialkyl cyanomethylphosphonate is used in the amount of 1 to 1.2 molar equivalents per one equivalent of the carbonyl compound.
  • the reaction is carried out with the addition of an inorganic or organic base.
  • the inorganic base can be metal carbonate, such as sodium, potassium or cesium carbonate, metal hydride, such as for example sodium hydride, or metal bis(trimethylsilyl)amide, such as for example lithium, sodium or potassium bis(trimethylsilyl)amides.
  • the organic base can be metal alkoxylate, such as for example potassium tert-butanolate or lithium tert-butanolate.
  • Preferred base is potassium carbonate.
  • the base is used in the amount of 1 to 2 molar equivalents per one equivalent of the carbonyl compound.
  • the reaction is carried out without or with addition of crown ether, such as for example 15-crown-5 or 18-crown-6, preferably 18-crown-6. Crown ether is used in the amount of from 0.01 to 0.02 molar equivalents per one equivalent of the carbonyl compound.
  • the reaction is carried out in an aprotic organic solvent, such as toluene, tetrahydrofuran, dioxane, dimethoxyethane or dimethylformamide, preferably toluene.
  • the reaction is carried at the temperature range from od 50 to 100 °C.
  • two isomers of the product are obtained - predominantly formed isomer (XXVI- (£)) and isomer (XXVI-(Z)).
  • Reaction products are obtained at the (XXVI-(£)):(XXVI- (Z ) ratio in the range from 5: 1 to 9: 1.
  • reaction is carried out between carbonyl compound (XXV) and cyanomethyltriphenylphosphonium ylide generated in situ from cyano- methyltriphenylphosphonium chloride under basic conditions.
  • Cyanomethyltriphenyl- phosphonium chloride is used in the amount from 1 to 2 molar equivalents per one equivalent of the carbonyl compound.
  • a base can be an aqueous solution of hydroxide of metal such as for example sodium or potassium at 30% to 50% by weight in the amount from 10 to 50 molar equivalents per one equivalent of the carbonyl compound.
  • the reaction is carried out in a water immiscible organic solvent such as dichloromethane or chloroform, preferably dichloromethane.
  • reaction is carried at the temperature range from od 0 to 30°C. In the reaction two isomers of the product are obtained - predominantly formed isomer (XXVI-(£)) and isomer (XXVI-(Z)). Reaction products are obtained at the (XXVI-(£)):(XXVI-(Z)) ratio in the range from 5 : 1 to 9: 1.
  • mixture of the isomers (XXVI-(£)) and (XXVI-(Z)) can be before further synthesis step separated by means of chromatographic separation using silica gel as an immobile phase and as a mobile phase non-polar system of organic solvents such as hydrocarbon C5-C7 and ethyl acetate at the concentration gradient of ethyl acetate in hydrocarbon from 0% to 5%.
  • the hydrocarbon used in the separation can be for example heptane, hexane or petroleum ether.
  • carbonyl compound is an aldehyde of the formula (XXV), wherein group Rio represents hydrogen atom, resulting mixture of the product isomers (XXVI-(£)) and (XXVI-(Z)) is not separated before further synthesis step.
  • the compounds (XXVI-(£)) and (XXVI-(Z)) are converted to the compounds of the general formula (XXVII) using reducing agents.
  • the type of reducing agent depends on the type of R 4 and Rio groups present in the compounds (XXVI-(E)) and (XXVI-(Z)).
  • the reducing agent can be hydrogen gas in the presence of a hydrogenation catalyst, such as 5% or 10% palladium on active carbon. Palladium on active carbon is used in the amount from 10% to 20% by weight.
  • a hydrogenation catalyst such as 5% or 10% palladium on active carbon. Palladium on active carbon is used in the amount from 10% to 20% by weight.
  • the reaction is carried out in an alcoholic solvent, such as methanol or ethanol, preferably ethanol, at room temperature.
  • the reducing agent can be system of reagents: silane such as for example polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, preferably polymethyl- hydrosiloxane; phosphine ligand such as for example Xantphos (9,9-dimethyl-4,5- bis(diphenylphosphine)xanthene), Josiphos SL-JOOl-1 ((R)-l-[(S)-2-(diphenylphosphine)- ferrocenyljethyldicyclohexylphosphine adduct with ethanol), Josiphos SL-J001-2 ((S)
  • silane such as for example polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, preferably polymethyl- hydrosiloxane
  • phosphine ligand such as for example Xantphos (9,9-
  • Silane preferably polymethylhydrosiloxane
  • Silane preferably polymethylhydrosiloxane
  • Phosphine ligand and copper(II) acetate are used in the amount from 0.01 to 0.05 molar equivalents per one equivalent of sum of the compounds (XXVI-(£)) and (XXVI- ⁇ )).
  • tert-Butanol is used in the amount from 1 to 4 molar equivalents per one equivalent of sum of the compounds (XXVI-(£)) and (XXVI-(Z)).
  • racemic mixture of the compound of the general formula (XXVII) is obtained when reducing agents such as hydrogen in the presence of a hydrogenation catalyst such as palladium on active carbon, or system polymethylhydrosiloxane, Xantphos, copper(II) acetate and tert-butanol, as described above, are used.
  • chiral phosphonium ligand such as Josiphos SL-JOOl-1 or Josiphos SL-JOOl-2 causes that reduction of the compound (XXVI- (£)) or (XXVI-(Z)) runs enantioselectively and to form as products two enantiomers of the compound of formula (XXVII), that for selected compounds are formed in the ratio from 96:4 to 99: 1.
  • Direction of the reaction and at the same time predominantly formed enantiomer of the product are determined by the selection of suitable isomer of the starting material compound (XXVI-(£)) or (XXVI-(Z)) and selection of suitable enantiomer of the chiral phosphonium ligand used in the reaction.
  • Stereochemical configuration of the chiral carbon atom bearing substituents R5 and 5 in the compound of invention of the general formula (I) is determined by stereochemical configuration of the chiral carbon atom bearing substituents R5 and R5 in the compound of the general formula (XXVII). I.e., there is no racemization or inversion of configuration at this chiral carbon in all subsequent steps of the preparation of the compound of the formula (I) from the compound of formula (XXVII).
  • the compound of the general formula (XXVII) is converted to the compound of the general formula (XXVIII) in the reaction with corresponding Cl-C4-alkyl carboxylate, such as methyl or ethyl carboxylate, in the presence of a base in an aprotic organic solvent such as tetrahydrofuran, dimethoxy ethane or dioxane.
  • Cl-C4-alkyl carboxylate is used in the amount of from 1 to 5 molar equivalents, preferably from 1.1 to 1.5, per one equivalent of the compound of formula (XXVII).
  • the base can be potassium tert-pentanolate as 25% toluene solution in the amount of from 2 to 5 molar equivalents, preferably 3 equivalents, per one equivalent of the compound of formula (XXVII).
  • the reaction is carried out at room temperature.
  • Reaction product can be recovered from the reaction mixture by extraction and can be used in a subsequent step as a raw product without purification.
  • the compound of the formula (XXVIII) is formed as a mixture of two isomers.
  • the newly formed stereogenic center participates in the cyclisation reaction and reacts to form 5- membered pyrazole ring with simultaneous loss of chirality at this center, therefore there is no need of determination of stereoselectivity of the step of the synthesis of the compound of formula (XXVIII).
  • the compound of the general formula (XXVIII) is converted to the compound of the general formula (XI) by reaction with hydrazine monohydrate and acetic acid in an alcoholic solvent such as methanol or ethanol.
  • Hydrazine monohydrate is used in the amount of from 1 to 3 molar equivalents, preferably 2 equivalents, per one equivalent of the compound of formula (XXVIII).
  • Acetic acid is used in the amount of from 1 to 2 molar equivalents, preferably 1.5 equivalents, per one equivalent of the compound of formula (XXVIII).
  • the reaction is carried out at the temperature in the range from 50 to 80 °C, preferably at the reflux temperature.
  • the product after two steps of synthesis is purified by liquid chromatography using silica gel as a stationary phase.
  • Acetonitrile is used in the amount from 1.2 to 1.5 molar equivalents per one equivalent of the compound of formula (XXIX).
  • the base can be for example «-butyllithium, tert-butyllithium, sec-butyllithium or z ' so-propyllithium, preferably «-butyllithium as a hexane solution.
  • the base is used in the amount from 1 to 1.1 molar equivalent per one equivalent of acetonitrile.
  • the reaction is carried out in an aprotic organic solvent such as tetrahydrofuran, dioxan, dimethoxyethane, preferably tetrahydrofuran at -78 °C and then at room temperature.
  • the compound of the formula (I) can be administered as a pharmaceutical composition containing them or pharmaceutical preparation containing them.
  • the object of the invention is therefore also a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient the compound or compounds of the formula (I) such as defined above, in admixture with pharmaceutically acceptable auxiliary substance(s).
  • the invention relates also to a method of treating proliferative disorders, cancer diseases or inflammatory conditions in a mammal, including human, comprising administration of a therapeutically effective amount of the compound of the general formula (I) as defined above or the pharmaceutical composition as defined above.
  • the compounds of the formula (I) of the invention can be administered as a chemical compound, however usually will be used in the form of a pharmaceutical composition comprising the compound of the invention or its pharmaceutically acceptable salt in combination with pharmaceutically acceptable carrier(s) and auxiliary substance(s).
  • the compounds of the formula (I) of the invention can be administered by any suitable route, preferably oraz, parenteral or inhalation route and will be in the form of a preparation destined for use in medicine, depending on the intended administration route.
  • compositions for oral administration can have the form of solid or liquid preparations.
  • Solid preparations can have, for example, the form of a tablet or capsule produced in a conventional manner from pharmaceutically acceptable inactive excipients such as binders (for example, pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylmethyl- cellulose); fillers (for example lactose, saccharose or calcium hydrogenphosphate), lubricants (for example magnesium stearate, talc or silica), wetting agents (for example sodium laurylsulphate). Tablets can be coated with coatings well known in the art, such as simple coatings, delayed/controlled-release coatings or enteric coatings.
  • Liquid preparations for oral administration can be in a form of, for example, solutions, syrups or suspensions, or can have the form of dry solid product for reconstitution in water or other suitable vehiculum before use.
  • Such liquid preparations can be prepared using conventional means from pharmaceutically acceptable excipients, such as suspending agents (for example sorbitol syrup, cellulose derivatives or hydrogenated edible oils), emulsifiers (for example lecithine or acacia gum), nonaqueous vehicles (for example mandelic oil, oil esters, ethyl alcohol or fractionated vegetable oils), and preservatives (for example methyl or propyl p-hydroxybenzoate or sorbic acid).
  • suspending agents for example sorbitol syrup, cellulose derivatives or hydrogenated edible oils
  • emulsifiers for example lecithine or acacia gum
  • nonaqueous vehicles for example mandelic oil, oil esters, ethyl alcohol or fractionated vegetable oils
  • preservatives for example
  • Preparations for oral administration can be formulated so as to obtain controlled release of the active compound using methods known for a person skilled in the art.
  • compositions for parenteral administration can, for example, have the form of a unit dosage form, such as ampoules, or multi-dosage containers, with the addition of a preservative.
  • Compositions can have the form such as suspension, solution or emulsion in an oily or aqueous vehiculum, and can include excipients such as suspending agents, stabilizers, and/or dispersing agents.
  • the active ingredient can be formulated as a powder for reconstitution before use in a suitable carrier, for example sterile, pyrogen-free water.
  • compositions for administration via inhalation route can have the inhalation form and administered by nebulization.
  • Such preparations include an active compound and auxiliary substance(s) administered as an aerosol, i.e. a system of finely divided small particles of solid or liquid substance suspended in a gas.
  • Auxiliary substances used in nebulization can be for example sodium chloride as an isotonicity agent, inorganic acids and hydroxides as pH regulators and stabilisers, benzalkonium chloride as a surfactant, ethanol and propylene glycol as a preservative, sodium citrate as a buffering agent, polysorbate 80 as a surfactant, ethanol and propylene glycol as a co-solvent, and sulphates(VI) as anti-oxidants.
  • sodium chloride as an isotonicity agent
  • inorganic acids and hydroxides as pH regulators and stabilisers
  • benzalkonium chloride as a surfactant
  • ethanol and propylene glycol as a preservative
  • sodium citrate as a buffering agent
  • polysorbate 80 as a surfactant
  • ethanol and propylene glycol as a co-solvent
  • sulphates(VI) as anti-oxidants.
  • the method of treatment with the use of the compounds of the present invention will comprise administration of a therapeutically effective amount of the compound of the invention, preferably in the form of a pharmaceutical composition, to the subject in need of such treatment.
  • Proposed dosage of the compounds of the invention is from 0.1 to about 1000 mg per day, in a single dose or in divided doses. It will be apparent for a person skilled in the art that selection of a dosage required for obtaining desirable biological effect will depend on many factors, for example specific compound, the indication, the manner of administration, the age and condition of a patient and that exact dosage will be ultimately determined by a responsible physician.
  • Step C 4-(4-Chloro-2-fluorobenzyl)-3-methyl-lH-pyrazol-5-amine and 4-(4-chloro-2- fluorobenzyl)-5-methyl-lH-pyrazol-3-amine
  • Step D 3 -(4-Chloro-2-fluorobenzyl)-2-methylpyrazolo [1,5 -a]pyrimidin-5 , 7-diol
  • Step E 5,7-Dichloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine
  • Step F 4-(5 -Chloro-3 -(4-chloro-2-fluorobenzyl)-2-methylpyrazolo [1,5 -a]pirymidyn-7-yl)- morpholine
  • Step G N-(l-tert-Butyl-3-methyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluorobenzyl)-2-methyl- 7-mo holinopyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Step H 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-morpholi- nopyrazolo[l,5-a]pyrimidin-5-amine
  • Example 7 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(l -methyl- lH-imi dazol-4-yl)-7-(4- (methylsulphonyl)piperazin-l-yl)pyrazolo[l,5-a]pyrimidin-5-amine
  • Example 8 3 -(4-Chloro-2-fluorobenzyl)-7-((3R, 5S)-3 , 5-dimethylpiperazin- 1 -yl)-2- meth l-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
  • Step C 3 -(4-Chloro-2-fluorobenzyl)-2-ethylpyrazolo [1,5 -a]pyrimidin-5 , 7-diol
  • Step D 5,7-Dichloro-3-(4-chloro-2-fluorobenzyl)-2-ethylpyrazolo[l,5-a]pyrimidine
  • Step E 4-(5-Chloro-3-(4-chloro-2-fluorobenzyl)-2-ethylpyrazolo[l,5-a]pirymidyn-7-yl)- morpholine
  • Step F N-(l-tert-Butyl-3-methyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluorobenzyl)-2-ethyl-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine
  • the product was prepared as an orange oil with a yield of 100% (257 mg, 0.489 mmol) from 4-(5-chloro-3-(4-chloro-2-fluorobenzyl)-2-ethylpyrazolo[l,5-a]pirymidyn-7-yl)mor- pholine obtained in Step E (200 mg, 0.489 mmol), following the procedure of Example 1, Step G.
  • Step G 3 -(4-Chloro-2-fluorobenzyl)-2-ethyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine
  • Step A tert-Butyldimethyl(prop-2-ynyloxy)silane
  • Step B Ethyl 4-(tert-butyldimethylsilyloxy)but-2-ynolate
  • Step D 3-(4-Chloro-2-fluorobenzyl)-7-(hydroxymethyl)-2-methylpyrazolo[l,5-a]- pyrimidin-5-ol
  • Step E 5-Chloro-3-(4-chloro-2-fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]- pyrimidine
  • Step F 4-((5-Chloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pirymidyn-7- yl)methyl)morpholine
  • the mixture of 5-chloro-3-(4-chloro-2-fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo- [l,5-a]pyrimidine obtained in Step E (2.62 g, 7.31 mmol), morpholine (1.15 mL, 13.2 mmol), triethylamine (5.09 mL, 35.5 mmol) and acetonitrile (5 mL) was heated to 40 °C for 24 hours.
  • Step G N-(l-tert-Butyl-3-methyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluorobenzyl)-2-methyl- 7-(mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Step H 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Example 14 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7- (piperidin- 1 -ylmethyl)pyrazolo[ 1 , 5-a]pyrimidin-5-amine
  • Example 18 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-((4- (methylsulphonyl)piperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine
  • Example 20 3-(4-Chloro-2-fluorobenzyl)-7-(((2R,65)-2,6-dimethylmorpholino)methyl)-2- methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
  • Example 21 3 -(4-Chloro-2-fluorobenzyl)-2-ethyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Step A ( J E)-3-(4-Chloro-2-fluorophenyl)but-2-enenitrile and (Z)-3-(4-chloro-2-fluoro- phenyl)but-2-enenitrile
  • the product was obtained as a raw light yellow oil (2.40 g) from (RAS)-3-(4-chloro-2- fluorophenyl)butanenitrile from Step B (2.23 g, 11.3 mmol) following the procedure of Example 1, Step B, and used in the subsequent step without further purification.
  • Step D (R/5)-4-(l-(4-Chloro-2-fluorophenyl)ethyl)-3-methyl-lH-pyrazol-5-amine
  • Step E (R/5)-7-((tert-Butyldimethylsilyloxy)methyl)-3-(l-(4-chloro-2-fluorophenyl)- ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-5-ol
  • Step F (R/5)-3-(l-(4-Chloro-2-fluorophenyl)ethyl)-7-(hydroxymethyl)-2-methyl- pyrazolo[l,5-a]pyrimidin-5-ol
  • the product was obtained as a raw white solid (1.32 g) from (R/,S)-7-((tert-butyl- dimethylsilyloxy)methyl)-3-(l-(4-chloro-2-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]- pyrimidin-5-ol from Step E (1.80 g, 4.01 mmol) following the procedure of Example 11, Step D, and used in the subsequent step without further purification.
  • Step G (R/5)-5-Chloro-7-(chloromethyl)-3-(l-(4-chloro-2-fluorophenyl)ethyl)-2-methyl- pyrazolo[l,5-a]pyrimidine
  • Step H (R/5)-4-((5-Chloro-3-(l-(4-chloro-2-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]- pirymidyn-7-yl)methyl)morpholine
  • the product was obtained as white crystals with a yield of 91% (1.48 g, 3.50 mmol) from (R/ ⁇ S)-5-chloro-7-(chloromethyl)-3-(l-(4-chloro-2-fluorophenyl)ethyl)-2-methylpyrazolo- [l,5-a]pyrimidine from Step G (1.40 g, 3.76 mmol), following the procedure of Example 11, Step F.
  • Step I (R/S)-N-( 1 -tert-Butyl-3 -methyl- lH-pyrazol-5 -yl)-3 -( 1 -(4-chloro-2-fluorophenyl)- ethyl)-2-methyl-7-(mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • the product was obtained as a raw yellow oil (257 mg) from (R/,S)-4-((5-chloro-3-(l-(4- chloro-2-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pirymidyn-7-yl)methyl)morpholine from Step H (200 mg, 0.472 mmol) following the procedure of Example 1, Step G, and used in the subsequent step without further purification.
  • Step J (R/5)-3-(l-(4-Chloro-2-fluorophenyl)ethyl)-2-methyl-N-(5-methyl-lH-pyrazol-3- yl)-7-(mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Step A 3-(2-Fluorophenyl)acrylonitrile - (a mixture of isomers (E) and (Z))
  • the mixture of 2-fluorobenzaldehyde (4.24 mL, 40.3 mmol), diethyl cyanomethylphospho- nate (7.17 mL, 44.3 mmol), 18-crown-6 (163 mg, 0.604 mmol), potassium carbonate (8.35 g, 60.4 mmol) and toluene (100 mL) was heated to 70 °C for 3 hours. Reaction mixture was cooled and added with water (100 mL). Phases were separated, and aqueous phase was extracted with toluene (100 mL). Organic phases were combined, washed with brine, dried (Na 2 S04) and evaporated under reduced pressure. The raw product in the form of a colorless crystallizing oil (7.60 g) was used in the next step without further purification.
  • Step C The title product was obtained as a white solid starting from 3-(2- fluorophenyl)propanenitrile from Step B and following successively the procedures described in Example 1, Steps B to H.
  • Example 28 3 -(2-Fluorobenzyl)-2-methyl-N-( 1 -methyl- lH-pyrazol-4-yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine
  • Example 26 The title product was obtained as an off-white solid starting from 3-(2-fluoro- phenyl)propanenitrile obtained in Example 26, Step B, and following successively the procedures described in Example 1, Steps B to F, and Example 2, using l-methyl-4-nitro- lH-imidazole in place of l-methyl-4-nitro-lH-pyrazole.
  • Example 26 The title product was obtained as a white solid, starting from 3-(2-fluorophenyl)propane- nitrile obtained in Example 26, Step B, following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to F, and Example 1, Steps G to H.
  • Example 30 3 -(2-Fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7-((4-methyl- piperazin- 1 -yl)methyl)pyrazolo[ 1 ,5-a]pyrimidin-5-amine
  • Example 26 The title product was obtained as a white solid, starting from 3-(2-fluorophenyl)- propanenitrile obtained in Example 26, Step B, following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to F, and Example 1, Steps G to H, and using 1-methylpiperazine in place of morpholine.
  • the title product was obtained as a brown amorphous solid starting from 3-(3-fluoro- phenyl)propanenitrile, obtained from 3-fluorobenzaldehyde analogously as in Example 26, Steps A to B, and following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to F, and Example 1, Steps G to H, using 2-methoxy ethylamine in place of morpholine.
  • Example 36 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(morpholino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine
  • Example 37 3 -(4-Fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7-((4-methyl- piperazin- 1 -yl)methyl)pyrazolo[ 1 ,5-a]pyrimidin-5-amine
  • Example 40 3 -(2,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine
  • Example 42 3 -(2,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Step A 3-Cyclopropyl-l-(4-methoxybenzyl)-lH-pyrazol-5-amine and 5-cyclopropyl-l-(4- methoxybenzyl)-lH-pyrazolo-3 -amine
  • Step B N-(3-Cyclopropyl-l-(4-methoxybenzyl)-lH-pyrazol-5-yl)-3-(2,4-difluorobenzyl)- 2-methyl-7-(mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Step C The mixture of raw N-(3-cyclopropyl-l-(4-methoxybenzyl)-lH-pyrazol-5-yl)-3- (2,4-difluorobenzyl)-2-methyl-7-(morpholinomethyl)pyrazolo[l,5-a]pyrimidin-5-amine obtained in Step B (220 mg) and trifluoroacetic acid (3.0 mL, 29.2 mmol) was heated to 105 °C for 7 days. The reaction mixture was cooled to room temperature, then water (10 mL) and saturated sodium carbonate solution (25 mL) were added and the mixture was extracted with AcOEt (3 ⁇ 25 mL).
  • Example 45 3 -(2,4-Difluorobenzy l)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7-((4- methylpiperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine
  • the title product was obtained as a white solid, starting from 3-(2,4-difluorophenyl)propa- nenitrile obtained from 2,4-difluorobenzaldehyde analogously as described in Example 26, Steps A and B, and following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to F, and Example 2, using 2-methoxyethylamine in place of morpholine.
  • Example 48 The title product was obtained as a yellow amorphous solid, starting from 3-(2,4-difluoro- phenyl)propanenitrile obtained from 2,4-difluorobenzaldehyde analogously as described in Example 26, Steps A and B, and following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to F, and Example 1, Steps G to H, using 2- mo holinoethylamine in place of morpholine.
  • Example 48 The title product was obtained as a yellow amorphous solid, starting from 3-(2,4-difluoro- phenyl)propanenitrile obtained from 2,4-difluorobenzaldehyde analogously as described in Example 26, Steps A and B, and following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to F, and Example 1, Steps G to H, using 2- mo holinoethylamine in place of morpholine.
  • Example 48 Example
  • Step A ( J E)-3-(2,4-Difluorophenyl)but-2-enenitrile and (Z)-3-(2,4-difluorophenyl)but-2- enenitrile
  • Method 1 The mixture of isomers (7 ⁇ -3-(2,4-difluorophenyl)but-2-enenitrile and (Z)-3- (2,4-difluorophenyl)but-2-enenitrile from Step A (3.70 g, 20.7 mmol) was dissolved in absolute ethanol (100 mL), 5% palladium on carbon (370 mg) was added and the mixture was degassed under reduced pressure. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 24 hours, then filtered over celite layer and washed with ethanol. The filtrate was concentrated under reduced pressure.
  • Method 2 The mixture of copper(II) acetate (6.1 mg, 0.034 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphine)xanthene (19.4 mg, 0.034 mmol) was placed in a Schlenk flask, degassed and purged with argon. Under argon atmosphere were successively added degassed toluene (1.5 mL), polymethylhydrosiloxane (271 ⁇ , 4.47 mmol), (£)-3-(2,4- difluorophenyl)but-2-enenitrile (200 mg, 1.12 mmol) and tert-butanol (331 mg, 4.47 mmol).
  • Step C The title product was obtained as a racemate in the form of a white solid from (R S)-3-(2,4-difluorophenyl)butanenitrile from Step B, following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to F, and Example 1, Steps G to H.
  • Example 50 Example 50.
  • Method 1 The product was obtained in accordance with the procedure of Method 2 in Example 49, Step B, from (£)-3-(2,4-difluorophenyl)but-2-enenitrile (200 mg, 1.12 mmol) obtained in Example 49, Step A, and ((R)-l-[(,S)-2-(diphenylphosphine)ferrocenyl]- ethyldicyclohexylphosphine adduct with ethanol (22.1 mg, 0.034 mmol).
  • Method 2 The product was obtained in accordance with the procedure of Method 2 in Example 49, Step B, from (Z)-3-(2,4-difluorophenyl)but-2-enenitrile (200 mg, 1.12 mmol) obtained in Example 49, Step A, and ((,S)-l-[(R)-2-(diphenylphosphine)ferrocenyl]- ethyldicyclohexylphosphine adduct with ethanol (22.1 mg, 0.034 mmol).
  • Step B The title product was obtained as a white amorphous solid from (3R)-3-(2,4- difluorophenyl)butanenitrile from Step A, following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to F, and Example 1, Steps G to H.
  • Method 1 The product was obtained as a light yellow oil starting from (£)-3-(2,4- difluorophenyl)but-2-enenitrile (200 mg, 1.12 mmol) obtained in Example 49, Step A, and ((,S)-l-[(R)-2-(diphenylphosphine)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct (22.1 mg, 0.034 mmol) following the procedure of Method 2 of Example 49, Step B,.
  • Method 2 The product was obtained as a light yellow oil starting from (Z)-3-(2,4- difluorophenyl)but-2-enenitrile (200 mg, 1.12 mmol) obtained in Example 49, Step A, and ((R-l-[(,S)-2-(diphenylphosphine)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct (22.1 mg, 0.034 mmol) following the procedure of Method 2 of Example 49, Step B,.
  • Example 56 3 -(3 ,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinomethyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Example 65 2 -Methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-morpholino-3 -(pyridin-3 -yl- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine
  • Step A l-(5-Fluoropyridin-2-yl)ethanone
  • Step D The title product was obtained as a racemate in the form of a white solid from (R/,S)-3-(5-fluoropyridin-2-yl)butanenitrile from Step C, following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to H, and Example 1, Steps G to H.
  • Example 70 2-Methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7-(morpholinomethyl)-3-(thiazol-2- ylmethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine
  • Example 72 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine
  • Step A (£)-3-(4-Fluorophenyl)but-2-enenitrile and (Z)-3-(4-fluorophenyl)but-2-enenitrile
  • Step B (R)-3-(4-Fluorophenyl)butanenitrile
  • Step C (,S)-5,7-Dichloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidine Obtained as white solid from (R)-3-(4-fluorophenyl)butanenitrile from Step B following successively the procedures described in Example 1, Steps B to E.
  • Step D (,S)-4-(5-Chloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-7- yl)morpholine
  • Step B (R)-5,7-Dichloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidine
  • Step C (R)-4-(5-Chloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-7- yl)morpholine
  • Step A (,S)-4-(5-Chloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-7- yl)- 1 , 1 -dioxothiomorpholine
  • Example 80 (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (l, l-dioxothiomo holino)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Example 90 ( ⁇ S)-3 - ( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4- yl)-7-((l, l-dioxothiomo holino)methyl)pyrazolo[l,5- ⁇ ]pyrimidin-5-amine
  • Tested compounds were dissolved in 100% DMSO and stock solutions thus obtained were diluted using serial dilutions in a reaction buffer (50 mM Tris pH 7.5, 10 mM MgCl 2 , 0.25 mM EGTA, 0.1 mM Na 3 V0 4 , 0.01% Triton X-100, 2.5 mM DTT).
  • Recombinant JAK2 kinase (Carna Biosciences) was diluted in dilution buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 10% glycerol, 0.05% Triton X-100, 1 mM DTT) to the final concentration 0.1 ng/ ⁇ . to obtain working stock.
  • reaction mastermix composed of 5x concentrated reaction buffer (50 mM Tris pH 7.5, 10 mM MgCl 2 , 0.25 mM EGTA, 0.1 mM Na 3 V0 4 , 0.01% Triton X-100, 2.5 mM DTT), water, 50 ⁇ ATP, 16.67 ⁇ peptide IGF-lRtide (Millipore)) was added and the plate was incubated for 1 hour at 25 °C in thermomixer with orbital shaking at 400 rpm. After the specified incubation time ADP formed was detected using ADP-Glo Kinase Assay.

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Abstract

L'invention concerne un composé de formule générale (I), utile pour traiter les maladies myéloprolifératives, cancéreuses ou inflammatoires, dans laquelle Q représente un noyau hétéroaromatique à six chaînons contenant 2 N atomes et R1 est un atome d'hydrogène, ou Q représente un noyau hétéroaromatique à cinq chaînons contenant 1 ou 2 hétéroatomes choisis dans le groupe consistant en N et S, un substituant R1 est attaché à l'atome C ou N dudit noyau Q, et R1 est choisi dans le groupe consistant en les groupes alkyle en C1-C4 et cycloalkyle en C3-C4 ; R2 représente -NR7aR7b ou -CH2-NR8aR8b ; R3 représente un groupe alkyle en C1-C4 ; R4 représente le groupe phényle ou un groupe hétéroaryle à 5 ou 6 chaînons contenant 1 ou 2 hétéroatomes choisis dans le groupe consistant en N et S, et R4 est non substitué ou est substitué par 1 ou 2 substituants choisis dans le groupe consistant en les atomes d'halogène, les groupes trifluorométhyle, hydroxyle et alcoxyle en C1-C4 ; R5 et R6 représentent chacun d'une manière indépendante un atome d'hydrogène ou un groupe alkyle en C1-C4, et au moins l'un de R5 et R6 représente un atome d'hydrogène ; et les autres substituants sont tels que définis dans la description ; et ses sels pharmaceutiquement acceptables.
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EP3498273A1 (fr) * 2017-12-14 2019-06-19 Universität Wien Composition pharmaceutique pour la modulation de la reponse du recepteur gaba-a
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CN110612302A (zh) * 2017-05-12 2019-12-24 赛隆制药股份公司 作为激酶JAK抑制剂的吡唑并[1,5-a]嘧啶衍生物
JP2020519631A (ja) * 2017-05-12 2020-07-02 セロン ファーマ エス．アー．Ｃｅｌｏｎ Ｐｈａｒｍａ Ｓ．Ａ． キナーゼＪＡＫ阻害剤としてのピラゾロ［１，５−ａ］ピリミジン誘導体
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EA038273B1 (ru) * 2017-05-12 2021-08-03 Целон Фарма С.А. Производные пиразоло[1,5-a]пиримидина в качестве ингибиторов киназы jak
WO2018206739A1 (fr) * 2017-05-12 2018-11-15 Celon Pharma S.A. Dérivés de pyrazole[1,5-a]pyrimidine utilisés en tant qu'inhibiteurs de kinase jak
AU2018265457B2 (en) * 2017-05-12 2022-06-30 Celon Pharma S.A. Pyrazole(1,5-a)pyrimidine derivatives as kinase JAK inhibitors
JP7157084B2 (ja) 2017-05-12 2022-10-19 セロン ファーマ エス．アー． キナーゼＪＡＫ阻害剤としてのピラゾロ［１，５－ａ］ピリミジン誘導体
EP3498273A1 (fr) * 2017-12-14 2019-06-19 Universität Wien Composition pharmaceutique pour la modulation de la reponse du recepteur gaba-a
EP4041241A1 (fr) 2019-09-27 2022-08-17 Disc Medicine, Inc. Procédés de traitement de la myélofibrose et d'affections associées
US12486274B2 (en) 2020-01-13 2025-12-02 Verge Analytics, Inc. Substituted pyrazolo-pyrimidines and uses thereof
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis
US12497452B2 (en) 2020-05-13 2025-12-16 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis

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