WO2015118434A1

WO2015118434A1 - PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS KINASE JAK-2 INHIBITORS

Info

Publication number: WO2015118434A1
Application number: PCT/IB2015/050715
Authority: WO
Inventors: Michal MROCZKIEWICZ; Joanna LIPNER; Pawel GUNERKA; Krzysztof DUBIEL; Maciej Wieczorek; Daria ZDZALIK; Aleksandra Stanczak; Monika Lamparska-Przybysz; Bartosz STYPIK
Original assignee: Celon Pharma SA
Current assignee: Celon Pharma SA
Priority date: 2014-02-05
Filing date: 2015-01-30
Publication date: 2015-08-13
Anticipated expiration: 2016-08-05
Also published as: PL407081A1

Abstract

A compound of the general formula (I), useful for treating myeloproliferative, cancer,or inflammatory diseases, wherein Q represents a six-membered heteroaromatic ring containing 2 N atoms and R₁ is hydrogen atom,or Q represents a five-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of N and S,one substituent R₁ is attached at C or N atom of said Q ringand R₁ is selected from the group consisting of C1-C4-alkyl and C3-C4-cycloalkyl;R₂ represents-NR_7aR_7bor-CH2-NR_8aR_8b;R₃represents C1-C4-alkyl;R₄ represents phenylora 5-or 6-membered heteroarylcontaining 1 or 2 heteroatoms selected from the group consisting of N and S, and R₄ is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl,hydroxyl and C1-C4-alkoxyl;R₅ and R₆ independently represent hydrogenatom or C1-C4-alkyl,and at least one of R₅ and R₆ represents hydrogen atom;and other substituents are as defined in the specification; and pharmaceutically acceptable salts thereof.

Description

PYRAZOLO[l,5-a]PYKJMIDINE DERIVATIVES AS KINASE JAK-2 INHIBITORS

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.

Many from among cytokines involved in the development and progress of inflammatory states are the factors that activate JAK-STAT pathway, thus this 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. This affects differentiation of T lymphocytes that stimulate enhanced production of E immunoglobulins by B lymphocytes and are responsible for eosinophiles recruitment and maturation, leading to development of local inflammatory reaction. 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.

In WO2009/017954 there are disclosed as JAK2 inhibitors the compounds of the general formula as below

which encompasses pyrazolo[l,5-a]pyrimidine derivatives (when A = N, D = N, B = C, and E = C) substituted at the position 6 of the core, wherein R⁶ does not represent hydrogen atom.

In WO2007/013673 there are disclosed the compounds of immunosuppressive activity of the formula as below

which encompasses pyrazolo[l,5-a]pyrimidine derivatives (when Y=C and Z=N). Substituent R⁵ in the position 7 of the pyrazolo[l,5-a]pyrimidine core can represent H, alkyl, halogen, -O-alkyl or aryl.

In EP 1505068 Al there are disclosed NAD(P)H-oxidase inhibitors of the below formula:

wherein Ri_a encompasses amine group, R₃ encompasses lower alkyl, and R₅ 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 need exists for new compounds having the activity of kinase JAK2 inhibition and high potency and/or selectivity of action and potential utility in the treatment of proliferative and cancer diseases or inflammatory conditions. The present invention relates to the compound of the general formula (I)

(I)

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;

- R₂ represents - R7_aR7b or -CH₂- R_8aR₈b;

- R₃ represents Cl-C4-alkyl;

- R₄ represents phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and R₄ is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;

- R₅ and 5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;

- R_7a and R₇b 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 -S0₂-Cl-C4-alkyl;

- R_8a and R₈b 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 R₈b 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 -S0₂-Cl-C4-alkyl; optically active enantiomers and enantiomeric mixtures thereof, and pharmaceutically acceptable salts thereof.

As it can be seen from the above formula (I), in the case when one of R₅ and 5 is hydrogen atom and the other one is Cl-C4-alkyl, especially methyl, carbon atom to which R5 and 5 are attached is a chiral atom and the compound of formula (I) can have optical isomers, i.e. enantiomers. Such a compound can be presented by the following formula (IA).

(IA)

It will be appreciated by a skilled person that the above formula (IA) is a specific case of the formula (I) as defined above.

It will be also appreciated by a skilled person that invention encompasses both the compound wherein R5 is hydrogen atom and R5 is Cl-C4-alkyl and the compound wherein R5 is hydrogen atom and R5 is Cl-C4-alkyl, and that such compounds are respective opposite enantiomers of the opposite stereochemical configuration.

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;

- R₂ represents - R7_aR7b or -CH₂- R_8aR₈b;

- R₃ represents Cl-C4-alkyl;

- R_7a and R₇b 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 -S0₂-Cl-C4-alkyl;

- R_8a and R₈b 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 R₈b 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 -S0₂-Cl-C4-alkyl; optically active enantiomers and enantiomeric mixtures thereof, and pharmaceutically acceptable salts thereof.

A second subgroup of the compounds of the invention are the compounds wherein:

- Ri is selected from the group consisting of Cl-C4-alkyl and C3-C4-cycloalkyl;

- R₂ represents - R7_aR7b or -CH₂- R8_aR8b;

- R₃ represents Cl-C4-alkyl;

- R_8a and R₈b 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-C1-C4- alkyl; or R_8a and R₈b 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 -S02-Cl-C4-alkyl; optically active enantiomers and enantiomeric mixtures thereof, and pharmaceutically acceptable salts thereof.

A third subgroup of the compounds of the invention are the compounds wherein:

- R₂ represents - R7_aR7b or -CH₂- R8_aR8b;

- R₃ represents Cl-C4-alkyl;

- 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 R₇b 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 R₈b 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.

Fourth 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; - R₂ represents - R7_aR7b or -CH₂- R_8aR₈b;

- R₃ represents Cl-C4-alkyl;

- R5 and R5 independently represent hydrogen atom or Cl-C4-alkyl, and at least one of R5 and R5 represents hydrogen atom;

- R_8a and R₈b 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-C1-C4- alkyl; or R_8a and R₈b 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 -S0₂-Cl-C4-alkyl; optically active enantiomers and enantiomeric mixtures thereof, and pharmaceutically acceptable salts thereof.

Fifth 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;

- R₂ represents - R_7aR₇b or -CH₂- R_8aR₈b; - R.3 represents Cl-C4-alkyl;

- R_8a and R₈b 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-C1-C4- alkyl; or R_8a and R₈b 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 -S0₂-Cl-C4-alkyl; optically active enantiomers and enantiomeric mixtures thereof, and pharmaceutically acceptable salts thereof.

Sixth subgroup of the compounds of the invention are the compounds wherein:

- R₂ represents - R_7aR₇b or -CH₂- R_8aR₈b;

- 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 R₄ is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and Cl-C4-alkoxyl;

It will be appreciated by a skilled person that 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.

In an embodiment of the compounds of the invention as defined above Q represents a 6- membered heteroaromatic ring containing 2 N atoms, especially pyrazine ring, such as pyrazin-2-yl, and Ri is hydrogen atom.

In another embodiment of the compounds of the invention as defined above 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.

In one group of the compounds of the invention Ri is Cl-C4-alkyl, which can be a straight or branched chain alkyl and encompasses methyl, ethyl, ^-propyl, z^'so-propyl, ¾-butyl, sec- butyl and tert-butyl. Preferably Ri is methyl.

In another group of the compounds of the invention Ri is cycloalkyl C3-C4 and encompasses cyclopropyl and cyclobutyl. Preferably Ri is cyclopropyl.

In one preferred group of the compounds of the invention 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.

In another preferred group of the compounds of the invention Q represents lH-pyrazole or lH-imidazole ring and R₅ and 5 both are hydrogen atoms.

In another preferred group of the compounds of the invention Q represents lH-pyrazole or lH-imidazole ring and R3 is methyl.

In another preferred group of the compounds of the invention Q represents lH-pyrazole or lH-imidazole ring, Ri is methyl, R5 and R5 both are hydrogen atoms and R3 is methyl.

When 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.

When 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.

In another preferred group of the compounds of the invention Q represents thiazole ring, including thiazol-2-yl, thiazol-4-yl and thiazol-5-il, especially thiazol-2-yl.

In one group of the compounds of the invention R5 and R5 are both hydrogen atoms.

In another group of the compounds of the invention one of R5 and R5 is hydrogen atom and the other is Cl-C4-alkyl, and Cl-C4-alkyl includes methyl, ethyl, zz-propyl, z^' o-propyl, n- butyl, sec-butyl and tert-butyl, especially methyl.

In the compounds of the invention R₃ 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. Preferably R₃ is methyl or ethyl, especially methyl.

In another group of the compounds of the invention R₄ 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, and 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. Preferably R₄ is phenyl substituted with one fluorine atom, two fluorine aroms or one fluorine and one chlorine atoms.

In another group of the compounds of the invention R₄ is a 5- or 6-membered heteroaryl, which includes 1 or 2 heteroatoms selected from the group consisting of N and S, and R₄ 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, and 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.

It will be appreciated by a skilled person that 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. Preferably R₄ is pyridinyl, especially pyridinyl substituted with fluorine atom, or thiazolyl.

In one group of the compounds R₂ is - R7_aR7b, wherein R_7a and R₇b 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 -S0₂-Cl-C4-alkyl.

It will be appreciated by the skilled person that in said 6-membered heteroalicyclic ring formed by R_7a and R₇b one of said 1 or 2 heteromoieties is said nitrogen atom to which R_7a and R₇b are attached. Preferably, 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 R₇b are attached.

C1-C4 alkyl encompasses groups such as discussed above for R₄, preferably methyl.

Preferably, R_7a and R₇b together with nitrogen atom to which they are attached form morpholine, piperidine or piperazine ring, which are unsubstituted or substituted with methyl or -S0₂-CH₃.

Also preferably, R_7a and R₇b together with nitrogen atom to which they are attached form unsubstituted 1, 1-dioxothiomorpholine ring.

In another group of the compounds R₂ is -CH₂- Rs_aR8b. In one of embodiments, R_8a and R₈b 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.

It will be appreciated by the skilled person that in said 6-membered heteroalicyclic ring formed by R_8a and R₈b one of said 1 or 2 heteroatoms is said nitrogen atom to which R_8a and R₈b are attached. Preferably, 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 R₈b are attached.

In another of embodiment, R_8a and R₈b 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

CI or C2 alkyl.

Preferably, said heteroalicyclic ring is morpholine, piperidine or piperazine ring, unsubstituted or substituted with methyl or -SO2-CH3.

Preferably, one of R_8a and R₈b is hydrogen atom, and the second is 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, 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.

It will be appreciated by a skilled person that when one of R_8a and R₈b 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. Preferably, one of its heteroatoms is in the position 4 with respect to said linking atom. Also preferably, 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.

It has been found that the 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 comprising as an active ingredient the compound of formula (I) as defined above, in admixture with pharmaceutically acceptable auxiliary substance(s).

As 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.

Other embodiment of the invention are the compounds selected from the group consisting of the compounds presented hereinbelow in Examples 72 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 1 to 76, 85-88 and 91-99 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.

It should be understood that the compound of the formula (I) of the invention may contain chiral center other than that at the carbon atom carrying substituents R⁵ and R⁶, 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:

Scheme 1

II III wherein Q, Ri, R₂, R₃, R4, R5 and Re are as defined above for formula (I). The 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). As inorganic or organic base 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.

In the case when Q in the compound of formula (I) is pyrazole, imidazole or other ring containing unsubstituted - H- moiety, wherein nitrogen atom is called pyrrole nitrogen atom, it is advantageous to use in the reaction of preparing the compound (I) corresponding aminoheteroaryl (III) in the form of aminopyrazole, aminoimidazole or other represented by the general formula (IV) wherein pyrrole nitrogen atom is protected by protecting group (PG). Protecting group (PG) protects the molecule before undesired competitive reaction of the compound (II) and pyrrole nitrogen atom. Protecting group (PG) is removed in the last step of synthesis of the compound of the general formula (I).

IV

In the reaction of suitably protected aminoheteroaryl (IV) with suitable chloro derivative of the formula (II) there is obtained (PG) group protected intermediate (VIII) that by deprotection, i.e. removing (PG) group is converted into compound represented by the general formula (I), in accordance with the following Scheme 2. Scheme 2

IV VIM

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 (Boc₂0), 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.

In the case when Q is 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. For example, 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. In an analogous manner other lH-pyrazol-5-amines functionalized in the position 3 and/or position 4 can be obtained.

Scheme 3

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.

Alternatively, 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.

The compounds of the general formula (II) are obtained according to two general methods, depending on the kind of R₂ group in the general formula (II). When R₂ represents - R7aR7b, the compounds of the general formula (II) can be represented by the general formula (IX). When R₂ represents -CH₂- RsaR8b, the compounds of the general formula (II) can be represented by the general formula (X).

Both the compounds of the general formula (IX) and the compounds of the general formula (X) are obtained from corresponding lH-pyrazol-5-amine derivatives represented by the general formula (XI).

H

XI

The compounds of the general formula (IX) are obtained from the compounds (XI) in accordance with the following Scheme 4.

Scheme 4

XI XII XIII

By reaction of 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_aR7b, wherein R_7a and R₇b are as defined above for the formula (I). Amine H- R_7aR₇b 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. The reaction is carried out at the temperature in the range from 20 to 50 °C.

The compound of the general formula (X) is obtained from the compound (XI) in accordance with the following Scheme 5.

Scheme 5

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. tert-Butyl dimethyl silyl group (TBMS-) protecting hydroxy group is removed from the compound of the general formula (XV) by reaction with 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_8aR₈b, wherein R_8a and R₈b are as defined above for the formula (I). Amine H- R_8aR₈b 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. 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.

Scheme 6

XX XIV

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.

Compound (XX) is converted to compound (XIV) in the reaction with alkyl chloroformate, such as methyl, ethyl or propyl, preferably ethyl chloroformate (R9 = ethyl). 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. 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.

Alternatively, the compound of the general formula (X) can be obtained in accordance with the following Scheme 7.

Scheme 7

XI XXIII XXIV

Propargyl halogenide (XXI), such as propargyl chloride or bromide, is reacted with amine H- R8aR8b, wherein R_8a and R₈b 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_8aR₈b 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

(XXIII) by reaction with alkyl chloroformate, such as methyl, ethyl or propyl chloroformate, preferably ethyl chloroformate (R9 = ethyl). 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.

In the last step, 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. Chlorinating agent is used in the amount from 1 to 15 molar equivalents per one equivalent of the compound of formula

(XXIV) , preferably above 10. The reaction is carried at the temperature in the range from 80 to 120 °C or at the reflux of the solvent. lH-Pyrazol-5-amine (XI) is obtained in accordance with the following Scheme 8, wherein group Rio in the formulae (XXV), (XXVI-(£)) and (XXVI-(Z)) has the same meaning as groups R5 and R5 in the compounds of the invention of the above general formula (I), i.e. Rio represents hydrogen atom or Cl-C4-alkyl, and R₄ is as defined above for the compounds of the general formula (I).

Scheme 8

XXV XXVI-(E) XXVI-(Z) XXVII XXVIII XI 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.

Under conditions of Horner-Wadswoth-Emmons 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. 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.

Under Wittig reaction conditions the 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. The 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.

Thus obtained 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.

If the 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 R₄ and Rio groups present in the compounds (XXVI-(E)) and (XXVI-(Z)).

If in the compounds (XXVI-(£)) and (XXVI-(Z)) R₄ is phenyl or C5-C6-heteroaryl, which is optionally substituted with a substituent other than chlorine atom, and Rio is hydrogen atom, 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. The reaction is carried out in an alcoholic solvent, such as methanol or ethanol, preferably ethanol, at room temperature. Compounds of the general formula (XXVII), wherein R₅ and 5 are hydrogen atoms are thus obtained.

If in the compounds (XXVI-(£)) and (XXVI-(Z)) R₄ is phenyl or C5-C6-heteroaryl, which is substituted with one or two substituents, at least one of which is chlorine atom, and Rio is hydrogen atom, 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)-l- [(R)-2-(diphenylphosphine)ferrocenyl]ethyldicyclohexylphosphine adduct with ethanol), (R)-BINAP ((R)-(2,2'-bis(diphenylphosphine)-l,r-binaphthyl)), (S)-BINAP ((S)-(2,2'- bis(diphenylphosphine)-l, l '-binaphthyl)), preferably Xantphos; copper(II) acetate; and tert-butanol. Silane, preferably polymethylhydrosiloxane, is used in the amount from 1 to 4 molar equivalents per one equivalent of sum of the compounds (XXVI-(£)) and (XXVI- {∑)). 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)). The reaction is carried out in an organic solvent such as toluene or xylene, preferably toluene, in a tightly closed Schlenk flask, at room temperature. The compounds of the general formula (XXVII), wherein R₅ and R6 are hydrogen atoms, are thus obtained.

If reduction reaction is performed on single isomers separated from the mixture of compounds (XXVI-(£)) and (XXVI-(Z)), wherein Rio is Cl-C4-alkyl, the type of reducing agent affects the enantio selectivity of the reaction and thus enantiomeric composition of the mixture of the compounds (XXVII) obtained in this reaction.

In the case if reduction reaction is performed on separated isomer (XXVI-(£)) or (XXVI- (Z)), wherein R₄ is phenyl or C5-C6-heteroaryl and is substituted with one or two substituents, at least one of which is chlorine atom, and Rio is Cl-C4-alkyl, racemic mixture of the compound of the general formula (XXVII) is obtained when such reducing system is used as polymethylhydrosiloxane, Xantphos, copper(II) acetate and tert-butanol, as described above.

In the case if reduction reaction is performed on separated isomer (XXVI-(£)) or (XXVI- (Z)), wherein R₄ is phenyl or C5-C6-heteroaryl which is optionally substituted with a substituent other than chlorine atom, and Rio is Cl-C4-alkyl, 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.

In the above two cases under described conditions there is obtained an equimolar mixture of two enantiomers of the compound of the general formula (XXVII). In one of the enantiomers (XXVII) R₅ is hydrogen atom and 5 is Cl-C4-alkyl. In the second of the enantiomers (XXVII) R5 is Cl-C4-alkyl and R5 is hydrogen atom.

In the reaction of separated isomer (XXVI-(£)) or (XXVI-(Z)), wherein R₄ is optionally substituted phenyl or C5-C6-heteroaryl, and Rio is Cl-C4-alkyl, non-equimolar mixture of two enantiomers of the compound of the general formula (XXVII) is obtained in the case of using reducing system such as polymethylhydrosiloxane, chiral non-racemic phosphonium ligand, such as for example SL-JOOl-1 or Josiphos SL-JOOl-2, copper(II) acetate and fert-butanol, as described above. Using 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.

It will be appreciated by a skilled person that said enantiomer of the compound of the general formula (XXVII) wherein one of R₅ and R6 is hydrogen atom and the other is Cl-C4-alkyl can be represented by the following general formula (XXVIIA).

(XXVIIA)

In accordance with literature data (Lee, D.; Kim, D.; Yun, J. Angew. Chem. Int. Ed. 2006, 45, 2785-2787; Lee, D.; Yang, Y.; Yun, J. Synthesis 2007, 14, 2233-2235):

- in the reaction of the isomeric compound (XXVI-(£)) with Josiphos SL-JOOl-1 ((R)- 1 -[(,S)-2-(diphenylphosphine)ferrocenyl]ethyldicyclohexylphosphine adduct with ethanol) the compound of the formula (XXVIIA) is formed, wherein R₄ is phenyl or C5- C6-heteroaryl, R₅ is hydrogen atom and 5 is Cl-C4-alkyl (enantiomer of the absolute configuration (R));

- in the reaction of the isomeric compound (XXVI-(£)) with Josiphos SL-JOOl-2 ((,S)-l-[(R)-2-(diphenylphosphine)ferrocenyl]ethyldicyclohexylphosphine adduct with ethanol) the compound of the formula (XXVIIA) is formed, wherein R₄ is phenyl or C5- C6-heteroaryl, R5 is Cl-C4-alkyl and R5 is hydrogen atom (enantiomer of the absolute configuration (5)); - in the reaction of the isomeric compound (XXVI-(Z)) with Josiphos SL-JOOl-1 ((R)- 1 -[(,S)-2-(diphenylphosphine)ferrocenyl]ethyldicyclohexylphosphine adduct with ethanol) the compound of the formula (XXVIIA) is formed, wherein R₄ is phenyl or C5- C6-heteroaryl, R₅ is Cl-C4-alkyl and 5 is hydrogen atom (enantiomer of the absolute configuration (5));

- in the reaction of the isomeric compound (XXVI-(Z)) with Josiphos SL-J001-2 ((,S)-l-[(R)-2-(diphenylphosphine)ferrocenyl]ethyldicyclohexylphosphine adduct with ethanol) the compound of the formula (XXVIIA) is formed, wherein R₄ is phenyl or C5- C6-heteroaryl, R5 is hydrogen atom and R5 is C l-C4-alkyl (enantiomer of the absolute configuration (R)).

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. There is obtained the compound of the formula (XXVIII), wherein new stereogenic center is formed in the position a with respect to the nitrile group. The compound of the formula (XXVIII) is formed as a mixture of two isomers. In the subsequent reaction step 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.

The compound of the general formula (XXVII) wherein R₅ and R6 are both hydrogen atoms can be alternatively obtained in the reaction of a corresponding halogenide of the general formula (XXIX) with acetonitrile in accordance with the following Scheme 9.

Scheme 9

XXIX XXVII

Halogenides of the general formula (XXIX), especially benzyl bromide and chloride, wherein R₅ and R6 are both hydrogen atoms and R₄ is unsubstituted or substituted phenyl or C5-C6-heteroaryl react with acetonitrile in the presence of a base to obtain the compound of the general formula (XXVII), wherein R₄, R₅ and 5 are as defined for the compounds of the formula (XXIX). 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 use of this method is advantageous in the case when in the compound of the general formula (XXIX) R₄ is phenyl substituted with one or two chlorine atoms and optionally with other substituents according to the invention. Subsequent steps of synthesis of compound (XI) are carried out analogously as described above.

For treating diseases, 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 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.

In the treatment of disorders, diseases, and conditions mentioned 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).

In the treatment of disorders, diseases, and conditions mentioned above 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). Preparations can also include suitable buffering agents, flavoring agents and sweeteners.

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.

Parenteral route of administration includes administration by intramuscular and intravenous injections, as well as intravenous infusions. 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. Alternatively, 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.

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.

The Examples that follow illustrate preparation of representative compounds of the invention. Below the title with the name of the compound there are presented structural formula and next to it analytical data of the invention.

Examples

Example 1. 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- m rpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

Step A: 3-(4-Chloro-2-fluorophenyl)propanenitrile

To the solution of acetonitrile (9.82 mL, 188 mmol) in dry tetrahydrofuran (600 mL) cooled to -78 °C a 2.5 M solution of «-butyllithium in hexane (79 mL, 197 mmol) was added during 15 minutes under argon atmosphere. After 15 minutes, the mixture was transferred through caniula to the solution of 4-chloro-2-fluorobenzyl bromide (30.0 g, 134 mmol) in dry tetrahydrofuran (400 mL) cooled to -78°C. Reaction mixture was stirred at -78 °C for 40 minutes and subsequently saturated solution of ammonium chloride was added (100 mL). The mixture was diluted with water (200 mL), phases were separated and aqueous phase was extracted with dichloromethane (3 ^χ 100 mL). Organic phases were combined, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptan:AcOEt = 10: 1 to 9: 1, v/v). The product was obtained in the form of a colorless oil with a yield of 81% (19.9 g, 108 mmol).

Step B: 2-(4-Chloro-2-fluorobenzyl)-3-oxobutanenitrile

To the solution of 3-(4-chloro-2-fluorophenyl)propanenitrile from Step A (15.0 g, 81.7 mmol) in dry tetrahydrofuran (300 mL) a 1 M solution of potassium tert-amylate in toluene (138 mL, 245 mmol) was added dropwise during 15 minutes and then ethyl acetate (8.05 mL, 81.7 mmol) was added. The reaction was carried out for 10 minutes at room temperature. Reaction mixture was poured out on the solution of hydrochloric acid (600 mL, 0.5 M). To the mixture dichloromethane was added (100 mL). Phases were separated and aqueous phase was extracted with dichloromethane (2 ^χ 100 mL). Organic phases were combined, dried (Na₂S04), and evaporated under reduced pressure. The product was obtained as a pale yellow oil (18.5 g) and used without further purification in the next step.

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

To the solution of 2-(4-chloro-2-fluorobenzyl)-3-oxobutanenitrile from Step B (18.5 g, 82.0 mmol) in anhydrous ethanol (300 mL) under argon atmosphere were added hydrazine monohydrate (13.0 mL, 184 mmol) and acetic acid (7.03 mL, 123 mmol). Reaction mixture was heated at reflux for 1 hour, cooled to room temperature, added with water (50 mL), and ethanol was evaporated under reduced pressure. To the residue were added dichloromethane (100 mL) and 2 M sodium hydroxide to obtain pH = 10. Phases were separated and aqueous phase was extracted with dichloromethane (2 ^χ 100 mL). Organic phases were combined and 1 M hydrochloric acid solution was added to obtain pH = 1. Phases were separated, aqueous phase was washed with dichloromethane (2 ^χ 50 mL), added with 2 M sodium hydroxide to obtain pH = 10 and then extracted with dichloromethane (4 ^χ 100 mL). White solid precipitated from the combined organic phases and was filtered and dried (tautomer I, 8.22 g, 34.3 mmol). Filtrate was concentrated to an oil that was purified by column chromatography (silicagel, mobile phase: AcOEt to AcOEt:methanol:Et₃N = 100:5:0.1, v/v/v) to obtain colorless oil (tautomer II, 9.44 g, 39.4 mmol). The product was obtained as two tautomers with a total yield for two steps of 90%.

Step D : 3 -(4-Chloro-2-fluorobenzyl)-2-methylpyrazolo [1,5 -a]pyrimidin-5 , 7-diol

To the solution of sodium ethanolate (1.47 g, 21.6 mmol) dissolved in absolute ethanol (29 mL) under argon atmosphere a solution of tautomer I from Step C (2.59 g, 10.8 mmol) in absolute ethanol (20 mL) and then diethyl malonate (3.28 mL, 21.6 mmol) were added. Reaction mixture was stirred at 90 °C for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to the dry mass. The residue was dissolved in water (100 mL) and 6 M hydrochloric acid solution was added to obtain pH = 1. Orange solid that precipitated was filtered, washed with water, hot-leached with methanol and then filtered and dried. The product was obtained as pale off-white crystals with a yield of 64% (2.13 g, 6.9 mmol) and used in the next step without further purification.

Step E: 5,7-Dichloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine

A mixture of 3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pirymidyne-5,7-diol from Step D (2.45 g, 7.64 mmol) and phosphorus(V) oxychloride (10.7 mL, 115 mmol) was heated while stirring at 100°C for 5.5 hours. The reaction mixture was cooled to room temperature and poured onto ice water (100 mL). To the mixture saturated sodium carbonate solution was added to obtain pH = 10. The mixture was extracted with ethyl acetate (3 ^χ 100 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and concentrated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptan:AcOEt = 9: 1, v/v). The product was obtained as a pale yellow amorphous solid with a yield of 79% (2.07 g, 6.0 mmol).

Step F : 4-(5 -Chloro-3 -(4-chloro-2-fluorobenzyl)-2-methylpyrazolo [1,5 -a]pirymidyn-7-yl)- morpholine

To the solution of 5,7-dichloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]- pyrimidine from Step E (2.07 g, 6.01 mmol) in acetonitrile (60 mL) were added sodium carbonate (0.64 g, 6.01 mmol) and morpholine (1.049 mL, 12.0 mmol). The reaction mixture was stirred at room temperature. White solid precipitated during the reaction. After 1 hour the reaction mixture was added with 10 mL of water and cooled in an ice-bath. After 10 minutes precipitated solid was filtered, washed with water and dried over phosphorus pentoxide. The product was obtained as white crystals with a yield of 91% (2.16 g, 5.46 mmol).

Step G: N-(l-tert-Butyl-3-methyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluorobenzyl)-2-methyl- 7-mo holinopyrazolo[l,5-α]pyrimidin-5-amine

The mixture of 4-(5-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pirymi- dyn-7-yl)morpholine from Step F (200 mg, 0.506 mmol), l-tert-butyl-3 -methyl- 1H- pyrazol-5-amine (155 mg, 1.012 mmol), tris(dibenzylideneacetone)dipalladium(0) (23.2 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (29.3 mg, 0.051 mmol) and sodium carbonate (107 mg, 1.012 mmol) were placed in a Schlenk flask and degassed under reduced pressure. Under argon atmosphere degassed toluene (5 mL) was added. Reaction mixture was purged with argon for 15 minutes and heated to 100 °C for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered over celite and washed with ethyl acetate (25 mL). The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptan:AcOEt = 9: 1 to 1 : 1, v/v). The product was obtained as a light yellow amorphous solid with a yield of 52% (134 mg, 0.262 mmol).

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

To N-(l-tert-butyl-3-methyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluorobenzyl)-2-methyl-7- mo holinopyrazolo[l,5-α]pyrimidin-5-amine from Step G trifluoroacetic acid (1.0 mL, 13.1 mmol) and water (4 mL) were added. Reaction mixture was heated to 100°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. To the residue 6% solution of sodium hydrogencarbonate (25 mL) was added and the whole was extracted with chloroform (3 ^χ 25 mL). Organic phases were combined, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by twice column chromatography (silicagel, eluent: AcOEt to AcOE methanol = 85: 15, and silicagel, eluent: chloroform 100% to chloroform:methanol, 96:4, v/v). The product was hot-crystallized from AcOEtheptane to obtain white crystals of the title product with a yield of 38% (53 mg, 37.6 mmol).

Example 2. 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

MS-ESI: (m/z) calculated for C22H24CIFN7O [M+H]⁺ = 456.2, found 456.2. ¾ MR (500 MHz, OMSO-d₆) δ 9.49 (s, 1H), 7.37

(dd, J=10.0, 2.0 Hz, 1H), 7.34 (s, 1H), 7.27 (s, 1H), 7.23 (t, J=8.4

Hz, 1H), 7.16 (dd, J=8.4, 2.0 Hz, 1H), 5.86 (s, 1H), 3.92 (s, 2H),

3.82-3.77 (m, 4H), 3.62 (s, 3H), 3.52-3.47 (m, 4H), 2.24 (s, 3H).

To the suspension of l-methyl-4-nitro-lH-imidazole (128 mg, 1.012 mmol) in ethanol (5 mL) 5% palladium on carbon (10 mg, 0.053 mmol) was added. The reaction mixture was degassed under reduced pressure and stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered over celite layer and washed with ethanol. The filtrate was concentrated under reduced pressure, dissolved in toluene, transferred to a Schlenk flask and again concentrated under reduced pressure. 4-(5-Chloro- 3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]piiymidyn-7-yl)morpholine obtained in Example 1, Step F (200 mg, 0.506 mmol), tris(dibenzylideneacetone)dipalladium(0) (23.2 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (29,3 mg, 0,051 mmol) and sodium carbonate (107 mg, 1.012 mmol) were added and the mixture was degassed under reduced pressure. Under argon atmosphere degassed toluene (5 mL) was added and the mixture was purged with argon for 15 minutes. Reaction mixture was heated to 100 °C for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered through celite layer and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: AcOEt 100% to AcOE methanol = 9: 1, v/v). The product was hot-crystallized from AcOE heptan to obtain white crystals with a yield of 27% (63 mg, 0.138 mmol).

Example 3. N-(3-(4-Chloro-2-fluorobenzyl)-2-methyl-7-morpholinopyrazolo[l,5-a]- pyrimidin-5-yl)-5-methylthiazol-2-amine

pirymidyn-7-yl)morpholine obtained in Example 1, Step F (213 mg, 0.539 mmol), 5- methyl-l,3-thiazol-2-amine (123 mg, 1.08 mmol), tris(dibenzylideneacetone)- dipalladium(O) (24.7 mg, 0.027 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (31.2 mg, 0.054 mmol) and sodium carbonate (114 mg, 1.08 mmol) was placed in a Schlenk flask and degassed under reduced pressure. Under argon atmosphere degassed toluene (5 mL) was added and the mixture was purged with argon for 15 minutes. Reaction mixture was heated at 100 °C for 24 hours. The mixture was cooled to room temperature, diluted with chloroform (10 mL), filtered through celite layer, washed with chloroform and then eluted with hot chloroform: methanol mixture (30 mL, 1 : 1, v/v). The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: chloroform 100% to chloroform: methanol = 95:5, v/v). The title product was obtained as an off-white amorphous solid with a yield of 42% (108 mg, 0.228 mmol).

Example 4. 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (piperidin- 1 -yl)pyrazolo[ 1 , 5-a]pyrimidin-5-amine

The title product was obtained as a white amorphous solid from 5,7-dichloro-3-(4-chloro- 2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine obtained in Example 1, Step E, following the procedures described in Example 1, Steps F to H, and using piped dine in place of morpholine.

Example 5. 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(4- methylpiperazin- 1 -yl)pyrazolo[ 1 , 5-a]pyrimidin-5-amine

The title product was obtained as a white amorphous solid, from 5,7-dichloro-3-(4-chloro- 2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine obtained in Example 1, Step E, following the procedures described in Example 1, Steps F to H, and using 1-methyl- piperazine in place of morpholine.

Example 6. 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(4- (methylsulphonyl)piperazin-l-yl)pyrazolo[l,5-a]pyrimidin-5-amine MS-ESI: (m/z) calculated for C23H27CIFN8O2S [M+H]⁺ = 533.2; found 533.2. ¾ NMR (500 MHz, OMSO-d₆) δ 11.86 (bs, 1H), 9.50 (bs, 1H), 7.36 (dd, J=9.9, 1.8 Hz, 1H), 7.19 (t, J=8.2 Hz, 1H), 7.14 (dd, J=8.3, 1.8 Hz, 1H), 6.30 (bs, 1H), 6.07 (bs, 1H), 3.89 (s, 2H), 3.66-3.59 (m, 4H), 3.38-3.28 (m, 4H), 2.96 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H).

The title product was obtained as a white amorphous solid, starting from 5,7-dichloro-3-(4- chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine obtained in Example 1, Step E, following the procedures described in Example 1, Steps F to H, and using l-(methyl- sulphonyl)piperazine in place of morpholine.

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

The title product in the form of an amorphous solid was obtained starting from 5,7- dichloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine obtained in Example 1, Step E, following the procedures described in Example 1, Step F, and Example 2, and using 1 -(methyl sulphonyl)piperazine in place of morpholine.

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

MS-ESI: (m/z) calculated for C24H29CIFN8 [M+H]⁺ = 483.2; found 483.2. ¾ NMR (500 MHz, OMSO-d₆) δ 11.80 (bs, 1H), 9.45 (bs, 1H), 7.35 (dd, J=9.9, 1.8 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H), 7.14 (dd, J=8.3, 1.7 Hz, 1H), 6.28 (bs, 1H), 6.03 (bs, 1H), 4.13 (d, J=10.7 Hz, 2H), 3.88 (s, 2H), 3.32 (bs, 1H), 2.97-2.89 (m, 2H), 2.33 (t, J=11.0

Hz, 2H), 2.22 (s, 3H), 2.19 (s, 3H), 1.01 (d, J=6.3 Hz, 6H). The title product was obtained as a white amorphous solid from 5,7-dichloro-3-(4-chloro- 2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine obtained in Example 1, Step E, following the procedures described in Example 1, Steps F to H, and using cis-2,6- dimethylpiperazine in place of morpholine.

Example 9. 3-(4-Chloro-2-fluorobenzyl)-7-((2R,65)-2,6-dimethylmorpholino)-2-methyl- N-(5 -methyl- lH-pyrazol-3 -yl)pyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as an amorphous light yellow solid from 5,7-dichloro-3-(4- chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pyrimidine obtained in Example 1, Step E, following the procedures described in Example 1, Steps F to H, and using cis-2,6- dimethylpiperazine in place of morpholine.

Example 10. 3-(4-Chloro-2-fluorobenzvO-2-ethvl-N-( 5 -methyl- lH-pyrazol-3-vlV7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

Step A: 2-(4-Chloro-2-fluorobenzyl)-3-oxopentanenitrile

The product was obtained as a light yellow oil with a yield of 67% (5.88 g, 24.5 mmol) from 3-(4-chloro-2-fluorophenyl)propanenitrile obtained in Example 1, Step A (6.70 g, 36.5 mmol) and methyl propionate (3.62 mL, 36.5 mmol), following the procedure of Example 1, Step B. Step B: 4-(4-Chloro-2-fluorobenzyl)-3-ethyl-lH-pyrazole-5-amine

The product was prepared as a white amorphous solid with a yield of 88% (5.50 g, 21.7 mmol) from 2-(4-chloro-2-fluorobenzyl)-3-oxopentanenitrile obtained in Step A (5.88 g, 24.5 mmol) following the procedure of Example 1, Step C.

Step C : 3 -(4-Chloro-2-fluorobenzyl)-2-ethylpyrazolo [1,5 -a]pyrimidin-5 , 7-diol

The product was prepared as white crystals with a yield of 89% (2.26 g, 7.02 mmol) from 4-(4-chloro-2-fluorobenzyl)-3-ethyl-lH-pyrazole-5-amine obtained in Step B (2.00 g, 7.88 mmol), following the procedure of Example 1, Step D.

Step D: 5,7-Dichloro-3-(4-chloro-2-fluorobenzyl)-2-ethylpyrazolo[l,5-a]pyrimidine

The product was prepared as a light-yellow amorphous solid with a yield of 73% (1.84 g, 5.12 mmol) from 3-(4-chloro-2-fluorobenzyl)-2-ethylpyrazolo[l,5-a]pyrimidin-5, 7-diol obtained in Step C, following the procedure of Example 1, Step E.

Step E: 4-(5-Chloro-3-(4-chloro-2-fluorobenzyl)-2-ethylpyrazolo[l,5-a]pirymidyn-7-yl)- morpholine

The product was prepared as white crystals with a yield of 98% (898 mg, 2.19 mmol) from 5,7-dichloro-3-(4-chloro-2-fluorobenzyl)-2-ethylpyrazolo[l,5-a]pyrimidine obtained in Step D (800 mg, 2.23 mmol) and morpholine (350 μΐ, 4.01 mmol), following the procedure of Example 1, Step F.

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

The title product was prepared as an amorphous off-white solid with a yield of 48% (110 mg, 0.234 mmol) from N-(l-tert-butyl-3-methyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluoro- benzyl)-2-ethyl-7-mo holinopyrazolo[l,5-α]pyrimidin-5-amine obtained in Step F, following the procedure of Example 1, Step H. Example 11. 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C₂₃H₂₆C1FN₇0 [M+H]⁺ = 407.2; found 470.2. ¾ NMR (500 MHz, CDC1₃) δ 8.06 (s, 1H), 7.12 (t, J=8.2 Hz, 1H), 7.04 (dd, J=9.7, 2.0 Hz, 1H), 6.97 (dd, J=8.3, 1.6 Hz, 1H), 6.57 (s, 1H), 6.23 (s, 1H), 3.98 (s, 2H), 3.94 (s, 2H), 3.78-3.70 (m, 4H), 2.69-2.60 (m, 4H), 2.34 (s, 3H), 2.31 (s, 3H).

Step A: tert-Butyldimethyl(prop-2-ynyloxy)silane

To the solution of propargyl alcohol (20.8 mL, 353 mmol) in dry dichloro methane (250 mL) cooled to 0 °C under argon atmosphere tert-butyldimethylsilyl chloride (55.9 g, 371 mmol) was added. Then to the mixture imidazole (48.1 g, 706 mmol) was added portionwise during 10 minutes. The reaction mixture was heated to room temperature and stirred for 16 hours. To the mixture water (100 mL) was added until dissolution of the solid precipitated during the reaction. Phases were separated and aqueous phase was extracted with dichloromethane (200 mL). Organic phases were combined, washed with brine, dried (Na₂S0₄) and evaporated under reduced pressure. The product was purified by distillation under reduced pressure (75 °C, 40 mmHg). The product was obtained as a colorless oil with a yield of 90% (54.3 g, 319 mmol).

Step B: Ethyl 4-(tert-butyldimethylsilyloxy)but-2-ynolate

To the solution of tert-butyldimethyl(prop-2-ynyloxy)silane obtained in Step A (11.9 mL, 56.9 mmol) in dry tetrahydrofuran (70 mL) cooled to -78 °C under argon atmosphere, 2.5 M solution of «-butyllithium in hexane (22.8 mL, 56.9 mmol) was added drop wise during 15 minutes. The mixture was stirred at -78 °C for 40 minutes, and then ethyl chloroformate (8.17 mL, 85.4 mmol) was added dropwise during 10 minutes. The reaction mixture was stirred for 4 hours while temperature was gradually increased up to 20 °C. Then the mixture was cooled in a water/ice bath to 0 °C and saturated solution of ammonium chloride (150 mL) was slowly added. Phases were separated and aqueous phase was extracted with dichloromethane (100 mL). Organic phases were combined, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptan:AcOEt = 95:5 to 90: 10). The product was obtained as a colorless oil with a yield of 94% (13.0 g, 53.5 mmol). Step C: 7-((tert-Butyldimethylsilyloxy)methyl)-3-(4-chloro-2-fluorobenzyl)-2-methyl- pyrazolo[l,5-a]pyrimidin-5-ol

The mixture of 4-(4-chloro-2-fluorobenzyl)-3-methyl-lH-pyrazol-5-amine obtained in Example 1, Step C (2.88 g, 12.0 mmol), ethyl 4-(tert-butyldimethylsilyloxy)but-2-ynolate obtained in Step B (3.50 g, 14.4 mmol) and ethanol (30 mL) was heated at reflux for 24 hours. The reaction mixture was cooled to room temperature. White crystals of the product precipitated from the mixture were filtered and washed with a small amount of cooled ethanol. The product was obtained with a yield of 53% (2.80 g, 6.42 mmol).

Step D: 3-(4-Chloro-2-fluorobenzyl)-7-(hydroxymethyl)-2-methylpyrazolo[l,5-a]- pyrimidin-5-ol

To 7-((tert-butyldimethylsilyloxy)methyl)-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo- [l,5-a]pyrimidin-5-ol obtained in Step C (2.80 g, 6.42 mmol) 1 M solution of tetrabutyl- ammonium fluoride in tetrahydrofuran (19.3 mL, 19.3 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue toluene (25 mL) was added and again the solvent was evaporated under reduced pressure. The residue (2.87 g) was used in the subsequent step without further purification.

Step E: 5-Chloro-3-(4-chloro-2-fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]- pyrimidine

The mixture of 3-(4-chloro-2-fluorobenzyl)-7-(hydroxymethyl)-2-methylpyrazolo[l,5-a]- pyrimidin-5-ol obtained in Step D (2.87 g of raw mixture, 6.42 mmol assuming full conversion) and phosphorous(V) oxychloride (10.0 mL, 107 mmol) was stirred and heated to 100 °C for 24 hours. The reaction mixture was cooled to room temperature and poured onto ice water (100 mL). The mixture was added with 2 M solution of sodium hydroxide to obtain pH = 12 and then extracted with dichloromethane (3 ^χ 100 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and concentrated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: toluene: methanol = 99.5 : 0.5 to 99 : 1, v/v). The product was obtained as a light yellow solid with a yield for two steps of 81% (1.84 g, 5.13 mmol).

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. Reaction mixture was cooled, then saturated sodium hydrogencarbonate solution (50 mL) and dichloromethane (50 mL) were added. Phases were separated and aqueous phase was extracted with dichloromethane (2 ^χ 50 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: dichloromethane: acetone = 98:2 to 95:5, v/v). The product was obtained as a white solid with a yield of 73% (2.19 g, 5.35 mmol).

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-α]pyrimidin-5-amine

The product was obtained as a yellow oil with a yield of 82% (1.150 g, 2.00 mmol) from 4- ((5-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pirymidyn-7-yl)methyl)- morpholine obtained in Step F (1.100 g, 2.44 mmol), following the procedure of Example 1, Step G.

Step H: 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The product was obtained as a white solid with a yield of 92% (850 mg, 1.81 mmol) from N-(l-tert-butyl-3-methyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluorobenzyl)-2-methyl-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine (1.140 g, 1.98 mmol) obtained in Step G, following the procedure of Example 1, Step H.

Example 12. 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C23H26CIFN7O [M+H]⁺ = 407.2; found 407.2. ¾ MR (300 MHz, CDCI3 + CD3OD) δ 7.39 (d, J=1.6 Hz, 1H), 7.29 (dd, J=1.6, 0.5 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 7.10 (dd, J=9.8, 2.0 Hz, 1H), 7.00 (ddd, J=8.3, 2.1, 0.7 Hz, 1H), 6.59 (s, 1H), 4.02 (s, 2H), 3.91 (s, 2H), 3.85-3.79 (m, 4H),

3.70 (s, 3H), 2.75-2.65 (m, 4H), 2.36 (s, 3H). The product was prepared as white crystals with a yield of 48% (580 mg, 1.23 mmol) from 4-((5-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pirymidyn-7-yl)methyl)- morpholine (1.160 g, 2.59 mmol) obtained in Example 1 1, Step F, following the procedure of Example 2.

Example 13. N-(3-(4-Chloro-2-fluorobenzvl)-2-methvl-7-(morpholinomethvl)- pyrazolo[l,5-a]pyrimidin-5-yl)-5-methylthiazol-2-amine

The product was prepared as a light yellow solid with a yield of 49% (82 mg, 0.168 mmol) from 4-((5-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylpyrazolo[l,5-a]pirymidyn-7-yl)- methyl)morpholine obtained in Example 1 1, Step F (140 mg, 0.342 mmol), following the procedure of Example 3.

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

The title product was obtained as a light pink solid, starting from 5-chloro-3-(4-chloro-2- fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]pyrimidine prepared in Example 11, Step E, and following successively the procedures described in Example 11, Step F, and Example 1, Steps G to H, using piperidine in place of morpholine.

Example 15. 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-((4- methylpiperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine MS-ESI: (m/z) calculated for C24H29CIFN8 [M+H]⁺ = 483.2; found 483.2. ¾ NMR (500 MHz, OMSO-d₆) δ 11.88 (s, IH), 9.74 (s, IH), 7.36 (dd, J=10.0, 2.0 Hz, IH), 7.22 (t, J=8.3 Hz, IH), 7.15 (dd, J=8.3, 1.9 Hz, IH), 6.72 (s, IH), 6.42 (s, IH), 3.91 (s, 2H), 3.83 (s, 2H), 2.63-2.52 (m, 4H), 2.47-2.35 (m, 4H), 2.23 (s, 3H),

2.21 (s, 3H), 2.19 (s, 3H).

The title product was obtained as a light pink solid, starting from 5-chloro-3-(4-chloro-2- fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]pyrimidine prepared in Example 11, Step E, and following successively the procedures described in Example 11, Step F, and Example 1, Steps G to H, and using 1-methylpiperidine in place of morpholine.

Example 16. 3 -(4-Chloro-2-fluorobenzyl)-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 white crystals, starting from 5-chloro-3-(4-chloro-2- fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]pyrimidine prepared in Example 11, Step E, and following successively the procedures described in Example 11, Step F, and Example 2, using 1-methylpiperazine in place of morpholine.

Example 17. 3 -(4-Chloro-2-fluorobenzyl)-7-((4-ethylpiperazin- 1 -yl)methyl)-2-methyl-N- (5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C25H31CIFN8 [M+H]⁺ = 497.2; found 497.2. ¾ NMR (500 MHz, DMSO-d) δ 11.96 (s, IH), 9.70 (s, IH), 7.36 (d, J=9.9 Hz, IH), 7.23 (t, J=8.2 Hz, IH), 7.15 (d, J=8.3 Hz, IH), 6.73 (s, IH), 6.41 (s, IH), 3.97 (s, 2H), 3.92 (s, 2H), 3.52- 3.40 (m, 2H), 3.20-3.05 (m, 4H), 3.03-2.94 (m, 2H), 2.83-2.72 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.27 (t, J=7.1 Hz, 3H). The title product was obtained as a white solid, starting from 5-chloro-3-(4-chloro-2- fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]pyrimidine prepared in Example 11, Step E, and following successively the procedures described in Example 11, Step F, and Example 1, Steps G to H, using 1-ethylpiperidine in place of morpholine.

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

The title product was obtained as a white solid, starting from 5-chloro-3-(4-chloro-2- fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]pyrimidine prepared in Example 11, Step E, and following successively the procedures described in Example 11, Step F, and Example 1, Steps G to H, using 1-methanesulphonylpiperazine in place of morpholine.

Example 19. 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7-((4- (methylsulphonyl)piperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained starting from 5-chloro-3-(4-chloro-2-fluorobenzyl)-7- (chloromethyl)-2-methylpyrazolo[l,5-a]pyrimidine obtained in Example 11, Step E, and following successively the procedures described in Example 11, Step F, and Example 2, using 1-methanesulphonylpiperazine in place of morpholine. 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

The title product was obtained as an off-white solid starting from 5-chloro-3-(4-chloro-2- fluorobenzyl)-7-(chloromethyl)-2-methylpyrazolo[l,5-a]pyrimidine, prepared in Example 11, Step E, and following successively the procedures described in Example 11, Step F, and Example 1, Steps G to H, using cz^'s-2,6-dimethylmorpholine in place of morpholine.

Example 21. 3 -(4-Chloro-2-fluorobenzyl)-2-ethyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as pale off-white crystals, starting from 4-(4-chloro-2- fluorobenzyl)-3 -ethyl- lH-pyrazol-5-amine obtained in Example 10, Step B, following successively the procedures described in Example 1 1, Steps C to F, and Example 1, Steps G to H.

Example 22. (R/5)-3-(l-(4-Chloro-2-fluorophenyl)ethyl)-2-methyl-N-(5 -methyl- 1H- pyrazol-3-yl)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine MS-ESI: (m/z) calculated for C24H28CIFN7O [M+H]⁺ = 484.2; found 484.2. ¾ MR (300 MHz, CDCI3) δ 8.09 (bs, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.08-6.96 (m, 2H), 6.54 (s, 1H), 6.26 (bs, 1H), 4.57 (q, J=7.2 Hz, 1H), 3.93 (s, 2H), 3.78-3.69 (m, 4H), 2.69-2.58 (m, 4H), 2.35 (s, 3H), 2.32 (s, 3H), 1.80 (d, J=7.3 Hz, 3H).

Step A: (_JE)-3-(4-Chloro-2-fluorophenyl)but-2-enenitrile and (Z)-3-(4-chloro-2-fluoro- phenyl)but-2-enenitrile

The mixture of 4'-chloro-2'-fluoroacetophenone (3.97 mL, 29.0 mmol), diethyl cyano- methylphosphonate (5.16 mL, 31.9 mmol), 18-crown-6 (117 mg, 0.435 mmol), potassium carbonate (6.01 g, 43.5 mmol) and toluene (80 mL) was heated to 70 °C for 20 hours. Reaction mixture was cooled and water (100 mL) was added. Phases were separated and aqueous phase was extracted with AcOEt (4 ^χ 100 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptane 100% to heptane:AcOEt = 98:2, v/v). (_JE)-3-(4-Chloro-2-fluorophenyl)but-2-enenitrile as white crystals and (Z)-3-(4-chloro-2-fluorophenyl)but-2-enenitrile as a light yellow oil were obtained with the yields of 74% (4.20 g, 21.5 mmol) and 3% (156 mg, 0,80 mmol), respectively. Also the mixture of isomers (E) and (Z) as a colorless oil was obtained with a yield of 22% (1.23 g, 6.28 mmol).

Step B: (3R/5)-3-(4-Chloro-2-fluorophenyl)butanenitrile

The mixture of copper(II) acetate (97.5 mg, 0.537 mmol) and 9,9-dimethyl-4,5-bis- (diphenylphosphine)xanthene (311 mg, 0.537 mmol) was placed in a Schlenk flask, degassed and purged with argon. Then under argon atmosphere degassed toluene (25 mL), polymethylhydrosiloxane (4.33 mL, 71.6 mmol), (_JE)-3-(4-chloro-2-fluorophenyl)but-2- enenitrile (3.5 g, 17.9 mmol) and tert-butanol (5.30 g, 71.6 mmol) were successively added. The mixture was put under argon atmosphere and the Schlenk flask was tightly closed. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was added with water (30 mL) and diethyl ether (50 mL) and stirred for 30 minutes. Phases were separated and aqueous phase was extracted with diethyl ether (3 ^χ 50 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptan:AcOEt 97:3 to 90: 10, v/v). The product was obtained as a racemate in the form of a light yellow oil with a yield of 92% (3.25 g, 16.5 mmol). Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tiu = 7.3 min, tm = 9.0 min.

Step C: (3R/5)-2-Acetyl-3-(4-chloro-2-fluorophenyl)butanenitrile

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

The product was obtained as a raw colorless oil with a yield of 70% (2.01 g, 7.92 mmol) from (3R/,S)-2-acetyl-3-(4-chloro-2-fluorophenyl)butanenitrile from Step C (2.40 g), following the procedure of Example 1, Step C.

Step E: (R/5)-7-((tert-Butyldimethylsilyloxy)methyl)-3-(l-(4-chloro-2-fluorophenyl)- ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-5-ol

The product was obtained as a white solid with a yield of 52% (1.80 g, 4.01 mmol) from (R/<S)-4-(l-(4-chloro-2-fluorophenyl)ethyl)-3-methyl-lH-pyrazol-5-amine from Step D (1.97 g, 7.76 mmol), following the procedure of Example 11, Step C.

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

The product was obtained as a raw a colorless oil with a yield for two steps of 96% (1.43 g, 3.85 mmol) from (R/,S)-3-(l-(4-chloro-2-fluorophenyl)ethyl)-7-(hydroxymethyl)-2-methyl- pyrazolo[l,5-a]pyrimidin-5-ol from Step F (1.32 g), following the procedure of Example 11, Step E.

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-α]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-α]pyrimidin-5-amine

The title product was obtained as a racemate in the form of a white solid with a yield for two steps of 57% (130 mg, 0.269 mmol) from (R/S)-N-(l -ter t-butyl-3 -methyl- lH-pyrazol- 5-yl)-3-(l-(4-chloro-2-fluorophenyl)ethyl)-2-methyl-7-(morpholinomethyl)pyrazolo[l,5- a]pyrimidin-5-amine from Step I (257 mg), following the procedure of Example 1, Step H. Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tRi = 34.9 min, tR₂ = 44.6 min.

Example 23. (R/S)-3 -( 1 -(4-Chloro-2-fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- 1H- imidazol-4-yl)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C24H28CIFN7O [M+H]⁺ = 484.2; found 484.2. ¾ MR (300 MHz, CDCI3) δ 9.99 (s, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.07-7.02 (m, 1H), 7.02-6.98 (m, 1H), 6.53 (s, 1H), 4.64 (q, J=7.4 Hz, 1H), 3.96 (d, J=l . l Hz, 2H), 3.86-3.76 (m, 4H), 3.74 (s, 3H),

2.76-2.63 (m, 4H), 2.36 (s, 3H), 1.86 (d, J=7.3 Hz, 3H).

The title product was obtained as white crystals starting from (R/,S)-4-((5-chloro-3-(l-(4- chloro-2-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pirymidyn-7-yl)methyl)morpholine obtained in Example 22, Step H, following the procedure of Example 2. Example 24. 3-Benzyl-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-mo holino- pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as a white amorphous solid starting from 3-phenylpropanenitrile and following successively the procedures described in Example 1, Steps B to H.

Example 25. 3-Benzyl-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(mo holinomethyl)- pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as an amorphous solid starting from 3-phenylpropanenitrile and following successively the procedures described in Example 1, Steps B and C, Example 11, Steps C to F, and Example 1, Steps G to H.

Example 26. 3 -(2-Fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-morpholino- pyrazolo[l,5-a]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 (Na₂S04) 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 B: 3-(2-Fluorophenyl)propanenitrile

Raw (_JE)-3-(2-fluorophenyl)acrylonitrile from Step A (7.60 g) was dissolved in ethanol (150 mL). To the solution 5% Pd/C (400 mg) was added. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. The reaction mixture was filtered through celite layer and washed with ethanol. The filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silicagel, mobile phase heptane: AcOEt = 85: 15, v/v). The product was obtained in the form of a colorless oil with a yield for two steps of 95% (5.69 g, 38.1 mmol).

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 27. 3 -(2-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C22H25FN7O [M+H]⁺ = 422.2; found 422.2. ¾ MR (500 MHz, OMSO-d₆) δ 9.47 (s, 1H), 7.34 (s, 1H), 7.32 (s, 1H), 7.26-7.18 (m, 2H), 7.18-7.11 (m, 1H), 7.06 (t, J=7.3 Hz, 1H), 5.85 (s, 1H), 3.94 (s, 2H), 3.83-3.76 (m, 4H), 3.61 (s, 3H), 3.52-3.47 (s, 4H), 2.24 (s, 3H).

The title product was obtained as an off-white solid starting from 3-(2- fluorophenyl)propanenitrile obtained in Example 26, Step B, and following successively the procedures described in Example 1, Steps B to F, and Example 2.

Example 28. 3 -(2-Fluorobenzyl)-2-methyl-N-( 1 -methyl- lH-pyrazol-4-yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine

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 29. 3 -(2-Fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7-(morpholino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

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

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.

Example 31. 3-(3-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(mo holino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as an off-white solid starting from 3-(3-fluorophenyl)- propanenitrile, obtained from 3-fluorobenzaldehyde analogously to the procedure 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 32. 3-(3-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(morpholino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as an off-white solid, starting from 3-(3-fluorophenyl)- propanenitrile, obtained from 3-fluorobenzaldehyde analogously as in Example 26, Step B, following successively the procedures described in Example 1, Steps B and C, Example 11, Steps C to F, and Example 2.

Example 33. 3-(3-Fluorobenzyl)-7-((2-methoxyethylamino)methyl)-2-methyl-N-(5- methyl- lH-pyrazol-3 -yl)pyrazolo [1,5 -ajpyrimidin- 5 -amine MS-ESI: (m/z) calculated for C22H27FN7O [M+H]+ = 424.2; found 424.2. ¾ NMR (300 MHz, CDCI3) δ 9.38 (s, 1H), 7.24- 7.14 (m, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.97 (d, J=10.2 Hz, 1H), 6.83 (td, J=8.6, 2.0 Hz, 1H), 6.48 (s, 1H), 6.45 (s, 1H), 4.15 (s, 2H), 4.00 (s, 2H), 3.59-3.48 (m, 2H), 3.34 (s, 3H), 2.97-2.84 (m,

2H), 2.30 (s, 3H), 2.25 (s, 3H).

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 34. 3 -(4-Fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as a white solid, starting from 3-(4-fluorophenyl)- propanenitrile, obtained from 4-fluorobenzaldehyde analogously as in Example 26, Steps A to B, following the procedures described in Example 1, Steps B to H.

Example 35. 3 -(4-Fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7-(morpholino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

MS-ESI: (m/z) calculated for C23H27FN7O [M+H]⁺ = 436.2; found 436.2. ¾ NMR (500 MHz, DMSO-d) δ 11.88 (ds, 1H), 9.73 (ds, 1H), 7.27 (dd, J=8.3, 5.8 Hz, 2H), 7.05 (t, J=8.9 Hz, 2H), 6.77 (s, 1H), 6.45 (s, 1H), 3.91 (s, 2H), 3.86 (s, 2H), 3.72-3.63 (m, 4H), 2.63-2.54 (m, 4H), 2.22 (s, 3H), 2.21 (s, 3H). The title product was obtained as a beige solid, starting from 3-(4-fluorophenyl)- propanenitrile obtained from 4-fluorobenzaldehyde analogously as in Example 26, Steps A to 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 36. 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(morpholino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as a yellow solid, starting from 3-(4-fluorophenyl)- propanenitrile, obtained from 4-fluorobenzaldehyde analogously as described in Example 26, Steps A to B, following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to F, and Example 2.

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

The title product was obtained as a white solid, starting from 3-(4-fluorophenyl)propane- nitrile, obtained from 4-fluorobenzaldehyde analogously as described 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 1-methylpiperazine in place of morpholine.

Example 38. 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-((4-methyl- piperazin- 1 -yl)methyl)pyrazolo[ 1 ,5-a]pyrimidin-5-amine MS-ESI: (m/z) calculated for C24H30FN8 [M+H]⁺ = 449.3; found 449.3. ¾ NMR (500 MHz, OMSO-d₆) δ 9.78 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.30 (dd, J=8.5, 5.7 Hz, 2H), 7.07 (t, J=8.9 Hz, 2H), 6.63 (s, 1H), 3.94 (s, 2H), 3.82 (s, 2H), 3.62 (s, 3H), 2.57 (s, 4H), 2.40 (s, 4H), 2.22 (s, 3H), 2.19 (s, 3H).

The title product was obtained as a white solid starting from 3-(4-fluorophenyl)propane- nitrile, obtained from 4-fluorobenzaldehyde analogously as described 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 2, using 1-methylpiperazine in place of morpholine.

Example 39. 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as a white solid, starting from 3-(2,4-difluorophenyl)- propanenitrile, obtained from 2,4-difluorobenzaldehyde, analogously as in Example 26, Steps A to B, following the procedures described in Example 1, Steps B to H.

Example 40. 3 -(2,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

MS-ESI: (m/z) calculated for C22H24F2N7O [M+H]⁺ = 440.2; found 440.2.

¾ NMR (500 MHz, OMSO-d₆) δ 9.51 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 7.25 (dd, J=15.6, 8.7 Hz, 1H), 7.18 (td, J=10.3, 2.5 Hz, 1H), 6.95 (td, J=8.5, 2.1 Hz, 1H), 5.85 (s, 1H), 3.91 (s, 2H), 3.83-

3.75 (m, 4H), 3.62 (s, 3H), 3.50 (d, J=4.2 Hz, 4H), 2.24 (s, 3H). The title product was obtained as pale off-white crystals, starting from 3-(2,4-difluoro- phenyl)propanenitrile, obtained from 2,4-difluorobenzaldehyde, analogously as described in Example 26, Steps A to B, following successively the procedures described in Example 1, Steps B to F, and Example 2.

Example 41. 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (morpholinomethyl)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 to 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 42. 3 -(2,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C23H26F2N7O [M+H]⁺ = 454.2; found 454.2.

¾ NMR (500 MHz, OMSO-de) δ 9.78 (s, 1H), 7.37 (bs, 1H), 7.36 (bs, 1H), 7.29 (dd, J=15.6, 8.6 Hz, 1H), 7.22-7.15 (m, 1H), 6.96 (td, J=8.4, 2.1 Hz, 1H), 6.66 (s, 1H), 3.94 (s, 2H), 3.83 (s, 2H),

3.69-3.65 (m, 4H), 3.64 (s, 3H), 2.59-2.53 (m, 4H), 2.25 (s, 3H).

The title product was obtained as a white solid, starting from 3-(2,4-difluorophenyl)- propanenitrile obtained from 2,4-difluorobenzaldehyde analogously as described 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 2. Example 43. N-(5-Cyclopropyl-lH-pyrazol-3-yl)-3-(2,4-difluorobenzyl)-2-methyl-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

Step A: 3-Cyclopropyl-l-(4-methoxybenzyl)-lH-pyrazol-5-amine and 5-cyclopropyl-l-(4- methoxybenzyl)-lH-pyrazolo-3 -amine

To the solution of 3-cyclopropyl-lH-pyrazole-5-amine (500 mg, 3.90 mmol) in dry dimethylformamide (5 mL) cooled to 0 °C sodium hydride (203 mg, 5.07 mmol, 60% suspension in oil) was added and the mixture was stirred for 30 minutes. 4-Methoxybenzyl chloride (705 μΐ, 3.90 mmol) was added to the mixture. Reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was added with water (15 mL) and extracted with ethyl acetate (2 ^χ 25 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and evaporated. The residue was purified by column chromatography to obtain two isomers of the compound with the yields of 27% (259 mg, 1.06 mmol) and 29% (277 mg, 1.14 mmol).

Step B: N-(3-Cyclopropyl-l-(4-methoxybenzyl)-lH-pyrazol-5-yl)-3-(2,4-difluorobenzyl)- 2-methyl-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

Obtained following the procedure of Example 1, Step G, from 3-cyclopropyl-l-(4- methoxybenzyl)-lH-pyrazole-5-amine obtained in Example 43, Step A, and 5-chloro-3- (2,4-difluorobenzyl)-2-methyl-7-(morpholin-4-ylmethyl)pyrazolo[l,5-a]pyrimidine obtained from 3-(2,4-difluorophenyl)propanenitrile, following the procedures described in Example 1, Steps B to C, and Example 1 1, Steps C to F. 3-(2,4-Difluorophenyl)- propanenitrile was obtained from 2,4-difluorobenzaldehyde analogously as described in Example 26, Steps A and B.

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 ^χ 25 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: chloroform 100% to chloroform:methanol = 85: 15, v/v). The title product was obtained as a light brown amorphous solid with a yield for two steps of 20% (50 mg, 0.104 mmol).

Example 44. 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-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)- propanenitrile, obtained from 2,4-difluorobenzaldehyde analogously as described in Example 26, Steps A to 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, and using 1- methylpiperazine in place of morpholine.

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 white crystals, starting from 3-(2,4-difluorophenyl)- propanenitrile, obtained from 2,4-difluorobenzaldehyde analogously as described in Example 26, Steps A to B, following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to F, and Example 2 and using 1-methylpiperazine in place of morpholine.

Example 46. 3-(2,4-Difluorobenzyl)-7-((2-methoxyethylamino)methyl)-2-methyl-N-(l- methyl-lH-imidazol-4-yl)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 47. 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-((2- mo holinoethylamino)methyl)pyrazolo[l ,5-α]pyrimidin-5-amine

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. 3 -(2,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7-((2- mo holinoethylamino)methyl)pyrazolo[l,5-α]pyrimidin-5-amine

F MS-ESI: (m/z) calculated for C25H31F2N8O [M+H]⁺ = 496.3;

found 496.3. ¾ NMR (300 MHz, OMSO-d₆) δ 9.88 (s, 1H), 7.39

H

(s, 2H), 7.33-7.24 (m, 1H), 7.19 (ddd, J=10.5, 9.4, 2.6 Hz, 1H), 6.97 (tdd, J=8.6, 2.6, 0.9 Hz, 1H), 6.50 (s, 1H), 3.96 (s, 2H), 3.94

(s, 2H), 3.64 (s, 3H), 3.48 (dd, J=8.5, 4.1 Hz, 4H), 2.62 (t, J=6.2

Hz, 2H), 2.38 (t, J=6.1 Hz, 2H), 2.28-2.21 (m, 7H).

The title product was obtained as a beige solid, starting from 3-(2,4-difluorophenyl)pro- panenitrile 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 11, Steps C to F, and Example 2, using 2-morpholinoethylamine in place of morpholine.

Example 49. (R/5)-3-(l-(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5-methyl-lH-pyrazol-3- l)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

Step A. (_JE)-3-(2,4-Difluorophenyl)but-2-enenitrile and (Z)-3-(2,4-difluorophenyl)but-2- enenitrile

The mixture of 2',4'-difluoroacetophenone (8.10 mL, 62.8 mmol), diethyl cyanomethyl- phosphonate (11.2 mL, 69.0 mmol), 18-crown-6 (254 mg, 0.942 mmol), potassium carbonate (13.0 g, 94.2 mmol) and toluene (150 mL) was heated to 70 °C for 2 days. The reaction mixture was cooled and water (100 mL) was added. Phases were separated and aqueous phase was extracted with AcOEt (4 ^χ 100 mL). Organic phases were combined, washed with brine, dried (Na2S0₄) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptane 100% to heptane:AcOEt = 98:2, v/v). (_JE)-3-(2,4-difluorophenyl)but-2-enenitrile and (Z)-3-(2,4-di- fluorophenyl)but-2-enenitrile were obtained as white crystals with the yields, respectively, of 68% (7.61 g, 42.5 mmol) and 2% (198 mg, 1.11 mmol). Also the mixture of isomers (E) and (Z) as a colorless oil was obtained with a yield of 30% (3.70 g, 20.7 mmol).

Step B: (R/5)-3-(2,4-Difluorophenyl)butanenitrile

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. The residue was purified by column chromatography (silicagel, eluent: heptane: AcOEt 97:3 to 90: 10, v/v). The product was obtained as racemate in the form of a colorless oil with a yield of 89% (3.33 g, 18.4 mmol).

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 μΐ, 4.47 mmol), (£)-3-(2,4- difluorophenyl)but-2-enenitrile (200 mg, 1.12 mmol) and tert-butanol (331 mg, 4.47 mmol). The mixture was put under argon atmosphere and Schlenk flask was tightly closed. The reaction mixture was stirred at room temperature for 20 hours, then added with water (10 mL) and diethyl ether (20 mL), and stirred for 30 minutes. Phases were separated and aqueous phase was extracted with diethyl ether (3 χ 20 mL). Organic phases were combined, washed with brine, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptane:AcOEt 97:3 to 90: 10, v/v). The product was obtained as a racemate in the form of a light yellow oil with a yield of 84% (170 mg, 0.938 mmol). Chiral HPLC: (column AS-H, isopropanokhexane 10:90, 0.5 mL/min); t_Ri = 7.2 min, t_R2 = 10.1 min.

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. Chiral HPLC: (column AS-H, isopropanokhexane 10:90, 0.5 mL/min); tRi = 33.7 min, tR₂ = 50.9 min. Example 50. (R)-3-(l-(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)- 7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

Step A: (3R)-3-(2,4-Difluorophenyl)butanenitrile

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). The product was obtained as a light yellow oil with a yield of 83% (168 mg, 0.927 mmol); >99% ee; Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 10.3 min.

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). The product was obtained as a light yellow oil with a yield of 81% (164 mg, 0.905 mmol); >99% ee; Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 10.1 min.

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. Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tRi = 34.2 min (98,8%), t_R2 = 53.1 min (1,2%).

Example 51. (S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)- 7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine MS-ESI: (m/z) calculated for C24H28F2N7O [M+H]⁺ 468.2: found 468.2.

¾ NMR (300 MHz, CDCI3) δ 7.50 (dd, J=15.3, 8.8 Hz, 1H), 7.21 (s, 1H), 6.86-6.67 (m, 2H), 6.52 (s, 1H), 6.20 (s, 1H), 4.57 (q, J=7.2 Hz, 1H), 3.95 (d, J=l . l Hz, 2H), 3.82-3.73 (m, 4H), 2.70- 2.60 (m, 4H), 2.36 (s, 3H), 2.33 (s, 3H), 1.81 (d, J=7.4 Hz, 3H).

Step A: (3,S)-3-(2,4-Difluorophenyl)butanenitrile

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,.

Step B: The title product was obtained as a white amorphous solid from (3S)-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. 96% ee; Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tRi = 34.2 min (1.8%), t_R2 = 49.7 min (98.2%).

Example 52. (R/5)-3-(l-(2,4-Difluorophenyl)ethyl)-2-methyl-N-(l-methyl-lH-imidazol-4- l)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a racemate in the form of white crystals from (R/S)-3- (2,4-difluorophenyl)butanenitrile obtained in Example 49, Step B, following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to F, and Example 2. Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); t = 31.4 min, tm = 35.6 min.

Example 53. (R)-3-(l-(2,4-Difluorophenyl)ethyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)- 7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C24H28F2N7O [M+H]⁺ = 468.2; found 468.2. ¾ MR (300 MHz, OMSO-d₆) δ 9.80 (s, 1H), 7.57 (td, J=8.7, 6.8 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J=1.2 Hz, 1H), 7.19- 7.07 (m, 1H), 7.01 (td, J=8.6, 2.2 Hz, 1H), 6.67 (s, 1H), 4.51 (q, J=7.4 Hz, 1H), 3.81 (s, 2H), 3.71-3.59 (m, 7H), 2.59-2.52 (m,

4H), 2.23 (s, 3H), 1.75 (d, J=7.3 Hz, 3H).

The title product was obtained as amorphous white solid from (3R)-3-(2,4-difluorophenyl)- butanenitrile obtained in Method 1 of Example 51, Step A, following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to F and Example 2. >99% ee; Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); t_R = 31.1 min.

Example 54. (S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)- 7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C24H28F2N7O [M+H]⁺ = 468.2; found 468.2.

¾ NMR (300 MHz, OMSO-de) δ 9.80 (s, 1H), 7.62-7.51 (m, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 7.19-7.08 (m, 1H), 7.07-6.97 (m, 1H), 6.66 (s, 1H), 4.51 (q, J=6.9 Hz, 1H), 3.82 (s, 2H), 3.69-3.62 (m,

7H), 2.64-2.51 (m, 4H), 2.24 (s, 3H), 1.76 (d, J=7.5 Hz, 3H).

The title product was obtained as amorphous white solid from (3,S)-3-(2,4-difluorophenyl)- butanenitrile obtained in Method 1 of Example 50, Step A, following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to F and Example 2. >99% ee; Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); t_R = 35.2 min.

Example 55. 3 -(3 ,4-Difluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine MS-ESI: (m/z) calculated for C23H26F2N7O [M+H]⁺ = 454.2; found 454.2.

¾ NMR (300 Hz; CDCI3) δ 8.48 (s, 1H), 7,01 (ddd; J=11.3, 7.2, 5.3 Hz, 3H); 6.58 (s, 1H), 6.29 (s, 1H), 3.96 (s, 2H), 3.95 (s, 2H), 3.76-3.71 (m, 4H), 2.67-2.61 (m, 4H), 2.31 (s, 3H), 2.29 (s, 3H).

The title product was obtained as an off-white solid, starting from 3-(3,4-difluoro- phenyl)propanenitrile obtained from 3,4-difluorobenzaldehyde 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.

Example 56. 3 -(3 ,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from 3-(3,4-difluorophenyl)- propanenitrile obtained from 3,4-difluorobenzaldehyde 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 2.

Example 57. 3-(2-Chlorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(mo holino- meth l)pyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as a white solid, starting from 3-(2-chlorophenyl)- propanenitrile 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.

Example 58. 3 -(4-Chloro-3-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as a white solid, starting from 4-chloro-3-fluorobenzyl bromide and following successively the procedures described in Example 1, Steps A to H.

Example 59. 3 -(4-Chloro-3-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from 4-chloro-3-fluorobenzyl bromide and following successively the procedures described in Example 1, Steps A to C, Example 11, Steps C to G, and Example 1, Steps G to H.

Example 60. 2-Methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7-(morpholinomethyl)-3 -(4- (trifluoromethyl)benzyl)pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as a white solid, starting from 4-trifluorobenzyl bromide and following successively the procedures described in Example 1, Steps A to C, Example 11, Steps C to F, and Example 1, Steps G to H.

Example 61. 2-Methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7-(morpholinomethyl)-3 -(4- trifluoromethyl)benzyl)pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as a white solid, starting from 4-trifluorobenzyl bromide and following successively the procedures described in Example 1, Steps A to C, Example 11, Steps C to F, and Example 2.

Example 62. 3 -(4-Methoxybenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7- mor holinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as an off-white solid, starting from 3 -(4-methoxy phenyl)- propanenitrile and following successively the procedures described in Example 1, Steps B to H. Example 63. 3 -(4-Methoxybenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as white crystals, starting from 3-(4-methoxyphenyl)- propanenitrile and following successively the procedures described in Example 1, Steps B to F, and Example 2.

Example 64. 4-((2-Methyl-5-(l -methyl- lH-imidazol-4-ylamino)-7-morpholino- pyrazolo[l,5-a]pyrimidin-3-yl)methyl)phenol

To the solution of 3 -(4-methoxybenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7- mo holinopyrazolo[l,5-α]pyrimidin-5-amine (Compound of Example 63) (60 mg, 0.138 mmol) in dichloromethane (5 mL) at 0 °C under argon atmosphere boron trichloride (100 μΐ, 1.04 mmol) was added dropwise. The reaction mixture was stirred until room temperature was reached for 2.5 hours. Then the reaction mixture was cooled to 0 °C and methanol was added dropwise until dissolution of a solid precipitated during the reaction (2 mL). To the mixture 6% sodium hydrogencarbonate (25 mL) was added. The mixture was extracted with chloroform (3 ^χ 25 mL). Organic phases were combined, dried (Na2S0₄) and evaporated under reduced pressure. Residual light yellow solid was hot- crystallized from chloroform: methanol to obtain the product as white crystals with a yield of 34% (20 mg, 0.048 mmol). 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

The title product was obtained as white crystals, starting from 3 -(pyridin-3 -yl)- propanenitrile obtained as described in Example 26, Steps A to B, and following successively the procedures described in Example 1, Steps B to H.

Example 66. 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from 3-(5-fluoropyridin-2-yl)- propanenitrile, obtained from 5-fluoropyridin-2-carboxyaldehyde using the procedure described in Example 26, Steps A to 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.

Example 67. 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)-7- (mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from 3-(5-fluoropyridin-2-yl)- propanenitrile, obtained from 5-fluoropyridin-2-carboxyaldehyde using the procedure described in Example 26, Steps A to B, and following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to F, and Example 2.

Example 68. (R/y)-3-(l-(5-Fluoropvridin-2-vnethvn-2-methvl-N-(5-methvl-lH-pyrazol-3- yl)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

Step A: l-(5-Fluoropyridin-2-yl)ethanone

To the solution of 5-fluoropyridine-2-carbonitrile (7.00 g, 57.3 mmol) in tetrahydrofuran (140 mL) cooled to -78 °C under argon atmosphere 3 M methylmagnesium bromide solution in diethyl ether (22.9 mL, 68.8 mmol) was added dropwise during 15 minutes. Reaction mixture was stirred at -78 °C for 2 hours, and then at room temperature for 5 hours. A solid precipitated from the reaction mixture. To the reaction mixture 2 M hydrochloric acid solution was added until reaching pH = 6 and dissolution of the precipitate. Then to the mixture 6% sodium hydrogencarbonate solution (100 mL) was added. The mixture was extracted with dichloromethane (3 ^χ 150 mL). Organic phases were combined, washed twice with water, brine, dried (Na₂S04) and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane 100% to dichloromethane: acetone, 97:3, v/v) to obtain the product as a light yellow oil with a yield of 95% (7.57 g, 54.4 mmol). Step B: (2/^-3-(5-Fluoropyridin-2-yl)but-2-enenitrile and (2Z)-3-(5-fluoropyridin-2-yl)- but-2-enenitrile

Obtained as white crystals with the yields 53% (4.60 g, 28.3 mmol) and 3% (224 mg, 1.38 mmol), respectively, from l-(5-fluoropyridin-2-yl)ethanone from Step A following the procedure of Example 49, Step A. Also the mixture of (E) and (Z) isomers as a colorless oil was obtained with a yield of 8% (698 mg, 4.30 mmol).

Isomer (E): ¹H MR (300 MHz, CDC1₃) δ 8.49 (dd, J=2.8, 0.5 Hz, 1H), 7.55 (ddd, J=8.8, 4.4, 0.6 Hz, 1H), 7.48 (dd, J=7.7, 2.8 Hz, 1H), 7.45 (dd, J=7.7, 2.8 Hz, 1H), 6.41-6.38 (m, 1H), 2.50 (d, J=l . l Hz, 3H).

Isomer (Z): ¹H MR (300 MHz, CDCI3) δ 8.55 (dd, J=2.8, 0.5 Hz, 1H), 7.83 (ddd, J=8.8, 4.3, 0.6 Hz, 1H), 7.50 (dd, J=8.0, 2.9 Hz, 1H), 7.47 (dd, J=8.0, 2.9 Hz, 1H), 5.59-5.56 (m, 1H), 2.36 (d, J=1.6 Hz, 3H).

Step C: (R/,S)-3-(5-Fluoropyridin-2-yl)butanenitrile

Obtained as a racemate in the form of a light yellow oil from (2i!r)-3-(5-fluoropyridin-2- yl)but-2-enenitrile from Step B following the procedure of Example 26, Step B. Chiral HPLC: (column Chiralpak-IA, ethanol: heptane 10:90, 0.5 mL/min); tRi = 7.7 min, tR₂ = 8.2 min.

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. Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tRi = 47.0 min, tR₂ = 56.5 min.

Example 69. (R/5)-3-(l-(5-Fluoropyridin-2-yl)ethyl)-2-methyl-N-(l-methyl-lH-imidazol-4- yl)-7-(mo holinomethyl)pyrazolo[l ,5-α]pyrimidin-5-amine

MS-ESI: (m/z) calculated for C₂₃H₂₈FN₈0 [M+H]⁺ = 451.2; found 451.2. ¾ MR (300 MHz, CDC1₃) δ 9.72 (s, 1H), 8.42 (d, J=2.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.32 (dd, J=8.7, 4.6 Hz, 1H), 7.26- 7.19 (m, 1H), 6.51 (s, 1H), 4.54 (q, J=7.3 Hz, 1H), 3.96 (d, J=l . l Hz, 2H), 3.85-3.76 (m, 4H), 3.73 (s, 3H), 2.75-2.64 (m, 4H), 2.32 (s, 3H), 1.89 (d, J=7.3 Hz, 3H). The product was obtained as a white solid starting from (R/,S)-3-(5-fluoropyridin-2-yl)- butanenitrile obtained in Example 68, Step C, following successively the procedures described in Example 1, Steps B to C, Example 11, Steps C to H and Example 2.

Example 70. 2-Methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7-(morpholinomethyl)-3-(thiazol-2- ylmethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as white crystals, starting from 3-(thiazol-2-yl)propane- nitrile obtained from l,3-thiazole-2-carboxyaldehyde using the procedure analogous to that described in Example 26, Steps A to 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.

Example 71. 2-Methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(morpholinomethyl)-3-(thiazol- 2-ylmethyl)pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as white crystals, starting from 3-(thiazol-2-yl)propane- nitrile obtained from l,3-thiazole-2-carboxyaldehyde using the procedure analogous to that described in Example 26, Steps A to B, and following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to H, and Example 2.

Example 72. 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as an amorphous white solid, starting from 3-(4- fluorophenyl)propanenitrile obtained from 4-fluorobenzaldehyde analogously as in Example 26, Steps A to B, following successively the procedures described in Example 1, Steps B to F, and Example 2.

Example 73. (S)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

Step A: (£)-3-(4-Fluorophenyl)but-2-enenitrile and (Z)-3-(4-fluorophenyl)but-2-enenitrile

Obtained as white solids (4.95 g, 30.5 mmol, 57% for isomer (E) and 0.22 g, 1.4 mmol, 3% for isomer (Z)) from 4'-fluoroacetophenone (7.50 g, 53.9 mmol) following the procedure of Example 49, Step A.

Step B: (R)-3-(4-Fluorophenyl)butanenitrile

Obtained as a pale yellow oil (5.35 g, 32.8 mmol, 88%) from (7^-3-(4-fluorophenyl)but-2- enenitrile (6.00 g, 37.2 mmol) following the procedure of Example 49, Step B, Method 2, and (R)-l-[(,S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct (0.738 g, 1.12 mmol). >99% ee; chiral HPLC: (AS-H column, isopropanol:hexane 10:90, v/v, 0.5 mL/min); = 10.0 min.

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

Obtained as white solid from (,S)-5,7-dichloro-3-(l-(4-fluorophenyl)ethyl)-2-methyl- pyrazolo[l,5-a]pyrimidine from Step C following the procedure of Example 1, Step F.

Step E: The title product was obtained as an amorphous white solid from (,S)-4-(5-chloro- 3 -( 1 -(4-fluorophenyl)ethyl)-2-methylpyrazolo [ 1 , 5 -a] pyrimidin-7-yl)morpholine from Step D following successively the procedures described in Example 1, Steps G to H. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 51.2 min.

Example 74. (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mor holinopyrazolo [1,5 -a]pyrimidin-5 -amine

Step A: (,S)-3-(4-Fluorophenyl)butanenitrile

Obtained as a pale yellow oil (5.20 g, 31.9 mmol, 86%) from (7^-3-(4-fluorophenyl)but-2- enenitrile (6.00 g, 37.2 mmol) obtained in Example 73, Step A, and (S)-l-[(R)-2- (diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct (0.738 g, 1.12 mmol) following the procedure of Example 49, Step B, Method 2. >99% ee; chiral HPLC: (AS-H column, isopropanol:hexane 10:90, v/v, 0.5 mL/min); = 7.2 min.

Step B: (R)-5,7-Dichloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidine

Obtained as white solid from (,S)-3-(4-fluorophenyl)butanenitrile from Step A following successively the procedures described in Example 1, Steps B to E.

Step C: (R)-4-(5-Chloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-7- yl)morpholine

Obtained as white solid from (R)-5,7-dichloro-3-(l-(4-fluorophenyl)ethyl)-2-methyl- pyrazolo[l,5-a]pyrimidine from Step B following the procedure of Example 1, Step F.

Step D: The title product was obtained as an amorphous white solid from (R)-4-(5-chloro- 3 -( 1 -(4-fluorophenyl)ethyl)-2-methylpyrazolo [ 1 , 5 -a] pyrimidin-7-yl)morpholine from Step C following successively the procedures described in Example 1, Steps G to H. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 33.4 min.

Example 75. (S)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as an amorphous white solid, starting from (,S)-4-(5-chloro- 3 -( 1 -(4-fluorophenyl)ethyl)-2-methylpyrazolo [ 1 , 5 -a] pyrimidin-7-yl)morpholine obtained in Example 73, Step D, following the procedure of Example 2. 99% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 30.2 min.

Example 76. (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mor holinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as an amorphous white solid, starting from (R)-4-(5-chloro- 3 -( 1 -(4-fluorophenyl)ethyl)-2-methylpyrazolo [ 1 , 5 -a] pyrimidin-7-yl)morpholine obtained in Example 74, Step C, following the procedure of Example 2. 99% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 34.8 min. Example 77. (S)-3 -(1 -(4-Fluorophenyl)ethyl)-2-methyl-7-morpholino-N-(py] pyrazolo[l,5-a]pyrimidin-5-amine

The mixture of (<S)-4-(5-chloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyri- midin-7-yl)morpholine (90 mg, 0.240 mmol) obtained in Example 73, Step D, pyrazin-2- amine (28 mg, 0.288 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (15 mg, 0.024 mmol), and sodium carbonate (51 mg, 0.480 mmol) were placed in a Schlenk flask and degassed under reduced pressure. Under argon atmosphere degassed toluene (5 mL) was added. Reaction mixture was purged with argon for 15 minutes and heated to 100 °C for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered over celite and washed with ethyl acetate (25 mL). The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel, eluent: heptan:AcOEt = 1 : 1 to 1 :2, v/v). The final product was obtained as a creamy solid with a yield of 76% (79 mg, 0.182 mmol). 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 24.7 min.

Example 78. (R)-3-(l-(4-Fluorophenyl)ethyl)-2-methyl-7-morpholino-N-(pyrazin-2-yl)- pyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained as an amorphous creamy solid, starting from (R)-4-(5- chloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-7-yl)morpholine obtained in Example 74. Step C, following the procedure of Example 77. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 26.9 min.

Example 79. (<S)-3 - ( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (l, l-dioxothiomo holino)pyrazolo[l,5-α]pyrimidin-5-amine

Step A: (,S)-4-(5-Chloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidin-7- yl)- 1 , 1 -dioxothiomorpholine

To the solution of (,S)-5,7-dichloro-3-(l-(4-fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]- pyrimidine obtained in Example 73, Step C (500 mg, 1.54 mmol) in acetonitrile (20 mL) were added sodium carbonate (165 mg, 1.54 mmol) and thiomorpholine 1, 1-dioxide (417 mg, 3.08 mmol). The reaction mixture was stirred at room temperature. White solid precipitated during the reaction. After 1 hour to reaction mixture was added with 10 mL of water and cooled in an ice-bath. After 10 minutes precipitated solid was filtered, washed with water and dried over phosphorus pentoxide. The product was obtained as white crystals with a yield of 73% (478 mg, 1.13 mmol).

Step B: The title product was obtained as an amorphous white solid from (,S)-4-(5-chloro- 3 -( 1 -(4-fluorophenyl)ethyl)-2-methylpyrazolo[ 1 , 5-a]pyrimidin-7-yl)- 1 , 1 -dioxothiomorpholine from Step A and following the procedures described in Example 1, Steps G to H. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 52.8 min.

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-α]pyrimidin-5-amine

The title product was obtained as an amorphous white solid from (R)-5,7-dichloro-3-(l-(4- fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidine of Example 74, Step B, following successively the procedures described in Example 79, Step A, and Example 1, Steps G to H. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 35.4 min.

Example 81. (S)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (l, l-dioxothiomo holino)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as an amorphous white solid from (,S)-4-(5-chloro-3-(l-(4- fluorophenyl)ethyl)-2-methylpyrazolo[ 1 , 5-a]pyrimidin-7-yl)- 1 , 1 -dioxothiomorpholine of Example 79, Step A, following the procedures described in Example 2. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 32.5 min.

Example 82. (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (l, l-dioxothiomo holino)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as an amorphous white solid from (R)-5,7-dichloro-3-(l-(4- fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidine of Example 74, Step B following successively the procedures described in Example 79, Step A, and Example 2. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 35.7 min. Example 83. (5)-3-(l-(4-Fluorophenyl)ethyl)-2-methyl-N-(pyrazin-2-yl)-7-(l, 1-dioxothio- morpholino)pyrazolo [1,5 -a]pyrimidin-5 -amine

MS-ESI: (m/z) calculated for C23H25FN7O2S [M+H]⁺ = 481.2; found 481.2.

¾ NMR (300 MHz, CDCI3) δ 9.31 (s, 1H), 8.26-8.16 (m, 2H), 7.38 (s, 1H), 7.34-7.25 (m, 2H), 6.94 (t, J=8.7 Hz, 2H), 6.22 (s, 1H), 4.38 (q, J=7.2 Hz, 1H), 4.22-4.14 (m, 4H), 3.37-3.27 (m, 4H), 2.27 (s, 3H), 1.80 (d, J=7.4 Hz, 3H).

The title product was obtained as an amorphous white solid from (,S)-4-(5-chloro-3-(l-(4- fluorophenyl)ethyl)-2-methylpyrazolo[ 1 , 5-a]pyrimidin-7-yl)- 1 , 1 -dioxothiomorpholine of Example 79, Step A, following the procedure of Example 77. 99% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 41.2 min.

Example 84. (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-(pyrazin-2-yl)-7-( 1 , 1 -dioxothio- morpholino)pyrazolo [1,5 -a]pyrimidin-5 -amine MS-ESI: (m/z) calculated for C23H25FN7O2S [M+H]⁺ = 481.2; found 481.2.

¾ NMR (300 MHz,CDCl₃) δ 9.32 (s, 1H), 8.26-8.16 (m, 2H), 7.52 (s, 1H), 7.36-7.25 (m, 2H), 6.93 (t, J=8.7 Hz, 2H), 6.23 (s, 1H), 4.38 (q, J=7.2 Hz, 1H), 4.22-4.14 (m, 4H), 3.39-3.27 (m, 4H), 2.27 (s, 3H), 1.80 (d, J=7.4 Hz, 3H).

The title product was obtained as an amorphous white solid from (R)-5,7-dichloro-3-(l-(4- fluorophenyl)ethyl)-2-methylpyrazolo[l,5-a]pyrimidine of Example 74, Step B following successively the procedures described in Example 79, Step A, and Example 77. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 49.3 min. Example 85. (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)- 7-morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained from (3R)-3-(2,4-difluorophenyl)butanenitrile obtained in Example 50, Step A, Method A, following successively the procedures described in Example 1, Steps B to H. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); t_R = 52.2 min.

Example 86. (S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)- 7-morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

MS-ESI: (m/z) calculated for C23H26F2N7O [M+H]⁺ = 453.2; found 453.2.

¾ NMR (300 MHz, CDC1₃) δ 7.50-7.40 (m, 1H), 7.22 (bs, 1H), 6.83-6.68 (m, 2H), 6.03 (s, 1H), 5.67 (s, 1H), 4.55 (q, J=7.3 Hz, 1H), 3.94-388 (m, 4H), 3.59-3.53 (m, 4H), 2.32 (s, 3H), 2.30 (s, 3H), 1.78 (d, J=7.4 Hz, 3H). The title product was obtained from (3,S)-3-(2,4-difluorophenyl)butanenitrile obtained in Example 51, Step A, Method A, following successively the procedures described in Example 1, Steps B to H. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); t_R = 35.0 min.

Example 87. (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4- yl)-7-morpholinopyrazolo[l,5-a]pyrimidin-5-amine

The title product was obtained from (3R)-3-(2,4-difluorophenyl)butanenitrile obtained in Example 50, Step A, Method A, following successively the procedures described in Example 1, Steps B to F, and Example 2. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 31.1 min.

Example 88. (S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4- yl)-7-morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained from (3,S)-3-(2,4-difluorophenyl)butanenitrile obtained in Example 51, Step A, Method A, following successively the procedures described in Example 1, Steps B to H, and Example 2. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 35.2 min.

Example 89. (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4- yl)-7-((l, l-dioxothiomo holino)methyl)pyrazolo[l,5-α]pyrimidin-5-amine MS-ESI: (m/z) calculated for C24H28F2N7O2S [M+H]⁺ = 515.2; found 515.2. ¾ NMR (300 MHz, DMSO-d) δ 9.81 (s, 1H), 7.72- 7.60 (m, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.23 (t, J=10.8 Hz, 1H), 7.11 (t, J=10.5 Hz, 1H), 6.08 (s, 1H), 4.65-4.55 (m, 1H), 4.13 (s, 2H), 3.74 (s, 3H), 3.35-3.25 (m, 4H), 3.21-3.13 (m, 4H), 2.33 (s, 3H), 1.85 (d, J=7.5 Hz, 3H).

The title product was obtained from (3R)-3-(2,4-difluorophenyl)butanenitrile obtained in Example 50, Step A, Method A, following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to E, Example 79, Step A, and Example 2. 98% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 33.6 min.

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-α]pyrimidin-5-amine

The title product was obtained from (3,S)-3-(2,4-difluorophenyl)butanenitrile obtained in Example 51, Step A, Method A, following successively the procedures described in Example 1, Steps B to C, Example 1 1, Steps C to E, Example 79, Step A, and Example 2. 99% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); t_R = 34.7 min.

Example 91. 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as a white solid, starting from 3-(5-fluoropyridin-2-yl)- propanenitrile, obtained from 5-fluoropyridin-2-carboxyaldehyde using the procedures described in Example 26, Steps A and B, and following the procedures described in Example 1, Steps B to H.

Example 92. 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)- 7-morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as a white solid, starting from 3-(5-fluoropyridin-2-yl)- propanenitrile, obtained from 5-fluoropyridin-2-carboxyaldehyde using the procedures described in Example 26, Steps A and B, and following successively the procedures described in Example 1, Steps B to F, and Example 2.

Example 93. (R)-3-(l -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3- yl)-7-morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

MS-ESI: (m/z) calculated for C22H26FN8O [M+H]⁺ = 436.2; found 436.2. ¾ NMR (300 MHz, CDCI3) δ 8.48 (s, IH), 8.10 (bs, IH), 7.27 (s, IH), 7.26-7.24 (m, IH), 7.24-7.22 (m, IH), 5.86 (s, IH), 5.55 (s, IH), 4.44 (q, J=7.3 Hz, IH), 3.90-3.83 (m, 4), 3.53-3.46 (m, 4H), 2.33 (s, 3H), 2.27 (s, 3H), 1.80 (d, J=7.3 Hz, 3H). The title product was obtained as a white solid, starting from (2/^-3-(5-fluoropyridin-2- yl)but-2-enenitrile, obtained from l-(5-fluoropyridin-2-yl)ethanone using the procedures described in Example 68, Step B, and following successively the procedures described in Example 50, Step A, Method 1, and Example 1, Steps B to H. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 57.0 min.

Example 94. (5)-3-(l -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3- yl)-7-morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

The title product was obtained as a white solid, starting from (2/^-3-(5-fluoropyridin-2- yl)but-2-enenitrile obtained from l-(5-fluoropyridin-2-yl)ethanone using the procedures described in Example 68, Step B, and following successively the procedures described in Example 51, Step A, Method 1, and Example 1, Steps B to H. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 48.2 min.

Example 95. (R)-3-(l -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3- l)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from (2/^-3-(5-fluoropyridin-2- yl)but-2-enenitrile obtained from l-(5-fluoropyridin-2-yl)ethanone using the procedures described in Example 68, Step B, and following successively the procedures described in Example 50, Step A, Method 1, and Example 1, Steps B to H. 96% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 56.6 min.

Example 96. (5)-3-(l -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3- l)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from (2/^-3-(5-fluoropyridin-2- yl)but-2-enenitrile obtained from l-(5-fluoropyridin-2-yl)ethanone using the procedures described in Example 68, Step B, and following successively the procedures described in Example 51, Step A, Method 1, and Example 1, Steps B to H. 96% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 47.0 min.

Example 97. (R/S)-3 -( 1 -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol- 4-yl)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from (2/^-3 -(5-fluoropyridin-2-yl)- but-2-enenitrile obtained from l-(5-fluoropyridin-2-yl)ethanone using the procedure described in Example 49, Step A, and following successively the procedures described in Example 49, Step B, Method 1, Example 1, Steps B to F, and Example 2. Chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tRi = 36.2 min, tR₂ = 41.5 min.

Example 98. (R)-3-(l -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-(l -methyl- lH-imidazol-4- yl)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from (2/^-3 -(5-fluoropyridin-2-yl)- but-2-enenitrile obtained from l-(5-fluoropyridin-2-yl)ethanone using the procedures described in Example 68, Step B, and following successively the procedures described in Example 50, Step A, Method 1, Example 1, Steps B to F, and Example 2. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 41.5 min.

Example 99. (5)-3-(l -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-(l -methyl- lH-imidazol-4- yl)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

The title product was obtained as a white solid, starting from (2£)-3-(5-fluoropyridin-2-yl)- but-2-enenitrile obtained from l-(5-fluoropyridin-2-yl)ethanone using the procedures described in Example 68, Step B, and following successively the procedures described in Example 51, Step A, Method 1, Example 1, Steps B to F, and Example 2. 97% ee., chiral HPLC: (column AS-H, isopropanol:hexane 10:90, 0.5 mL/min); tR = 36.1 min.

Determination of biological activity of compounds

Inhibition of JAK2 kinase in vitro

Activity of compounds of the invention was determined in vitro using kinase inhibition assay with subsequent ADP detection, as described below.

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 MgCl₂, 0.25 mM EGTA, 0.1 mM Na₃V0₄, 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/μΐ. to obtain working stock. To the wells of a 96-well plate 5 μΙ_, of single concentrations of a tested compound and 5 μΙ_, of working stock of JAK2 kinase were added and the plate was incubated for 10 minutes at 25 °C in thermomixer with orbital shaking at 400 rpm. Negative controls (0% of signal) did not contain kinase nor tested compounds and positive controls (100% of signal) did not contain tested compounds. In order to start the reaction, 15 μΐ. of reaction mastermix composed of 5x concentrated reaction buffer (50 mM Tris pH 7.5, 10 mM MgCl₂, 0.25 mM EGTA, 0.1 mM Na₃V0₄, 0.01% Triton X-100, 2.5 mM DTT), water, 50 μΜ ATP, 16.67 μΜ 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. Briefly, 25 μΐ_^ of ADP-Glo Reagent was added to the reaction, and the plate was incubated for 40 minutes, as above. After the specified time, 50 μΐ_^ of Kinase Detection Reagent was added to the reaction and the plate was incubated for 30 minutes, as above. After the incubation, luminescent signal was read using Victor Light luminometer (Perkin Elmer, Inc.). Using obtained data, IC50 values were calculated using non-linear regression curve fitting in GraphPad 5.03. Compounds were tested in at least 6 single reaction wells, using at least 3 wells of each control.

The mean IC50 values obtained with JAK2 kinase inhibition assay for the representative compounds of the invention are presented of Table 1 below:

Table 1

Ex.1 <10nM Ex.34 <10nM Ex.67 10-100 nM

Ex.2 <10nM Ex.35 <10nM Ex.68 <10nM

Ex.3 10-100 nM Ex.36 <10nM Ex.69 <10nM

Ex.4 10-100 nM Ex.37 <10nM Ex.70 100-1000 nM

Ex.5 10-100 nM Ex.38 <10nM Ex.71 100-1000 nM

Ex.6 10-100 nM Ex.39 10-100 nM Ex.72 <10nM

Ex.7 10-100 nM Ex.40 <10nM Ex.73 10-100 nM

Ex.8 10-100 nM Ex.41 <10nM Ex.74 10-100 nM

Ex.9 10-100 nM Ex.42 <10nM Ex.75 <10nM

Ex.10 10-100 nM Ex.43 10-100 nM Ex.76 <10nM

Ex.11 10-100 nM Ex.44 <10nM Ex.77 10-100 nM

Ex.12 <10nM Ex.45 <10nM Ex.78 <10nM

Ex.13 100-1000 nM Ex.46 <10nM Ex.79 <10nM

Ex.14 10-100 nM Ex.47 <10nM Ex.80 <10nM

Ex.15 10-100 nM Ex.48 <10nM Ex.81 <10nM

Ex.16 <10nM Ex.49 10-100 nM Ex.82 <10nM

Ex.17 10-100 nM Ex.50 10-100 nM Ex.83 <10nM

Ex.18 10-100 nM Ex.51 <10nM Ex.84 <10nM

Ex.19 10-100 nM Ex.52 <10nM Ex.85 10-100 nM

Ex.20 10-100 nM Ex.53 <10nM Ex.86 10-100 nM

Ex.21 10-100 nM Ex.54 <10nM Ex.87 <10nM

Ex.22 10-100 nM Ex.55 10-100 nM Ex.88 <10nM

Ex.23 <10nM Ex.56 <10nM Ex.89 <10nM

Ex.24 10-100 nM Ex.57 10-100 nM Ex.90 <10nM

Ex.25 10-100 nM Ex.58 10-100 nM Ex.91 <10nM

Ex.26 10-100 nM Ex.59 10-100 nM Ex.92 <10nM

Ex.27 <10nM Ex.60 100-1000 nM Ex.93 <10nM

Ex.28 100-1000 nM Ex.61 100-1000 nM Ex.94 <10nM

Ex.29 10-100 nM Ex.62 100-1000 nM Ex.95 <10nM

Ex.30 10-100 nM Ex.63 100-1000 nM Ex.96 <10nM

Ex.31 10-100 nM Ex.64 10-100 nM Ex.97 <10nM

Ex.32 10-100 nM Ex.65 10-100 nM Ex.98 <10nM

Ex.33 10-100 nM Ex.66 <10nM Ex.99 <10nM

Claims

1. A compound of the general formula (I):

(I)

wherein:

- Q represents a six-membered heteroaromatic ring containing 2 N atoms and Ri is hydrogen atom, or

- Q represents a five-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;

- R₂ represents - R7_aR7b or -CH₂-NR8_aR8b;

- R₃ represents Cl-C4-alkyl;

- R_7a and R₇b together with nitrogen atom to which they are attached form a six- 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 -S0₂-Cl-C4-alkyl;

- R_8a and R₈b independently represent hydrogen atom, Cl-C4-alkoxy-Cl-C4-alkyl, or Cl-C4-alkyl substituted with a six-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 R₈b together with nitrogen atom to which they are attached form a six- 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 -S0₂-Cl-C4-alkyl;

optically active enantiomers and enantiomeric mixtures thereof,

and pharmaceutically acceptable salts thereof.

2. A compound of the general formula I):

(I)

wherein:

- Q represents a five-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;

- R₂ represents - R7_aR7b or -CH₂-NR_8aR₈b;

- R₃ represents Cl-C4-alkyl;

- R_7a and R₇b together with nitrogen atom to which they are attached form a six- 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;

- R_8a and R₈b independently represent hydrogen atom, Cl-C4-alkoxy-Cl-C4-alkyl, or Cl-C4-alkyl substituted with a six-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 R₈b together with nitrogen atom to which they are attached form a six- 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;

optically active enantiomers and enantiomeric mixtures thereof,

and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 or 2, wherein R₅ and 5 both represent hydrogen atoms.

4. The compound according to claim 1 or 2, wherein one of R5 and R5 represents hydrogen atom and the other of R5 and R5 represents Cl-C4-alkyl.

5. The compound according to any one of claims 1 to 4, wherein Q represents \H- pyrazole or lH-imidazole ring.

6. The compound according to claim 5, wherein Q represents lH-pyrazol-3-yl or \H- imidazol-4-yl.

7. The compound according to any one of claims 1 to 6, wherein R₃ represents methyl or ethyl.

8. The compound according to any one of claims 1 to 7, wherein Ri represents C1-C4- alkyl.

9. The compound according to claim 8, wherein Ri represents methyl.

10. The compound according to any one of claims 1 to 7, wherein Ri represents cyclopropyl.

11. The compound according to any one of claims 1 to 10, wherein R₄ represents phenyl, said phenyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluorom ethyl, hydroxyl and Cl-C4-alkoxyl.

12. The compound according to any one of claims 1 to 10, wherein R₄ represents the 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N and S, and is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluorom ethyl, hydroxyl and Cl-C4-alkoxyl.

13. The compound according to claim 12, wherein R₄ represents 6-membered heteroaryl which contains 1 or 2 N atoms and is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxyl and C1-C4- alkoxyl.

14. The compound according to any one of claims 1 to 13, wherein R₂ represents -

15. The compound according to claim 14, wherein R_7a and R₇b together with nitrogen atom to which they are attached form unsubstituted or substituted morpholine or piperazine ring.

16. The compound according to any one of claims 1 to 13, wherein R₂ represents -CH₂- RsaRsb.

17. The compound according to claim 16, wherein R_8a and R₈b together with nitrogen atom to which they are attached form unsubstituted or substituted morpholine or piperazine ring.

18. The compound according to claim 16, wherein R_8a and R₈b independently represent hydrogen atom, methoxyl or morpholinoethyl.

19. The compound according to claim 1 selected from the group consisting of the following:

1) 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

2) 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine

3) N-(3-(4-Chloro-2-fluorobenzyl)-2-methyl-7-morpholinopyrazolo[l,5-a]pirymidyn-5- yl)-5-methylthiazol-2-amine

4) 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-5-amine

5) 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(4-methyl- piperazin-l-yl)pyrazolo[l,5-a]pyrimidin-5-amine 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(4-(methyl- sulfonyl)piperazin- 1 -yl)pyrazolo [1,5 -ajpyrimidin- 5 -amine

3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(4- (methylsulfonyl)piperazin-l-yl)pyrazolo[l,5-a]pyrimidin-5-amine

3-(4-Chloro-2-fluorobenzyl)-7-((3R,55)-3,5-dimethylpiperazin-l-yl)-2-methyl-N-(5- methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine

3-(4-Chloro-2-fluorobenzyl)-7-((2R,65)-2,6-dimethylmorpholino)-2-methyl-N-(5- methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(4-Chloro-2-fluorobenzyl)-2-ethyl-N-(5-methyl-lH-pyrazol-3-yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3- yl)-7-(mo holinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7- (morpholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) N-(3-(4-Chloro-2-fluorobenzyl)-2-methyl-7-(mo holinomethyl)pyrazolo[l,5-α]- pirymidyn-5-yl)-5-methylthiazol-2-amine

) 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-(piperidin- 1 - ylmethyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-((4-methyl- piperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3 -(4-Chloro-2-fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-((4-methyl- piperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(4-Chloro-2-fluorobenzyl)-7-((4-ethylpiperazin-l-yl)methyl)-2-methyl-N-(5- methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-((4- (methylsulfonyl)piperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(4-Chloro-2-fluorobenzyl)-2-methyl-N-(l-methyl-7H-imidazol-4-yl)-7-((4- (methylsulfonyl)piperazin- 1 -yl)methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3-(4-Chloro-2-fluorobenzyl)-7-(((2R,65)-2,6-dimethylmorpholino)methyl)-2-methyl- N-(5 -methyl- lH-pyrazol-3 -yl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3-(4-Chloro-2-fluorobenzyl)-2-ethyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(morpholino- methyl)pyrazolo[l,5-a]pyrimidin-5-amine ) (R/S)-3 -( 1 -(4-Chloro-2-fluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)- 7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

) (R/S)-3 -( 1 -(4-Chloro-2-fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4- yl)-7-(mo holinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

) 3-Benzyl-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-morpholinopyrazolo[l,5-a]- pyrimidin-5-amine

) 3-Benzyl-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(morpholinomethyl)pyrazolo- [l,5-a]pyrimidin-5-amine

) 3-(2-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-morpholinopyrazolo- [l,5-a]pyrimidin-5-amine

) 3-(2-Fluorobenzyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)-7-morpholinopyrazolo- [l,5-a]pyrimidin-5-amine

) 3-(2-Fluorobenzyl)-2-methyl-N-(l-methyl-lH-pyrazol-4-yl)-7-morpholinopyrazolo- [l,5-a]pyrimidin-5-amine

) 3-(2-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(mo holinomethyl)- pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(2-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-((4-methylpiperazin- l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(3-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(mo holinomethyl)- pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(3-Fluorobenzyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)-7-(moφholinomethyl)- pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(3-Fluorobenzyl)-7-((2-methoxyethylamino)methyl)-2-methyl-N-(5-methyl-lH- pyrazol-3 -yl)pyrazolo[ 1 , 5-a]pyrimidin-5-amine

) 3-(4-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-moφholinopyrazolo- [l,5-a]pyrimidin-5-amine

) 3-(4-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(moφholinomethyl)- pyrazolo[l,5-a]pyrimidin-5-amine

) 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(moφholino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3-(4-Fluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-((4-methylpiperazin- l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine ) 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-((4-methylpiperazin l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-mo holino- pyrazolo[l,5-a]pyrimidin-5-amine

) 3 -(2,4-Difluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-mo holino- pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(mo holino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3 -(2,4-Difluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(mo holino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) N-(5-Cyclopropyl-lH-pyrazol-3-yl)-3-(2,4-difluorobenzyl)-2-methyl-7-(moφholino methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-((4-methyl- piperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3 -(2,4-Difluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-((4-methyl- piperazin-l-yl)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(2,4-Difluorobenzyl)-7-((2-methoxyethylamino)methyl)-2-methyl-N-(l-methyl- lH-imidazol-4-yl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3-(2,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-((2-moφholino- ethylamino)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3 -(2,4-Difluorobenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-((2-moφholino ethylamino)methyl)pyrazolo[l,5-a]pyrimidin-5-amine

) (R/S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (moφholinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine

) (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) (<S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) (R/5)-3-(l-(2,4-Difluorophenyl)ethyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine ) (<S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (morpholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3-(3,4-Difluorobenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(mo holino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3 -(3 ,4-Difluorobenzyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7-(morpholino- methyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3 -(2-Chlorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-(mo holinomethyl)- pyrazolo[l,5-a]pyrimidin-5-amine

) 3 -(4-Chloro-3-fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-morpholino- pyrazolo[l,5-a]pyrimidin-5-amine

) 3 -(4-Chloro-3 -fluorobenzyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (mo holinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 2-Methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-(morpholinomethyl)-3-(4-(trifluoro- methyl)benzyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 2-Methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(mo holinomethyl)-3-(4-(trifluoro- methyl)benzyl)pyrazolo[l,5-a]pyrimidin-5-amine

) 3-(4-Methoxybenzyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- rt ^holinopyrazolo [1,5 -a]pyrimidin-5 -amine

) 3 -(4-Methoxybenzyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7-moq)holino- pyrazolo[l,5-a]pyrimidin-5-amine

) 4-((2-Methyl-5-(l -methyl- lH-imidazol-4-ylamino)-7-moq)holinopyrazolo[l,5-a]- pirymidyn-3-yl)methyl)phenol

) 2-Methyl-N-(5-methyl-lH-pyrazol-3-yl)-7-moq)holino-3-(pyridin-3-ylmethyl)- pyrazolo[l,5-a]pyrimidin-5-amine

) 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) (RAS)-3-(l -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

) (R/S)-3 -( 1 -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-y l)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine 70) 2-Methyl-N-(5-methyl-7H-pyrazol-3-yl)-7-(morpholinomethyl)-3-(thiazol-2-yl- methyl)pyrazolo[l,5-a]pyrimidin-5-amine,

71) 2-Methyl-N-(l -methyl- lH-imidazol-4-yl)-7-(mo holinomethyl)-3-(thiazol-2-yl- methyl)pyrazolo[l,5-a]pyrimidin-5-amine,

72) 3 -(4-Fluorobenzyl)-2-methyl-N-(l -methyl- 17J-imidazol-4-yl)-7-morpholino- pyrazolo [1,5 -a]pyrimidin-5 -amine,

73) (5)-3-(l-(4-Fluorophenyl)ethyl)-2-methyl-N-(l -methyl- lH-imidazol-4-yl)-7- morpholinopyrazolo [1,5 -a]pyrimidin-5 -amine,

74) (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinopyrazolo [1,5 -a]pyrimidin-5 -amine,

75) (<S)-3 -( 1 -(4-Fluorophenyl)ethy l)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinopyrazolo [1,5 -a]pyrimidin-5 -amine,

76) (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinopyrazolo [1,5 -a]pyrimidin-5 -amine,

77) (S)-3 -( 1 -(4-Fluorophenyl)ethy l)-2-methyl-7-moφholino-N-(pyrazin-2-yl)pyrazolo- [l,5-a]pyrimidin-5-amine,

78) (R)-3 -(1 -(4-Fluorophenyl)ethyl)-2-methyl-7-moφholino-N-(pyrazin-2-yl)pyrazolo- [l,5-a]pyrimidin-5-amine,

79) S)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-( 1, 1- dioxothiomoφholino)pyrazolo[l,5-α]pyrimidin-5-amine,

80) (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7-( 1, 1- dioxothiomoφholino)pyrazolo[l,5-α]pyrimidin-5-amine,

81) (<S)-3 -( 1 -(4-Fluorophenyl)ethy l)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7-( 1, 1- dioxothiomoφholino)pyrazolo[l,5-α]pyrimidin-5-amine,

82) (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7-( 1, 1- dioxothiomoφholino)pyrazolo[l,5-α]pyrimidin-5-amine,

83) (5)-3-(l-(4-Fluorophenyl)ethyl)-2-methyl-N-(pyrazin-2-yl)-7-(l, l-dioxothio- n ^holino)pyrazolo [1,5 -a]pyrimidin-5 -amine,

84) (R)-3 -( 1 -(4-Fluorophenyl)ethyl)-2-methyl-N-(pyrazin-2-yl)-7-( 1 , 1 -dioxothio- moφholino)pyrazolo[l,5-α]pyrimidin-5-amine,

85) (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- rt ^holinopyrazolo [1,5 -a]pyrimidin-5 -amine, 86) (S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-(5 -methyl- lH-pyrazol-3 -yl)-7- mo holinopyrazolo [1,5 -a]pyrimidin-5 -amine,

87) (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinopyrazolo [1,5 -a]pyrimidin-5 -amine,

88) (S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- mo holinopyrazolo [1,5 -a]pyrimidin-5 -amine,

89) (R)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- ((l, l-dioxothiomo holino)methyl)pyrazolo[l,5-α]pyrimidin-5-amine,

90) (S)-3 -( 1 -(2,4-Difluorophenyl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- ((l, l-dioxothiomoφholino)methyl)pyrazolo[l,5-α]pyrimidin-5-amine,

91) 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- moφholinopyrazolo [1,5 -a]pyrimidin-5 -amine,

92) 3-((5-Fluoropyridin-2-yl)methyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)-7- moφholinopyrazolo [1,5 -a]pyrimidin-5 -amine,

93) (R)-3-(l-(5-Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- moφholinopyrazolo [1,5 -a]pyrimidin-5 -amine,

94) (5)-3-(l-(5-Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- moφholinopyrazolo [1,5 -a]pyrimidin-5 -amine,

95) (R)-3-(l-(5-Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

96) (5)-3-(l-(5-Fluoropyridin-2-yl)ethyl)-2-methyl-N-(5-methyl-lH-pyrazol-3-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine

97) (R/S)-3 -( 1 -(5 -Fluoropyridin-2-yl)ethyl)-2-methyl-N-( 1 -methyl- lH-imidazol-4-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine,

98) (R)-3-(l-(5-Fluoropyridin-2-yl)ethyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)-7- (moφholinomethyl)pyrazolo[l,5-α]pyrimidin-5-amine, and

99) (R)-3-(l-(5-Fluoropyridin-2-yl)ethyl)-2-methyl-N-(l-methyl-lH-imidazol-4-yl)-7- (moφholinomethyl)pyrazolo [1,5 -a]pyrimidin-5 -amine,

optically active enantiomers and enantiomeric mixtures thereof,

and pharmaceutically acceptable salts thereof.

20. Pharmaceutical composition comprising as an active ingredient a compound of the general formula (I) as defined in any one of claims 1 to 19 in a mixture with pharmaceutically acceptable auxiliary substance(s).

21. The compound of the general formula (I) as defined in any one of claims 1 to 19 for use as a medicament.

22. Use of the compound of the general formula (I) as defined in any one of claims 1 to 19 for the preparation of a medicament for treating myeloproliferative, cancer, or inflammatory diseases.

23. The compound of the general formula (I) as defined in any one of claims 1 to 19 for use in a method of treating myeloproliferative, cancer, or inflammatory diseases.

24. A method of treating myeloproliferative, cancer, or inflammatory diseases in a mammal, including human, comprising administration of a therapeutically effective amount of the compound of the general formula (I) as defined in any one of claims 1 to 19 or the pharmaceutical composition as defined in claim 20.