WO2014008992A1 - Pyrimidine pyrazolyl derivatives - Google Patents

Pyrimidine pyrazolyl derivatives Download PDF

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Publication number
WO2014008992A1
WO2014008992A1 PCT/EP2013/001950 EP2013001950W WO2014008992A1 WO 2014008992 A1 WO2014008992 A1 WO 2014008992A1 EP 2013001950 W EP2013001950 W EP 2013001950W WO 2014008992 A1 WO2014008992 A1 WO 2014008992A1
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WO
WIPO (PCT)
Prior art keywords
pyrazol
methyl
phenyl
pyrimidin
pyrimidine
Prior art date
Application number
PCT/EP2013/001950
Other languages
French (fr)
Inventor
Stefano Crosignani
Catherine Jorand-Lebrun
Patrick Gerber
Mathilde Muzerelle
Original Assignee
Ares Trading S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to SG11201500005SA priority Critical patent/SG11201500005SA/en
Priority to US14/406,389 priority patent/US9216991B2/en
Priority to JP2015520844A priority patent/JP6189434B2/en
Priority to EP13737134.0A priority patent/EP2872501B1/en
Priority to DK13737134.0T priority patent/DK2872501T3/en
Priority to RU2015104123A priority patent/RU2015104123A/en
Priority to CN201380047170.9A priority patent/CN104662014B/en
Priority to CA2878621A priority patent/CA2878621C/en
Application filed by Ares Trading S.A. filed Critical Ares Trading S.A.
Priority to MX2015000129A priority patent/MX2015000129A/en
Priority to ES13737134.0T priority patent/ES2589558T3/en
Priority to KR20157003049A priority patent/KR20150033716A/en
Priority to AU2013289615A priority patent/AU2013289615B2/en
Priority to BR112015000399A priority patent/BR112015000399A2/en
Publication of WO2014008992A1 publication Critical patent/WO2014008992A1/en
Priority to IL236542A priority patent/IL236542B/en
Priority to ZA2015/00917A priority patent/ZA201500917B/en
Priority to HK15111580.6A priority patent/HK1210778A1/en

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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Definitions

  • the present invention provides Pyrimidine pyrazolyl derivatives of Formula (I) as IRAK inhibitors and their use in the treatment of cancer, and other diseases related to IRAK overexpression, like rheumatoid arthritis, systemic lupus erythematosus or lupus nephritis.
  • Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play key roles in all aspects of eukaryotic cell physiology.
  • protein kinases and lipid kinases participate in the signaling events which control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines.
  • protein kinases are classified in two groups, those that preferentially
  • Kinases are important therapeutic targets for the development of anti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology 21 , 1-8), for example kinases that are involved in the orchestration of adaptive and innate immune responses.
  • Kinase targets of particular interest are members of the IRAK family.
  • IRAKs interleukin-1 receptor-associated kinases
  • TLRs toll-like receptors
  • IRAK4 is thought to be the initial protein kinase activated downstream of the interleukin-1 (IL-1) receptor and all toll-like-receptors (TLRs) except TLR3, and initiates signaling in the innate immune system via the rapid activation of IRAKI and slower activation of IRAK2.
  • IRAKI was first identified through biochemical purification of the IL-1 dependent kinase activity that co-immunoprecipitates with the IL-1 type 1 receptor (Cao et al., 1996. Science 271 (5252): 1128-31). IRAK2 was identified by the search of the human expressed sequence tag (EST) database for sequences homologous to IRAKI (Muzio et al., 1997. Science 278(5343): 1612-5).
  • EST human expressed sequence tag
  • IRAK3 also called IRAKM was identified using a murine EST sequence encoding a polypeptide with significant homology to IRAKI to screen a human phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNA library (Wesche et al., 1999. J. Biol. Chem. 274(27): 19403-10).
  • IRAK4 was identified by database searching for IRAK-like sequences and PCR of a universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572).
  • mice that express a catalytically inactive mutant of IRAK4 instead of the wild-type kinase are completely resistant to septic shock triggered by several TLR agonists and are impaired in their response to IL-1.
  • Children who lack IRAK4 activity due to a genetic defect suffer from recurring infection by pyogenic bacteria. It appears that IRAK- dependent TLRs and IL-1 Rs are vital for childhood immunity against some pyogenic bacteria but play a redundant role in protective immunity to most infections in adults. Therefore IRAK4 inhibitors may be useful for the treatment of chronic inflammatory diseases in adults without making them too susceptible to bacterial and viral infections (Cohen, 2009. Current Opinion in Cell Biology 21 , 1-8).
  • IRAKI is essential for the TLR7 -mediated and TLR9-mediated activation of IRF7 and the production of interferon- alpha (IFN-a) suggesting that IRAKI inhibitors may be useful for the treatment of Systemic lupus erythematosus (SLE).
  • IRAK2 is activated downstream of IRAK4 and plays a role in proinflammatory cytokine production. Therefore IRAK2 inhibitors may be useful for inflammatory diseases.
  • compounds of Formula (I) which are suitable for the treatment and/or prevention of disorders related to IRAK.
  • compounds which are able to modulate, especially inhibit the activity or function of IRAK in disease states in mammals, especially in humans.
  • disorders selected from auto-immune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergy, asthma, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases and ischemic conditions.
  • the present invention provides compounds of Formula (I) which are selective of IRAK-4 and/or IRAK-1 over the other isoforms.
  • kits or a set comprising at least one compound of Formula (I), preferably in combination with immunomodulating agents.
  • the kit consists of separate packs of:
  • the present invention provides a compound of Formula (I)
  • R 1 denotes absent or denotes A or Q-Het
  • X denotes O, S or N
  • Y denotes C or N
  • T denotes C or N, or
  • Z denotes a pyridine or a pyridazine group
  • R a is absent or denotes OR 3 , CF 3 , Hal, N0 2 ,
  • R b is absent or denotes one of the groups selected from A and COHet, denotes H, Het, Q-Het, Cyc, A or OA,
  • Het denotes a 4-9 membered monocyclic ring or a fused, spiro or bridged bicyclic ring, which is saturated, unsaturated, or aromatic, which contains 1 to 3 heteroatoms independently selected from N, O, S and a group CO, SO or S0 2 , and wherein 1 or 2 H atoms may be replaced by A, OA, COA, CN, Hal, N0 2 ,
  • Q denotes a 4-8- membered bivalent heterocyclic ring, which is saturated, unsaturated or aromatic and which contains 1 to 3 heteroatoms independently selected from N, O and S, denotes a linear or branched alkyl having 1 to 10 carbon atoms wherein 1 to 7 H atoms may be replaced by a group independently selected from -OR 3 , Hal, NHS0 2 A, S0 2 A, SOA, N(R 3 ) 2 , and wherein 1 , 2 or 3 non-adjacent -CH 2 - groups may be replaced by a group independently selected from -CO-, NR 3 and/or -0-, Hal denotes F, CI, Br or I, denotes H or C Cealkyl wherein 1 H atom may be replaced by a group selected from OH, O-C Ce-alkyl, and Hal,
  • Het 1 denotes a five- or six membered saturated monocyclic heterocycle, which
  • Cyc 1 denotes cycloalkyl with 3-7 atoms
  • Z may denote a group
  • Z is selected from the following specific groups:
  • Z, in Formula (I) and related Formulae preferably denotes a group selected from a pyridazine, a pyrazole, and a 4-pyridine.
  • R in Formula (I) and related Formulae preferably denotes a linear or branched C-
  • the group Z-R 1 in Formula (I) and related Formulae is selected from the following groups:
  • the group R 2 in Formula (I) and related Formulae denotes a piperidine or the group Cyc defined above.
  • group R 2 in Formula (I) and related Formulae is preferably selected from the following groups:
  • the group R b in Formula (I) and related Formulae preferably denotes H.
  • R b may denote a group selected from COHet or a linear or branched C C 6 -alkyl group wherein 1 H atoms may be replaced by a group selected from NR 3 or OR 3 , and wherein 1 CH 2 group may be replaced by a group CO.
  • R b in Formula (I) and related Formulae may be selected from the following groups:
  • Het, in Formula (I) and related Formulae preferably denotes a saturated 4-6-membered single ring containing 1 heteroatom selected from nitrogen, wherein 1 H atom may be replaced by a group selected from COCi-C 6 -alkyl, and an oxacyclohexane.
  • Het in Formula (I) and related Formulae denotes a 4-9-membered spiro- or bridged bicyclcic ring, containing 1 to 2 heteroatoms selected from Nitrogen and oxygen, and optionally monosubstituted by a group A.
  • Het denotes a piperidine group wherein 1 or 2 H atom may be independently replaced by a group selected from A, OA, COA, CN, Hal, N0 2) OR 3 , SOA and S0 2 A.
  • Cyc 1 is cyclopropyl, cyclobytyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the compounds of the present invention also include compounds of Formula (la)
  • T denotes a group NCOA, whereby A is as defined above or T denotes a carbon atom which may be substituted by CON(R 3 ) 2 whereby R 3 is as defined above, and wherein R 1 in Formula (la) is as defined above.
  • the most preferred compounds are piperidines as examples 5, 30, 259, 263, 265, and 284.
  • the most preferred compounds are amides and spiro-amides as examples 121 , 233, 234, 278, 250, 251 , 260, 262, 285, 286, and 287.
  • the most preferred compounds are sulfonyl as examples 279 and 288 and cyclic amides: 254, and 255 and spiro ether from example 267.
  • CVCe-alkyl or “CVCs-alkyl group” denotes a linear or branched alkyl chain having 1 to 6 carbon atoms.
  • CVCs-alkyl or “C Cs-alkyl” may also include halo-alkyl.
  • Halo-alkyI contains 1 to 10 halogen atoms, preferably 1 to 3 halogen atoms.
  • Halo-alkyI contains for example a group -CF 3 , -CHF 2 or -CH 2 F.
  • A denotes alkyl, this is unbranched (linear) or branched, and has 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
  • A preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1 ,1- , 1 ,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1- , 2- , 3- or 4-methylpentyl, 1 ,1- , 1 ,2- , 1 ,3- , 2,2- , 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2- methylpropyl, 1 ,1 ,2- or 1 ,2,2-trimethylprop
  • A denotes preferably CH 2 OCH 3 , OCH 2 CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 ,
  • Hal preferably denotes CI or F.
  • R 3 preferably denotes H oder CH 3 .
  • Q preferably is absent or preferably denotes NR 3 COCH 2 , CH 2 CONR 3 , COCH(CH 3 ),
  • CH(CH 3 )CO COCH 2 CH 2 , CH 2 CH 2 CO, CH 2 , CH 2 CH 2 , CH 2 CO, COCH 2 , CH(OH)CH 2 ,
  • a “leaving group” denotes a chemical moiety which can be removed or replaced by another chemical group.
  • leaving group preferably denotes CI, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifiuoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p tolylsulfonyloxy).
  • a reactively modified OH group such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifiuoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p tolylsulfonyloxy).
  • Cyclic alkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl or cycloheptyl.
  • Het denotes, for example, 2- or 3-furyl, 2- or
  • 5- , 6-, 7- or 8-quinazolinyl 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1 ,4- oxazinyl, further preferably 1 ,3-benzodioxol-5-yl, 1 ,4-benzodioxan-6-yl, 2,1 ,3-benzothia- diazol-4-, -5-yl or 2, 1 ,3-benzoxadiazol-5-yl, azabicyclo[3.2.1 joctyl or dibenzofuranyl.
  • the heterocyclic radicals may also be partially or fully hydrogenated.
  • Het can thus also denote, for example, 2,3-dihydro- 2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1 ,3-di- oxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5- dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4- imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3-
  • Z preferably denotes isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyridazinyl, triazolyl, pyridyl, pyrazolyl or furyl, each of which is unsubstituted or mono- or disubstituted by methyl, Hal, NH 2 , CH 2 COHet 2 and/or benzyl.
  • Z very particularly preferably denotes 1-methyl-1H-pyrazol-4-yl or 6-methyl-pyridazin-4-
  • Het 2 preferably denotes piperidinyl or pyrrolidinyl.
  • R 2 preferably denotes H, Het, Q-Het, Cyc or A.
  • the invention preferably relates to compounds of the formula (I)
  • R 1 is absent
  • Z denotes isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyridazinyl, triazolyl, pyridyl, pyrazolyl or furyl, each of which is unsubstituted or mono- or disubstituted by A, Hal, N(R 3 ) 2 , CH 2 COHet 2 and/or benzyl,
  • R a is absent or denotes Hal
  • R b is absent or denotes CONH 2 , COOH, CONHA, COHet or CH 2 OH
  • R 2 denotes H, Het, Q-Het, Cyc, A, OA, CH 2 COOH, NHA, NA 2 , CH 2 CONH 2 ,
  • Het denotes tetrahydrothiopyranyl, 2-oxa-6-aza-spiro[3.3]heptyl, 2-oxy-7-aza- spiro[3.5]nonyl, 8-aza-bicyclo[3.2.1]octyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, oxetanyl, tetrahydropyranyl, imidazolyl, oxazolyl, piperazinyl, thiazolyl, azepanyl, tetrahydrofuranyl, isoxazolyl, azetidinyl, oxazolidinyl, hexahydroisobenzofuranyl, piperidyl, furyl, pyrrolidinyl, morpholinyl, 1 ,9-dioxa-spiro[5.5]undecyl, 2,5-diaza- bicyclo[2.2.1]heptyl,
  • [1 ,4]oxazepanyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl or 9-aza-bicyclo[3.3.1]nonyl, each of which is unsubstituted or mono-, di- or trisubstituted by CON(R 3 ) 2 , A, COA, (CH 2 ) n Het ⁇ Hal, Ar , (CH 2 ) n OH, (CH 2 ) n OA, Cyc 1 , COCyc 1 , S0 2 A, COHet 1 and/or 0,
  • A denotes a linear or branched alkyl having 1 to 10 carbon atoms wherein 1 to 7 H atoms may be replaced by a group independently selected from -OR 3 , Hal, NHS0 2 A, S0 2 A, SOA, N(R 3 ) 2 , and wherein 1, 2 or 3 non-adjacent -CH 2 - groups may be replaced by a group independently selected from -CO-, NR 3 and/or -0-,
  • Hal denotes F, CI, Br or I
  • Ar 1 denotes phenyl, optionally substituted by Hal
  • R 3 denotes H or Cn-Ce-alkyl wherein 1 H atom may be replaced by a group selected from OH, O-C ⁇ Ce-alkyl, and Hal,
  • Het denotes 2,5-diaza-bicyclo[2.2.1]heptyl, piperazinyl, morpholinyl, azetidinyl,
  • Het 2 denotes piperidinyl or pyrrolidinyl
  • the compounds according to Formula (I) and related formulae of this invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they may be prepared by standard synthetic techniques. In general, the synthesis pathways for any individual compound of Formula (I) and related formulae will depend on the specific substituents of each molecule, such factors being appreciated by those of ordinary skilled in the art. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of Formula (I) and related formulae. Reaction conditions depicted in the following schemes, such as temperatures, solvents, or co-reagents, are given as examples only and are not restrictive. It will be appreciated that where typical or preferred experimental conditions (i.e.
  • reaction temperatures, time, moles of reagents, solvents etc. are given, other experimental conditions can also be used unless otherwise stated.
  • Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3 rd Edition 1999.
  • R 1 , R 2 , R a , R b and Z different synthetic strategies may be selected for the synthesis of compounds of Formula (I).
  • R 1 , R 2 , R a , R and Z are as above defined in the description unless otherwise mentioned.
  • an aryl halide of Formula (II) and a boronic acid or ester of Formula (III) are heated in a suitable solvent, such as THF, toluene, DMF or dioxane, in the presence or absence of water as a co-solvent, in the presence of a base, such as Cs 2 C0 3 , K 2 C0 3, CsF, and with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh 3 ) 4 or 1 , 'Tbis(diphenylphosphino)ferrocenedichloro palladium(ll), Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(CI) 2 (PPh 3 ) 2 or Pd/C in the presence or absence of
  • compounds of Formula (I Is), wherein R 1 , R a and Z are as above defined and X is bromine can be obtained as outlined in Scheme 2.
  • Compounds of Formula (IV), wherein R 1 and Z are as above defined and R is H or an alkyl group can be coupled with a compound of Formula (V), wherein R a is as above defined, by a Suzuki-Miyura coupling reaction to give a compound of general formula (VI) wherein R , R a and Z are as above defined.
  • compounds of formula (I) wherein R 1 , R 2 , R a , R b and Z are as above defined can be prepared by Suzuki-Miyura coupling reaction between a compound of Formula (VIII), wherein R , R a and Z are as above defined and R is H or an alkyl group, and a compound of Formula (IX) wherein R 2 and R b are as above defined and X is an halogen (preferably bromine or iodine) or a triflate group as outlined in Scheme 3.
  • General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling (see for example Miyaura, N.; Suzuki, A. Chem. Rev.
  • an aryl halide of Formula (II) and a boronic acid or ester of Formula (III) are heated in a suitable solvent, such as THF, toluene or dioxane, in the presence or absence of water as a co-solvent, in the presence of a base, such as as Cs 2 C0 3 , K 2 C0 3 CsF, and with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh 3 ) 4 or 1 ,1'-bis(diphenylphosphino)ferrocenedichloro palladium(ll), Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(CI) 2 (PPh 3 ) 2 or Pd/C in the presence or absence of an addition
  • a suitable solvent such as THF, toluene or dioxane
  • a base such as as Cs 2 C0 3 , K 2 C0
  • Compounds of Formula (VIII), wherein R 1 , R a and Z are as above defined and R is H or an alkyl group can be prepared from compounds of Formula II, wherein R 1 , R a and Z are as above defined and X is an halogen (preferably bromine or iodine) or a triflate group, by reaction with an appropriate diboron derivative, such as but not limited to bis(pinacolato)diboron, bis(catecholate)diboron, bis(diethyl-D-tartrate glycolato)diboron, bis(hexyleneglycolato)diboron, bis(neopentylglycolato)diboron, preferably bis(pinacolato)diboron, in the presence of a suitable catalyst, such as but not limited to 1 ,1 'bis(diphenylphosphino)ferrocenedichloro palladium(ll), dichlorobis(triphenylphosphine)palladium
  • the resulting 2-aminopyridine of Formula (XI), wherein R 2 and R b are as above defined, can be converted to a 2-iodopyrimidine of Formula (XII), wherein R 2 and R b are as above defined, for example by reaction with a suitable source of iodine, such as but not limited to diiodomethane, iodine, /V-iodosuccinimide, in the presence of an alkyl nitrite such as but not limited to ferf-butyl nitrite or so-pentyl nitrite, in the presence of copper (I) iodide, in a suitable solvent, such as but not limited to THF or dioxane, at a temperature between about 20 °C to about 150 °C, preferably at about 80-100 °C, for a few hours
  • a suitable source of iodine such as but not limited to diiodomethane, iodine,
  • Conversion of compounds of Formula (XIV), wherein R 2 , R a , and R b are as above defined, to compounds of Formula (XV), wherein R 2 , R a , and R b are as above defined can be accomplished using similar conditions as described above for the conversion of an aromatic or heteroaromatic amine into an aromatic or heteroaromatic iodide, for example by reaction with a suitable source of iodine, such as but not limited to diiodomethane, iodine, /V-iodosuccinimide, in the presence of an alkyl nitrite such as but not limited to terf-butyl nitrite or so-pentyl nitrite, in the presence of copper (I) iodide, in a suitable solvent, such as but not limited to THF or dioxane, at a temperature between about 20 °C to about 150 °C, preferably at about 80-100 °C, for a few hours.
  • compounds of Formula I wherein R 1 , R 2 , R a , R b and Z are as above defined, can be obtained by coupling of a compound of Formula (XV), wherein R 2 , R a , and R b are as above defined, with a boronic acid deribative of Formula (IV), wherein R 1 and Z are as above defined and R is H or an alkyl group, under Suzuki-Miyaura conditions, well known to those skilled in the art to perform such couplings, as described above.
  • compounds of Formula I wherein R 1 , R 2 , R a , R b and Z are as above defined, can be prepared as depicted in Scheme 5.
  • Aryl iodides of Formula (XV), wherein R 2 , R a and R b are as above defined, can be converted to compounds of Formula (XVI), wherein R 2 , R a and R b are as above defined and R is H or an alkyl group, by reaction with an appropriate diboron derivative, such as but not limited to bis(pinacolato)diboron, bis(catecholate)diboron, bis(diethyl-D-tartrate glycolato)diboron, bis(hexyleneglycolato)diboron, bis(neopentylglycolato)diboron, preferably bis(pinacolato)diboron, in the presence of a suitable catalyst, such as but not limited to 1 ,1'bis(diphenylphosphino)ferrocened
  • compounds of formula (I) wherein R 1 , R 2 , R a , R b and Z are as above defined can be prepared by Suzuki-Miyura coupling reaction between a compound of Formula (XII), wherein R 2 and R b are as above defined, and a compound of Formula (VII) wherein R 1 , R a and Z are as above defined and R is H or an alkyl group as outlined in Scheme 6.
  • the reaction can be carried out using the general conditions described above. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such couplings.
  • compounds of Formula (I), wherein R , R 2 , R a , R b and Z are as above defined can be prepared as depicted in Scheme 7 from compounds of Formula (la), wherein R 1 , R a , R b and Z are as above defined and R 2 is H, prepared following one of the routes described above, by reaction with a compound of Formula (XVIII), wherein R 2 is as above defined, but not H and LG is a leaving group, such as bromine, chlorine, alkylsulfonate or any other suitable leaving group known to those skilled in the art.
  • LG is a leaving group, such as bromine, chlorine, alkylsulfonate or any other suitable leaving group known to those skilled in the art.
  • a compound of Formula (la) is treated with a base, such as but not limited to NaH, K 2 C0 3 , Cs 2 C0 3 , LDA, LHMDS, preferably NaH, and with a compound of Formula (XVIII), in a suitable solvent like THF, dioxane, DMF, DMA, at a temperature between -20 °C to about 150 °C, for a time between a few minutes to a few hours.
  • a base such as but not limited to NaH, K 2 C0 3 , Cs 2 C0 3 , LDA, LHMDS, preferably NaH
  • a compound of Formula (XVIII) in a suitable solvent like THF, dioxane, DMF, DMA, at a temperature between -20 °C to about 150 °C, for a time between a few minutes to a few hours.
  • compounds of Formula (I), wherein R 1 , R 2 , R a , R b and Z are as above defined can be prepared from compounds of Formula (lb), wherein R 1 , R a , R b and Z are as above defined and R 2 is H, prepared following one of the routes described above, by reaction with an alcohol of Formula (XIX), wherein R 2 is as above defined, but n ot H , using conditions well known to those skilled in the art for a Mitsunobu reaction (see for example Hughes, D. L. Organic Reactions (New York), 1992, 42, 335-656; Reynolds, A. J.; Kassiou, M. Current Organic Chemistry, 2009, 13 (16); 1610-1632).
  • the reaction takes place in the presence of a phosphine, such as but not limited to P(fBu) 3 , PPBu 3 , P(oTol) 3 , PPh 3 , in the presence of an azadicarboxylate, such as but not limited to diethylazadicarboxylate, diisopropylazadicarboxylate, Tetramethylazodicarboxamide, in a solvent such as THF, dioxane, DCM, DCE, at a temperature between -20 °C to about 150 °C, preferably at room temperature, for a time between a few minutes to a few hours.
  • a phosphine such as but not limited to P(fBu) 3 , PPBu 3 , P(oTol) 3 , PPh 3
  • an azadicarboxylate such as but not limited to diethylazadicarboxylate, diisopropylazadicarboxylate, Tetramethylazodicarboxamide
  • the pharmaceutically acceptable anionic salts of the compounds of Formula (I), which contain a basic center may be prepared in a conventional manner.
  • a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • the pharmaceutically acceptable cationic salts of the compounds of Formula (I), which contain an acidic center may be prepared in a conventional manner.
  • a solution of the free acid may be treated with a suitable base, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • salts can be prepared by mixing a solution of the acid with a solution of an alkali or earth alkali salt (such as sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired alkali or earth alkali salt of the compounds of formula (I) precipitates, or can be otherwise isolated by concentration and addition of a non-solvent.
  • an alkali or earth alkali salt such as sodium ethylhexanoate, magnesium oleate
  • Both types of salts may be formed or interconverted using ion-exchange resin techniques.
  • the reaction times are generally between a few minutes and 14 days.
  • the reaction temperature is between about -30°C and about 140°C, normally between -10°C and 90°C, in particular between about 0°C and 70°C.
  • Compounds of the formula (I) and related formulae can furthermore be obtained by liberating compounds of the formula (I) from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R * -N group, in which R* denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a -COOR ** group, in which R ** denotes a hydroxyl-protecting group, instead of a -COOH group.
  • amino-protecting group is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups.
  • acyl group is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl;
  • aralkanoyi such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyi, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl;
  • aralkoxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr.
  • Preferred amino-protecting groups are BOC and Mtr, further-rnore CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl-protecting group is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
  • the nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms.
  • hydroxyl-protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
  • the compounds of the formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature).
  • the BOC, OtBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of
  • Protecting groups which can be removed hydrogenolytically can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon).
  • a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
  • Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 20-30°C and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or
  • dichloromethane ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyhformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene;
  • Esters can be hydrolysed, for example, using HCI, H 2 S0 4 , or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100°C.
  • Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and +30°C.
  • an inert solvent such as dichloromethane or THF
  • a base such as triethylamine or pyridine
  • the formula (I) and related formulae also encompasses the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
  • prodrug derivatives is taken to mean, for example, the salts of the compounds of the formula f and so-called pro ⁇ drug compounds.
  • prodrug derivatives is taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the active compounds.
  • prodrug as of the compounds of formula I, refers to derivative compounds that are rapidly transformed in vivo to yield the parent compound of the formula I, as for example by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.
  • esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York ( 987). It is intended that these references, and any others cited throughout this specification, are incorporated herein by reference.
  • biodegradable polymer derivatives of the compounds according to the invention as described, for example, in Int. J. Pharm. 1 5, 61-67 (1995).
  • the formula (I) and related formulae also encompasses mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 : 10, 1 :100 or 1 :1000.
  • compositions can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit.
  • a unit can comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit.
  • Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient.
  • pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.
  • compositions can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including
  • compositions adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in- water liquid emulsions or water-in-oil liquid emulsions.
  • the active-ingredient component can be combined with an oral, non-toxic and
  • powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol.
  • a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol.
  • a flavour, preservative, dispersant and dye may likewise be present.
  • Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith.
  • Glidants and lubricants such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation.
  • disintegrant or solubiliser such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica-ment after the capsule has been taken.
  • suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • the disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets.
  • a powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate.
  • a binder such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone
  • a dissolution retardant such as, for example, paraffin
  • an absorption accelerator such as, for example, a quaternary salt
  • an absorbant such as, for example, bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve.
  • a binder such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials
  • the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules.
  • the granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets.
  • the active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry- pressing steps.
  • a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
  • Oral liquids such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compounds.
  • Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle.
  • Suspensions can be for-mulated by dispersion of the compounds in a non-toxic vehicle.
  • Solubilisers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.
  • the dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules.
  • the formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.
  • the compounds of the formula (I), and related formulae and salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the formula (I), and related formulae and the salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled to soluble polymers as targeted medicament carriers.
  • Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamidophenol,
  • the compounds may furthermore be coupled to a class of
  • biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient.
  • the active ingredient can be delivered from the plaster by
  • Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as topical ointment or cream.
  • the active ingredient can be employed either with a paraffinic or a water-miscible cream base.
  • the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or sus-pended in a suitable carrier, in particular an aqueous solvent.
  • Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
  • compositions adapted for rectal administration can be administered in the form of suppositories or enemas.
  • Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose.
  • Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.
  • compositions adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurised dispensers with aerosols, nebulisers or insuf-flators.
  • compositions adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration- include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners.
  • the formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
  • Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
  • formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavours.
  • a therapeutically effective amount of a compound of the formula (I), and related formulae and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of
  • an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day.
  • the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be
  • the present invention furthermore relates to a method for treating a subject suffering from a IRAK related disorder, comprising administering to said subject an effective amount of a compound of formula I and related formulae.
  • the present invention preferably relates to a method, wherein the IRAK associated disorder is an autoimmune disorder or condition associated with an overactive immune response or cancer.
  • the present invention furthermore relates to a method of treating a subject suffering from an immunoregulatory abnomality, comprising administering to said subject a compound of formula (I), and related formulae in an amount that is effective for treating said immunoregulatory abnormality.
  • the present invention preferably relates to a method wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma.
  • ALS
  • the present invention furthermore relates to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft- versus-host disease.
  • the present invention furthermore relates to a method wherein the immunoregulatory abnormality is selected from the group consisting of: transplantation of organs or tissue, graft-versus-host diseases brought about by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post- infectious autoimmune diseases including rheumatic fever and post-infectious
  • glomerulonephritis inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vo
  • osteoporosis sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergy sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's
  • disorders associated with IRAK are selected from Rheumatoid Arthritis Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh's Disease and Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin- associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA ( Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, Parkinson's disease, Cancer.
  • compositions of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent.
  • the pharmaceutically acceptable acid addition salts of the compounds of formula (I), and related formulae which contain a basic center may be prepared in a conventional manner.
  • a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of formula (I), and related formulae, which contain an acid center, with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
  • UV detection (maxplot) for all conditions.
  • the microwave chemistry was performed on a single mode microwave reactor EmrysTM Optimiser or InitiatorTM Sixty from Biotage.
  • the compounds of invention have been named according to the standards used in the program Autonom.
  • the compounds according to formula (I) can be prepared from readily available starting materials by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols or mixed solution and solid phase protocols. Examples of synthetic pathways are described below in the examples. Unless otherwise stated, compounds of Formula (I) and related formulae obtained as a racemic mixture can be separated to provide an enantiomerically enriched mixture or a pure enantiomer.
  • Tetrakis(triphenyl phospine)Palladium(O) (2.02 g, 0.17 mmol) was added and the reaction mixture was heated at 100 ° C O/N. It was filtered through a celite pad and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (EtOAc/hexane) afforded the title compound as a yellow solid (2.5 g, 45%).
  • Step 1 Formation of tert-butyl 4- ⁇ 4-f2-(3-aminophenyl)pyrimidin-5-yri-1 H-pyrazol- 1-yl ⁇ piperidine-1 -carboxylate
  • Step 2 Formation of tert-butyl 4-(4-i2-(3-iodophenyl)pyrimidin-5-yl '
  • Isopentyl nitrite (192 ⁇ ; 1.43 mmol; 3.0 eq.) was added to a solution of tert-butyl 4-4-[2- (3-aminophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5, step 1 , 200 mg; 0.48 mmol; 1.0 eq.), Copper(l) iodide (91 mg; 0.48 mmol; 1.0 eq.) and diiodomethane (193 ⁇ ; 2.38 mmol; 5.0 eq.) in dry THF (8.0 mL) and the reaction mixture was refluxed for 2 hours.
  • reaction mixture was filtered through a Celite pad and the filtrate was concentrated to dryness. Purification by flash chromatography (EtOAc:heptane, gradient from 20:80 to 50:50) afforded the title compound as a white solid (200 mg; 67 %).
  • Step 2 Formation of tert-butyl 4-f4-(2-iodopyrimidin-5-yl)-1 H-pyrazol-1-vnpiperidine-1- carboxylate
  • Step 1 Formation of tert-Butyl roxypiperidine-1-carboxylate
  • Step 2 Formation of tert-butyl-cis 3-fluoro-4-[(methylsulfonyl)oxy]piperidine-1- carboxylate
  • Methane sulfonyl chloride (142 ⁇ ; 1.84 mmol; 1.2 eq.) was added to a solution of tert- butyl ester-trans-3-Fluoro-4-hydroxy-piperidine-1-carboxylic acid (336 mg; 1.53 mmol; 1.0 eq.) in DCM (5 mL) and TEA (320 ul, 2.3 mmol, 1.5 eq.) maintained at 0°C under nitrogen atmosphere. The reaction mixture was then stirred at RT for 3h. It was poured into a saturated solution of NH 4 CI. The phases were separated and aqueous phase was extracted twice with DCM. Combined organic phases were washed with sta.
  • Step 1 Formation of 3-f5-(1 H-Pyrazol-4-yl)-pyhmidin-2-yll-phenylamine
  • Step 2 Formation of 2-(3-lodo-phenyl)-5-(1 H-pyrazol-4-yl)-pyrimidine
  • the resulting green solid was suspended in dioxane (100 mL) and stirred at 100°C for 30 minutes. The solid was then filtered off and the two filtrates were combined and concentrated under reduced pressure. The dark brown residue was sonicated in EtOAc (20 mL) and pentane (80 mL). The resulting brown solid was filtered, further washed with pentane and dried few hours under high vacuum to give the title compound as a brown solid (7.0 g; 38%).
  • Methane sulfonyl chloride (71 ⁇ ; 0.92 mmol; 1.0 eq.) was added to a solution of 2- hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (200 mg; 0.92 mmol; 1.0 eq.) and TEA (190 uL; 1.38 mmol; 1.5 eq.) in anhydrous DCM (3 mL) maintained at 0°C and under nitrogen atmosphere. The reaction mixture was stirred at RT O/N. The reaction mixture was washed with 10% citric acid solution and brine. Organic phase was dried over magnesium sulfate, filtered and concentratred to give the title compound as a brown oil (250 mg, 92%).
  • Step 2 Formation of tert-butyl 4- ⁇ 4-[2-(3-iodophenyl)pyrimidin-5-yll-1 H-pyrazol-1- yl ⁇ piperidine-1-carboxylate
  • Step 1 Formation of Toluene-4-sulfonic acid 1 4-dioxa-spiror4.5ldec-8-yl ester
  • Step 1 Formation of N'-(2-Oxo-1-aza-spiror4.5ldec-8-yl)-hvdrazinecarboxylic acid tert- butyl ester
  • Step 2 Formation of 8-(4-Bro -pyrazol-1-yl)-1-aza-spiror4.5ldecan-2-one
  • Step 1 Formation of 4-(N'-tert-Butoxycarbonyl-hvdrazino)-3,3-difluoro-piperidine-1- carboxylic acid tert-butyl ester
  • Step 2 Formation of 4-(4-Bromo- razol-1-yl)-3,3-difluoro-piperidine
  • Step 1 Formation of Methyl 1 , 4-dioxaspiro [4.51 dec-8-ylideneacetate
  • Step 2 Formation of Methyl [8-(nitromethyl)-1 , 4-dioxaspiro [4.51 dec-8-yll acetate
  • Step 5 Formation of terf-bu -(3-oxo-2-azaspiro ⁇ 4.51 dec-8-yl) hvdrazinecarboxylate
  • Step 5 Formation of 8-(4-bromo-1H-pyrazol-1-vD-2-azaspiro [4.51 decan-3-one
  • Step 7 separation isomers of 8-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro [4.51 decan-3-one
  • the mixture obtained in step 6 was separated by preparative HPLC (Chiralpak AD-H, hexane:IPA:DEA 80:20:0.1).
  • Stepl Formation of 8-(4-bromo-1H-pyrazol-1-yl)-2-methyl-2-azaspiro [4.51 decan-3-one
  • 8-(4-bromo-1/-/-pyrazol-1-yl)-2-azaspiro [4.5] decan-3-one mixture of intermediate 30 and 31 obtained in step 5; 4 g, 3.4 mmol
  • DMF 10 ml_
  • sodium hydride 60%) (0.8g, 0.01 16 mol) followed by methyl iodide (2.2mL, 14.8 mmol) at 0°C.
  • the reaction mixture was slowly allowed to warm to RT and stirred for 1 h.
  • step 1 The mixture obtained in step 1 was separated by preparative HPLC (Zorbax RX-SIL, hexane:EtOH:DEA; 90:10:0.1)
  • Step 1 Formation of Methyl -6-(2-tert-butoxycarbonylhvdrazino)-cis-7a-hydroxy- 1 ,3,4,5,6,7-hexahvdroisobenzofuran-3a-carboxylate
  • Lithium borohydride (2M in THF, 4.13 ml_ of a 2M solution in THF, 8.6 mmol) was added slowly over 10 minutes to a solution of methyl -6-(4-bromopyrazol-1-yl)-cis-7a-hydroxy- 1 ,3,4,5,6,7-hexahydroisobenzofuran-3a-carboxylate (1.2 g, 3.4 mmol) in THF (10 ml.) at 0-5 °C under nitrogen atmosphere.
  • the reaction mixture was allowed to warm to 25-26 °C and stirred for 8h. It was then quenched with ice (50 g) and acetic acid (5 mL) and extracted with DCM (3 times).
  • Step 1 Formation of 4-(N'-tert-Butoxycarbonyl-hvdrazino)-3-fluoro-piperidine-1- carboxylic acid tert-butyl ester
  • Example 1 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4- yl)-pyrimidine hydrochloride Step 1 : Formation of tert-butyl 4-(4-(2-i3-(1-methyl- H-pyrazol-4-yl)phenyllpyrimidin-5- ylH H-pyrazol-1-yl)piperidine-1-carboxylate
  • Step 2 Formation of 2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of 4- ⁇ 4-f2-(3-Pyridin-3-yl-phenyl)-pyrimidin-5-vn-pyrazol-1-yl)- piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 Formation of 5-(1-(piperidin-4-yl)-1 H-pyrazol-4-yl)-2-(3-(pyridin-3- vDphenvDpyrimidine hydrochloride
  • Trifluoroacetic anhydride (44 ⁇ ; 0.31 mmol; 1.0 eq.) was added to a solution of 2-[3-(1- Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine (example 1 , 200 mg; 0.31 mmol; 1.0 eq.) in DCM (3 mL) and TEA (130 u!; 0.93 mmol; 3.0 eq.) maintained at 0°C. The reaction mixture was then stirred at RT for 3h. It was quenched by addition of a saturated solution of NaHC0 3 at 0°C.
  • Example 5 1 -[4-(4- ⁇ 2-[3-(1 -Methyl-1 H-py razol-4-y l)-pheny l]-py rimidin-5-yl ⁇ -py razol- 1-yl)-piperidin-1-yl]-ethanone
  • Acetyl chloride (222 ⁇ ; 3.1 mmol; 2.0 eq.) was added to a solution of 2-[3-( -Methyl-1 H- pyrazol-4-yl)-phenyl]-5-(1 -piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride (example 1 , 655 mg; 1.55 mmol; 1.0 eq.) and ⁇ (503 ⁇ ; 3.88 mmol; 2.5 eq.) in dry DMF (12 mL) and the reaction mixture was stirred at RT and under nitrogen for 2h. The reaction mixture was diluted with DCM and washed with water.
  • Step 1 Formation of tert-butyl 4-(4- ⁇ 2-f3-(3-furyl)phenvnpyrimidin-5-yl)- H-pyrazol-1- yl)piperidine-1-carboxylate
  • Step 2 Formation of 2-(3-Furan-3-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidine hydrochloride
  • Example 8 4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl ⁇ -pyrazol-1-yl)- acetic acid
  • the title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 eq.) and 1-Pyrrolidin-1-yl-2-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethanone (intermediate 7, 77 mg; 0.25 mmol; LOOeq.) as a yellow powder (57 mg; 54 %).
  • Example 10 4-[2-(4- ⁇ 2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ - py razol-1 -y l)-ethyl]-m
  • the title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 eq.) and 1-(2-Morpholinoethyl)-1 H-pyrazole-4-boronic acid pinacol ester (78 mg; 0.25 mmol; 1.0 eq.) as a white powder (71 mg; 68 %).
  • the title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 eq.) and dimethyl-2-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan- 2-yl)-pyrazol-1-yl]-ethyl-amine (67 mg; 0.25 mmol; 1 .0 eq.) as a white solid (69 mg, 73%).
  • the title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 150 mg; 0.48 mmol; 1.0 eq.) and 1-(Tetrahydro-furan-3-yl)-4-(4,4,5,5-tetramethyI- [1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (CombiPhos Catalysts, Inc.; 126 mg; 0.48 mmol; 1.0 eq.) as a white solid (113 mg; 64 %).
  • Step 1 Formation of tert-butyl 4-(4-f2-(3-isoxazol-4-ylphenyl)pyrimidin-5-yll-1 H-pyrazol- 1-yl)piperidine-1-carboxylate
  • Step 2 Formation of 2-(3-lsoxazol-4-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidine hydrochloride
  • Step 1 Formation of tert-butyl 4-(4 2-r3-(1 ,3-dimethyl-1 H-pyrazol-4- yl)phenvnpyrimidin-5- -1 H-pyrazol-1-yl)piperidine-1-carboxylate
  • Step 2 Formation of 2-[3-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-phenyll-5-(1-pipe din-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of tert-butyl 4-(4- ⁇ 2-i3-(1 ,5-dimethyl-1 H-pyrazol-4-yl)phenyllpyrimidin- 5-yl)-1 H-pyrazol-1-yl)piperidine-1-carboxylate
  • Step 2 formation of 2-r3-(1 ,5-Dimethyl-1 H-pyrazol-4-yl)-phenvn-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of tert-butyl 4-(4-f2-(3- ⁇ 1-r2-fluoro-1-(fluoromethyl)ethvn-1 H-pyrazol-4- yl>phenyl)pyrimidin- -vn-1 H-pyrazol-1-yl)piperidine-1-carboxylate
  • Step 2 Formation of 2- ⁇ 3-[1-(2-Fluoro-1-fluoromethyl-ethyl)-1 H-pyrazol-4-yll-phenyl)-5- (1-piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
  • Example 17 2-(4- ⁇ 3-[5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]-phenyl ⁇ - py razol-1 -y l)-1 -py rrolidin-1 -y l-ethanone hydrochloride
  • Stepl Formation of tert-butyl 4-i4-(2-(3-f1-(2-oxo-2-pyrrolidin-1-ylethyl)-1 H-pyrazol-4- yllphenyl)pyrimidin-5-yl)-1 H-pyrazol-1-yl iperidine-1-carboxylate
  • Step 2) Formation of 2-(4- ⁇ 3-[5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidin-2-yll-phenyl)- pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone hydrochloride
  • Step 1 Formation of tert-butyl 4-(4- ⁇ 2-f3-(1 H-pyrazol-4-yl)phenvnpyrimidin-5-yl)-1 H- pyrazol-1 -yl)piperidin -1 -carboxylate
  • Step 1 Formation of tert-butyl 4-(4-(2-f3-(1-propyl-1 H-pyrazol-4-yl)phenyl
  • Step 2 Formation of 5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-f3-(1-propyl-1 H-pyrazol-4-yl)- phenyll-pyrimidine hydrochloride
  • Example 20 2-[3-(1 -Isopropy 1-1 H-py razol-4-y l)-phenyl]-5-(1 -piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of tert-butyl 4-(4-(2-[3-(1-isopropyl-1 H-pyrazol-4-yl)phenyllpyrimidin-5- yl ⁇ - 1 H-pyrazol-1 -vDpiperidine- 1 -carboxylate
  • Step 2 Formation of 2-[3-(1-lsopropyl-1 H-pyrazol-4-yl)-phenyll-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of tert-butyl 4-(4-(2-r3-(1-benzyl-1 H-pyrazol-4-yl)phenyllpyrimidin-5-
  • Step 2 Formation of 2-f3-(1-Benzyl-1 H-pyrazol-4-yl)-phenvn-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of 5-[1-(2-(rtert-butyl(dimethyl)silylloxy ⁇ ethvn-1 H-pyrazol-4-vn-2-r3-(1- methyl-1 H-pyrazol-4-yl)phenyllpyhmidine
  • Step 2 Formation of 2-(4- ⁇ 2-f3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl ⁇ - pyrazol-1 -yl)-ethanol
  • reaction mixture was then heated in MW at 100°C for 30 min.
  • 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .37 g; 6.58 mmol; 3.0 eq.) and bis(triphenylphosphine)palladium(ll) chloride (80 mg; 0.1 1 mmol; 0.05 eq.) were added to the reaction suspension and heating continued for a further 30 min.
  • On cooling the reaction suspension was filtered through celite, then poured into a 1 N HCI solution and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated.
  • the crude obtained was purified by flash chromatography on silica (DCM: eOH, gradient from 95:5 to 50:50).
  • the pure residue was redissolved in HCI/dioxane (4 ml_ of a 1 N solution; 16 mmol; 70 eq.) and MeOH (4 ml_) and the resulting solution was stirred at RT for 1h. It was then concentrated and triturated with acetonitrile. The solid was finally filtered and dried under vacuum to give the title compound as an orange solid.
  • Example 28 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(1-oxetan-3-yl-piperidin-4- yl)-1 H-pyrazol-4-yl]-pyrimidine
  • Step 1 Formation of 4-(4- ⁇ 2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-ylV- pyrazol-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester
  • the title compound was obtained following procedure described for example 13, step 2, but starting from of 4-(4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol- 1-ylmethyl)-piperidine-1-carboxylic acid tert-butyi ester (200 mg; 0.40 mmol; 1.0 eq.) as a yellow powder (160 mg, 92%).
  • Step 1 Formation of Trans-3-Fluoro-4-(4-f2-r3-(1-methyl-1 H-pyrazol-4-yl)-phenyl1- pyrimidin-5-ylVpyrazol-1-yl)- iperidine-1-carboxylic acid tert-butyi ester
  • Step2 Formation of Trans-5-ri-(3-Fluoro-piperidin-4-yl)-1 H-pyrazol-4-yll-2-[3-(1-methyl- 1 H-pyrazol-4-yl)-phenvn-pyrimidine hydrochloride
  • the title compound was obtained following procedure described for example 13, step 2, but starting from Trans-3-Fluoro-4-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin- 5-yl ⁇ -pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (320 mg; 0.64 mmol; 1.0 eq.). After the first precipitation, a purification by autopreparative LC/MS afforded the title compound as a white foam (67 mg, 24%).
  • Example 31 1 ,1 ,1 -Trifluoro-3-[4-(4- ⁇ 2-[3-(1 -methyl-1 H-py razol-4-y l)-phenyl]- pyrimidin-5-yl ⁇ -pyrazol-1-yl)-piperidin-1-yl]-propan-2-ol
  • the title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 100 mg; 0.32 mmo!; 1.0 eq.) and 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- 2-yl)-1 H-pyrazole (99 mg; 0.48 mmol; 1.5 eq.) as a white powder (56 mg; 55%).
  • Step 1 Formation of 4- ⁇ 4-f2-(3-Pyridin-4-yl-phenyl)-pyrimidin-5-vn-pyrazol-1-yl)- piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 Formation of 5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-(3-pyridin-4-yl-phenyl)- pyrimidine hydrochloride
  • reaction mixture was cooled down to RT and diluted with DC . It was filtered through celite. Organic phase was washed sequentially with a 1 N HCI solution and brine, dried over magnesium sulfate, filtered and concentrated.
  • This crude was purified by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 75:25) and then redissolved in MeOH and HCI/dioxane (10 mL of a 4N solution; 40 mmol; 37 eq.). Reaction mixture was stirred at RT for 2h and concentrated under reduced pressure. Purification by autopreparative LC/MS afforded the title compound as a white foam (11 mg, 4%).
  • Example 35 1-Methoxy-3-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl ⁇ -pyrazol-1-yl)-propa -2-ol
  • Example 36 2-(4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1 - y l)-1 -morpholin-4-y l-ethanone
  • the title compound was obtained following procedure described for example 25 but starting from 4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and Morpholine (24 mg; 0.28 mmol; 1.0 eq.) as a white solid (45 mg , 38%).
  • Step 1 Formation of 1-Pyrrolidin-1-yl-2-(4- ⁇ 2-r3-(4,4,5,5-tetramethyl-f1 ,3,2ldioxaborolan-
  • the reaction mixture solution was used as it in the next step.
  • Step 2 Formation of 2-(4-(2-f3-(3-Methyl-3H-imidazol-4-yl)-phenvn-pyrimidin-5-yl>- pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone
  • Example 38 ⁇ , ⁇ -Dimethy l-2-(4- ⁇ 2-[3-(1 -methyl-1 H-py razol-4-yl)-pheny l]-pyrimidin- 5-yl ⁇ -pyrazol-1-yl)-acetamide
  • Example 40 1 -(3-Methoxy-azetidin-1 -y l)-2-(4- ⁇ 2-[3-(1 -methy 1-1 H-py razol-4-y I)- phenyl]-pyrimidin-5- -pyrazol-1 -yl)-ethanone
  • the title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 80 mg; 0.26 mmol; 1.0 eq.) and 2-Chloro-1-(3-methoxy-azetidin-1-yl)- ethanone (from Butt Park Ltd., 86 mg; 0.53 mmol; 2.0 eq.) as a white foam (25mg, 21 %).
  • Step 1 Formation of 2-(4-f2-f3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-pyriinidin-5-yl ⁇ - pyrazol-1-ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester
  • Step 2 Formation of 2-(4-(2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl ⁇ - pyrazol-1 -ylmethvD-morpholine hydrochloride
  • Example 42 2-[4-(2- ⁇ 3-[1 -(3-Amino-propyl)-1 H-pyrazol-4-yl]-pheny l ⁇ -py rimidin-5- yl)-pyrazol-1-yl]-1-pyrr
  • the title compound was obtained following procedure described for example 27 but starting from 2-[3-(1 -methyl- 1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 75 mg; 0.25 mmol; 1.0 eq.) and 1-Chloro-propan-2-one (59 ⁇ ; 0.74 mmol; 3.0 eq.) as a white powder (25 mg, 28%).
  • the title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 2-Chloromethyl-oxazole (39 mg; 0.33 mmol; 1.0 eq) as a beige powder (27 mg, 21 %).
  • Example 48 2-[2-Fluoro-3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl- 1 H-pyrazol-4-yl)-pyrimidine Formate
  • Example 50 2-[4-(2- ⁇ 3-[1-(2-Amino-ethyl)-1 H-pyrazol-4-yl]-phenyl ⁇ -pyrimidin-5-yl)- pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone hydrochloride
  • Stepl formation of (2-f4-(3-(5-ri-(2-Oxo-2-pyrrolidin-1-yl-ethyl)- H-pyrazol-4-vn- pyrimidin-2-yl phenyl)-pyrazol-1-vH-ethyl
  • the title compound was obtained following procedure described for example 27 but starting from 2-(4- ⁇ 2-[3-(1 H-Pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1-yl)-1- pyrrolidin-1-yl-ethanone (intermediate 14, 150 mg; 0.38 mmol; 1.0 eq.) and (2-Bromo- ethyl)-carbamic acid tert-butyl ester (17 mg; 0.08 mmol; 0.2 eq.) as a white solid (70 mg, 34%).
  • Example 51 1-(4-Methyl-piperazin-1-yl)-2-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl ⁇ - razol-1-yl)-ethanone hydrochloride
  • the title compound was obtained following procedure described for example 25 but starting from (4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1 -yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.00 eq.) and 1-Methyl-piperazine (55 mg; 0.55 mmol; 2.0 eq.) as a white solid (20 mg, 15%).
  • Example 52 1 -(3-Hydroxy-piperidin-1 -l)-2-(4- ⁇ 2-[3-(1 -methy 1-1 H-py razol-4-y I)- phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1 -yl)-ethanone
  • Example 54 2-(4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1- yl)-N-(tetrahydro-pyran-4- -acetamide
  • the title compound was obtained following procedure described for example 25 but starting from (4- ⁇ 2-[3-(1 -Methyl- 1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and tetrahydro-pyran-4-ylamine (56 mg; 0.55 mmol; 2.0 eq.) as a white powder (9 mg, 14%).
  • the title compound was obtained following procedure described for example 25 but starting from 4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and 2-Oxa-6-aza-spiro[3.3]heptane oxalate (105 mg; 0.55 mmol; 2.0 eq.) as a white powder (40 mg, 33%).
  • Example 56 2-(4- ⁇ 2-[3-(2- ethyl-thiazol-5-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1-yl)- 1-pyrrolidin-1-yl-ethanone
  • the title compound was obtained following procedure described for example 37 but starting from 2- ⁇ 4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl ⁇ -1-pyrrolidin-1-yl- ethanone (intermediate 12, 200 mg; 0.44 mmol; 1.0 eq.) and 5-Bromo-2-methyl-thiazole (77 mg; 0.44 mmol; 1.0 eq.) as a white solid (30 mg, 16%).
  • the title compound was obtained following procedure described for example 27 but starting from 2-[3-(1 -methyl- 1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 eq.) and 1-(2-Chloro-ethyl)-piperidine hydrochloride (110 mg; 0.60 mmol; 1.5 eq.) as a white solid (80 mg, 49%).
  • the title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 eq.) and 1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (101 mg; 0.60 mmol; 1.5 eq.) as a beige foam (75 mg, 47%).
  • Example 60 N-(1-Hydroxymethyl-propyl)-2-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1 -yl)-acetamide
  • the title compound was obtained following procedure described for example 25 but starting from (4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and 2-Amino-butan-1-ol (49 mg; 0.55 mmol; 2.0 eq.) as a white powder (14 mg, 12%).
  • Example 62 4-(4- ⁇ 2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1 - yl)-cyclohexanecarboxylic acid
  • Step 1 formation of 4-(4-(2-f3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl1-pyrimidin-5-yl)-pyrazol- 1-yP-cyclohexanecarboxylic acid ethyl ester
  • Step 2 Formation of 4-(4-(2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-pyrimidin-5-yl ' ⁇ - pyrazol-1 -yl)-cvclohexanecarboxylic acid
  • Example 63 2-[3-(1 -Meth -1 H-pyrazol-4-yl)-pheny l]-5-(1 H-py razol-4-yl)-py rimidine
  • Example 64 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5- ⁇ 1-[2-(1-methyl-pyrrolidin-2- yl)-ethyI]-1 H-pyrazol-4- -pyrimidine
  • Example 65 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-pyrrolidin-3-ylmethyl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of 3-(4-(2-f3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-pyrimidin-5-yl>- pyrazol-1-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 1 Formation of 3-(4- ⁇ 2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl ⁇ -
  • the title compound was obtained following procedure described for example 66, step 1 , but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (255 mg; 0.84 mmol; 1.0 eq.) and methanesulfonic acid 2,2-difluoro-ethyl ester (prepared as described in Journal of Organic Chemistry, 74(12), 4547-4553; 2009, 150 mg, 0.84 mmol, 1.0 eq.) as a white solid (140 mg, 45%).
  • Example 68 1-Morpholin-4-yl-2- ⁇ 4-[2-(3-pyridin-4-yl-phenyl)-pyrimidin-5-yl]- py razol-1 -y l ⁇ -ethanone
  • the title compound was obtained following procedure described for example 66, stepl , but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 4-(2-Bromo-ethyl)-tetrahydropyran (96 mg; 0.50 mmol; 1.5 eq.) as a white foam (57 mg, 42%).
  • Example 70 2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-(S)-1-pyrrolidin-2- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of (S)-2-(4- ⁇ 2-r3-(1-Methyl-1 H-pyrazol-4-ylVDhenvn-pyrimidin-5-ylV-
  • Step 2 Formation of 2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-5-(1-(S)-1-pyrrolidin-2- ylmethyl- H-pyrazol-4-yl)-pyrimidine hydrochloride
  • Example 71 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-(R)-1-pyrrolidin-2- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of iR)-2-(4- ⁇ 2-f3-n-Methyl-1H-pyrazol-4-yl)-phenyl1-pyrimidin-5-yl>- pyrazol-1-ylmethyl -pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 2 Formation of 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-5-(1-(R)-1-pyrrolidin-2- ylmethyl-1 H-pyrazo -4-yl)-pyrimidine hydrochloride
  • Example 72 2-[3-(1-Methyl-1 H-[1,2,3]triazol-4-yl)-phenyl]-5-(1 -piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Step 1 Formation of 4-(4-(2-r3-i1-Trimethylsilanylmethyl-1 H-ri.2.3ltriazol-4-yl)-phenvn- pyrimidin-5-ylVpyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 Formation of 2-r3-(1-Methyl-1 H-ri .2.3ltriazol-4-yl)-phenvn-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
  • Tetrabutylammonium fluoride (56 mg; 0.21 mmol; 2.0 eq.) was added to a solution of 4- (4- ⁇ 2-[3-(1-Trimethylsilanylmethyl-1 H-[1 ,2,3]triazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1- yl)-piperidine-1-carboxylic acid tert-butyl ester (60 mg; 0.11 mmol; 1.0 eq.) in THF (1 mL) and the reaction mixture was stirred at RT for 2h. It was then diluted with a saturated solution of NaHC0 3 and extracted with EtOAc (three times).
  • Example 73 1-(3-Hydroxy-azetidin-1-yl)-2-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl ⁇ -py
  • Example 74 1-(3-Hydroxy-pyrrolidin-1-yl)-2-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)- pheny l]-pyrimidin-5-y l ⁇ -py razol-1 -y l)-ethanone
  • Trimethylaluminium (1.50 mL; 3.0 mmol; 5.4 eq.) was added dropwise over 1 min to a solution of dimethylamine (2.50 mL; 5.0 mmol; 9.1 eq.) in DCE (50 mL) at 0°C.
  • Example 135 Cis-4-(4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ - pyrazol-1-yl)-cyclohexanecarbox lic acid dimethylamide
  • the reaction mixture was then heated at reflux under nitrogen for 4 h. The temperature was reduced to 70°C before the addition of trans-4-(4-lodo-pyrazol-1-yl)-cyclohexanol (intermediate 22; 714 mg; 2.44 mmol; 1.10eq.), potassium carbonate (921 mg; 6.66 mmol; 3.0 eq.), trans-Dichlorobis(tricyclohexylphosphine)palladium(ll), 99% (16.4 mg; 0.02 mmol; 0.01 eq.) and water (5 mL). The new reaction mixture was heated again at 100°C for 30 min. It was allowed to cool to RT and diluted with EtOAc.
  • Example 250 cis-8-(4 ⁇ 2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ - pyrazol-1 -yl)-1 -aza-spiro[4.5]decan-2-one (first isomer)
  • the title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 160 mg; 0.51 mmol; 1.0 eq.) and cis-8-(4-Bromo-pyrazol-1-yl)-1-aza-spiro[4.5]decan- 2-one (intermediate 23; 166 mg; 0.56 mmol; 1.1 eq.). The crude was purified by autopreparative LC/MS to afford the title compound as a white solid (45 mg, 20%).
  • Example 251 Trans-8-(4- ⁇ 2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ - pyrazol-1-yl)-1-az -spiro[4.5]decan-2-one (second isomer)
  • the title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 200 mg; 0.63 mmol; 1.0 eq.) and trans-8-(4-Bromo-pyrazol-1-yl)-1-aza- spiro[4.5]decan-2-one (intermediate 24; 208 mg; 0.7 mmol; 1.1 eq.).
  • the crude was purified by autopreparative LC/MS to afford the title compound as a white solid (25 mg, 9%).
  • Example 254 4-[4-(4- ⁇ 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl ⁇ - pyrazol-1-yl)-cyclohex l]-morpholin-3-one
  • the title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 230 mg; 0.73 mmol; 1.0 eq.) and trans-4-[4-(4-lodo-pyrazol-1-yl)-cyclohexyl]- morpholin-3-one (intermediate 26; 274 mg; 0.73 mmol; 1.0 eq.).
  • the crude was purified by recrystallisation in methylisobutylketone.
  • the title compound was obtained as a beige solid (16 mg, 5%).
  • the title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 200 mg; 0.63 mmol; 1.0 eq.) and trans-3-[4-(4-lodo-pyrazol-1-yl)-cyclohexyl]- oxazolidin-2-one (intermediate 27; 231 mg; 0.63 mmol; 1.0 eq.). The crude was triturated in acetonitrile and the suspension filtered and dried under vacuum to afford the title compound as a brown solid (151 mg, 51 %).
  • Example 258 Cis-1-Hydroxymethyl-4-(4- ⁇ 2-[3-(1 -methyl-1 H-pyrazoI-4-yl)-phenyl]- pyrimidin-5-yl ⁇ -pyrazol-1 - l)-cyclohexanol
  • Example 259 5-[1-(3,3-Difluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine
  • reaction mixture was degasified for 15 min and then 1 ,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (20.88 mg; 0.02 mmol; 0.05 eq.) was added.
  • the reaction mixture was then heated at 100° C for 90 min. It was concentrated under reduced pressure, diluted with Water (15 ml_) and extracted with ethylacetate (2 X 25 ml_). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, 9:1) afforded the title compound as a brown solid (24 mg; 11 %).
  • Example 260 trans-2-Methyl-8-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl ⁇ -py
  • Example 262 cis-2- ethyl-8-(4- ⁇ 2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin- 5-yl ⁇ -pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one
  • Example 265 cis-3-Fluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine
  • the title compound was obtained following procedure described for example 164 but starting from 4-(4-Bromo-pyrazol-1-yl)-3-fluoro-piperidine (Intermedaite 37; 200 mg; 0.80 mmol; 1.0 eq.) and 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 15; 296 mg; 0.80 mmol; 1.0 eq.).
  • Example 280 (3aS,7aS)-7a-Hydroxy methy l-5-((R)-4- ⁇ 2-[3-(1 -methy 1-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1 -yl)-hexahydro-isobenzofuran-3a-ol
  • Example 281 (3aR,5R,7aR)-7a-Hydroxymethy l-5-(4- ⁇ 2-[3-(1 -methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl ⁇ -pyrazol-1 -yl)-hexahydro-isobenzofuran-3a-ol
  • the title compound was obtained following procedure described for example 164 but starting from 8-(4-Bromo-pyrazol-1-yl)-1-methyl-1-aza-spiro[4.5]decan-2-one (intermediate 38; 130.0 mg; 0.41 mmol; 1.0 eq.)) and 2-[3-(1 -Methyl-1 H-pyrazol-4-yl)- phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 15; 171 mg; 0.45 mmol; 1.1 eq.) as Brown Solid ( 35 mg, 17%).
  • Example 286 trans-8-(4- ⁇ 2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-py rimidin-5-yl ⁇ - pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one
  • Example 287 cis-8-(4-(2-(3-(1 -methyl-1 H-pyrazol-4-y l)phenyl)pyrimidin-5-y l)-1 H- pyrazol-1-yl)-2-azasp
  • IRAKI is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712)) In this assay, IRAK-1 hydrolyses ATP and autophosphorylates.
  • His-TEV-IRAK-1 (15ng/well), ATP (1 ⁇ , [33P]ATP 0.25pCi/well) and compounds in DMSO (range of concentrations from 20 ⁇ to 1 nM) or controls (2%DMSO) are incubated for 3 hours at 30°C in assay buffer : Hepes pH7.0 50mM, Fatty acid-free BSA 0.1%, Dithiothreitol DTT 2mM, MgCI2 10mM, EGTA 0.5mM, Triton-X-100 0.01 %. Kinase reaction is stopped by addition of EDTA. Supernatant is discarded, plates are washed three times with 150 mM NaCI and radioactivity is then measured in a Microbeta Trilux reader.
  • IRAK4 is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712) IRAK4 hydrolyses ATP, autophosphorylates and phosphorylates a Serine/Threonine generic peptidic substrate (STK: 61 ST1 BLC from CisBio International based in Bagnols/Ceze FR).
  • IRAK-4 inhibition is performed in streptavidin coated 384well FlashPlate (PerkinElmer #SMP410A). His-TEV-IRAK4 (20ng/well), ATP (2 ⁇ , [ 33 P]ATP 0.25pCi/well), STK1-biotin peptide (300nM) and compounds in DMSO (range of concentrations from 20 ⁇ to 1 nM) or controls (2%DMSO) are incubated for 3 hours at 30°C in assay buffer: Hepes pH7.0 50mM, Fatty acid-free BSA 0.1 %, Dithiothreitol DTT 2mM, MgCI2 10mM, EGTA 0.5mM, Tween-20 0.01 %, MnCI2 5mM.
  • Kinase reaction is stopped by addition of EDTA. Supernatant is discarded, plates are washed three times with 150 mM NaCI and radioactivity is then measured in a Microbeta Trilux reader.

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Abstract

The present invention provides compounds of Formula (I) for the treatment of cancer, rheumatoid arthritis and other diseases (I).

Description

Pyrimidine pyrazolyl derivatives
The present invention provides Pyrimidine pyrazolyl derivatives of Formula (I) as IRAK inhibitors and their use in the treatment of cancer, and other diseases related to IRAK overexpression, like rheumatoid arthritis, systemic lupus erythematosus or lupus nephritis.
Background
Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play key roles in all aspects of eukaryotic cell physiology.
Especially, protein kinases and lipid kinases participate in the signaling events which control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. In general, protein kinases are classified in two groups, those that preferentially
phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues.
Kinases are important therapeutic targets for the development of anti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology 21 , 1-8), for example kinases that are involved in the orchestration of adaptive and innate immune responses. Kinase targets of particular interest are members of the IRAK family.
The interleukin-1 receptor-associated kinases (IRAKs) are critically involved in the regulation of intracellular signaling networks controlling inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7). IRAKs are expressed in many cell types and can mediate signals from various cell receptors including toll-like receptors (TLRs). IRAK4 is thought to be the initial protein kinase activated downstream of the interleukin-1 (IL-1) receptor and all toll-like-receptors (TLRs) except TLR3, and initiates signaling in the innate immune system via the rapid activation of IRAKI and slower activation of IRAK2. IRAKI was first identified through biochemical purification of the IL-1 dependent kinase activity that co-immunoprecipitates with the IL-1 type 1 receptor (Cao et al., 1996. Science 271 (5252): 1128-31). IRAK2 was identified by the search of the human expressed sequence tag (EST) database for sequences homologous to IRAKI (Muzio et al., 1997. Science 278(5343): 1612-5). IRAK3 (also called IRAKM) was identified using a murine EST sequence encoding a polypeptide with significant homology to IRAKI to screen a human phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNA library (Wesche et al., 1999. J. Biol. Chem. 274(27): 19403-10). IRAK4 was identified by database searching for IRAK-like sequences and PCR of a universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572).
Mice that express a catalytically inactive mutant of IRAK4 instead of the wild-type kinase are completely resistant to septic shock triggered by several TLR agonists and are impaired in their response to IL-1. Children who lack IRAK4 activity due to a genetic defect suffer from recurring infection by pyogenic bacteria. It appears that IRAK- dependent TLRs and IL-1 Rs are vital for childhood immunity against some pyogenic bacteria but play a redundant role in protective immunity to most infections in adults. Therefore IRAK4 inhibitors may be useful for the treatment of chronic inflammatory diseases in adults without making them too susceptible to bacterial and viral infections (Cohen, 2009. Current Opinion in Cell Biology 21 , 1-8). Potent IRAK4 inhibitors have been developed (Buckley et al., 2008. Bioorg Med Chem Lett. 18(12):3656-60). IRAKI is essential for the TLR7 -mediated and TLR9-mediated activation of IRF7 and the production of interferon- alpha (IFN-a) suggesting that IRAKI inhibitors may be useful for the treatment of Systemic lupus erythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays a role in proinflammatory cytokine production. Therefore IRAK2 inhibitors may be useful for inflammatory diseases.
Summary of the invention
According to one aspect of the invention, are provided compounds of Formula (I).
According to another aspect of the invention, are provided compounds of Formula (I) which are suitable for the treatment and/or prevention of disorders related to IRAK.
According to another aspect of the invention, are provided compounds, which are able to modulate, especially inhibit the activity or function of IRAK in disease states in mammals, especially in humans.
According to another aspect of the invention, are provided methods for the treatment and/or prevention of disorders selected from auto-immune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergy, asthma, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases and ischemic conditions.
According to another aspect, the present invention provides compounds of Formula (I) which are selective of IRAK-4 and/or IRAK-1 over the other isoforms.
According to another aspect of the invention is provided a kit or a set comprising at least one compound of Formula (I), preferably in combination with immunomodulating agents. Preferably, the kit consists of separate packs of:
(a) an effective amount of a compound of the formula (I) and/or pharmaceutically usable derivatives, solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios, and
(b) an effective amount of a further medicament active ingredient. According to another aspect of the invention, is provided a process for the synthesis of compounds of Formulae (I) and related Formulae.
Detailed description of the invention:
In one embodiment, the present invention provides a compound of Formula (I)
Figure imgf000004_0001
(I)
wherein
R1 denotes absent or denotes A or Q-Het,
Figure imgf000004_0002
wherein X denotes O, S or N,
Y denotes C or N,
T denotes C or N, or
Z denotes a pyridine or a pyridazine group,
Ra is absent or denotes OR3, CF3, Hal, N02,
Rb is absent or denotes one of the groups selected from A and COHet, denotes H, Het, Q-Het, Cyc, A or OA,
Het denotes a 4-9 membered monocyclic ring or a fused, spiro or bridged bicyclic ring, which is saturated, unsaturated, or aromatic, which contains 1 to 3 heteroatoms independently selected from N, O, S and a group CO, SO or S02, and wherein 1 or 2 H atoms may be replaced by A, OA, COA, CN, Hal, N02,
OR3, SOA and/or S02A, denotes a 4-8 saturated carbocyclic ring optionally containing a group SO, S02, CO, and optionally substituted once or twice by a group selected from C0(NR3)2 and COHet, OR3, Het1, A, CH2Het1, NH2, NHCOA, OCH2Cyc1, S02A and/or - SA(=NH)(=0), denotes a linear or branched alkylene, having 1 to 6 carbon atoms wherein 1-5 H atoms may be replaced by a groupe independently selected from OR3, Hal, N(R3)2, and wherein 1 or 2 CH2 groups may be replaced by a group
independently selected from CO, SO, S02 and NR3, or Q denotes a 4-8- membered bivalent heterocyclic ring, which is saturated, unsaturated or aromatic and which contains 1 to 3 heteroatoms independently selected from N, O and S, denotes a linear or branched alkyl having 1 to 10 carbon atoms wherein 1 to 7 H atoms may be replaced by a group independently selected from -OR3, Hal, NHS02A, S02A, SOA, N(R3)2, and wherein 1 , 2 or 3 non-adjacent -CH2- groups may be replaced by a group independently selected from -CO-, NR3 and/or -0-, Hal denotes F, CI, Br or I, denotes H or C Cealkyl wherein 1 H atom may be replaced by a group selected from OH, O-C Ce-alkyl, and Hal,
Het1 denotes a five- or six membered saturated monocyclic heterocycle, which
contains 1-3 N- and/or O-atoms, which optionally is monosubstituted by A,
Cyc1 denotes cycloalkyl with 3-7 atoms,
and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios.
In the definitions above and below, when a group is mentioned several times, like R3 in CO(NR3)2, It independently takes any values given in the corresponding definition.
In the compounds of Formula (I) and related formulae, Z may denote a group
Alternatively, Z is selected from the following specific groups:
Figure imgf000006_0002
Z, in Formula (I) and related Formulae preferably denotes a group selected from a pyridazine, a pyrazole, and a 4-pyridine. R in Formula (I) and related Formulae preferably denotes a linear or branched C-|-C6- alkyl group.
Alternatively, the group Z-R1 in Formula (I) and related Formulae is selected from the following groups:
Figure imgf000007_0001
Figure imgf000008_0001
In a specific embodiment, the group R2 in Formula (I) and related Formulae denotes a piperidine or the group Cyc defined above.
Alternativelly, the group R2 in Formula (I) and related Formulae is preferably selected from the following groups:
Figure imgf000008_0002
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001

Figure imgf000017_0001
The group Rb in Formula (I) and related Formulae preferably denotes H.
Alternative! ly, Rb may denote a group selected from COHet or a linear or branched C C6-alkyl group wherein 1 H atoms may be replaced by a group selected from NR3 or OR3, and wherein 1 CH2 group may be replaced by a group CO.
More specifically, Rb in Formula (I) and related Formulae may be selected from the following groups:
Figure imgf000018_0001
Het, in Formula (I) and related Formulae preferably denotes a saturated 4-6-membered single ring containing 1 heteroatom selected from nitrogen, wherein 1 H atom may be replaced by a group selected from COCi-C6-alkyl, and an oxacyclohexane. Alternatively, Het in Formula (I) and related Formulae denotes a 4-9-membered spiro- or bridged bicyclcic ring, containing 1 to 2 heteroatoms selected from Nitrogen and oxygen, and optionally monosubstituted by a group A.
More preferably, Het denotes a piperidine group wherein 1 or 2 H atom may be independently replaced by a group selected from A, OA, COA, CN, Hal, N02) OR3, SOA and S02A.
Cyc1 is cyclopropyl, cyclobytyl, cyclopentyl, cyclohexyl or cycloheptyl.
The compounds of the present invention also include compounds of Formula (la)
Figure imgf000019_0001
(la)
Wherein T denotes a group NCOA, whereby A is as defined above or T denotes a carbon atom which may be substituted by CON(R3)2 whereby R3 is as defined above, and wherein R1 in Formula (la) is as defined above.
The following compounds are the most preferred:
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Ex
193
HPLC (max plot) 100 %; (254nm) 100%; Rt (min) 3.11 ; MS: (ESI+) 470.3.
194
HPLC (max plot) 99.2 %; (254nm) 98.0%; Rt (min) 3.33; MS: (ESI+) 498.4.
195
O
HPLC (max plot) 99.0 %; (254nm) 99.0%; Rt (min) 3.40; MS: (ESI+) 399.3.
196
HPLC (max plot) 97.1 %; (254nm) 96.3%; Rt (min) 3.19; MS: (ESI+) 401.3.
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
HPLC (max plot) 100 %; (254nm) 100 %; Rt (min) 2.65; MS: (ESI+) 470.4.
HPLC (max plot) (ESI+) 424.4.
HPLC (max plot ) 387.4.
HPLC (max plot ) 377.3.
Figure imgf000067_0001
HPLC (max plot) 84.7 %; (254nm) 84.0 %; Rt (min) 3.17; MS: (ESI+) 500.4. HPLC (max pl (ESI+) 419.4.
Figure imgf000068_0001
HPLC (max plot) 95.5 %; (254nm) 94.7%; Rt (min) 2.44; MS: (ESI+) 424.4.
Figure imgf000068_0002
HPLC (max plot) 98.0 %; (254nm) 97.8 %; Rt (min) 3.80; MS: (ESI+) 389.4. m.p. 193.0 - 19 ° C.
HPLC (ma 9.4.
Figure imgf000068_0003
HPLC (max plot) 100 %; (254nm) 100 %; Rt (min) 3.80; MS: (ESI+) 459.4.
Figure imgf000069_0001
Figure imgf000070_0001
HPLC (max plot) 99.0%; (254nm) 98.7 %; Rt (min) 3.73; MS: (ESI+) 473.6.
Figure imgf000070_0002
HPLC (Chiralpak IC ; EtOH :DEA ; 100 :0.1 ) ; (max plot) 99.2% ; Rt (min) 11.02.
HPLC (Chiralpak IC ; EtOH :DEA ; 100 :0.1 ) ; (max plot) 98.2% ; Rt (min) 13.7.
HPLC (max plot) I-) 498.7.
Figure imgf000070_0003
HPLC (max plot) 93.2 %; (254nm) 92.3 %; Rt (min) 2.99; MS: (ESI+) 500.6. HPLC (max pl ) 467.5.
Figure imgf000071_0001
HPLC (max plot) 97.9 %; (254nm) 93.3 %; Rt (min) 3.14; MS: (ESI+) 467.4.
HPLC (max pl 385.4.
Figure imgf000071_0002
HPLC (max plot) 97.9 %; (254nm) 93.3 %; Rt (min) 3.14; MS: (ESI+) 467.4.
Figure imgf000071_0003
HPLC (max plot) 90.2 %; (254nm) 86.4 %; Rt (min) 2.88; MS: (ESI+) 454.5.
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
HPLC (max plot) 99.23%; (254nm) 98.04%; Rt (min) 3.52; MS: (ESI+) 428.30.
/
HPLC (max plot) 99.0 %; (254nm) 98.5 %; Rt (min) 3.17; MS: (ESI+) 484.4. m.p. : 176.30- 180 ° C
Figure imgf000080_0002
HPLC (max plot) 96.7 %; (254nm) 98.6%; Rt (min) 3.38; MS: (ESI+) 457.30; m.p.: 182.00- 214.80 °C
Figure imgf000080_0003
HPLC (max plot) 97.41%; (254nm) 96.82%; Rt (min) 3.67; MS: (ESI+) 445.00. m.p.: 218.70-223.30 ° C
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
In another embodiment the most preferred compounds are piperidines as examples 5, 30, 259, 263, 265, and 284.
In a further embodiment the most preferred compounds are amides and spiro-amides as examples 121 , 233, 234, 278, 250, 251 , 260, 262, 285, 286, and 287.
In another embodiment the most preferred compounds are sulfonyl as examples 279 and 288 and cyclic amides: 254, and 255 and spiro ether from example 267. "CVCe-alkyl" or "CVCs-alkyl group" denotes a linear or branched alkyl chain having 1 to 6 carbon atoms.
"CVCs-alkyl" or "C Cs-alkyl" may also include halo-alkyl. Halo-alkyI contains 1 to 10 halogen atoms, preferably 1 to 3 halogen atoms. Halo-alkyI contains for example a group -CF3, -CHF2 or -CH2F.
A denotes alkyl, this is unbranched (linear) or branched, and has 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1 ,1- , 1 ,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1- , 2- , 3- or 4-methylpentyl, 1 ,1- , 1 ,2- , 1 ,3- , 2,2- , 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2- methylpropyl, 1 ,1 ,2- or 1 ,2,2-trimethylpropyl, furthermore preferably, for example, trifluoromethyl.
A very particularly preferably denotes alkyl having 1 , 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1 ,1 , -trifluoroethyl.
Moreover, A denotes preferably CH2OCH3, OCH2CH2OCH3, CH2OH, CH2NH2,
NHCH2CH2OH, CH2CH2OH, CH2NHCH2 or NHCH2CH3.
Hal preferably denotes CI or F.
R3 preferably denotes H oder CH3.
Q preferably is absent or preferably denotes NR3COCH2, CH2CONR3, COCH(CH3),
CH(CH3)CO, COCH2CH2, CH2CH2CO, CH2, CH2CH2, CH2CO, COCH2, CH(OH)CH2,
CH2CH(OH), CO-C(CH3)2 or (CH3)2C-CO. A "leaving group" denotes a chemical moiety which can be removed or replaced by another chemical group.
Throughout the specification, the term leaving group preferably denotes CI, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifiuoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p tolylsulfonyloxy).
Radicals of this type for activation of the carboxyl group in typical acylation reactions are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme- Verlag, Stuttgart).
Activated esters are advantageously formed in situ, for example through addition of HOBt or N hydroxysuccinimide. Cyclic alkyl (cycloalkyl) preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl or cycloheptyl.
Irrespective of further substitutions, Het denotes, for example, 2- or 3-furyl, 2- or
3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1 ,2,3-triazol-1-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-
3- or -5-yl, 1 ,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-,
4- , 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-,
5- , 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1 ,4- oxazinyl, further preferably 1 ,3-benzodioxol-5-yl, 1 ,4-benzodioxan-6-yl, 2,1 ,3-benzothia- diazol-4-, -5-yl or 2, 1 ,3-benzoxadiazol-5-yl, azabicyclo[3.2.1 joctyl or dibenzofuranyl. The heterocyclic radicals may also be partially or fully hydrogenated.
Irrespective of further substitutions, Het can thus also denote, for example, 2,3-dihydro- 2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1 ,3-di- oxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5- dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4- imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1 ,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1 ,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1 ,4- dioxanyl, 1 ,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2- _4_ or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1 ,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1 ,2,3,4-tetrahydro-l -,-2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo-1 ,4-oxazinyl, furthermore preferably 2,3-methylene- dioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4- ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or also 3,4-dihydro-2H-1 ,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4- dihydro-2-oxo-1 H-quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl, 1 ,3-dihydroindole, 2-oxo-1 ,3-dihydroindole or 2-oxo-2,3- dihydrobenzimidazolyl.
Z preferably denotes isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyridazinyl, triazolyl, pyridyl, pyrazolyl or furyl, each of which is unsubstituted or mono- or disubstituted by methyl, Hal, NH2, CH2COHet2 and/or benzyl.
Z very particularly preferably denotes 1-methyl-1H-pyrazol-4-yl or 6-methyl-pyridazin-4-
Het
Het2 preferably denotes piperidinyl or pyrrolidinyl.
R2 preferably denotes H, Het, Q-Het, Cyc or A.
The invention preferably relates to compounds of the formula (I)
Figure imgf000086_0001
(I)
wherein
R1 is absent,
Z denotes isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyridazinyl, triazolyl, pyridyl, pyrazolyl or furyl, each of which is unsubstituted or mono- or disubstituted by A, Hal, N(R3)2, CH2COHet2 and/or benzyl,
Ra is absent or denotes Hal,
Rb is absent or denotes CONH2, COOH, CONHA, COHet or CH2OH
R2 denotes H, Het, Q-Het, Cyc, A, OA, CH2COOH, NHA, NA2, CH2CONH2,
CH2CONHA, CH(A)CONHA or NR3S02A,
or denotes phenyl, optionally mono- or disubstituted by OA,
Het denotes tetrahydrothiopyranyl, 2-oxa-6-aza-spiro[3.3]heptyl, 2-oxy-7-aza- spiro[3.5]nonyl, 8-aza-bicyclo[3.2.1]octyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, oxetanyl, tetrahydropyranyl, imidazolyl, oxazolyl, piperazinyl, thiazolyl, azepanyl, tetrahydrofuranyl, isoxazolyl, azetidinyl, oxazolidinyl, hexahydroisobenzofuranyl, piperidyl, furyl, pyrrolidinyl, morpholinyl, 1 ,9-dioxa-spiro[5.5]undecyl, 2,5-diaza- bicyclo[2.2.1]heptyl, 3-oxa-bicyclo[3.3.1]nonyl, tetrahydrothiophenyl, 1-aza- spiro[4.5]decyl, 2-aza-spiro[4.5]decyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl,
[1 ,4]oxazepanyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl or 9-aza-bicyclo[3.3.1]nonyl, each of which is unsubstituted or mono-, di- or trisubstituted by CON(R3)2, A, COA, (CH2)nHet\ Hal, Ar , (CH2)nOH, (CH2)nOA, Cyc1, COCyc1, S02A, COHet1 and/or =0,
Cyc denotes cyclohexyl, spiro[3.3]heptyl, cyclopentyl or cyclopentenyi, each of which is unsubstituted or mono- or disubstituted by A, OCH2Cyc1, CONHCH2CN, NHCOA, (CH2)nCONHA, (CH2)nCONA2, COOH, NH2, COHet1, CONHCyc1, CONHHet1, S02A, CH2OH, =0, Het1 and/or SR3(=0)(=NH), Q is absent or denotes NR3COCH2, CH2CONR3, COCH(CH3), CH(CH3)CO, COCH2CH2, CH2CH2CO, CH2, CH2CH2, CH2CO, COCH2, CH(OH)CH2,
CH2CH(OH), CO-C(CH3)2 or (CH3)2C-CO,
A denotes a linear or branched alkyl having 1 to 10 carbon atoms wherein 1 to 7 H atoms may be replaced by a group independently selected from -OR3, Hal, NHS02A, S02A, SOA, N(R3)2, and wherein 1, 2 or 3 non-adjacent -CH2- groups may be replaced by a group independently selected from -CO-, NR3 and/or -0-,
Hal denotes F, CI, Br or I,
Ar1 denotes phenyl, optionally substituted by Hal,
R3 denotes H or Cn-Ce-alkyl wherein 1 H atom may be replaced by a group selected from OH, O-C^Ce-alkyl, and Hal,
Het denotes 2,5-diaza-bicyclo[2.2.1]heptyl, piperazinyl, morpholinyl, azetidinyl,
tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl or piperidinyl, each of which is unsubstituted or mono- or disubstituted by CH2OH, OA, Hal and/or A,
Het2 denotes piperidinyl or pyrrolidinyl,
Cyc1 denotes cycloalkyl with 3-7 atoms, optionally mono-, di- or trisubstituted by A, =0 and/or OH, n denotes 0, 1 , 2 or 3
and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios.
CHEMISTRY PART
The following abbreviations refer to the abbreviations used below:
Ac (acetyl), BINAP (2,2'-bis(disphenylphosphino)-1 ,1 '-binaphthalene), dba (dibenzylidene acetone), Bu (Butyl), tBu (fe/t-Butyl), DCE (dichloroethane), DCM (Dichloromethane), DIEA (di-isopropyl ethylamine), DMA (dimethyl acetamide), DMSO (Dimethyl Sulfoxide), DMF (Ν,Ν-Dimethylformamide), Dppf (1 ,1 -bis (diphenyl phosphine ferrocene)), EtOAc (Ethyl acetate), EtOH (Ethanol), g (gram), cHex (Cyclohexane), HATU (N-[(Dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N- methylmethanaminiumhexafluoro phosphate), HPLC (High Performance Liquid Chromatography), hr (hour), LDA (lithium diisopropyl amine), LiHMDS (lithium bis(trimethylsilyl)amide), MHz (Megahertz), MeOH (Methanol), min (minute), mL (milliliter), mmol (millimole), mM (millimolar), mp (melting point), MS (Mass Spectrometry), MW (microwave ), NMR (Nuclear Magnetic Resonance), O/N (overnight), PBS (Phosphate Buffered Saline), PPh3 (triphenylphosphine), RT (room temperature), TEA (Triethyl amine), TFA (Trifluoroacetic acid), THF (Tetrahydrofuran), TLC (Thin Layer Chromatography), oTol (ortho-tolyl), UV (Ultraviolet).
In general, the compounds according to Formula (I) and related formulae of this invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they may be prepared by standard synthetic techniques. In general, the synthesis pathways for any individual compound of Formula (I) and related formulae will depend on the specific substituents of each molecule, such factors being appreciated by those of ordinary skilled in the art. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of Formula (I) and related formulae. Reaction conditions depicted in the following schemes, such as temperatures, solvents, or co-reagents, are given as examples only and are not restrictive. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999.
Depending on the nature of R1, R2, Ra, Rb and Z different synthetic strategies may be selected for the synthesis of compounds of Formula (I). In the process illustrated in the following schemes, R1, R2, Ra, R and Z are as above defined in the description unless otherwise mentioned. Compounds of formula (I) wherein R1, R2, Ra, Rb and Z are as above defined can be prepared by Suzuki-Miyura coupling reaction between a compound of Formula (II), wherein R1 , Ra and Z are as above defined and X is an halogen (preferably bromine or iodine) or a inflate group, and a boronic acid or ester of Formula (III) wherein R2 and Rb are as above defined and R is H or an alkyl group as outlined in Scheme 1. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Takahiro I. and Toshiaki M., Tetrahedron Lett. 2005, 46, 3573-3577). In a typical procedure, an aryl halide of Formula (II) and a boronic acid or ester of Formula (III) are heated in a suitable solvent, such as THF, toluene, DMF or dioxane, in the presence or absence of water as a co-solvent, in the presence of a base, such as Cs2C03, K2C03, CsF, and with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh3)4 or 1 , 'Tbis(diphenylphosphino)ferrocenedichloro palladium(ll), Pd(OAc)2, Pd2(dba)3, Pd(CI)2(PPh3)2 or Pd/C in the presence or absence of an additionnal ligand, such as but not limited to P(iBu)3, P(oTol)3, PPh3, BINAP. This coupling reaction can be carried out at a temperature between about 20 °C to about 150 °C, preferably at about 120 °C, for a few minutes to a few hours, possibly under microwave irradiation.
Scheme 1
Figure imgf000090_0001
(I)
Generally, compounds of Formula (I Is), wherein R1, Ra and Z are as above defined and X is bromine, can be obtained as outlined in Scheme 2. Compounds of Formula (IV), wherein R1 and Z are as above defined and R is H or an alkyl group can be coupled with a compound of Formula (V), wherein Ra is as above defined, by a Suzuki-Miyura coupling reaction to give a compound of general formula (VI) wherein R , Ra and Z are as above defined. General protocols for such coupling are given below in the Examples: in a typical procedure, the aryl halide of Formula (V) and the boronic acid or ester of Formula (IV) are heated in a suitable solvent, such as THF, toluene, DMF or dioxane, in the presence or absence of water as a co-solvent, in the presence of a base, such as as Cs2C03, K2C03, CsF, and with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh3)4 or 1 ,1'- bis(diphenylphosphino)ferrocenedichloro palladium(ll), Pd(OAc)2, Pd2(dba)3, Pd(CI)2(PPh3)2 or Pd/C in the presence or absence of an additionnal ligand, such as but not limited to P(fBu)3, P(oTol)3, PPh3, BINAP. This coupling reaction can be carried out at a temperature between about 20 °C to about 150 °C, preferably at about 120 °C, for a few minutes to a few hours, possibly under microwave irradiation.
Compounds of Formula (VI), wherein R , Ra and Z are as above defined, can be converted in compounds of Formula (VII), wherein R1, Ra and Z are as above defined, by reaction with an appropriate source of boron, such as but not limited to bis(pinacolato)diboron, bis(catecholate)diboron, bis(diethyl-D-tartrate glycolato)diboron, bis(hexyleneglycolato)diboron, bis(neopentylglycolato)di boron, preferably bis(pinacolato)diboron in the presence of a suitable catalyst, such as but not limited to 1 ,1'bis(diphenylphosphino)ferrocenedichloropalladium(ll), dichlorobis(triphenylphosphine )palladium(ll), Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3, Pd(CI)2(PPh3)2, preferably 1 ,1'bis(diphenylphosphino)ferrocenedichloro palladium(ll), in the presence of a suitable base such as but not limited to potassium acetate, cesium fluoride, potassium carbonate, preferably potassium acetate, in the presence of a solvent such as but not limited to THF, dioxane, DCE, DMF, preferably THF or dioxane, at a temperature between about 20 °C to about 150 °C, preferably at about 120 °C, for a few minutes to a few hours, possibly under microwave irradiation.
The compounds of Formula (VII), wherein R1, Ra and Z are as above defined, can be reacted with 5-bromo-2-iodopyrimidine to give the compounds of Formula (Ha), wherein R1, Ra and Z are as above defined, by a Suzuki-Miyura coupling reaction. General protocols for such coupling are given below in the Examples: in a typical procedure, the 5-bromo-2-iodopyrimidine and the boronic acid or ester (xx) are heated in a suitable solvent, such as THF, toluene or dioxane, in the presence or absence of water as a co- solvent, in the presence of a base, such as as Cs2C03, K2C03i CsF, and with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh3)4 or 1 ,1 '- bis(diphenylphosphino)ferrocenedichloro palladium(ll), Pd(OAc)2, Pd2(dba)3, Pd(CI)2(PPh3)2 or Pd/C in the presence or absence of an additionnal ligand, such as but not limited to P(iBu)3, P(oTol)3, PPh3> BINAP. This coupling reaction can be carried out at a temperature between about 20 °C to about 150 °C, preferably at about 120 °C, for a few minutes to a few hours, possibly under microwave irradiation.
Scheme 2
Figure imgf000092_0001
Alternatively, compounds of formula (I) wherein R1, R2, Ra, Rb and Z are as above defined can be prepared by Suzuki-Miyura coupling reaction between a compound of Formula (VIII), wherein R , Ra and Z are as above defined and R is H or an alkyl group, and a compound of Formula (IX) wherein R2 and Rb are as above defined and X is an halogen (preferably bromine or iodine) or a triflate group as outlined in Scheme 3. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such coupling (see for example Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Takahiro I. and Toshiaki M., Tetrahedron Lett. 2005, 46, 3573-3577). In a typical procedure, an aryl halide of Formula (II) and a boronic acid or ester of Formula (III) are heated in a suitable solvent, such as THF, toluene or dioxane, in the presence or absence of water as a co-solvent, in the presence of a base, such as as Cs2C03, K2C03 CsF, and with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh3)4 or 1 ,1'-bis(diphenylphosphino)ferrocenedichloro palladium(ll), Pd(OAc)2, Pd2(dba)3, Pd(CI)2(PPh3)2 or Pd/C in the presence or absence of an additionnal ligand, such as but not limited to P(fBu)3, P(oTol)3, PPh3, BINAP. This coupling reaction can be carried out at a temperature between about 20 °C to about 150 °C, preferably at about 120 °C, for a few minutes to a few hours, possibly under microwave irradiation.
Compounds of Formula (VIII), wherein R1, Ra and Z are as above defined and R is H or an alkyl group, can be prepared from compounds of Formula II, wherein R1, Ra and Z are as above defined and X is an halogen (preferably bromine or iodine) or a triflate group, by reaction with an appropriate diboron derivative, such as but not limited to bis(pinacolato)diboron, bis(catecholate)diboron, bis(diethyl-D-tartrate glycolato)diboron, bis(hexyleneglycolato)diboron, bis(neopentylglycolato)diboron, preferably bis(pinacolato)diboron, in the presence of a suitable catalyst, such as but not limited to 1 ,1 'bis(diphenylphosphino)ferrocenedichloro palladium(ll), dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3, Pd(CI)2(PPh3)2, preferably 1 ,1'bis(diphenylphosphino)ferrocenedichloro palladium(ll), in the presence of a suitable base such as but not limited to potassium acetate, cesium fluoride, potassium carbonate, preferably potassium acetate, in the presence of a solvent such as but not limited to THF, dioxane, DCE, DMF, preferably THF or dioxane, at a temperature between about 20 °C to about 150 °C, preferably at about 120 °C, for a few minutes to a few hours, possibly under microwave irradiation.
Scheme 3
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000094_0003
Alternatively, compounds of Formula I, wherein R , R2, Ra, Rb and Z are as above defined, can be prepared as depicted in Scheme 4. A 2-aminopyrimidine of Formula (X), wherein X is an halogen (preferably iodine or bromine) or a trifluoromethanesulfonate group, is coupled with a boronic acid derivative of Formula (III), wherein R2, Rb are as above defined and R is H or an alkyl group to give a compound of general folrmula (XI) wherein wherein R2 and Rb are as above defined under Suzuki-Miyaura conditions, well known to those skilled in the art to perform such couplings, as described above.
. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such couplings. The resulting 2-aminopyridine of Formula (XI), wherein R2 and Rb are as above defined, can be converted to a 2-iodopyrimidine of Formula (XII), wherein R2 and Rb are as above defined, for example by reaction with a suitable source of iodine, such as but not limited to diiodomethane, iodine, /V-iodosuccinimide, in the presence of an alkyl nitrite such as but not limited to ferf-butyl nitrite or so-pentyl nitrite, in the presence of copper (I) iodide, in a suitable solvent, such as but not limited to THF or dioxane, at a temperature between about 20 °C to about 150 °C, preferably at about 80-100 °C, for a few hours.
Compounds of Formula (XIV), wherein R2, Ra, and Rb are as above defined, can be obtained by coupling of a compound of Formula (XII), wherein R2 and Rb are as above defined, with a boronic acid deribative of Formula (XIII), wherein Ra is as above defined and R is H or an alkyl group, under Suzuki-Miyaura conditions, well known to those skilled in the art to perform such couplings, as described above.
Conversion of compounds of Formula (XIV), wherein R2, Ra, and Rb are as above defined, to compounds of Formula (XV), wherein R2, Ra, and Rb are as above defined, can be accomplished using similar conditions as described above for the conversion of an aromatic or heteroaromatic amine into an aromatic or heteroaromatic iodide, for example by reaction with a suitable source of iodine, such as but not limited to diiodomethane, iodine, /V-iodosuccinimide, in the presence of an alkyl nitrite such as but not limited to terf-butyl nitrite or so-pentyl nitrite, in the presence of copper (I) iodide, in a suitable solvent, such as but not limited to THF or dioxane, at a temperature between about 20 °C to about 150 °C, preferably at about 80-100 °C, for a few hours.
Finally, compounds of Formula I, wherein R1, R2, Ra, Rb and Z are as above defined, can be obtained by coupling of a compound of Formula (XV), wherein R2, Ra, and Rb are as above defined, with a boronic acid deribative of Formula (IV), wherein R1 and Z are as above defined and R is H or an alkyl group, under Suzuki-Miyaura conditions, well known to those skilled in the art to perform such couplings, as described above.
Scheme 4
Figure imgf000096_0001
(IV) (I)
Alternatively, compounds of Formula I, wherein R1, R2, Ra, Rb and Z are as above defined, can be prepared as depicted in Scheme 5. Aryl iodides of Formula (XV), wherein R2, Ra and Rb are as above defined, can be converted to compounds of Formula (XVI), wherein R2, Ra and Rb are as above defined and R is H or an alkyl group, by reaction with an appropriate diboron derivative, such as but not limited to bis(pinacolato)diboron, bis(catecholate)diboron, bis(diethyl-D-tartrate glycolato)diboron, bis(hexyleneglycolato)diboron, bis(neopentylglycolato)diboron, preferably bis(pinacolato)diboron, in the presence of a suitable catalyst, such as but not limited to 1 ,1'bis(diphenylphosphino)ferrocenedichloro palladium(ll), dichlorobis(triphenylphosphine)palladium(ll), Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3, Pd(CI)2(PPh3)2, preferably 1 ,1'bis(diphenylphosphino)ferrocenedichloro palladium(ll), in the presence of a suitable base such as but not limited to potassium acetate, cesium fluoride, potassium carbonate, preferably potassium acetate, in the presence of a solvent such as but not limited to THF, dioxane, DCE, DMF, preferably THF or dioxane, at a temperature between about 20 °C to about 150 °C, preferably at about 120 °C, for a few minutes to a few hours, possibly under microwave irradiation.
Compounds of Formula I, wherein R1, R2, Ra, Rb and Z are as above defined, can be obtained by coupling of a compound of Formula (XVI), wherein R2, Ra and Rb are as above defined and R is H or an alkyl group, with a compound of Formula (XVII), wherein R1 and Z are as above defined, under Suzuki-Miyaura conditions, well known to those skilled in the art to perform such couplings, as described above. Scheme 5
Figure imgf000097_0001
(I)
Alternatively, compounds of formula (I) wherein R1, R2, Ra, Rb and Z are as above defined can be prepared by Suzuki-Miyura coupling reaction between a compound of Formula (XII), wherein R2 and Rb are as above defined, and a compound of Formula (VII) wherein R1, Ra and Z are as above defined and R is H or an alkyl group as outlined in Scheme 6. The reaction can be carried out using the general conditions described above. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to perform such couplings.
Scheme 6
Figure imgf000097_0002
Alternatively, compounds of Formula (I), wherein R , R2, Ra, Rb and Z are as above defined, can be prepared as depicted in Scheme 7 from compounds of Formula (la), wherein R1 , Ra, Rb and Z are as above defined and R2 is H, prepared following one of the routes described above, by reaction with a compound of Formula (XVIII), wherein R2 is as above defined, but not H and LG is a leaving group, such as bromine, chlorine, alkylsulfonate or any other suitable leaving group known to those skilled in the art. General protocols for such transformation are given below in the Examples, using conditions and methods well known to those skilled in the art. In a typical procedure, a compound of Formula (la) is treated with a base, such as but not limited to NaH, K2C03, Cs2C03, LDA, LHMDS, preferably NaH, and with a compound of Formula (XVIII), in a suitable solvent like THF, dioxane, DMF, DMA, at a temperature between -20 °C to about 150 °C, for a time between a few minutes to a few hours.
Alternatively, as depicted in Scheme 7, compounds of Formula (I), wherein R1, R2, Ra, Rb and Z are as above defined, can be prepared from compounds of Formula (lb), wherein R1, Ra, Rb and Z are as above defined and R2 is H, prepared following one of the routes described above, by reaction with an alcohol of Formula (XIX), wherein R2 is as above defined, but n ot H , using conditions well known to those skilled in the art for a Mitsunobu reaction (see for example Hughes, D. L. Organic Reactions (New York), 1992, 42, 335-656; Reynolds, A. J.; Kassiou, M. Current Organic Chemistry, 2009, 13 (16); 1610-1632). Typically, the reaction takes place in the presence of a phosphine, such as but not limited to P(fBu)3, PPBu3, P(oTol)3, PPh3, in the presence of an azadicarboxylate, such as but not limited to diethylazadicarboxylate, diisopropylazadicarboxylate, Tetramethylazodicarboxamide, in a solvent such as THF, dioxane, DCM, DCE, at a temperature between -20 °C to about 150 °C, preferably at room temperature, for a time between a few minutes to a few hours.
Scheme 7
Figure imgf000098_0001
(lb) (XIX) (I)
Compounds of this invention can be isolated in association with solvent molecules by crystallization from an appropriate solvent or by evaporation of an appropriate solvent.
The pharmaceutically acceptable anionic salts of the compounds of Formula (I), which contain a basic center, may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
The pharmaceutically acceptable cationic salts of the compounds of Formula (I), which contain an acidic center, may be prepared in a conventional manner. For example, a solution of the free acid may be treated with a suitable base, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. In some cases, salts can be prepared by mixing a solution of the acid with a solution of an alkali or earth alkali salt (such as sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired alkali or earth alkali salt of the compounds of formula (I) precipitates, or can be otherwise isolated by concentration and addition of a non-solvent.
Both types of salts may be formed or interconverted using ion-exchange resin techniques. Depending on the conditions used, the reaction times are generally between a few minutes and 14 days. The reaction temperature is between about -30°C and about 140°C, normally between -10°C and 90°C, in particular between about 0°C and 70°C.
Compounds of the formula (I) and related formulae can furthermore be obtained by liberating compounds of the formula (I) from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R*-N group, in which R* denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a -COOR** group, in which R** denotes a hydroxyl-protecting group, instead of a -COOH group. It is also possible for a plurality of - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively. The term "amino-protecting group" is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl;
aralkanoyi, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyi, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl;
aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protecting groups are BOC and Mtr, further-rnore CBZ, Fmoc, benzyl and acetyl.
The term "hydroxyl-protecting group" is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms. Examples of hydroxyl-protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred. The compounds of the formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature). The BOC, OtBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of
dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
Protecting groups which can be removed hydrogenolytically (for example CBZ, benzyl or the liberation of the amidino group from the oxadiazole derivative thereof) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 20-30°C and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or
dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n- butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyhformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
Esters can be hydrolysed, for example, using HCI, H2S04, or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100°C.
Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and +30°C.
The formula (I) and related formulae also encompasses the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. The term "solvates of the compounds" is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
The term "pharmaceutically usable derivatives" is taken to mean, for example, the salts of the compounds of the formula f and so-called pro^drug compounds. The term "prodrug derivatives" is taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the active compounds. Preferably "prodrug", as of the compounds of formula I, refers to derivative compounds that are rapidly transformed in vivo to yield the parent compound of the formula I, as for example by hydrolysis in blood. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.
Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York ( 987). It is intended that these references, and any others cited throughout this specification, are incorporated herein by reference.
These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 1 5, 61-67 (1995).
The formula (I) and related formulae also encompasses mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 : 10, 1 :100 or 1 :1000.
These are particularly preferably mixtures of stereoisomeric compounds.
Pharmaceutical formulations can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.
Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including
subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s). Pharmaceutical formulations adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in- water liquid emulsions or water-in-oil liquid emulsions. Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active-ingredient component can be combined with an oral, non-toxic and
pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavour, preservative, dispersant and dye may likewise be present.
Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. A
disintegrant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica-ment after the capsule has been taken.
In addition, if desired or necessary, suitable binders, lubricants and disintegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry- pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
Oral liquids, such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compounds. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be for-mulated by dispersion of the compounds in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added. The dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.
The compounds of the formula (I), and related formulae and salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
The compounds of the formula (I), and related formulae and the salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled to soluble polymers as targeted medicament carriers. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamidophenol,
polyhydroxyethylaspartamido-phenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds may furthermore be coupled to a class of
biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels. Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the plaster by
iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as topical ointment or cream. In the case of formulation to give an ointment, the active ingredient can be employed either with a paraffinic or a water-miscible cream base. Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or sus-pended in a suitable carrier, in particular an aqueous solvent. Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas. Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.
Pharmaceutical formulations adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurised dispensers with aerosols, nebulisers or insuf-flators.
Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration- include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavours. A therapeutically effective amount of a compound of the formula (I), and related formulae and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of
administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be
administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se. The present invention furthermore relates to a method for treating a subject suffering from a IRAK related disorder, comprising administering to said subject an effective amount of a compound of formula I and related formulae. The present invention preferably relates to a method, wherein the IRAK associated disorder is an autoimmune disorder or condition associated with an overactive immune response or cancer. The present invention furthermore relates to a method of treating a subject suffering from an immunoregulatory abnomality, comprising administering to said subject a compound of formula (I), and related formulae in an amount that is effective for treating said immunoregulatory abnormality.The present invention preferably relates to a method wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma. The present invention furthermore relates to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft- versus-host disease. The present invention furthermore relates to a method wherein the immunoregulatory abnormality is selected from the group consisting of: transplantation of organs or tissue, graft-versus-host diseases brought about by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post- infectious autoimmune diseases including rheumatic fever and post-infectious
glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper- responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia,
osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergy sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic" liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, parkison diseases.trauma, and chronic bacterial infection.
Preferrably, disorders associated with IRAK are selected from Rheumatoid Arthritis Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh's Disease and Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin- associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA ( Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, Parkinson's disease, Cancer. Preferred compounds of formula (I), and related formulae exhibit a IC50 for the binding to IRAK of less than about 5 μΜ, preferably less than about 1 μΜ and even more preferably less than about 0.100 μΜ.
Compounds according to formula formula (I), and related formulae may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation
procedures.
In general, the synthesis pathways for any individual compound of formula (I), and related formulae will depend on the specific substitutents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
Compounds of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent. The pharmaceutically acceptable acid addition salts of the compounds of formula (I), and related formulae which contain a basic center may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of formula (I), and related formulae, which contain an acid center, with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
If the above set of general synthetic methods is not applicable to obtain compounds according to Formula (I) and/or necessary intermediates for the synthesis of compounds of Formula (I), suitable methods of preparation known by a person skilled in the art should be used. In general, the synthesis pathways for any individual compound of Formula (I) will depend on the specific substituents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art. For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999.
In the following the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention.
EXPERIMENTAL PART. In the following the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention.
General:
The HPLC data provided in the examples described below were obtained as followed. Condition A: Column Waters XbridgeT C8 50 mm x 4.6 mm at a flow of 2 mL/min; 8 min gradient H20:CH3CN:TFA from 100:0:0.1 % to 0:100:0.05 %.
UV detection (maxplot) for all conditions.
The MS data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Waters ZMD (ESI).
The NMR data provided in the examples described below were obtained as followed: 1 H-NMR: Bruker DPX-300MHz or Bruker AV-400 MHz.
Autopreparative LC/MS purifications were performed with a mass directed autopurification Fractionlynx from Waters equipped with a Sunfire Prep C18 OBD column 19x100 mm 5 μΐη, unless otherwise reported. All HPLC purifications were performed with a gradient of ACN/H20 or ACN/H20/HCOOH (0.1 %).
The microwave chemistry was performed on a single mode microwave reactor Emrys™ Optimiser or Initiator™ Sixty from Biotage.
The compounds of invention have been named according to the standards used in the program Autonom.
The compounds according to formula (I) can be prepared from readily available starting materials by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols or mixed solution and solid phase protocols. Examples of synthetic pathways are described below in the examples. Unless otherwise stated, compounds of Formula (I) and related formulae obtained as a racemic mixture can be separated to provide an enantiomerically enriched mixture or a pure enantiomer.
The commercially available starting materials used in the following experimental description were purchased from Aldrich or Sigma or ABCR unless otherwise reported. SPE cartridges were purchased from 1ST and used following supplier recommendations. Intermediate 1 : 1-methyl-4-[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]-1 H-pyrazoIe
Figure imgf000113_0001
To a solution of 4-(3-Bromo-phenyl)-1-methyl-1 H-pyrazole (Otava, 410 mg, 1.7 mmol) in dry DMF (10 mL) was added bis(pinacolato)diborane (525 mg, 2.0 mmol) and dried KOAc (340 mg, 3.4 mmol). The reaction mixture was degassed for 20 min before the addition of dppf (48 mg, 0.09 mmol) and (dppf)PdCb CH2CI2 (71 mg, 0.09 mmol). The reaction mixture was then heated at 80°C O/N. It was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (550 mg, 92%). H NMR (300 MHz, DMSO-d6) δ 8.24 - 8.15 (s, 1 H), 7.89 - 7.82 (d, J - 0.9 Hz, 1 H), 7.82 - 7.76 (t, J = 1.3 Hz, 1 H), 7.73 - 7.64 (m, 1H), 7.53 - 7.45 (m, 1 H), 7.42 - 7.29 (m, 1 H), 3.89 - 3.82 (s, 3H), 1.34 - 1.26 (s, 12H).
Intermediate 2: 5-bromo-2- -(1-methyl-1 H-pyrazol-4-yI)phenyl]pyrimidine
Figure imgf000113_0002
To a solution of 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenyl]-1 H-pyrazole (intermediate 1 , 5.0 g, 17.5 mmol) in 1 ,4-dioxane (80 mL) was added 5-Bromo-2-iodo-pyrimidine (6.0 g, 21.0 mmol) and potassium carbonate (7.3 g, 5.25 mmol) in a sealed tube. The reaction mixture was purged with nitrogen for 30 min. Then Tetrakis(triphenyl phospine)Palladium(O) (2.02 g, 0.17 mmol) was added and the reaction mixture was heated at 100°C O/N. It was filtered through a celite pad and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (EtOAc/hexane) afforded the title compound as a yellow solid (2.5 g, 45%). 1H NMR (400 MHz, DMSO-d6): 5 9.09 (s, 1 H), 8.49 (t, J = 1.64 Hz, 1 H), 8.25 (s, 1 H), 8.18 (dd, J = 1.2, 4.74 Hz, 1 H), 7.90 (d, J = 1.2 Hz, 1 H), 7.75-7.73 (m, 1 H), 7.52 (t, J = 4.0 Hz, 1 H), 3.88 (s, 3H). HPLC (Condition A): Rt 4.19 min (purity 98.9%). MS (ESI+): 317.0. Intermediate 3: 5-Bromo-2-(3-pyridin-3-yl-phenyl)-pyrimidine
Figure imgf000114_0001
The title compound was obtained following procedure described for intermediate 2, but starting from 5-Bromo-2-iodo-pyrimidine and 3-[3-(4,4,5,5-Tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-pyridine (prepared as described in Chemical Communications, 2008, 7, 889-890) as a yellow solid. MS (ESI+): 312.0.
Intermediate 4: 3-(5-bromopyrimidin-2-yl)aniline
Figure imgf000114_0002
A mixture of 5-Bromo-2-iodo-pyrimidine (9.0 g; 31.6 mmol; 1.0 eq.), 3- aminophenyl boronic acid (4.3 g; 31.6 mmol; 1.0 eq.), K2C03 (17.5 g; 126.4 mmol; 4.0 eq.) and Pd(PPh3)4 (1.83 g; 1.58 mmol; 0.05 eq.) in water/dioxane (67: 135 ml_) was heated overnight at 100°C. The reaction mixture was then diluted with EtOAc and organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige solid (7.6 g; 96 %). HPLC (Condition A): Rt 1.90 min (purity 78.0%). MS (ESI+): 250.1.
Intermediate 5: tert-butyl 4-{4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1- y l}piperidine-1 -carboxylate
Step 1 : Formation of tert-butyl 4-{4-f2-(3-aminophenyl)pyrimidin-5-yri-1 H-pyrazol- 1-yl}piperidine-1 -carboxylate
Figure imgf000114_0003
A mixture of 3-(5-bromopyrimidin-2-yl)aniline (intermediate 4, 220 mg; 0.88 mmol; 1.0 eq.), 1-(1-Boc-piperidino)pyrazole-4-boronic acid (389 mg; 1.3 mmol; 1.5 eq.), Pd(PPh3)4 (51 mg; 0.04 mmol; 0.05 eq.) and K2C03 (365 mg; 2.6 mmol; 3.0 eq.) in dioxane/water (3.3: 1.65 mL) was heated at 120X for 30 min in a sealed tube in MW. The reaction mixture was then diluted with EtOAc. The two phases were separated and aqueous phase was extracted with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated. Flash chromatography on silica (EtOAc: heptane, gradient from 50:50 to 100:0) afforded the title compound a beige solid (240 mg; 65 %). H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.52 (s, 1 H), 8.11 (s, 1 H), 7.67 (t, J= 2.0 Hz, 1H), 7.57-7.53 (m, 1 H), 7.14 (t, J= 7.8 Hz, 1 H), 6.69-6.66 (m, 1 H), 5.25 (s, 2H), 4.46-4.36 (m, 1 H), 4.08-4.04 (m, 2H), 2.94 (m, 2H), 2.08-2.04 (m, 2H), 1.87-1.75 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 3.03 min (purity 99.0%). MS (ESI+): 421.4.
Step 2: Formation of tert-butyl 4-(4-i2-(3-iodophenyl)pyrimidin-5-yl'|-1 H-pyrazol-1- yl)piperidine-1-carboxylate
Figure imgf000115_0001
Isopentyl nitrite (192 μΙ; 1.43 mmol; 3.0 eq.) was added to a solution of tert-butyl 4-4-[2- (3-aminophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5, step 1 , 200 mg; 0.48 mmol; 1.0 eq.), Copper(l) iodide (91 mg; 0.48 mmol; 1.0 eq.) and diiodomethane (193 μΙ; 2.38 mmol; 5.0 eq.) in dry THF (8.0 mL) and the reaction mixture was refluxed for 2 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to dryness. Purification by flash chromatography (EtOAc:heptane, gradient from 20:80 to 50:50) afforded the title compound as a white solid (200 mg; 67 %).1H NMR (300 Mz, DMSO-d6) δ 9.17 (s, 2H), 8.71 (t, J= 1.7 Hz, 1 H), 8.56 (s, 1H), 8.40-8.37 (m, 1 H), 8.15 (s, 1 H), 7.90 -7.86 (m, 1 H), 7.35 (t, J= 7.9 Hz, 1 H), 4.48-4.38 (m, 1 H), 4.08-4.03 (m, 2H), 2.95 (m, 2H), 2.08-2.05 (m, 2H), 1.87-1.73 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 5.47 min (purity 91.0%). MS (ESI+): 532.4
Intermediate 6: tert-butyl 4-[4-(2-iodopyrimidin-5-yl)-1 H-pyrazol-1 -yl]piperidine-1- carboxylate Step 1 : Formation of tert-butyl 4-f4-(2-aminopyrimidin-5-yl)-1 H-pyrazol-1-yllpipe dine-1- carboxylate
Figure imgf000116_0001
The title compound was obtained following procedure described for intermediate 5, step 1 , but starting from 2-amino-5-bromopyrimidine (1.28 g; 7.36 mmol; 1.0 eq.) and 4-[4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1 -yl]-piperidine-1 -carboxylic acid tert-butyl ester (2.57 g; 6.81 mmol; 1.00 eq.), as a yellow solid (1.39 g, 49%1 H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 2H), 8.19 (s, 1 H), 7.82 (s, 1 H), 6.58 (s, 2H), 4.41 - 4.27 (m, 1 H), 4.04 (m, 2H), 2.91 (m, 2H), 2.08 - 1.95 (m, 2H), 1.86 - 1.67 (m, 2H), 1.42 (s, 9H). MS (ESI+): 345.5.
Step 2: Formation of tert-butyl 4-f4-(2-iodopyrimidin-5-yl)-1 H-pyrazol-1-vnpiperidine-1- carboxylate
Figure imgf000116_0002
The title compound was obtained following procedure described for intermediate 5, step 2, but starting from tert-butyl 4-[4-(2-aminopyrimidin-5-yl)-1 H-pyrazol-1-yl]piperidine-1- carboxylate (1.4 g; 3.31 mmol; 1.0 eq.) as a yellow solid (980 mg, 61 %). 1 H NMR (300 MHz, DMSO-d6) 88.84 (s, 2H), 8.52 (s, 1 H), 8.09 (s, 1 H), 4.48 - 4.32 (m, 1 H), 4.15 - 3.95 (m, 2H), 3.07 - 2.76 (m, 2H), 2.08-2.00 (m, 2H), 1.87 - 1.68 (m, 2H), 1.42 (s, 9H). MS (ESI+): 456.4. Intermediate 7: 1-Pyrrolidin-1-yl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- pyrazol-1 -yI]-ethanone
Figure imgf000117_0001
A solution of 1-(bromoacetyl)pyrrolidine (Chemical Diversity Labs; 3.0 g, 15.6 mmol, 1.2 eq.) in acetonitrile (15 mL) was slowly added over a suspension of pyrazole-4-boronic acid pinacol ester (2.5g, 12.9 mmol, 1 eq.) in acetonitrile and stirred overnight at RT. The reaction mixture was filtered and the filtrate was diluted with DCM and washed with water then brine. Separated organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (2.72 g, 100%).
Intermediate 8: 1-[2-fluoro-1-(fluoromethyl)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole
Figure imgf000117_0002
To a stirred solution of Pyrazole-4-boronic acid pinacol ester (6.6 g, 34 mmol, 1 eq.) in dry THF (150mL) was added 1 ,3-Difluoro-2-propanol (5.1 g, 51 mmol, 1.5 eq.) followed by triphenylphosphine (13,5 g, 51 mmol, 1.5 eq.) and Diisopropyl azodicarboxylate (10.5 g, 51 mmol, 1.5 eq.) at 0 °C under nitrogen atmosphere. After the addition, the reaction mixture was stirred at RT for 48 h. The reaction mixture was concentrated under vacuum and the residue was solubilized in EtOAc, washed with water (three times), dried over sodium sulfate, filtered and concentrated. The crude product was redissolved in EtOAc and Pet. Ether was added. The precipitate obtained was filtered off and the filtrate concentrated under reduced pressure to give the title compound as a oil (contaminated with triphenyl phosphine oxide). Intermediate 9: tert-butyl-trans- 3-fluoro-4-[(methylsulfonyl)oxy]piperidine-1- carboxylate
Step 1 : Formation of tert-Butyl roxypiperidine-1-carboxylate
Figure imgf000118_0001
Sodium borohydride (1.53 g, 40.5 mmol) was added to a stirred solution of tert-butyl 3- fluoro-4-oxopiperidine-1-carboxylate ( OmegaChem, 8 g, 36.8 mmol) in dry methanol (100 mL) maintained at 0 °C. The reaction mixture was stirred at same temperature for 45 min, it was then quenched with dry acetone (20 mL) and evaporated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine. It was dried over sodium sulfate, filtered and concentrated. Purification by flash
chromatography on silica (Pet. Ether: EtOAc, 80:20) afforded the titled compound as white solid (4.0 g, 50 %). 1 H NMR (400MHz, DMSO-d6) d 4.61 (ddd, J = 39, 8.6, 3.2 Hz, 1 H), 3.93 (m, 2H), 3.71 (bs, 1 H), 3.42 (brs, 1 H), 3.06-3.00 (m, 1 H), 1.88-1.83 (m, 2H), 1.45 (s, 9H). HPLC (Condition A): Rt 2.7 min (purity 97 %).
Step 2: Formation of tert-butyl-cis 3-fluoro-4-[(methylsulfonyl)oxy]piperidine-1- carboxylate
Figure imgf000118_0002
Methane sulfonyl chloride (142 μΙ; 1.84 mmol; 1.2 eq.) was added to a solution of tert- butyl ester-trans-3-Fluoro-4-hydroxy-piperidine-1-carboxylic acid (336 mg; 1.53 mmol; 1.0 eq.) in DCM (5 mL) and TEA (320 ul, 2.3 mmol, 1.5 eq.) maintained at 0°C under nitrogen atmosphere. The reaction mixture was then stirred at RT for 3h. It was poured into a saturated solution of NH4CI. The phases were separated and aqueous phase was extracted twice with DCM. Combined organic phases were washed with sta. NaHC03 and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a white solid (432 mg, 95%). 1 H NMR (300 MHz, DMSO) δ 4.81 -4.95 (m, 2H), 4.05 (m ,1 H), 3.84 (m, 1 H), 3.25 (s, 3H), 3.13 (m, 1 H), 2.94 (m, 1H), 1.84 (m, 2H), 1.38 (s, 9H).
Intermediate 10: 3-Bromo-5-(1-methyl-1 H-pyrazol-4-yl)-phenol
Figure imgf000119_0001
1-Methyl-4-(4,4,5l5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (750 mg; 3.6 mmol; 1.0 eq.), 3,5-Dibromo-phenol (4.54 g; 18.0 mmol; 5.0 eq.), bis(triphenylphosphine)palladium(ll) chloride (253 mg; 0.36 mmol; 0.1 eq.) and potassium carbonate (2.49 g; 18.02 mmol; 5 eq.) were suspended in DMF (80 mL) and water (1 mL). The reaction mixture was then heated at 80°C for 16h in a sealed tube. It was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 10:90) afforded the title compound as a clear oil (337mg, 30%). 1 H NMR (300 MHz, DMSO-d6) 510.01 (brs, 1 H), 8.14 (s, 1 H), 7.83 (d, J = 0.7 Hz, 1 H), 6.96 (d, J = 1.7 Hz, 1 H), 6.92 (dd, J = 2.1 , 1.5 Hz, 1 H), 6.76 (t, J = 2.0 Hz, 1 H), 3.84 (s, 3H).
Intermediate 11 : 2-(3-lodo-phenyl)-5-(1H-pyrazol-4-yl)-pyrimidine
Step 1 : Formation of 3-f5-(1 H-Pyrazol-4-yl)-pyhmidin-2-yll-phenylamine
Figure imgf000119_0002
4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (20.7 g; 70.4 mmol; 1.0 eq.), 3-(5-Bromo-pyrimidin-2-yl)-phenylamine (intermediate 4, 17.6 g; 70.4 mmol; 1.0 eq.), bis(triphenylphosphine)palladium(ll) chloride (4.94 g; 7.04 mmol; 0.10 eq.) and potassium carbonate (14.6 g; 105 mmol; 1.5 eq.) were suspended in dioxane (540 mL) and water (273 mL). The reaction mixture was then heated at 90°C for 16h. It was filtered through Celite and the filtrate was extracted with EtOAc. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The gum obtained was then triturated Et20 (100 mL). The resulting solid was filtered off and dried under high vacuum to give the title compound as a beige solid (14 g, 87%).1 H NMR (300 MHz, DMSO-d6) δ 13.21 (brs, 1 H), 9.12 (s, 2H), 8.44 (m, 1 H), 8.14 (m, 1 H), 7.67 (t, J= 2.0 Hz, 1 H), 7.57-7.54 (m, 1 H), 7.14 (t, J= 7.8 Hz, 1 H), 5.25 (s, 2H), 6.68 (ddd, J= 7.8 Hz, 2.0 Hz, 1.0 Hz, 1 H). HPLC (Condition A): Rt 1.24 min (purity 72.1 %). MS (ESI+): 238.2.
Step 2: Formation of 2-(3-lodo-phenyl)-5-(1 H-pyrazol-4-yl)-pyrimidine
Figure imgf000120_0001
To a suspension of 3-[5-(1 H-PyrazoI-4-yl)-pyrimidin-2-yl]-phenylamine (12.6 g; 53.2 mmol; 1.0 eq.) in Dioxane (500 mL) were added diiodomethane (21.6 mL; 266 mmol; 5.0 eq.), Copper(l) iodide (10.1 g; 53.2 mmol; 1.0 eq.) and isopentyl nitrite (21.5 mL; 159 mmol; 3.0 eq.). The reaction mixture was stirred at 100°C for 2 hours and filtered. The filtrate was kept in a flask. The resulting green solid was suspended in dioxane (100 mL) and stirred at 100°C for 30 minutes. The solid was then filtered off and the two filtrates were combined and concentrated under reduced pressure. The dark brown residue was sonicated in EtOAc (20 mL) and pentane (80 mL). The resulting brown solid was filtered, further washed with pentane and dried few hours under high vacuum to give the title compound as a brown solid (7.0 g; 38%). 1 H NMR (300 MHz, DMSO-d6) δ 13.27 (brs, 1 H), 9.20 (s, 2H), 8.71 (t, J= 1.5 Hz, 1 H), 8.52 (m, 1 H), 8.39 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.21 (m, 1 H), 7.89-7.86 (m, 1 H), 7.35 (t, J= 8.0 Hz, 1 H). HPLC (Condition A): Rt 3.86 min (purity 67.6%). MS (ESI+): 349.3
Intermediate 12: 2-<'4-r2-(3-lodo-phenyl)-pyrimidin-5-vn-pyrazol-1-v -1-pyrrolidin-1 - yl-ethanone
Figure imgf000120_0002
A solution of cesium carbonate (17.3 g; 53 mmol; 2.5 eq.) and 2-(3-lodo-phenyl)-5-(1 H- pyrazol-4-yl)-pyrimidine (intermediate 11 , 7.4 g; 21 mmol; 1.0 eq.) in DMF (150 mL) was stirred at RT for 30 minutes before the addition of a solution of 2-Bromo-1-pyrrolidin-1-yl- ethanone (Chemical Diversity Labs; 4.08 g; 21.3 mmol; 1.0 eq.) in DMF (65 mL). The reaction mixture was then stirred at RT O/N. It was diluted with DCM and washed with water and brine (three times). Organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting residue was sonicated in DCM and the solid obtained was filtered, washed with EtOAc and pentane and dried under vacuum to give the title compound as a beige solid (3.70 g; 38%). 1 H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.72 (t, J= 1.7 Hz, 1 H), 8.41-8.38 (m, 2H), 8.14 (d, J= 0.5 Hz, 1H), 7.89 (ddd, J= 7.8 Hz, 1.7 Hz, 1.0 Hz, 1H), 7.35 (t, J= 7.8 Hz, 1 H), 5.12 (s, 2H), 3.53 (t, J= 6.7 Hz, 2H), 3.32 (t, J= 6.7 Hz, 2H), 1.93 (quint, J= 6.7 Hz, 2H), 1.80 (quint., J= 6.7 Hz, 2H). HPLC (Condition A): Rt 3.97 min (purity 95.9%). MS (ESI+): 460.4.
Intermediate 13: 2- ethanesulfonyloxymethyl-morpholine-4-carboxylic acid tert- butyl ester
Figure imgf000121_0001
Methane sulfonyl chloride (71 μΙ; 0.92 mmol; 1.0 eq.) was added to a solution of 2- hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (200 mg; 0.92 mmol; 1.0 eq.) and TEA (190 uL; 1.38 mmol; 1.5 eq.) in anhydrous DCM (3 mL) maintained at 0°C and under nitrogen atmosphere. The reaction mixture was stirred at RT O/N. The reaction mixture was washed with 10% citric acid solution and brine. Organic phase was dried over magnesium sulfate, filtered and concentratred to give the title compound as a brown oil (250 mg, 92%). H NMR (300 MHz, DMSO) δ 4.33 - 4.13 (m, 2H), 3.91 - 3.78 (m, 2H), 3.75 - 3.55 (m, 4H), 3.42 (td, J = 1 1.6, 2.8 Hz, 1 H), 3.20 (s, 3H), 1.41 (s, 9H). Intermediate 14: 2-(4-{2-[3-(1H-Pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-1- pyrrolidin-1-yl-ethanone
Figure imgf000122_0001
The title compound was obtained following procedure described for intermediate 5, step 1 , but starting from 2-{4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1 -yl}-1-pyrrolidin-1-yl- ethanone (Intermediate 12, 1.0 g; 2.18 mmol; 1.0 eq.) and 4-(4,4,5,5-Tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (704 mg; 2.4 mmol; 1.1 eq.) as a beige solid (695 mg; 80%). 1 H NMR (300 MHz, DMSO-d6) : 9.15 (s, 2H), 8.57-8.56 (m, 1 H), 8.37 (s, 1 H), 8.21 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.14-8.13 (m, 3H), 7.75 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.51 (t, J= 8.0 Hz, 1 H), 5.12 (s, 2H), 3.53 (t, J= 6.8 Hz, 2H), 3.33 (t, J= 6.8 Hz, 2H), 1.93 (quint., J= 6.8 Hz, 2H), 1.80 (quint., J= 6.8 Hz, 2H). MS (ESI+): 400.5.
Intermediate 15: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-
Figure imgf000122_0002
A mixture of 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 700 mg; 2.22 mmol; 1.0 eq.), bis(pinacolato)diboron (508 mg; 2.00 mmol; 0.9 eq.), potassium acetate (436 mg; 4.44 mmol; 2.0 eq.) and (dppf)PdCI2.CH2Cl2 (162 mg; 0.22 mmol; 0.10 eq.)
in Dioxane-1 ,4 (4 mL) was heated at 100°C for 1 h in the MW. Reaction mixture was diluted with a saturated solution of NaHC03 and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a dark oil (1 g, 89%) which was used in the next steps without further purification. H NMR (300 MHz, DMSO) δ 9.03 (s, 2H), 8.56 (s, 1 H), 8.34 - 8.18 (m, 2H), 7.92 (s, 1 H), 7.76 (d, J = 7.6 Hz, 1 H), 7.53 (t, J = 7.7 Hz, 1 H), 3.89 (s, 3H), .35 (s, 12H). ntermediate 16: exo-3-(4-lodo-1H-pyrazol-1-yl)-8-methyl-8-azabicvclor3.2.noctane
Figure imgf000123_0001
To a stirred solution of 4-lodopyrazole (50 g, 0.257 mol) in dry THF (500 mL) was added Tropine (40 g, 0.283 mol) followed by triphenylphosphine (135 g, 0.5154 mol) and Diisopropyl azodicarboxylate (104 g, 0.5154 mol) at 0 °C under nitrogen atmosphere. After the addition, the reaction mixture was stirred at RT for 48 h. The reaction mixture was concentrated under vacuum. The crude product was purified by flash column chromatography (HCCI3:MeOH, gradient from 95:5 to 92:8) to afford the titled compound as white crystalline solid (8.5 g, 10 %). H NMR ( 400 MHz, CDCI3): δ 7.50 (s, 1 H), 7.46 (s, 1 H), 4.54 (m, 1 H), 3.32 (brs, 2H), 2.39 (s, 3H), 2.15-2.11 (m, 4H), 1.97-1 .93 (m, 2H), 1.74-1.70 (m, 2H).
Intermediate 17: 2-{4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1 -yl}-1- morpholin-4-yl-ethanone
Figure imgf000123_0002
The title compound was obtained following procedure described for intermediate 12, but starting from 2-(3-lodo-phenyl)-5-(1 H-pyrazol-4-yl)-pyrimidine (intermediate 1 1 , 850 mg; 2.44 mmol; 1.0 eq.) and 2-Chloro-1-morpholin-4-yl-ethanone (599 mg; 3.66 mmol; 1.5 eq.) as a beige solid (730 mg, 63%). 1 H NMR (300 MHz, DMSO-d6) d 9.18 (s, 2H), 8.72 (t, J= 1.6 Hz, 1 H), 8.41-8.37 (m, 2H), 8.15 (s, 1 H), 7.90-7.87 (m, H), 7.35 (t, J= 7.8 Hz, 1 H), 5.25 (s, 2H), 3.64-3.45 (m 8H). HPLC (Condition A): Rt 3.76 min (purity 94.6%). MS (ESI+): 476.3.
Intermediate 18: tert-butyl 4-{4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1- yl}piperidine-1-carboxylate Step 1 : Formation of tert-butyl 4-(4-r2-(3-aminophenyl)pyrimidin-5-yll-1 H-pyrazol-1 - vDpiperidine-1-carboxylate
Figure imgf000124_0001
The title compound was obtained following procedure described for intermediate 11 , stepl , but starting from 3-(5-bromopyrimidin-2-yl)aniline (intermediate 4, 7.50 g; 21 mmol; 1.0 eq.) and 4-[4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]- piperidine-1-carboxylic acid tert-butyl ester (11.9 g; 31.5 mmol; 1 .5 eq.) as a yellow powder (5g, 51 %). 1H NMR (300 MHz, DMSO) δ 9.09 (s, 2H), 8.52 (s, 1 H), 8.12 (s, 1 H), 7.75 - 7.49 (m, 2H), 7.23 - 7.09 (m, 1 H), 6.69 (ddd, J = 7.9, 2.5, 1.1 Hz, 1 H), 5.26 (s, 2H), 4.42 (td, J = 7.3, 3.5 Hz, 1 H), 4.05 (dd, J = 13.2, 7.7 Hz, 2H), 2.95 (s, 2H), 2.07 (dd, J = 13.3, 3.7 Hz, 2H), 1.91 - 1.70 (m, 2H), 1.43 (s, 9H). MS, (ESI+) 421.5
Step 2: Formation of tert-butyl 4-{4-[2-(3-iodophenyl)pyrimidin-5-yll-1 H-pyrazol-1- yl}piperidine-1-carboxylate
Figure imgf000124_0002
The title compound was obtained following procedure described for intermediate 1 1 , step 2, but starting from tert-butyl 4-4-[2-(3-aminophenyl)pyrimidin-5-yl]-1 H-pyrazol-1- ylpiperidine-1-carboxylate (4.50 g; 10.70 mmol; 1.00 eq.) as a beige solid (3.3 g; 58 %). 1 H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.71 (t, J= 1.5 Hz, 1 H), 8.56 (s, 1 H), 8.38 (dt, J= 7.8 Hz, 1.5 Hz, 1 H), 8.15 (s, 1 H), 7.88 (dt, J= 7.8 Hz, 1.5 Hz, 1 H), 7.34 (t, J= 7.8 Hz, 1 H), 4.46-4.37 (m, 1 H), 4.08 (m, 2H), 2.94 (m, 2H), 2.08-2.04 (m, 2H), 1 .87-1.74 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 5.48 min (purity 85.8%). MS (ESI+): 532.5.
Intermediate 19: 4-{4-[2-(3-Trimethylsilanylethynyl-phenyl)-pyrimidin-5-yl]-pyrazol- 1 -yl}-piperidine-1 -carboxylic acid tert-butyl ester
Figure imgf000125_0001
A mixture of tert-butyl 4-{4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-yl}piperidine-1 - carboxylate (intermediate 18, 315 mg; 0.59 mmol; 1.0 eq.), Ethynyl-trimethyl-silane (83 μΙ; 0.59 mmol; 1 .0 eq.), (dppf)PdCI2.CH2Cl2 (26 mg; 0.04 mmol; 0.06 eq.), Cul (7 mg; 0.04 mmol; 0.06 eq.) and TEA (115 μΙ; 0.89 mmol; 1.5 eq.) in dry THF (3.6 mL) and dry DMF (1 mL) was heated in a sealed vial at 80°C for 48h. The reaction mixture was then diluted with EtOAc and washed with sat. NH4CI and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (heptanes: EtOAC, gradient form 90;10 to 50:50) afforded the title compound as a beige solid (1 15 mg, 39%). 1 H NMR (300 MHz, DMSO-d6) d 9.17 (s, 2H), 8.57 (s, 1 H), 8.41-8.38 (m, 1 H), 8.15 (s, 2H), 7.61-7.54 (m, 2H), 4.08-4.03 (m, 2H), 2.96 (m, 2H9, 2.08-2.05 (m, 2H), 1.83-1.77 (m, 2H), 1.43 (s, 9H), 0.26 (s, 9H). MS (ESI+): 502.5. Intermediate 20: 4-(4-lodo-pyrazol-1 -yl)-cyclohexanone
Step 1 : Formation of Toluene-4-sulfonic acid 1 4-dioxa-spiror4.5ldec-8-yl ester
Figure imgf000125_0002
4-Methyl-benzenesulfonyl chloride (5.51 g; 29 mmol; 1.0 eq.) was added portionwise to a solution of 1 ,4-Dioxa-spiro[4.5]decan-8-ol (4.44 g; 28 mmol; 1 .0 eq.) in anhydrous Pyridine (13.5 mL) maintained at 5°C with an ice bath. The reaction mixture was then allowed to warm to RT and stirred O/N. It was then quenched by addition of water and diluted with EtOAc. Organic phase was washed with a 1 N HCI solution, saturated NaHC03 solution and brine. It was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6.9 g of a pale yellow oil. Purification by flash chromatography on silica (heptane / EtOAc 60:40) afforded the title compound as a white powder (4.7g, 52%). HPLC (Condition A): Rt 4.04min (purity 100 %). MS (ESI+):
330.3 Step 2: Formation of 1-(1 ,4-Diox -spiro[4.5ldec-8-yl)-4-iodo-1 H-pyrazole
Figure imgf000126_0001
A mixture of Toluene-4-sulfonic acid 1 ,4-dioxa-spiro[4.5]dec-8-yl ester (4.47 g; 13.9 mmol; 1.0 eq.), 4-lodo-1 H-pyrazole (2.69 g; 13.9 mmol; 1.0 eq.) and cesium carbonate (6.78 g; 20.8 mmol; 1.5 eq.) was heated in DMA (50.0 mL) at 100°C for 3h. It was then allowed to cool to RT, diluted with EtOAc and washed with water and brine. Aqueous phases were back-extracted with EtOAc. Combined organic phases were finally dried over sodium sulfate, filtered and concentrated to give 6.32 g of a yellow oil. Recrystallisation in iPrOH afforded the title compound as awhite powder (2.81 g, 61 %). HPLC (Condition A): Rt 3.46 min (purity 100 %). MS (ESI+): 335.1.
Figure imgf000126_0002
A solution of 1-(1 ,4-Dioxa-spiro[4.5]dec-8-yl)-4-iodo-1 H-pyrazole (2.81 g; 8.41 mmol; 1.00eq.) and pyridinium para-toluenesulfonate (4.23 g; 16.8 mmol; 2.0 eq.) in acetone (40 mL) and water (40 mL) was heated at reflux O/N. It was then allowed to cool to RT and diluted with EtOAc. Aqueous phase was extracted with EtOAc (twice) and combined organic phases were washed with water and brine, dried over sodium sulftate, filtered and concentrated to give the title compound as a white powder (2.34 g, 96%). HPLC (Condition A): Rt 2.83 min (purity 99.2 %). MS (ESI+): 291.1.
Intermediate 21 and 22: cis and trans-4-(4-lodo-pyrazol-1-yl)-cyclohexanol
Figure imgf000126_0003
Sodium borohydride (86 mg; 2.27 mmol; 0.5 eq.) was added portionwise to a suspension of 4-(4-lodo-pyrazol-1-yl)-cyclohexanone (1.33 g; 4.55 mmol; 1.0 eq.) in EtOH (10 mL). The reaction mixture was stirred at RT for 30 min and concentrated under vacuum. The residue was taken up with EtOAc (50 mL) and washed with NH4CI aq sat (50 mL). The aqueous phase was back-extracted with EtOAc (twice). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give 1.42 g of an oil. Purification by flash chromatography on silica (heptane/EtOAc, gradient from 80:20 to 40:60) afforded the title compounds.
1st eluting compound: colorless glue (234 mg, 18%). Cis-4-(4-!odo-pyrazol-1 -yl)- cyclohexanol. HPLC (Condition A): Rt 2.69 min (purity 99.7 %). MS (ESI+): 293.1.
2nd eluting compound: white powder (730 mg, 55%). Trans-4-(4-lodo-pyrazol-1 -yl)- cyclohexanol. HPLC (Condition A): Rt 2.65 min (purity 100 %). MS (ESI+): 293.1.
Intermediates 23 and 24: Cis-8-(4-Bromo-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-one
Step 1 : Formation of N'-(2-Oxo-1-aza-spiror4.5ldec-8-yl)-hvdrazinecarboxylic acid tert- butyl ester
Figure imgf000127_0001
A solution of 1-Aza-spiro[4.5]decane-2,8-dione (Chembridge corporation, 800 mg; 4.78 mmol; 1.0 eq.) and hydrazinecarboxylic acid tert-butyl ester (309 mg; 2.34 mmol; 1.1 eq.) in AcOH (5 ml.) was stirred at RT for 5 min. Sodium cyanoborohydride (133 mg; 2.13 mmol; 1.0 eq.) was then added and the reaction mixture was stirred O/N at RT. It was then diluted with water and basified to pH 9 by addition of a 5N solution of NaOH. During the addition, the reaction mixture was maintained at 20 °C by addition of crushed ice. It was extracted with DCM and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (1.0 g, 98%) which was used without further purification.
Step 2 : Formation of 8-(4-Bro -pyrazol-1-yl)-1-aza-spiror4.5ldecan-2-one
Figure imgf000127_0002
Hydrobromic acid (1.04 mL of a 48 w†% solution in water; 9.18 mmol; 2.0 eq.) was added to a solution of N'-(2-Oxo-1-aza-spiro[4.5]dec-8-yl)-hydrazinecarboxylic acid tert-butyl ester (1.30 g; 4.59 mmol; 1.0 eq.) and 2-Bromo-malonaldehyde (865 mg; 5.51 mmol; 1.2 eq.) in AcOH (13 mL). The reaction mixture was stirred at RT for 2 hour. It was then basified to pH 5 by addition of a 5N NaOH solution and extracted with DCM (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by autopreparative LC/MS afforded the title compound as as the pure cis-isomer (1.0 g, 94%).
Separation by chiral preparative HPLC (Chiralpak IC 250 x 4.6 mm); EtOH/DEA) afforded the two pure isomers (attributed arbitrarily).
First eluting isomer (174 mg, Rt = 4.68 min): intermediate 23
Figure imgf000128_0001
Second eluting isomer (224 mg = 6.22 min): Intermediate 24
Figure imgf000128_0002
Intermediate 25: 2-[4-(4-lodo-pyrazol-1-yl)-cyclohexylamino]-ethanol
Figure imgf000128_0003
2-Amino-ethanol (0.30 mL; 4.96 mmol; 1.4 eq.) was added in one portion to a solution of 4-(4-lodo-pyrazol-1-yl)-cyclohexanone (intermediate 20; 1.00 g; 3.45 mmol; 1.0 eq.) in EtOH. After 1 h the reaction solution was cooled to 0°C and NaBH4 (290 mg; 7.67 mmol; 2.2 eq.) added portionwise over 1 min. After a further 1 h the reaction suspension was poured into 1 N NaOH solution and extracted with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification using a SCX-2 cartridge afforded the title compound as a white solid (1.00 g; 84%). 1 H NMR (300 MHz, DMSO) δ 7.94 (s, 1 H), 7.49 (s, 1 H), 4.47 (brs, 1 H), 4.12 (m, 1 H), 3.45 (m, 2H), 2.60 (t, J = 5.8 Hz, 2H), 2.41 (m, 1 H), 2.95 (m, 4H), 1.72 (m, 2H), 1.13 (m, 2H).
Intermediate 26: trans-4-[4-(4-lodo-py razol-1 -yl)-cyclohexyl]-morpholin-3-one
Figure imgf000128_0004
Chloro-acetyl chloride (0.25 mL; 3.14 mmol; 1.1 eq.) was added dropwise over 2 min to a solution of 2-[4-(4-lodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 1.0 g; 2.89 mmol; 1.0 eq.) and DIEA (2.00 ml; 11.45 mmol; 3.96 eq.) in THF (80.00 mL) at - 30°C. The reaction solution was allowed to warm slowly to RT and stirred for 16 h. It was then poured into a 1 N HCI solution and extracted with DCM. Combined organic phases were washed with saturated NaHC03 solution, dried over magnesium sulfate, filtrated and concentrated to give 2-Chloro-N-(2-hydroxy-ethyl)-N-[4-(4-iodo-pyrazo!-1-yl)- cyclohexyl]-acetamide as a brown oil. This oil was redissolved in THF (30 ml_; 370 mmol; 128 eq.) and sodium tert-butoxide (2M solution in THF; 30 ml_; 60.0 mmol; 21 eq.) was added in one portion. The reaction solution was heated at 40°C for 1 h then cooled to RT and poured into 1 N HCI solution. It was extracted with DCM (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated sequentially with EtOAc and Et20, filtered and dried to give the title compound as a yellow solid (275 mg; 21%). 1H NMR (300 MHz, DMSO) 57.98 (s, 1 H), 7.50 (s, 1 H), 4.40 - 4.25 (m, 1 H), 4.25 - 4.10 (m, 1 H), 4.03 (s, 2H), 3.87 - 3.75 (m, 2H), 3.32 - 3.23 (m, 2H), 2.14 - 1.99 (m, 2H), 1.93 - 1.60 (m, 6H). MS (ESI+): 376.2. Intermediate 27: trans-3-[4-(4-lodo-pyrazol-1-yl)-cyclohexyl]-oxazolidin-2-one
Figure imgf000129_0001
Di-imidazo!-1-yl-methanone (1.32 g; 8.14 mmol; 2.9 eq.) was added in one portion to a solution of 2-[4-(4-lodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 997 mg; 2.83 mmol; 1.0 eq.) and Dimethyl-pyridin-4-yl-amine (60 mg; 0.49 mmol; 0.17 eq.) in CHCI3 (30 ml_). The reaction suspension was heated at 60°C for 20 min then cooled and poured into a 1 N HCI solution. It was extracted with DCM (twice), combined organic phases were washed with brine, dried over magnesium sulfate, filtered and and concentrated. Purification by flash chromatography on silica (DCM: MeOH; 96:4) followed by a trituration in Acetonitrile afforded the title compound as a white solid (239 mg; 23%). 1 H NMR (300 MHz, DMSO) δ 7.96 (d, J = 0.5 Hz, 1 H), 7.51 (d, J = 0.5 Hz, 1 H), 4.30 - 4.12 (m, 3H), 3.63 - 3.46 (m, 3H), 2.11 - 2.00 (m, 2H), 1.91 - 1.58 (m, 6H). HPLC (Condition A): Rt 2.98 min (purity 99.0 %). MS (ESI+): 362.2.
Intermediate 28: 4-lodo-1-(1-oxa-spiro[2.5]oct-6-yl)-1H-pyrazole
Figure imgf000129_0002
2-Methyl-propan-2-ol potassium (466 mg; 4.15 mmol; 1.2 eq.) was added in one portion to a solution of 4-(4-lodo-pyrazol-1-yl)-cyclohexanone (1.02 g; 3.50 mmol; 1.0 eq.) and trimethylsulfoxonium chloride (531 mg; 4.13 mmol; 1.2 eq.) in DMSO (50 mL). The reaction mixture was stirred at RT for 16 h. It was then poured into EtOAc . Organic phase was separated and washed with brine (three times), dried over magnesium sulfate, filtered and concentrated to give the title compound a white solid (813 mg, 76%). 1 H NMR (300 MHz, DMSO) 68.01 (d, J = 0.5 Hz, 1 H), 7.52 (d, J = 0.5 Hz, 1 H), 4.41 - 4.26 (m, 1 H), 2.66 (s, 2H), 2.13 - 1.85 (m, 6H), 1.34 - 1.21 (m, 2H). MS (ESI+): 305.1 . Intermediate 29: 4-(4-Bromo-pyrazol-1-yl)-3,3-difluoro-piperidine
Step 1 : Formation of 4-(N'-tert-Butoxycarbonyl-hvdrazino)-3,3-difluoro-piperidine-1- carboxylic acid tert-butyl ester
Figure imgf000130_0001
The title compound was obtained following procedure described for Intermediate 23, step 1 but starting from 3,3-Difluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (OmegaChem; 500 mg; 2.06 mmol; 1.0 eq.) as a white solid (495 mg; 1.40 mmol; 68 %). 1H NMR (400 MHz, DMSO; 1H) δ 8.33 (s, 1 H), 4.72 (s, 1 H), 3.97-3.91 (m, 1 H), 3.72- 3.60 (m, 1 H), 3.56-3.44 (m, 2H), 3.32-3.28 (m, 1 H), 1.78-1.71 (m, 1 H), 1.37 (s, 18H). HPLC (Condition A): Rt 4.75 min (purity 99.5%).
Step 2: Formation of 4-(4-Bromo- razol-1-yl)-3,3-difluoro-piperidine
Figure imgf000130_0002
The title compound was obtained following procedure described for Intermediate 23, step 2 but starting from 4-(N'-tert-Butoxycarbonyl-hydrazino)-3,3-difluoro-piperidine-1- carboxylic acid tert-butyl ester (490 mg; 1.39 mmol; 1.0 eq.) as a yellow solid (152 mg, 36%). HPLC (Condition A): Rt 2.09 min (purity 88.0%). MS (ESI+): 268.0.
Intermediate 30 and 31 : Cis and trans-8-(4-bromo-1H-pyrazol-1 -yl)-2-azaspiro Γ4.5Ί decan-3-one
Step 1 : Formation of Methyl 1 , 4-dioxaspiro [4.51 dec-8-ylideneacetate
Figure imgf000131_0001
A solution of methyl (triphenylphosphoranylidene) acetate (13.9 g, 41.6 mmol) and cyclohexanedionemonoethyleneacetal (5 g, 32 mmol, 1.0 eq.) in dry toluene (50 mL) was heated at reflus under nitrogen atmosphere for 18h. The solvent was removed under reduced pressure and the crude was purified by flash chromatography on silica (pet. ether: ethyl acetate). The title compound was isolated as a colorless liquid (4g, 60%). H NMR (400MHz, DMSO) δ 5.7 (s,1 H), 3.88 (s, 1 H), 3.59 ( s, 3H), 3.32-2.84 (m, 2H), 2.32-2.29 (m, 2H), 1.69-1.65 (m, 4H).
Step 2: Formation of Methyl [8-(nitromethyl)-1 , 4-dioxaspiro [4.51 dec-8-yll acetate
Figure imgf000131_0002
A solution of Methyl 1 , 4-dioxaspiro [4.5] dec-8-ylideneacetate (4 g, 18.8 mmol) in dry THF (20 mL) was treated by nitromethane (1.5 mL, 28.3 mmol) followed by tertbutylammonium fluoride (18.8 mLot a 1 M solution in THF, 0.0188 mol). The resulting mixture was stirred at reflux for 18h under nitrogen. After cooling to RT, the mixture was diluted with water and extracted with MTBE (3 x 100mL). Combined organic layers were washed with 10% sodium bicarbonate solution (20 mL), water (100 mL) and brine (50 mL), dried over sodium sulphate filtered and concentrated. Purification by flash chromatography on silica (Pet. Ether: EtOAc) afforded the title compound as a colorless liquid (2.5g, 49%). H NMR (400MHz, DMSO) δ 4.7 (s,2H), 3.94 (s, 4H), 3.69 ( s, 3H), 2.57 (s, 2H), 1.74 (m, 8H). Step 3: Formation of 1 , 4-Dioxa-10-azadispiro Γ4.2.4.21 tetradecan-11-one
Figure imgf000132_0001
To a slurry of Methyl [8-(nitromethyl)-1 , 4-dioxaspiro [4.5] dec-8-yl] acetate (1g, 4.7 mmol) in Methanol (20 ml_) was added Pd/C (1 g, 10%) under N2 atmosphere. The reaction mixture was stirred at room temperature under 5 kg/cm2 H2 pressure for 12h. After completion, the reaction mixture was filtered through celite pad, washed with methanol and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (0.7 g, 70%). 1H NMR (400MHz, DMSO-d6) δ 7.46 (s,1 H), 3.83 (s,4H), 3.00 ( s, 2H), 2.00(s, 2H), 1.56-1.51 (m, 8H).
Figure imgf000132_0002
A solution of 1 ,4-dioxa-10-azadispiro [4.2.4.2] tetradecan-11-one (10.5 g, 49.8 mmol) in aq.HCI (2N, 20 mL) was stirred at RT for 2h. The reaction mixture was then concentrated under reduced pressure and diluted with water. It was extracted with ethyl acetate (Three times) and the combined organic phases were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purifiaction by flash chromatography on silica (Pet. Ether: EtOAc) afforded the title compound as a white solid (7.5g, 92%). 1H NMR (400MHz, DMSO-d6) δ 7.58 (m,1 H),3.15-3.15 (s, 2H), 2.30 ( s, 4H), 2.28-2.25 (m, 2H), 1.82-1.79 (m, 4H).
Step 5: Formation of terf-bu -(3-oxo-2-azaspiro Γ4.51 dec-8-yl) hvdrazinecarboxylate
Figure imgf000132_0003
The title compound was obtained following procedure described for Intermediate 23, step 1 but starting from 2-azaspiro [4.5] decane-3, 8-Dione (3.8 g, 22.7 mmol) as a white solid (4.6g, 72%). 1H NMR (400MHz, DMSO-d6) δ 8.17 (s, 1 H), 7.46-7.44 (m, 1 H), 4.20 (s, 1 H), 2.97-2.93 (m, 2H), 2.64 (bs, 1 H), 1.96-1.93 (m, 2H), 1.61-1.58 (m,4H), 1.36 (s, 9H), 1.28-1.24 (m, 2H), 1.22-1.09 (m, 2H).
Step 5: Formation of 8-(4-bromo-1H-pyrazol-1-vD-2-azaspiro [4.51 decan-3-one
Figure imgf000133_0001
The title compound was obtained following procedure described for Intermediate 23, step 1 but starting from terf-butyl 2-(3-oxo-2-azaspiro [4.5] dec-8-yl) hydrazinecarboxylate (4 g, 14.1 mmol) as a white solid (2 g, 48%). H NMR (400MHz, DMSO-d6) δ 8.04-8.04 (d, 1 H), 7.52-7.50 (m, 2H), 4.15-4.09 (m, 1H), 3.12 (s, 1 H), 2.98 (s, 1 H), 2.12 (s, 1 H), 1.98 (s, 1 H), 1.88-1.86 (m, 2H), 1.78-1.69 (m, 4H), 1.50-1.45 (m, 2H).
Step 7: separation isomers of 8-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro [4.51 decan-3-one The mixture obtained in step 6 was separated by preparative HPLC (Chiralpak AD-H, hexane:IPA:DEA 80:20:0.1).
First eluting compound: intermediate 30, Rt = 19.32 min
Second eluting compound: inte min
Figure imgf000133_0002
Intermediate 32 and 33: cis and trans-8-(4-bromo-1H-pyrazol-1-yl)-2-methyl-2- azaspiro [4.5] decan-3-one
Figure imgf000133_0003
Stepl : Formation of 8-(4-bromo-1H-pyrazol-1-yl)-2-methyl-2-azaspiro [4.51 decan-3-one To a solution of 8-(4-bromo-1/-/-pyrazol-1-yl)-2-azaspiro [4.5] decan-3-one (mixture of intermediate 30 and 31 obtained in step 5; 4 g, 3.4 mmol) in DMF (10 ml_) was added sodium hydride (60%) (0.8g, 0.01 16 mol) followed by methyl iodide (2.2mL, 14.8 mmol) at 0°C. The reaction mixture was slowly allowed to warm to RT and stirred for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic phases were washed with water (50 mL) and brine (50 mL), dried over sodium sulphate, filtered and concentrated. Purification by flash chromatography on silica (Pet. ether: ethyl acetate) afforded the title compound (mixture of two isomers) as an off white solid (1.8 g, 43%). 1H NMR (400MHz, DMSO-d6) δ 8.04-8.03 (m, 1H), 7.51 -7.50 (m, 1 H), 4.16-4.10 (m, 1 H), 3.24 (s, 1 H), 3.09 (s, 1H), 2.70-2.69 (m, 3H), 2.21 (s, 1 H), 2.09 (s, 1 H), 1.90-1.86 (m, 6H), 1.79-1.54 (m, 2H).
Step 2: Separation Cis and trans 8-(4-bromo-1H-pyrazol-1-yl)-2-methyl-2-azaspiro [4.51 decan-3-one
The mixture obtained in step 1 was separated by preparative HPLC (Zorbax RX-SIL, hexane:EtOH:DEA; 90:10:0.1)
First eluting compound: intermediate 32 Rt = 12.87 min
Figure imgf000134_0001
Second eluting compound: intermediate 33; Rt
Figure imgf000134_0002
Intermediate 34: Cis-8-(4-Bromo-pyrazol-1-yl)-1-methyI-1-aza-spiro[4.5]decan-2- one
Figure imgf000134_0003
The title compound was obtained following procedure described for intermediate 32 and 33, step 1 but starting from 8-(4-Bromo-pyrazol-1-yl)-1-aza-spiro [4.5] decan-2-one (intermediate 23; 150 mg; 0.50 mmol; 1.0 eq.) as a brown gum (130 mg, 82%). HPLC (max plot) 98.8 % (ELSD); (220nm) 69.4 %; Rt (min) 3.29; MS: (ESI+) 314.0 (M+H2). Intermediates 35 and 36: (3aS,5S,7aS) and (3aR,5R,7aR)-5-(4-bromopyrazol-1-yl)- 7a-(hydroxymethyl)-1 ,3,4,5,6,7-hexahydroisobenzofuran-3a-ol.
Step 1 : Formation of Methyl -6-(2-tert-butoxycarbonylhvdrazino)-cis-7a-hydroxy- 1 ,3,4,5,6,7-hexahvdroisobenzofuran-3a-carboxylate
Figure imgf000135_0001
The title compound was obtained following procedure described for Intermediate 23, step 1 but starting from Methyl cis-7a-hydroxy-6-oxo-3,4,5,7-tetrahydro-1 H- isobenzofuran-3a-carboxylate (prepared as described in Synthesis, 2010, p895, 1.0 g, 4.6 mmol) as a brown oil (0.85 g, 55%). 1 H NMR (400MHz, DMSO): δ 12.00 (brs, 1 H), 8.20 (brs, 1 H), 4.91 (s, 1H), 4.17-4.10 (m, 1 H), 4.08-3.58 (m, 1 H), 3.57 (s, 3H), 3.56-3.32 (m, 1 H), 1.91-1.61 (m, 10 H), 1.37 (s, 9H). HPLC (Condition A): Rt 2.40; 2.47 min (purity 11.6, 86.7%). MS (ESI+): 331.2. Step 2 : Formation of methyl -6-(4-bromopyrazol-1-yl)-cis-7a-hydroxy- ,3,4,5,6,7- hexahydroisobenzofuran-3a-carboxylate
Figure imgf000135_0002
The title compound was obtained following procedure described for Intermediate 23, step 2 but starting from Methyl-6-(2-tert-butoxycarbonylhydrazino)-cis-7a-hydroxy- 1 ,3,4,5,6,7-hexahydroisobenzofuran-3a-carboxylate (0.8 g, 2.4 mmol) as a colorless oil (0.2 g, 24%). 1 H NMR (400MHz, DMSO): δ 7.48-7.46 (m, 2H), 4.55 (m, 1 H), 4.30-4.24 (m, 2H), 4.13-4.08 (m, 2H), 3.92 (s, 3H), 3.76-3.60 (m, 1 H), 2.36-2.24 (m, 3H), 2.12-2.01 (m, 3H). HPLC (Condition A): Rt 3.14 min (purity 95.4%). MS (ESI+): 345.0. Step 3 : Formation of 5-(4-bromopyrazol-1-yl)-cis-7a-(hvdroxymethyl)-1 ,3,4,5,6,7- hexahydroisobenzofuran-3a-ol
Figure imgf000136_0001
Lithium borohydride (2M in THF, 4.13 ml_ of a 2M solution in THF, 8.6 mmol) was added slowly over 10 minutes to a solution of methyl -6-(4-bromopyrazol-1-yl)-cis-7a-hydroxy- 1 ,3,4,5,6,7-hexahydroisobenzofuran-3a-carboxylate (1.2 g, 3.4 mmol) in THF (10 ml.) at 0-5 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to 25-26 °C and stirred for 8h. It was then quenched with ice (50 g) and acetic acid (5 mL) and extracted with DCM (3 times). Combined organic phases were washed with water, brine, dried over sodium sulfate, filtered and concentrated to give the title compound as light yellow liquid (0.8 g) containing the cis and trans isomers (95:5) which were separated by preparative HPLC.
Minor isomer: 50 mg ; HPLC (Condition A): Rt 3.72 min (purity 93.8%)
Major isomer : 0.5 g. 1 H NMR (400MHz; DMSO): δ 7.47 (s, 2H), 4.48-4.44 (m, 1 H), 4.22-4.20 (d, J = 11.08 Hz, 1 H), 3.99-3.93 (m, 2H), 3.70-3.68 (d, J = 8.32 Hz, 1 H), 3.54- 3.51 (d, J = 10.0Hz, 2H), 2.28-2.10 (m, 4H), 2.02-1.95 (m, 1 H), 1.64-1.59 (m, 1 H). HPLC (Condition A): Rt 2.95 min (purity 99.9 %). MS (ESI+): 319.0. Cis-cis isomer as shown by NOE experiments performed on compound described in example Step 4: Enantiomers separation of cis-5-(4-bromopyrazol-1-yl)-cis-7a-(hvdroxymethyl)- 1.3,4,5,6,7-hexahydroisobenzofuran-3a-ol
Figure imgf000136_0002
The enantiomers of major isomer obtained in step 3 were separated by SFC (Lux A2, C02:MeOH). First eluting enantiomer: intermediate 35; 200 mg; Rt = 15.6 min (Chiralcel OD-H, 250x4.6 mm; 5 uM; eluant : hexane:IPA,:TFA, 90:10:0.1).
Second eluting enantiomer: intermediate 36; 200mg; Rt = 16.78 min (Chiralcel OD-H , 250x4.6 mm; 5 uM; eluant : hexane:IPA,:TFA, 90:10:0.1).
Intermediate 37: 4-(4-Bromo-pyrazol-1-yl)-3-fluoro-piperidine
Step 1 : Formation of 4-(N'-tert-Butoxycarbonyl-hvdrazino)-3-fluoro-piperidine-1- carboxylic acid tert-butyl ester
Figure imgf000137_0001
The title compound was obtained following procedure described for Intermediate 23, step 1 but starting from_3-Fluoro-4-oxo-piperidine-1 -carboxylic acid tert-butyl ester (OmegaChem; 1.00 g; 4.47 mmol; 1.0 eq.) as a white solid (1.0 g, 73%). MS (ESI+): 222.2.
Step 2: Formation of 4-(4-Bromo-pyrazol-1-yl)-3-fluoro-piperidine
Figure imgf000137_0002
The title compound was obtained following procedure described for Intermediate 23, step 2 but starting from 4-(N'-tert-Butoxycarbonyl-hydrazino)-3-fluoro-piperidine-1- carboxylic acid tert-butyl ester (1.10 g; 3.25 mmol; 1.0 eq.) a white solid (mixture of cis:trans isomer, 7:3; 600 mg, 74%). 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 0.3H), 7.97 (s, 0.7H), 7.59 (brs, 1 H), 4.82 (d, J = 52 Hz, 0.7H), 4.70 (m, 0.3H), 4.45 (m, 0.7H), 4.30 (m, 0.3H), 3.31-2.62 (m, 3.3H), 2.45 (m, 1 H), 2.10 (m, 0.7H), 1.93-1.82 (m, 2H).
Example 1 : 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4- yl)-pyrimidine hydrochloride Step 1 : Formation of tert-butyl 4-(4-(2-i3-(1-methyl- H-pyrazol-4-yl)phenyllpyrimidin-5- ylH H-pyrazol-1-yl)piperidine-1-carboxylate
Figure imgf000138_0001
A solution of 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2, 160 mg, 0.50 mmol), 4-[4-(4,4,5>5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]- piperidine-1-carboxylic acid tert-butyl ester (Combi-blocks, 287 mg, 0.76 mmol) and Na2C03 (140 mg, 0.12 mmol) in dry Toluene : Ethanol(1 :1) (5 mL) was purged with nitrogen for 30 min before the addition of Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction mixture was then heated at 100°C O/N and filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the crude product. Purification by Flash chromatography on silica (hexane:EtOAc) afforded the title compound as a yellow solid (230 mg, 93%). H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 2H), 8.53 (d, J = 8.0 Hz, 2H), 8.25 (s, 1 H), 8.21 (d, J = 7.76 Hz, 1 H), 8.14 (s, 1 H), 7.91 (s, 1 H), 7.91-7.48 (m, 10H), 4.45-4.44 (m, 1 H), 4.07-4.04(m, 2H), 3.88 (s, 3H), 2.12 (s, 2H), 2.70 (d, J = 3.44 Hz, 1 H), 2.08-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): Rt 4.68 min (purity 87%). MS (ESI+): 486.2.
Step 2: Formation of 2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000138_0002
A solution of HCI/dioxane (4N solution in dioxane, 10 mL) was added slowly to a solution of ieri-butyl 4-[4-[2-[3-(3-pyridyl) phenyl] pyrimidin-5-yl] pyrazol-1-yl] piperidine- - carboxylate (200 mg, 0.63 mmol) at 0 °C under nitrogen atmosphere. After 2h, the reaction mixture was concentrated under reduced pressure. The residue was washed with ether and dried under reduced pressure to afford the title compound as a beige solid (32 mg, 81%). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 3H), 8.52 (t, J = 4.0 Hz, 2H), 8.25-8.19 (m, 3H), 7.91-7.89 (m, 1 H), 7.72-7.69 (m, 1 H), 7.51 (t, J = 7.72 Hz, 1 H), 3.89 (s, 3H), 3.41-3.37 (m, 2H), 3.1 1-3.08 (m, 2H), 2.27-2.14 (m, 4H). HPLC (Condition A): Rt 2.97 min (purity 95%). MS (ESI+): 386.3.
Example 2: 5-(1 -(piperidin-4-yl)-1 H-pyrazol-4-yl)-2-(3-(py ridin-3- yl)phenyl)pyrimidine ^hydrochloride
Step 1 : Formation of 4-{4-f2-(3-Pyridin-3-yl-phenyl)-pyrimidin-5-vn-pyrazol-1-yl)- piperidine-1-carboxylic acid tert-butyl ester
Figure imgf000139_0001
The title compound was obtained following procedure described for example 1 , step 1 , but starting from 5-Bromo-2-(3-pyridin-3-yl-phenyl)-pyrimidine (intermediate 3) and 1-(1- Boc-4-piperidyl)pyrazole-4-boronic acid pinacol ester (combi-Blocks) as a yellow solid. MS (ESI+): 483.2.
Step 2: Formation of 5-(1-(piperidin-4-yl)-1 H-pyrazol-4-yl)-2-(3-(pyridin-3- vDphenvDpyrimidine hydrochloride
Figure imgf000139_0002
The title compound was obtained following procedure described for example 1 , step 2, but starting from 4-{4-[2-(3-Pyridin-3-yl-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-piperidine-1- carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 9.21-9.18 (m, 2H), 9.00-8.95 (m, 1 H), 8.74-8.67 (m, 3H), 8.57-8.44 (m, 2H), 8.24-8.20 (m, 2H), 7.90 (d, J = 7.80 Hz, 1 H), 7.70-7.60 (m, 2H), 4.59-4.53 (m, 1 H), 3.45-3.43 (m, 2H), 3.15- 3.10 (m, 2H), 2.30-2.10 (m, 4H). HPLC (Condition A): Rt 2.18 min (purity 98%). MS (ESI+): 383.3. Example 3: 2-[3-(1-methyl-1 -pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine
Figure imgf000140_0001
The title compound was obtained following procedure described for intermediate 4, but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 5.0 g; 15.9 mmol; 1.0 eq.) and 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazole- 1-carboxylic acid tert-butyl ester (5.1 g; 17.4 mmol; 1.1 eq.) as a beige solid (4g, 85%). 1 H NMR (300 MHz, DMSO-d6) 513.25 (s, 1 H), 9.20 (s, 2H), 8.59 - 8.40 (m, 2H), 8.30 - 8.11 (m, 3H), 7.93 (d, J = 0.9 Hz, 1 H), 7.71 (ddd, J = 7.6, 1.8, 1.1 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 3.90 (s, 3H). HPLC (Condition A): Rt 2.94 min (purity 95.5%). MS (ESI+): 303.1 , (ESI-): 301.1.
Example 4: 2,2,2-Trifluoro-1 -[4-(4-{2-[3-(1 -methy 1-1 H-pyrazol-4-yl)-pheny I]- pyrimidin-5-yl}-pyrazo -1-yl)-piperidin-1-yl]-ethanone
Figure imgf000140_0002
Trifluoroacetic anhydride (44 μΙ; 0.31 mmol; 1.0 eq.) was added to a solution of 2-[3-(1- Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine (example 1 , 200 mg; 0.31 mmol; 1.0 eq.) in DCM (3 mL) and TEA (130 u!; 0.93 mmol; 3.0 eq.) maintained at 0°C. The reaction mixture was then stirred at RT for 3h. It was quenched by addition of a saturated solution of NaHC03 at 0°C. The aqueous phase was extracted with DCM (twice) and the combined organic phases were washed with sat. NH4CI and brine, dried over magnesium sulfate, filtered and concentrated. Purification by autopreparative LC/MS afforded the title compound as a white foam (61 mg, 41 %). 1 H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.61 - 8.55 (m, 1 H), 8.53 (t, J = 1.6 Hz, 1 H), 8.29 - 8.25 (m, 1 H), 8.22(dt, J = 7.8, 1.4 Hz, 1 H), 8.19 - 8.16 (m, 1 H), 7.93 (d, J = 0.8 Hz, 1 H), 7.75 - 7.68 (m, 1 H), 7.52(t, J = 7.7 Hz, 1 H), 4.70 - 4.56 (m, 1 H), 4.47 - 4.35 (m, 1 H), 4.06 - 3.94 (m, 1 H), 3.89(s, 3H), 3.58 - 3.42 (m, 1 H), 3.24 - 3.10 (m, 1 H), 2.32 - 2.14 (m, 2H), 2.07 - 1.86 (m, 2H). HPLC (Condition A): Rt 4.02 min (purity 98.7%). MS (ESI+): 482.2.
Example 5: 1 -[4-(4-{2-[3-(1 -Methyl-1 H-py razol-4-y l)-pheny l]-py rimidin-5-yl}-py razol- 1-yl)-piperidin-1-yl]-ethanone
Figure imgf000141_0001
Acetyl chloride (222 μΙ; 3.1 mmol; 2.0 eq.) was added to a solution of 2-[3-( -Methyl-1 H- pyrazol-4-yl)-phenyl]-5-(1 -piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride (example 1 , 655 mg; 1.55 mmol; 1.0 eq.) and ΤΕΞΑ (503 μΙ; 3.88 mmol; 2.5 eq.) in dry DMF (12 mL) and the reaction mixture was stirred at RT and under nitrogen for 2h. The reaction mixture was diluted with DCM and washed with water. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, gradient 100:0 to 80:20) afforded the title compound as a white solid (370 mg, 56%). 1 H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.58 - 8.50 (m, 2H), 8.26 (s, 1 H), 8.21 (dt, J = 8.0, 1.5 Hz, 1 H), 8.15 (s, 1 H), 7.92 (s, 1 H), 7.71 (dt, J = 8.0, 1.5 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 4.58 - 4.43 (m, 2H), 4.01 - 3.83 (m, 4H), 3.29 - 3.17 (m, 1 H), 2.74 (dd, J = 14.1 , 9.2 Hz, 1 H), 2.19 - 2.02 (m, 5H), 1.98 - 1.69 (m, 2H). HPLC (Condition A): Rt 2.90 min (purity 98.0%). MS (ESI+): 428.36.
Example 6: 5-[1 -(1 -Methyl-piperidin-4-yl)-1 H-py razol-4-y l]-2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine
Figure imgf000142_0001
Sodium triacetoxyborohydride (50 mg; 0.24 mmol; 2.0 eq.) was added to a solution of 2- [3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)pyrimidine (example 1 , 50 mg; 0.12 mmol; 1.0 eq.), formaldehyde (16 μΙ of a 36% aq. solution; 0.21 mmol; 1.8 eq.) and DIEA (24 μΙ; 0.14 mmol; 1.2 eq.) in DCE (2 mL). The reaction mixture was heated at 50°C for 1 hour. It was then diluted with DCM and poured into a saturated solution of NaHC03. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a white solid (25 mg; 53 %). H NMR (300 MHZ, DMSO-d6) δ 9.17 (s, 2H), 8.54-8.52 (m, 2H), 8.26 (s, 1 H), 8.22 (dt, J= 7.8 Hz, 1.5 Hz, 1 H), 8.15 (s, 1 H), 7.92 (d, J= 1.5 Hz, 1 H), 7.51 (dt, J= 7.8 Hz, 1.5 Hz, 1H), 7.51 (t, J= 7.8 Hz, 1 H), 4.31-4.20 (m, 1H), 3.89 (s, 3H), 3.04-3.01 (m, 2H), 2.36- 2.23 (m, 5H), 2.10-2.03 (m, 4H). HPLC (Condition A): Rt 2.48 min (purity 99.3%). MS (ESI+): 400.50. Example 7: 2-(3-Furan-3-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine Hydrochloride
Step 1 : Formation of tert-butyl 4-(4-{2-f3-(3-furyl)phenvnpyrimidin-5-yl)- H-pyrazol-1- yl)piperidine-1-carboxylate
Figure imgf000142_0002
Tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5; 100 mg; 0.19 mmol; 1.0 eq.), furan-3-boronic acid (25 mg; 0.23 mmol; 1.2 eq.), Pd(Ph3)4 (11 mg; 0.01 mmol; 0.05 eq.) and potassium carbonate (78 mg; 0.56 mmol; 3.0 eq.) were flushed with nitrogen before the addition of dioxane: water (1.5:0.75 mL). The reaction mixture was heated in MW at 120°C for 30 min. It was then diluted with EtOAc and water. Aqueous phase was extracted with EtOAc ( three times) and combined organic phases were dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (heptane :EtOAc, gradient from 80:20 to 50:50 afforded the title compound as a white solid (92 mg; 100 %). 1H NMR (300 MHz, DMSO- d6) δ 9.17 (s, 2H), 8.57-8.54 (m, 2H), 8.30-8.27 (m, 2H), 8.15 (s, 1 H), 7.75 (t, J= 1.7 Hz, 1 H), 7.78-7.74 (m, 1 H), 7.55 (t, J= 7.8 Hz, 1 H), 7.03 (dd, J= 1.7 Hz, 1.0 Hz, 1 H), 4.47- 4.40 (m, 1 H), 4.09-4.05 (m, 2H), 2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 5.13 min (purity 92.1%). MS (ESI+): 472.3.
Step 2: Formation of 2-(3-Furan-3-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidine hydrochloride
Figure imgf000143_0001
A solution of HCI/dioxane (4N solution in dioxane, 0.76mL, 3.0 mmol, 15 eq.) was added slowly to a solution of tert-butyl 4-(4-2-[3-(3-furyl)phenyl]pyrimidin-5-yl-1 H-pyrazol-1- yl)piperidine-1-carboxylate (95 mg; 0.20 mmol; 1.0 eq.) in DCM (0.95 mL) and MeOH (0.95 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at RT for 1h and concentrated under reduced pressure. Purification by autopreparative LC/MS afforded the title compound a as a white powder (40 mg; 49%). 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.78 (bs, 2H), 8.57 (t, J= 1.6 Hz, 1 H), 8.52 (s, 1 H), 8.31-8.27 (m, 2H), 8.21 (s, 1 H), 7.80 (t, J= 1.6 Hz, 1 H), 7.79-7.75 (m, 1 H), 7.56 (t, J= 7.8 Hz, 1 H), 7.03-7.02 (m, 1 H), 4.58-4.52 (m, 1H), 3.46-3.38 (m, 2H), 3.16-3.06 (m, 2H), 2.28-2.1 1 (m, 4H). HPLC (Condition A): Rt 3.11 min (purity 99.8%). MS (ESI+): 372.4.
Example 8: 4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid
Figure imgf000143_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2; 80 mg; 0.25 mmol; 1.0 eq.) and 1-(Ethoxycarbonylmethyl)-1 H-pyrazole-4-boronic acid, pinacol ester (71 mg; 0.25 mmol; 1.0 eq.) as a white solid (21 mg, 23%). H NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 9.18 (s, 2H), 8.54 (s, 1 H), 8.44 (s, 1H), 8.27 (s, 1 H), 8.23 (d, J = 7.8 Hz, 1H), 8.17 (s, 1 H), 7.93 (s, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.05 (s, 2H), 3.90 (s, 3H). HPLC (Condition A): Rt 2.61 min (purity 97.5%). MS (ESI+): 361.3
Example 9: 2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-1 -pyrrolidin-1 -yl-ethanone
Figure imgf000144_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 eq.) and 1-Pyrrolidin-1-yl-2-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethanone (intermediate 7, 77 mg; 0.25 mmol; LOOeq.) as a yellow powder (57 mg; 54 %). 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.38 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.17 (m, 1H), 8.15 (s, 1 H), 7.93 (s, 1 H), 7.77 - 7.67 (m, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 5.13 (s, 2H), 3.90 (s, 3H), 3.53 (t, J = 6.7 Hz, 2H), 3.34 (t, 2H), 2.02 - 1.69 (m, 4H). HPLC (Condition A): Rt 2.83 min (purity 96.3%). MS (ESI+): 414.3
Example 10: 4-[2-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- py razol-1 -y l)-ethyl]-m
Figure imgf000144_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 eq.) and 1-(2-Morpholinoethyl)-1 H-pyrazole-4-boronic acid pinacol ester (78 mg; 0.25 mmol; 1.0 eq.) as a white powder (71 mg; 68 %). H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.53 (t, J = 1.6 Hz, 1 H), 8.46 (s, 1 H), 8.26 (s, 1 H), 8.25 - 8.19 (m, 1H), 8.13 (s, 1H), 7.92 (d, J = 0.6 Hz, 1 H), 7.76 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.30 (t, J = 6.5 Hz, 2H), 3.90 (s, 3H), 3.63 - 3.51 (m, 4H), 2.76 (t, J = 6.6 Hz, 2H), 2.48 - 2.34 (m, 4H). ). HPLC (Condition A): Rt 2.31 min (purity 98.3%). MS (ESI+): 416.3
Example 11 : Dimethyl-[2-(4~{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-ethyl]-amine
Figure imgf000145_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 eq.) and dimethyl-2-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan- 2-yl)-pyrazol-1-yl]-ethyl-amine (67 mg; 0.25 mmol; 1 .0 eq.) as a white solid (69 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.53 (t, J = 1.6 Hz, 1 H), 8.46 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.17 (m, 1 H), 8.13 (s, 1 H), 7.92 (d, J = 0.6 Hz, 1 H), 7.77 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.27 (t, J = 6.5 Hz, 2H), 3.90 (s, 3H), 2.72 (t, J = 6.5 Hz, 2H), 2.19 (d, J = 10.3 Hz, 6H). HPLC (Condition A): Rt 2.23 min (purity 97.3%). MS (ESI+): 374.3
Example 12 : 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-furan-3-yl)- 1 H-pyrazol-4-yl]-pyrimid
Figure imgf000145_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 150 mg; 0.48 mmol; 1.0 eq.) and 1-(Tetrahydro-furan-3-yl)-4-(4,4,5,5-tetramethyI- [1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (CombiPhos Catalysts, Inc.; 126 mg; 0.48 mmol; 1.0 eq.) as a white solid (113 mg; 64 %). H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.53 (s, 2H), 8.34 - 8.14 (m, 3H), 7.94 (s, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 5.15 - 5.04 (m, 1 H), 4.15 - 3.75 (m, 7H), 2.48 - 2.24 (m, 2H). HPLC (Condition A): Rt 3.16 min (purity 95.0%). MS (ESI+): 373.3
Example 13: 2-(3-lsoxazol-4-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4-f2-(3-isoxazol-4-ylphenyl)pyrimidin-5-yll-1 H-pyrazol- 1-yl)piperidine-1-carboxylate
Figure imgf000146_0001
Tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5, 150 mg; 0.24 mmol; 1.0 eq.), 4-lsoxazoleboronic acid pinacol ester (47 mg; 0.24 mmol; 1.0 eq.), bis(triphenylphosphine)palladium(ll)chloride (17 mg; 0.02 mmol; 0.10 eq.) and cesium fluoride (109 mg; 0.72 mmol; 3.0 eq.) were flushed with nitrogen before the addition of dioxane: water (2.25:1.1 mL). The reaction mixture was heated in MW at 120°C for 30 min. It was then diluted with EtOAc and water. Aqueous phase was extracted with EtOAc and combined organic phases were dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (cyclohexane: EtOAc, gradient from 80:20 to 30:70) afforded the title compound as a white beige solid (70 mg; 62%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1 H), 9.27 (s, 1 H), 9.17 (s, 2H), 8.64 (t, J= 1.5 Hz, 1 H), 8.56 (s, 1 H), 8.35 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.16 (s, 1 H), 7.87-7.83 (m, 1 H), 7.61 (t, J= 8.0 Hz, 1 H), 4.47-4.35 (m, 1H), 4.09-4.04 (m, 2H), 2.95 (m, 2H), 2.09-2.06 (m, 2H), 1.87-1.72 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 4.70 min (purity 97.4%). MS (ESI+): 473.5.
Step 2: Formation of 2-(3-lsoxazol-4-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidine hydrochloride
Figure imgf000147_0001
A solution of HCI/dioxane (4N solution in dioxane, 0.55 mL, 2.2 mmol, 15 eq.) was added slowly to a solution tert-butyl 4-4-[2-(3-isoxazol-4-ylphenyl)pyrimidin-5-yl]-1 H-pyrazol-1- ylpiperidine-1-carboxylate (70 mg; 0.15 mmol; 1.0 eq.) in DCM (0.7 mL) and MeOH (0.7 mL). The reaction mixture was stirred at RT for 3h and concentrated under reduced pressure. The solid obtained was suspended in DCM (3 mL), sonicated, filtered off and dried overnight under reduced pressure to give the title compound as a yellow solid (60 mg; 99 %). 1H NMR (300 MHz, DMSO-d6) : 9.61 (s, 1 H), 9.27 (s, 1 H), 9.25-9.21 (m, 3H), 8.98 (brs, 1H), 8.64 (t, J= 1.5 Hz, 1H), 8.55 (s, 1 H), 8.36 (dt, J= 8.0 Hz, 1.5 Hz, 1H), 8.22 (s, 1 H), 7.86 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.62 (t, J= 8.0 Hz, 1 H), 3.43-3.30 (m, 3H), 3.17- 3.06 (m, 2H), 2.29-2.13 (m, 4H). HPLC (Condition A): Rt 2.62 min (purity 98.1 %). MS (ESI+): 373.3.
Example 14: 2-[3-(1,3-Dimethyl-1H-pyrazol-4-yl)-phenyl]-5-(1-piperid
pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4 2-r3-(1 ,3-dimethyl-1 H-pyrazol-4- yl)phenvnpyrimidin-5- -1 H-pyrazol-1-yl)piperidine-1-carboxylate
Figure imgf000147_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine- 1-carboxylate (intermediate 5, 150 mg; 0.28 mmol; 1.0 eq.) and 1 ,3-dimethyl-1 H- pyrazole-4-boronic acid, pinacolester (63 mg; 0.28 mmol; 1.0 eq.) as a brown gum (120 mg, 85%). HPLC (Condition A): Rt 4.37 min (purity 89.4%). MS (ESI+): 500.5. Step 2: Formation of 2-[3-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-phenyll-5-(1-pipe din-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000148_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from tert-butyl 4-(4-2-[3-(1 ,3-dimethyl-1 H-pyrazol-4-yl)phenyl]pyrimidin-5-yl- 1 H-pyrazol-1-yl)piperidine-1-carboxylate (120 mg; 0.24 mmol; 1.0 eq.) as a brown solid (60 mg; 57 %). 1H NMR (300 MHz, DMSO-d6) δ 9.20 (m, 3H), 8.95 (brs, 1 H), 8.52 (s, 1H), 8.47-8.46 (m, 1 H), 8.25 (dt, J= 7.0 Hz, 1.8 Hz, 1 H), 8.20 (s, 1 H), 8.03 (s, 1 H), 7.60- 7.51 (m, 2H), 4.60-4.52 (m, 1 H), 3.82 (s, 3H), 3.42-3.38 (m, 2H), 3.15-3.05 (m, 2H), 2.36 (s, 3H), 2.28-2.11 (m, 4H). HPLC (Condition A): Rt 2.49 min (purity 99.9%). MS (ESI+): 400.5.
Example 15: 2-[3-(1,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4-{2-i3-(1 ,5-dimethyl-1 H-pyrazol-4-yl)phenyllpyrimidin- 5-yl)-1 H-pyrazol-1-yl)piperidine-1-carboxylate
Figure imgf000148_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine- 1-carboxylate (intermediate 5, 150 mg; 0.28 mmol; 1.0 eq.) and 1 ,5-dimethyl-1 H- pyrazole-4- boronic acid,pinacolester (63 mg; 0.28 mmol; 1.0 eq.) as a beige solid (96 mg; 68 %). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.54 (s, 1H), 8.41 (s, 1 H), 8.28-8.25 (m, 1 H),8.14 (s, 1 H), 7.64 (s, 1 H), 7.59-7.54 (m, 2H), 4.47-4.37 (m, 1 H), 4.08- 4.04 (m, 2H), 3.81 (s, 3H), 2.96 (m, 2H), 2.43 (s, 3H), 2.09-2.05 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 4.25 min (purity 98.5%). MS (ESI+): 500.6. Step 2: formation of 2-r3-(1 ,5-Dimethyl-1 H-pyrazol-4-yl)-phenvn-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000149_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from tert-butyl 4-(4-2-[3-(1 ,5-dimethyl-1 H-pyrazol-4-yl)phenyl]pyrimidin-5-yl- 1 H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate 5, 95 mg; 0.19 mmol; 1.0 eq.) as a yellow solid (80 mg; 96 %). 1H NMR (300 MHz, DMSO-d6) δ 9.27-9.21 (m, 3H), 9.05- 8.86 (m, 1 H), 8.52 (s, 1 H), 8.43-8.41 (m, 1 H), 8.29-8.24 (m, 1 H), 8.20 (s, 1 H), 7.67 (s, 1 H), 7.59-7.53 (m, 2H), 4.62-4.49 (m, 1 H), 3.82 (s, 3H), 3.42-3.38 (m, 2H), 3.16-3.05 (m, 2H), 2.43 (s, 3H), 2.28-2.12 (m, 4H). HPLC (Condition A): Rt 2.54 min (purity 99.7%). MS (ESI+): 400.5.
Example 16: 2-{3-[1-(2-Fluoro-1-fluoromethyl-ethyI)-1 H-pyrazol-4-yl]-phenyl}-5-(1- piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4-f2-(3-{1-r2-fluoro-1-(fluoromethyl)ethvn-1 H-pyrazol-4- yl>phenyl)pyrimidin- -vn-1 H-pyrazol-1-yl)piperidine-1-carboxylate
Figure imgf000149_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine- 1-carboxylate (Intermediate 5, 150 mg; 0.28 mmol; 1.0 eq.) and 1-[2-fluoro-1- (fluoromethyl)ethyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole (intermediate 8, 77 mg; 0.28 mmol; 1.0 eq.) as a white solid (120 mg; 77 %). H NMR (300 MHz, DMSO-d6) : 9.16 (s, 2H), 8.57 (t, J= 1.5 Hz, 1 H), 8.55 (s, 1 H), 8.48 (s, 1H), 8.24 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.15 (s, 1 H), 8.07 (s, 1 H), 7.76 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.52-7.55 (m, 1 H), 5.08-4.92 (m, 3H), 4.88-4.77 (m, 2H), 4.47-4.40 (m, 1 H), 4.09-4.04 (m, 2H), 2.95 (m, 2H), 2.09-2.05 (m, 2H), 1.88-1.75 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 4.77 min (purity 84.5%). MS (ESI+): 550.7.
Step 2: Formation of 2-{3-[1-(2-Fluoro-1-fluoromethyl-ethyl)-1 H-pyrazol-4-yll-phenyl)-5- (1-piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000150_0001
The title compound was obtained following procedure described for example 7, step 2, but starting from tert-butyl 4-4-[2-(3-1-[2-fluoro-1-(fluoromethyl)ethyl]-1 H-pyrazol-4- ylphenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine-1-carboxylate (120 mg; 0.22 mmol; 1.0 eq.) as a white amorphous solid (30 mg; 28 %). 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 2H), 8.72 (bs, 2H), 8.57 (t, J= 1.5 Hz, 1 H), 8.52 (s, H), 8.47 (s, 1H), 8.25 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.21 (s, 1 H), 8.07 (s, 1 H), 7.76 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.54 (t, J= 8.0 Hz, 1 H), 5.11-4.92 (m, 3H), 4.87-4.77 (m, 2H), 4.60-4.52 (m, 1 H), 3.45-3.40 (m, 2H), 3.16-3.07 (m, 2H), 2.29-2. 1 (m, 4H). HPLC (Condition A): Rt 2.83 min (purity 98.8%). MS (ESI+): 450.4.
Example 17: 2-(4-{3-[5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]-phenyl}- py razol-1 -y l)-1 -py rrolidin-1 -y l-ethanone hydrochloride
Stepl : Formation of tert-butyl 4-i4-(2-(3-f1-(2-oxo-2-pyrrolidin-1-ylethyl)-1 H-pyrazol-4- yllphenyl)pyrimidin-5-yl)-1 H-pyrazol-1-yl iperidine-1-carboxylate
Figure imgf000150_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine- 1-carboxylate (intermediate 5, 150 mg; 0.28 mmol; 1.0 eq.) and 1-Pyrrolidin-1-yl-2-[4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethanone (Intermediate 7; 103 mg; 0.34 mmol; 1.2 eq.) as a grey solid (148 mg; 90 %). 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.55-8.54 (m, 2H), 8.24-8.21 (m, 2H), 8.15 (s, 1 H), 7.94 (s, 1 H), 7.73 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.52 (t, J= 8.0 Hz, 1 H), 5.06 (s, 2H), 4.48-4.39 (m, 1 H), 4.09-4.01 (m, 2H), 3.52 (t, J= 6.6 Hz, 2H), 3.35-3.31 (m, 2H), 2.94 (m, 2H), 2.09-2.06 (m, 2H), 1.98-1.76 (m, 6H), 1.43 (s, 9H). HPLC (Condition A): Rt 4.20 min (purity 98.6%). MS (ESI+): 583.7.
Step 2) Formation of 2-(4-{3-[5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidin-2-yll-phenyl)- pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone hydrochloride
Figure imgf000151_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from tert-butyl 4-[4-(2-3-[1-(2-oxo-2-pyrrolidin-1-ylethyl)-1 H-pyrazol-4- yl]phenylpyrimidin-5-yl)-1 H-pyrazol-1-yl]piperidine-1-carboxylate (145 mg; 0.25 mmol; 1.0 eq.) as a yellow solid (85.00 mg; 65.81 %). 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 2H), 9.12 (m, 1 H), 8.86 (m, 1 H), 8.55 (t, J= 1.7 Hz, 1 H), 8.53 (s, 1 H), 8.25-8.21 (m, 3H), 7.95 (d, J= 0.8 Hz, 1 H), 7.75-7.71 (m, 1 H), 7.53 (t, J= 8.0 Hz, 1 H), 5.06 (s, 2H), 4.61- 4.51 (m, 1 H), 3.52 (t, J= 6.8 Hz, 2H), 3.43-3.39 (m, 2H), 3.33 (t, J= 6.8 Hz, 2H), 3.16- 3.05 (m, 2H), 2.30-2.12 (m, 4H), 1.93 (quint., J= 6.8 Hz, 2H), 1.80 (quint., J= 6.8 Hz, 2H). ). HPLC (Condition A): Rt 2.41 min (purity 99.4%). MS (ESI+): 483.6. Example 18 : 5-(1-Piperidin-4-yl-1H-pyrazol-4-yl)-2-[3-(1H-pyrazol-4-yl)-phenyl]- pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4-{2-f3-(1 H-pyrazol-4-yl)phenvnpyrimidin-5-yl)-1 H- pyrazol-1 -yl)piperidin -1 -carboxylate
Figure imgf000151_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1 -ylpiperidine- 1-carboxylate (intermediate 5; 200 mg; 0.38 mmol; 1.0 eq.) and 1-Boc-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole (133 mg; 0.45 mmol; 1.2 eq.) as a beige solid (177 mg; 99 %). 1H NMR (300 MHz, DMSO) δ 13.03 (bs, 1 H), 9.17 (s, 2H), 8.59 - 8.52 (m, 2H), 8.29 (s, 1 H), 8.22 (dt, J = 8.0, 1.5 Hz, 1 H), 8.15 (s, 1 H), 7.96 (s, 1 H), 7.75 (dt, J = 8.0, 1.5 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 4.51 - 4.36 (m, 1 H), 4.15 - 4.01 (m, 2H), 3.07 - 2.80 (m, 2H), 2.15 - 2.03 (m, 2H), 1.90 - 1.72 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 4.06 min (purity 88.0%). MS (ESI+): 472.4. Step 2: Formation of 5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-r3-(1 H-pyrazol-4-yl)-phenvn- pyrimidine hydrochlori
Figure imgf000152_0001
The title compound was obtained following procedure described for example 7, step 2, but starting from tert-butyl 4-[4-(2-3-[1-(tert-butoxycarbonyl)-1 H-pyrazol-4- yl]phenylpyrimidin-5-yl)-1 H-pyrazol-1-yl]piperidine-1-carboxylate (215 mg; 0.38 mmol; 1.0 eq.) as a white amorphous solid (50 mg; 33 %). 1H NMR (300 MHz, DMSO-d6) δ 13.05 (brs, 1 H), 9.20 (s, 2H), 8.90 (brs, 2H), 8.56 (t, J= 1.7 Hz, 1 H), 8.52 (s, 1 H), 8.30 (brs, 1 H), 8.24-8.21 (m, 2H), 7.98 (brs, 1 H), 7.76 (dt, J= 7.8 Hz, 1.7 Hz, 1 H), 7.52 (t, J= 7.8 Hz, 1 H), 4.62-4.52 (m, 1 H), 3.47-3.39 (m, 2H), 3.15-3.06 (m, 2H), 2.29-2.08 (m, 4H). HPLC (Condition A): Rt 2.08 min (purity 100.0%). MS (ESI+): 372.4.
Example 19 : 5-(1 -Piperidin-4-yl-1 H-pyrazol-4-yl)-2-[3-(1-propyl-1H-pyrazol-4-yl)- phenyl]-pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4-(2-f3-(1-propyl-1 H-pyrazol-4-yl)phenyl|pyrimidin-5-yl)- 1 H-pyrazol-1-vDpiperidine-1-carboxylate
Figure imgf000152_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine- 1-carboxylate (intermediate 5, 200 mg; 0.38 mmol; 1.0 eq.) and 1-propyl-1 H-pyrazole-4- boronic acid, pinacol ester (89 mg; 0.38 mmol; 1.0 eq.) as a beige solid (160 mg, 83%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.55 (s, 1 H), 8.54 (t, J= 1.5 Hz, 1 H), 8.30 (s, 1 H), 8.21 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.15 (s, 1 H), 7.93 (s, 1H), 7.72 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.51 (t, J= 8.0 Hz, 1 H), 4.47-4.38 (m, 1 H), 4.13-4.00 (m, 4H), 2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.90-1.75 (m, 4H), 1.43 (s, 9H), 0.86 (t, J= 7.5 Hz, 3H). HPLC (Condition A): Rt 4.85 min (purity 91.2%). MS (ESI+): 514.6.
Step 2: Formation of 5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-f3-(1-propyl-1 H-pyrazol-4-yl)- phenyll-pyrimidine hydrochloride
Figure imgf000153_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from tert-butyl 4-(4-2-[3-(1-propyl-1 H-pyrazol-4-yl)phenyl]pyrimidin-5-yl-1 H- pyrazol-1-yl)piperidine-1-carboxylate (160 mg; 0.31 mmol; 1.00eq.) as a Pale yellow solid (126 mg; 90 %). 1 H NMR (300 MHZ, DMSO-d6) δ 9.28-9.20 (m, 3H), 9.01-8.98 (m, 1 H), 8.55-8.53 (m, 2H), 8.31 (s, 1 H), 8.23-8.21 (m, 2H), 7.94 (s, 1 H), 7.73 (dt, J= 7.8 Hz, 1.6 Hz, 1 H), 7.51 (t, J= 7.8 Hz, 1 H), 4.57 (quint., J= 5.0 Hz, 1 H), 4.11 (t, J= 7.0 Hz, 2H), 3.42-3.38 (m, 2H), 3.16-3.04 (m, 2H), 2.29-2.13 (m, 4H), 1.84 (sext, J= 7.0 Hz, 2H), 0.86 (t, J= 7.0 Hz, 3H). HPLC (Condition A): Rt 2.82 min (purity 100.0%). MS (ESI+): 414.5.
Example 20: 2-[3-(1 -Isopropy 1-1 H-py razol-4-y l)-phenyl]-5-(1 -piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4-(2-[3-(1-isopropyl-1 H-pyrazol-4-yl)phenyllpyrimidin-5- yl}- 1 H-pyrazol-1 -vDpiperidine- 1 -carboxylate
Figure imgf000154_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine- 1-carboxy!ate (intermediate 5; 200 mg; 0.38 mmol; 1.0 eq.) and 1-lsopropyl-4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (98 mg; 0.41 mmol; 1.1 eq.) as a yellow solid (153 mg; 79 %). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.55-8.53(m, 2H), 8.34 (s, 1 H), 8.21 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.15 (s, 1H), 7.92 (s, 1 H), 7.73 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.51 (t, J= 8.0 Hz, 1 H), 4.54 (sept., J= 6.7 Hz, 1H), 4.47-4.38 (m, 1 H), 4.09-4.00 (m, 2H), 2.94 (m, 2H), 2.09-2.06 (m, 2H), 1.88-1.75 (m, 2H), 1.47 (d, J= 6.7 Hz, 6H), 1.43 (s, 9H) HPLC (Condition A): Rt 4.83 min (purity 98.1 %). MS (ESI+): 514.6.
Step 2: Formation of 2-[3-(1-lsopropyl-1 H-pyrazol-4-yl)-phenyll-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000154_0002
The title compound was obtained following procedure described for example 13, step 2, but starting from tert-butyl 4-(4-2-[3-(1-isopropyl-1 H-pyrazol-4-yl)phenyl]pyrimidin-5-yl- 1 H-pyrazol-1-yl)piperidine-1-carboxylate (150 mg; 0.29 mmol; 1.0 eq.) as a yellow solid (95 mg; 72 %). 1 H NMR (300 MHz, DMSO-d6) δ 9.26-9.20 (m, 3H), 8.99-8.95 (m, 1 H), 8.55 (t, J= 1.6 Hz, 1 H), 8.53 (s, 1 H), 8.34 (s, 1 H), 8.23-8.21 (m, 2H), 7.93 (s, 1 H), 7.73 (dt, J= 7.8 Hz, 1.6 Hz, 1 H), 7.51 (t, J= 7.8 Hz, 1H), 4.60-4.50 (m, 2H), 3.43-3.38 (m, 2H), 3.16-3.06 (m, 2H), 2.28-2.22 (m, 4H), 1.47 (d, J= 6.6 Hz, 6H). HPLC (Condition A): Rt 2.81 min (purity 99.0%). MS (ESI+): 414.4. Example 21 : 2-[3-(1-Benzyl-1H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol- 4-yl)-pyrimidine hydrochloride
Step 1 : Formation of tert-butyl 4-(4-(2-r3-(1-benzyl-1 H-pyrazol-4-yl)phenyllpyrimidin-5-
Figure imgf000155_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1-ylpiperidine- 1-carboxylate (intermediate 5; 200 mg; 0.38 mmol; 1.0 eq.), 1-benzyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (107 mg; 0.38 mmol; 1.0 eq.) as a beige solid (165 mg; 78 %). 1 H NMR (300 MHz, DMSO-d6) : 9.18 (s, 2H), 8.55-8.53 (m, 2H), 8.44 (s, 1 H), 8.21 (dt, J= 7.8 Hz, 1.5 Hz, 1 H), 8.15 (s, 1 H), 7.94 (d, J= 0.8 Hz, 1 H), 7.73 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.73 (m, 1 H), 7.51 (t, J= 8.0 Hz, 1 H), 7.40-7.28 (m, 5H), 5.37 (s, 2H), 4.47-4.39 (m, 1 H), 4.08 (m, 2H), 2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.87-1.74 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 5.15 min (purity 88.9%). MS (ESI+): 562.5.
Step 2: Formation of 2-f3-(1-Benzyl-1 H-pyrazol-4-yl)-phenvn-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000155_0002
The title compound was obtained following procedure described for example 13, step 2, but starting from tert-butyl 4-(4-2-[3-(1-benzyl-1 H-pyrazol-4-yl)phenyl]pyrimidin-5-yl-1 H- pyrazol-1-yl)piperidine-1-carboxylate (165 mg; 0.29 mmol; 1.0 eq.) as a yellow solid (125 mg; 85 %). 1 H NMR (300 MHz, DMSO-d6) δ 9.34-9.30 (m, 1 H), 9.19 (s, 2H), 9.08-9.05 (m, 1 H), 8.57-8.53 (m, 2H), 8.44 (s, 1 H), 8.24-8.20 (m, 2H), 7.98 (d, J= 0.8 Hz, 1 H), 7.73 (dt, J= 7.8 Hz, 1.5 Hz, 1 H), 7.52 (t, J= 7.8 Hz, 1 H), 7.40-7.27 (m, 5H), 5.38 (s, 2H), 4.57 (quint., J= 5.0 Hz, 1 H), 3.42-3.37 (m, 2H), 3.15-3.08 (m, 2H), 2.30-2.13 (m, 4H). HPLC (Condition A): Rt 3.30 min (purity 99.6%). MS (ESI+): 462.6. Example 22 : 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-pyridin-3-ylmethyl-1 H- pyrazol-4-yl)-pyrimidine
Figure imgf000156_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 100 mg; 0.32 mmol; 1.0 eq.) and 1-(Pyridin-3-ylmethyl)- H-pyrazole-4-boronic acid, pinacol ester (90 mg; 0.32 mmol; 1.0 eq.) as a white solid (14 mg; 12%). H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.60 (s, 2H), 8.56 - 8.49 (m, 2H), 8.30 - 8.17 (m, 3H), 7.92 (s, 1 H), 7.72 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1 H), 7.41 (dd, J = 7.9, 4.8 Hz, 1 H), 5.48 (s, 2H), 3.89 (s, 3H). HPLC (Condition A): Rt 2.33 min (purity 100%). MS (ESI+): 394.3
Example 23: 2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-ethanol
Step 1 : Formation of 5-[1-(2-(rtert-butyl(dimethyl)silylloxy}ethvn-1 H-pyrazol-4-vn-2-r3-(1- methyl-1 H-pyrazol-4-yl)phenyllpyhmidine
Figure imgf000156_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate
2;
100 mg; 0.32 mmol; 1.0 eq.) and 1-(Tetrahydro-furan-3-yl)-4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (1 12 mg; 0.32 mmol; 1.0 eq.) as a beige oil (1 16 mg; 79 %). MS (ESI+): 461.4
Step 2: Formation of 2-(4-{2-f3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl}- pyrazol-1 -yl)-ethanol
Figure imgf000157_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from 5-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1 H-pyrazol-4-yl]-2-[3-(1- methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (1 16 mg; 0.25 mmol; 1 .0 eq.) as a white powder (59 mg; 68%). 1 H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.53 (t, J = 1.6 Hz, 1 H), 8.44 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.18 (m, 1 H), 8.15 (d, J = 0.5 Hz, 1 H), 7.93 (d, J = 0.7 Hz, 1 H), 7.76 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.99 (brs, 1 H), 4.21 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.79 (d, J = 4.0 Hz, 2H). HPLC (Condition A): Rt 2.68 min (purity 97.7%). MS (ESI+): 347.3. mp = 234-236°C
Example 24: 2-[3-Fluoro-5-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl- 1 H-pyrazol-4-yl)-pyri
Figure imgf000157_0002
tert-butyl 4-[4-(2-iodopyrimidin-5-yl)-1 H-pyrazol-1 -yl]piperidine-1 -carboxylate (intermediate 6; 104 mg; 0.23 mmol; 1 .0 eq.), 3-bromo-5-fluorophenyl boronic acid (527 mg; 2.41 mmol; 1.1 eq.), bis(triphenylphosphine)palladium(ll) chloride (14 mg; 0.02 mmol; 0.09 eq.) and cesium fluoride (272 mg; 1.79 mmol; 1 .0 eq.) were suspended in DMF (4 mL) and water (1 mL). The reaction mixture was then heated in MW at 100°C for 30 min. 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .37 g; 6.58 mmol; 3.0 eq.) and bis(triphenylphosphine)palladium(ll) chloride (80 mg; 0.1 1 mmol; 0.05 eq.) were added to the reaction suspension and heating continued for a further 30 min. On cooling the reaction suspension was filtered through celite, then poured into a 1 N HCI solution and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was purified by flash chromatography on silica (DCM: eOH, gradient from 95:5 to 50:50). The pure residue was redissolved in HCI/dioxane (4 ml_ of a 1 N solution; 16 mmol; 70 eq.) and MeOH (4 ml_) and the resulting solution was stirred at RT for 1h. It was then concentrated and triturated with acetonitrile. The solid was finally filtered and dried under vacuum to give the title compound as an orange solid. (0.72 g; 69%), H NMR (300 MHz, DMSO) δ 9.22 (s, 2H), 9.16 (br, 1 H), 8.92 (br, 1 H), 8.55 (s, 1 H), 8.38 (t, J = 1.4 Hz, 1H), 8.35 (s, 1 H), 8.23 (s, 1 H), 8.00 (d, J = 0.7 Hz, 1H), 7.95 - 7.86 (m, 1 H), 7.66 - 7.57 (m, 1 H), 4.58 - 4.46 (m, 1 H), 3.89 (s, 3H), 3.47 - 3.35 (m, 2H), 3.19 - 3.02 (m, 2H), 2.34 - 2.12 (m, 4H). HPLC (Condition A): Rt 2.60 min (purity 92.6%). MS (ESI+): 404.5.
Example 25: 2-(4-{2-t3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-1 -piperidin-1 -yl-ethanone
Figure imgf000158_0001
A mixture of (4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidin-5-yl}-1 H-pyrazol-1- yl)acetic acid (example 9, 110 mg; 0.31 mmol; 1.0 eq.), piperidine (52 mg; 0.61 mmol; 2.0 eq.), HATU (174 mg; 0.46 mmol; 1.50eq.) and DIEA (152 μΙ; 0.92 mmol; 3.0 eq.) in DMF (2 mL) was stirred at 50°C O/N. The reaction mixture was poured into water and extracted with DCM (three times). Combined organic phases were then concentrated under reduced pressure and the residue was recrystallised in MeOH/Ether. The solid obtained was filtered and dried under reduced pressure to give the title compound as a white solid (20 mg, 15%). H NMR (300 MHz, DMSO) δ 9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1H), 8.37 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.19 (m, 1 H), 8.14 (s, 1 H), 7.93 (s, 1 H), 7.77 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.22 (s, 2H), 3.90 (s, 3H), 3.55 - 3.39 (m, 4H), 1.69 - 1.39 (m, 6H).HPLC (Condition A): Rt 3.16 min (purity 99.9%). MS (ESI+): 428.3 Example 26: 5-(1-Azetidin-3-yl-1 H-pyrazol-4-yl)-2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenylj-pyrimidine hydrochloride Step 1 : Formation of tert-butyl 3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl1pyrimidin-5-
Figure imgf000159_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2; 100 mg; 0.32 mmol; 1.00 eq.) and 3-[4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- pyrazol-1-yl]-azetidine-1-carboxylic acid tert-butyl ester (111 mg; 0.32 mmol; 1.0 eq.) as a beige solid (150 mg; 100 %). HPLC (Condition A): Rt 4.01 min (purity 86.3%). MS (ESI+): 458.3 Step 2: Formation of 5-(1-Azetidin-3-yl-1 H-pyrazol-4-yl)-2-[3-(1-methyl- H-pyrazol-4-yl)- phenyll-pyrimidine hydrochloride
Figure imgf000159_0002
.HCI
The title compound was obtained following procedure described for example 13, step 2, but starting from tert-butyl 3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidin-5-yl}-1 H- pyrazol-1-yl)azetidine-1-carboxylate (150 mg; 0.32 mmol; 1.0 eq.) as a white solid (3 mg, 3%). 1 H NMR (300 MHz, DMSO-d6) δ 9.36 (brs, 2H), 9.20 (s, 2H), 8.64 (s, 1 H), 8.54 (t, J = 1.6 Hz, 1H), 8.38 (s, 1 H), 8.30 - 8.18 (m, 2H), 7.93 (d, J = 0.7 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.59 - 5.38 (m, 1 H), 4.49 - 4.21 (m, 4H), 3.90 (s, 3H). HPLC (Condition A): Rt 2.23 min (purity 98.6%). MS (ESI+): 358.3 Example 27: 5-[1-(3-Methoxy-propyl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin
Figure imgf000160_0001
A solution of 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 130 mg; 0.43 mmol; 1.0 eq.) in dry DMF (1 mL) was added over a suspension of NaH (60% in oil, 21 mg; 0.86 mmol; 2.0 eq.) in dry DMF (1 mL) maintained at 0°C under nitrogen atmosphere. The resulting mixture was stirred for one hour at 0°C then heated at 100°C O/N after the addition of a solution of 1-chloro-3- methoxypropane (47 mg; 0.43 mmol; 1.0 eq.) in DMF (2 mL). Reaction mixture was then cooled down to RT, quenched with water and extracted with EtOAc (three times). Combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting solid was dried O/N at 60°C under reduced pressure to give the title compound a beige powder (165 mg; 75%).1 H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.58 - 8.49 (m, 1 H), 8.46 (s, 1 H), 8.30 - 8.17 (m, 2H), 8.17 - 8.11 (m, 1 H), 7.96 - 7.89 (m, 1 H), 7.75 - 7.68 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.22 (t, J = 7.0 Hz, 2H), 3.90 (s, 3H), 3.39 - 3.30 (m, 2H), 3.25 (s, 3H), 2.15 - 1.97 (m, 2H). HPLC (Condition A): Rt 3.34 min (purity 97.1 %). MS (ESI+):375.5.
Example 28: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(1-oxetan-3-yl-piperidin-4- yl)-1 H-pyrazol-4-yl]-pyrimidine
Figure imgf000160_0002
Sodium triacetoxyborohydride (0.13 g; 0.62 mmol; 2.0 eq.) was slowly added to a solution of 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4- yl)pyrimidine (example 1 , 200 mg; 0.31 mmol; 1.0 eq.), DIEA (53 μΙ; 0.31 mmol; 1.0 eq.) and 3-oxetanone (39 μΙ; 0.62 mmol; 2.0 eq.) in DCE (4 mL). The reaction mixture was then stirred at 50°C for 3h. It was then quenched by addition of water. Aqueous phase was basified to pH 12 and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige powder (100 mg, 73%). 1 H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.59 - 8.50 (m, 2H), 8.27 (s, 1 H), 8.25 - 8.18 (m, 1 H), 8.18 - 8.1 1 (m, 1 H), 7.96 - 7.89 (m, 1 H), 7.77 - 7.66 (m, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 4.23 (s, 1 H), 3.90 (s, 3H), 3.51 - 3.40 (m, 1 H), 2.87 - 2.73 (m, 2H), 2.17 - 1.90 (m, 6H). HPLC (Condition A): Rt 2.49 min (purity 97.2%). MS (ESI+):442.5. Example 29: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yImethyl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of 4-(4-{2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-ylV- pyrazol-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester
Figure imgf000161_0001
The title compound was obtained following procedure described for example 27, but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 150 mg; 0.50 mmol; 1.0 eq.) and tert-butyl 4- {[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (145 mg; 0.50 mmol; 1.0 eq.) as a beige powder (200 mg, 81 %). HPLC (Condition A): Rt 4.44 min (purity 97.2%). MS (ESI+): 500.5
Step2: Formation of 2-f3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-5-(1-piperidin-4-ylmethyl-
1 H-pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000161_0002
The title compound was obtained following procedure described for example 13, step 2, but starting from of 4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1-ylmethyl)-piperidine-1-carboxylic acid tert-butyi ester (200 mg; 0.40 mmol; 1.0 eq.) as a yellow powder (160 mg, 92%). 1 H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 9.10 - 8.96 (m, 1 H), 8.84 - 8.68 (m, 1 H), 8.53 (t, J = 1.6 Hz, 1 H), 8.49 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.16 (m, 2H), 7.93 (d, J = 0.7 Hz, 1H), 7.75 - 7.68 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.17 - 4.07 (m, 2H), 3.90 (s, 3H), 3.31 - 3.17 (m, 2H), 2.93 - 2.75 (m, 2H), 2.24 - 2.06 (m, 1 H), 1.76 - 1.62 (m, 2H), 1.55 - 1.33 (m, 2H). HPLC (Condition A): Rt 2.50 min (purity 97.5%). MS (ESI+):400.4.
Example 30: trans-5-[1-(3-Fluoro-piperidin-4-yl)-1H-pyrazol-4-yl]-2-[3-(1 -methyl-1H- pyrazol-4-yl)-phenyl]-pyrimidine hydrochloride
Step 1 : Formation of Trans-3-Fluoro-4-(4-f2-r3-(1-methyl-1 H-pyrazol-4-yl)-phenyl1- pyrimidin-5-ylVpyrazol-1-yl)- iperidine-1-carboxylic acid tert-butyi ester
Figure imgf000162_0001
The title compound was obtained following procedure described for example 27, but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 150 mg; 0.50 mmol; 1.0 eq.) and tert-butyi 3-fluoro-4- [(methylsulfonyl)oxy]piperidine-1-carboxylate (intermediate 9; 147 mg; 0.50 mmol; 1.0 eq.) as an off-white solid ( 10 mg, 44%). HPLC (Condition A): Rt 4.53 min (purity 87.5%). MS (ESI+): 504.4
Step2: Formation of Trans-5-ri-(3-Fluoro-piperidin-4-yl)-1 H-pyrazol-4-yll-2-[3-(1-methyl- 1 H-pyrazol-4-yl)-phenvn-pyrimidine hydrochloride
Figure imgf000162_0002
The title compound was obtained following procedure described for example 13, step 2, but starting from Trans-3-Fluoro-4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin- 5-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (320 mg; 0.64 mmol; 1.0 eq.). After the first precipitation, a purification by autopreparative LC/MS afforded the title compound as a white foam (67 mg, 24%). 1 H NMR (300 MHz, DMSO-d6) δ 9.87 (brs, 1 H), 9.63 (brs, 1 H), 9.21 (s, 2H), 8.55 (d, J = 8.1 Hz, 2H), 8.35 - 8.17 (m, 3H), 7.93 (s, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 5.38 - 5.08 (m, 1H), 4.89 - 4.72 (m, 1 H), 3.90 (s, 3H), 3.79 - 3.64 (m, 1 H), 3.49 - 3.33 (m, 1H), 3.32 - 3.01 (m, 2H), 2.46 - 2.18 (m, 2H). HPLC (Condition A): Rt 2.58 min (purity 98.4%). MS (ESI+): 404.3.
Example 31 : 1 ,1 ,1 -Trifluoro-3-[4-(4-{2-[3-(1 -methyl-1 H-py razol-4-y l)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-2-ol
Figure imgf000163_0001
1 ,2-Epoxy-3,3,3-trifiuoropropane(84 mg; 0.72 mmol; 2.4 eq.) was added to a solution of 2-[3-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 -pi peridin-4-yl-1 H-pyrazol-4-yl)pyrimidine (example 1 , 200 mg; 0.31 mmol; 1.0 eq.) and DIEA (53 μΙ; 0.31 mmol; 1.0 eq.) in DMF (4 mL). The reaction mixture was stirred at 50°C O/N. It was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:EtOAc, gradient from 40:60 to 0:100) afforded the title compound as a beige powder (56 mg, 36%). 1 H NMR (300 MHz, DMSO-d6) δ 9. 7 (s, 2H), 8.59 - 8.49 (m, 2H), 8.27 (s, 1 H), 8.25 - 8.18 (m, 1 H), 8.14 (s, 1 H), 7.93 (s, 1 H), 7.75 - 7.67 (m, 1H), 7.52 (t, J = 7.7 Hz, 1 H), 6.24 - 6.13 (m, 1 H), 4.28 - 4.08 (m, 2H), 3.90 (s, 3H), 3.12 - 2.97 (m, 2H), 2.66 - 2.53 (m, 2H), 2.36 - 2.17 (m, 2H), 2.12 - 1.86 (m, 4H). HPLC (Condition A): Rt 2.85 min (purity 98.4%). MS (ESI+):498.4.
Example 32: 5-(1 -Methyl-1 H-pyrazol-4-yl)-2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidine
Figure imgf000164_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 100 mg; 0.32 mmo!; 1.0 eq.) and 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- 2-yl)-1 H-pyrazole (99 mg; 0.48 mmol; 1.5 eq.) as a white powder (56 mg; 55%). 1 H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.53 (t, J = 1.6 Hz, 1 H), 8.41 (s, 1 H), 8.26 (s, 1 H), 8.24 - 8.16 (m, 1 H), 8.12 (d, J = 0.7 Hz, 1 H), 7.92 (d, J = 0.7 Hz, 1 H), 7.76 - 7.66 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 3.92 (s, 3H), 3.90 (s, 3H). HPLC (Condition A): Rt 2.86 min (purity 97.4%). MS (ESI+): 317.3, mp = 199-200°C.
Example 33: 5-(1 -Piperidin-4-y 1-1 H-py razol-4-y l)-2-(3-pyridin-4-yl-phenyl)- pyrimidine hydrochloride
Step 1 : Formation of 4-{4-f2-(3-Pyridin-4-yl-phenyl)-pyrimidin-5-vn-pyrazol-1-yl)- piperidine-1-carboxylic acid tert-butyl ester
Figure imgf000164_0002
The title compound was obtained following procedure described for example 7, step 1 , but starting from tert-butyl 4-{4-[2-(3-iodophenyl)pyrimidin-5-yl]-1 H-pyrazol-1- yl}piperidine-1-carboxylate (intermediate 5, 200 mg; 0.38 mmol; 1.0 eq.) and 4- Pyridineboronic acid (93 mg; 0.75 mmol; 2.0 eq.) as a yellow solid (121 mg, 67%). HPLC (Condition A): Rt 3.31 min (purity 99.6%). MS (ESI+): 483.5
Step 2: Formation of 5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-(3-pyridin-4-yl-phenyl)- pyrimidine hydrochloride
Figure imgf000165_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from 4-{4-[2-(3-Pyridin-4-yl-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-piperidine-1- carboxylic acid tert-butyl ester (120 mg; 0.25 mmol; 1.0 eq.) as a beige solid (100 mg, 97%).
1 H NMR (300 MHz, DMSO-d6) d 9.41-9.26 (m, 1 H), 9.25 (s, 2H), 9.20-9.10 (m, 1 H), 8.99 (d, J= 6.8 Hz, 2H), 8.89 (t, J= 1.5 Hz, 1 H), 8.62 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.57 (s, 1 H), 8.44 (d, J= 6.8 Hz, 2H), 8.23 (s, 1 H), 8.18-8.14 (m, 1 H), 7.81 (t, J= 8.0 Hz, 1 H), 4.61-4.52 (m, 1 H), 3.42-3.37 (m, 2H), 3.16-3.04 (m, 2H), 2.29-2.17 (m, 4H). HPLC (Condition A): Rt 1.69 min (purity 99.2%). MS (ESI+): 383.3.
Example 34: 3-(1 -Methyl-1 H-pyrazol-4-yl)-5-[5-(1 -piperidin-4-yl-1 H-py razol-4-yl)- pyrimidin-2-yl]-phenol Formate
Figure imgf000165_0002
3-Bromo-5-(1-methyl-1 H-pyrazol-4-yl)-phenol (337 mg; 1.09 mmol; 1.0 eq.), bis(pinacolato)diborane (245 mg; 0.96 mmol; 0.9 eq.), 1 ,1- Bis(diphenylphosphino)ferrocenedichloropalladium(ll) (98 mg; 0.13 mmol; 0.12 eq.) and Potassium acetate (432 mg; 4.40 mmol; 4.0 eq.) were suspended in 1 ,4 dioxane (8 mL). The reaction suspension was degassed with argon and heated in MW at 80°C for 30 min. A further portion of bis(pinacolato)diborane (108 mg; 0.43 mmol; 0.4 eq.) was added and heating repeated (80°C for 30 min in MW). Tert-butyl 4-[4-(2-iodopyrimidin-5- yl)-1 H-pyrazol-1-yl]piperidine-1-carboxylate (intermediate 6, 265 mg; 0.58 mmol; 0.53 eq.), bis(triphenylphosphine)palladium(ll) chloride (100 mg; 0.14 mmol; 0.13 eq.) and potassium carbonate (446 mg; 3.23 mmol; 3.0 eq.) were added in one portion and the reaction solution diluted with water (3 mL), degassed with argon and heated again in MW at 100°C for 30 min. The reaction mixture was cooled down to RT and diluted with DC . It was filtered through celite. Organic phase was washed sequentially with a 1 N HCI solution and brine, dried over magnesium sulfate, filtered and concentrated. This crude was purified by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 75:25) and then redissolved in MeOH and HCI/dioxane (10 mL of a 4N solution; 40 mmol; 37 eq.). Reaction mixture was stirred at RT for 2h and concentrated under reduced pressure. Purification by autopreparative LC/MS afforded the title compound as a white foam (11 mg, 4%). 1 H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 1 H), 9.16 (s, 2H), 8.50 (s, 1H), 8.18 (d, J = 4.1 Hz, 2H), 8.00 (t, J = 1.5 Hz, 1 H), 7.83 (d, J = 0.7 Hz, 1 H), 7.71 - 7.67 (m, 1 H), 7.10 - 7.05 (m, 1 H), 4.62 - 4.48 (m, 1 H), 3.88 (s, 3H), 3.47 - 3.35 (m, 2H), 3.15 - 3.01 (m, 2H), 2.32 - 2.04 (m, 4H). HPLC (Condition A): Rt 1.86 min (purity 91.2%). MS (ESI+): 402.5.
Example 35: 1-Methoxy-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-propa -2-ol
Figure imgf000166_0001
The title compound was obtained following procedure described for example 7, step 1 , but starting from 5-bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]pyrimidine (intermediate 2, 100 mg; 0.32 mmol; 1.0 eq.) and 1-Methoxy-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (prepared as described in Bioorganic & Medicinal Chemistry Letters, 18(19), 5299-5302; 2008; 134 mg; 0.48 mmol; 1.5 eq.) as a white solid (27 mg, 22%). 1 H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.53 (s, 1 H), 8.41 (s, 1 H), 8.27 (s, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 8.15 (s, 1 H), 7.93 (s, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.24 (d, J = 5.2 Hz, 1 H), 4.25 (dd, J = 13.3, 3.6 Hz, 1 H), 4.15 - 3.95 (m, 2H), 3.90 (s, 3H), 3.40 - 3.23 (m, 5H). HPLC (Condition A): Rt 2.68 min (purity 96.6%). MS (ESI+): 391.3
Example 36: 2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 - y l)-1 -morpholin-4-y l-ethanone
Figure imgf000167_0001
The title compound was obtained following procedure described for example 25 but starting from 4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and Morpholine (24 mg; 0.28 mmol; 1.0 eq.) as a white solid (45 mg , 38%). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.37 (s, 1H), 8.27 (s, 1 H), 8.25 - 8.18 (m, 1 H), 8.15 (s, 1 H), 7.93 (d, J = 0.6 Hz, 1 H), 7.77 - 7.67 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.26 (s, 2H), 3.90 (s, 3H), 3.71 - 3.42 (m, 8H). HPLC (Condition A): Rt 2.60 min (purity 97.6%). MS (ESI+): 430.3.
Example 37: 2-(4-{2-[3-(3-Methyl-3H-imidazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
1- yl)-1-pyrrolidin-1-yl-ethanone
Step 1 : Formation of 1-Pyrrolidin-1-yl-2-(4-{2-r3-(4,4,5,5-tetramethyl-f1 ,3,2ldioxaborolan-
2- yl)-phenyll-pyrimidin-5-ylVpyrazol-1-yl)-ethanone
Figure imgf000167_0002
A mixture of 2-{4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1 -yl}-1-pyrrolidin-1-yl- ethanone (intermediate 12, 700 mg; 1.52 mmol; 1.0 eq.), bis(pinacolato)diborane (426 mg; 1.68 mmol; 1.10 eq.), (dppf)PdCI2.CH2CI2 (111 mg; 0.15 mmol; 0.1 eq.) and
Potassium acetate (449 mg; 4.57 mmol; 3.0 eq.) in THF (15 mL) and DMF (5 ml.) was heated in MW at 100°C for 2h.
The reaction mixture solution was used as it in the next step.
Step 2: Formation of 2-(4-(2-f3-(3-Methyl-3H-imidazol-4-yl)-phenvn-pyrimidin-5-yl>- pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone
Figure imgf000168_0001
A mixture of 1-Pyrrolidin-1-yl-2-(4-{2-[3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone (4 mL of the solution obtained in step 1), 5-bromo-1-methyl-1 H-imidazole (35 mg; 0.22 mmol; 1.0 eq.), Pd(Ph3)4 (13 mg; 0.01 mmol; 0.05 eq.) and potassium carbonate (90 mg; 0.65 mmol; 3.0 eq.) in water (0.73 mL) was heated at 120°C in MW for 30 min. Addition of 5-bromo-1-methyl-1 H-imidazole (35 mg; 0.22 mmol; 1.0 eq.) and heating at 120°C for 30 min had to be repeated twice to complete the reaction. The reaction mixture was then diluted with water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 80:20) gave a black gum which was redissoived in DCM. Addition of cyclohexane afforded a brown precipitate which was filtered and dried under vacuum to give the title compound as a beige solid (40 mg, 44%). 1 H NMR (300 MHz, DMSO-d6) d 9.20 (s, 2H), 8.47-8.46 (m, 1 H), 8.41-8.37 (m, 2H), 8.14 (d, J= 0.6 Hz, 1 H), 7.76 (s, 1 H), 7.68-7.60 (m, 2H), 7.15 (s, 1 H), 5.12 (s, 2H), 3.74 (s, 3H), 3.52 (t, J= 6.8 Hz, 2H), 3.32 (t, J= 6.8 Hz, 2H), 1.93 (quint., J= 6.8 Hz, 2H), 1.80 (quint., J= 6.8 Hz, 2H). HPLC (Condition A): Rt 2.21 min (purity 96.2%). MS (ESI+): 414.4.
Example 38: Ν,Ν-Dimethy l-2-(4-{2-[3-(1 -methyl-1 H-py razol-4-yl)-pheny l]-pyrimidin- 5-yl}-pyrazol-1-yl)-acetamide
Figure imgf000168_0002
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8and dimethylamine as a white solid (18 mg, 47%). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.35 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.17 (m, 1 H), 8.14 (d, J = 0.6 Hz, 1 H), 7.93 (d, J = 0.8 Hz, 1 H), 7.77 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.21 (s, 2H), 3.90 (s, 3H), 3.07 (s, 3H), 2.88 (s, 3H). HPLC (Condition A): Rt 2.59 min (purity 99.3%). MS (ESI+): 388.3. Example 39: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1-[1 -(tetrahydro-pyran-4-yl)- piperidin-4-yl]-1 H-pyrazol-4- l}-pyrimidine
Figure imgf000169_0001
The title compound was obtained following procedure described for example 28 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4- yl)pyrimidine (example 1 , 200 mg; 0.31 mmol; 1.0 eq.) and tetrahydro-4H-pyran-4-one (62 mg; 0.62 mmol; 2.0 eq.) as a white powder (25 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.59 - 8.49 (m, 2H), 8.27 (s, 1 H), 8.20 (dt, J = 8, 3Hz, 1 H), 8.13 (s, 1 H), 7.93 (d, J = 0.6 Hz, 1 H), 7.76 - 7.66 (m, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 4.25 - 4.10 (m, 1 H), 3.95 - 3.84 (m, 2H), 3.89 (s, 3H), 3.33 - 3.21 (m, 2H), 3.08 - 2.94 (m, 2H), 2.59 - 2.43 (m, 1 H), 2.37 - 2.21 (m, 2H), 2.14 - 1.84 (m, 4H), 1.77 - 1.63 (m, 2H), 1.56 - 1.36 (m, 2H). HPLC (Condition A): Rt 2.55 min (purity 97.6%). MS (ESI+):470.4.
Example 40: 1 -(3-Methoxy-azetidin-1 -y l)-2-(4-{2-[3-(1 -methy 1-1 H-py razol-4-y I)- phenyl]-pyrimidin-5- -pyrazol-1 -yl)-ethanone
Figure imgf000169_0002
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 80 mg; 0.26 mmol; 1.0 eq.) and 2-Chloro-1-(3-methoxy-azetidin-1-yl)- ethanone (from Butt Park Ltd., 86 mg; 0.53 mmol; 2.0 eq.) as a white foam (25mg, 21 %). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.56 - 8.51 (m, 1 H), 8.40 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.19 (m, 1 H), 8.17 (s, 1 H), 7.93 (s, 1 H), 7.75 - 7.68 (m, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 4.97 (s, 2H), 4.40 - 4.31 (m, 1 H), 4.30 - 4.20 (m, 1 H), 4.15 - 3.99 (m, 2H), 3.89 (s, 3H), 3.72 (dd, J = 10.3, 3.6 Hz, 1 H), 3.23 (s, 3H). HPLC (Condition A): Rt 2.87 min (purity 94.1%). MS (ESI+):430.3.
Example 41 : 2-(4-{2-[3-(1-Methyl-1 H-yrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- ylmethyl)-morpholine hydrochloride
Step 1 : Formation of 2-(4-f2-f3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-pyriinidin-5-yl}- pyrazol-1-ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester
Figure imgf000170_0001
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 150 mg; 0.50 mmol; 1.0 eq and 2-Methanesulfonyloxymethyl-morpholine-4- carboxylic acid tert-butyl ester (intermediate 13, 146 mg; 0.50 mmol; 1.0 eq.) as a white powder ( 10mg, 44%). MS (ESI+):502.3.
Step 2: Formation of 2-(4-(2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl}- pyrazol-1 -ylmethvD-morpholine hydrochloride
Figure imgf000170_0002
The title compound was obtained following procedure described for example 13, step 2 but starting from 2-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester (105 mg; 0.22 mmol; 1.0 eq.) as a yellow powder (50 mg, 52%). 1 H NMR (300 MHz, DMSO-d6) δ 9.50 (brs, 2H), 9.19 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.44 (s, 1 H), 8.30 - 8.17 (m, 3H), 7.93 (d, J = 0.6 Hz, 1 H), 7.75 - 7.67 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.48 - 4.23 (m, 2H), 4.23 - 4.10 (m, 1 H), 4.05 - 3.91 (m, 1 H), 3.90 (s, 3H), 3.81 - 3.64 (m, 1 H), 3.36 - 3.28 (m, 1 H), 3.25 - 3.12 (m, 1 H), 3.04 - 2.74 (m, 2H). HPLC (Condition A): Rt 2.57 min (purity 100.0%). MS (ESI+):402.3.
Example 42: 2-[4-(2-{3-[1 -(3-Amino-propyl)-1 H-pyrazol-4-yl]-pheny l}-py rimidin-5- yl)-pyrazol-1-yl]-1-pyrr
Figure imgf000171_0001
A solution of 2-(4-{2-[3-(1 H-Pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-1- pyrrolidin-1-yl-ethanone (intermediate 14, 100 mg; 0.25 mmol; 1.0 eq.) in dry DMF (1 mL) was added over a suspension of NaH (60% in oil, 21mg; 0.86 mmol; 2.0 eq.) in dry DMF (1 mL) maintained at 0°C under nitrogen atmosphere. The resulting mixture was stirred for one hour at 0°C then heated at 100°C O/N after the addition of a solution of (3-Bromo-propyl)-carbamic acid tert-butyl ester (60 mg; 0.25 mmol; 1.0 eq.) in DMF (2 mL). Reaction mixture was then cooled down to RT, quenched with water and extracted with EtOAc (three times). Combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. This crude was directly redissolved in DCM (1 mL) and treated with HCI/dioxane (0.94 mL of a 4N solution; 3.76 mmol; 15.0 eq.). The resulting reaction mixture was stirred at RT for 1 hour, concentrated under reduced pressure and purified byautopreparative LC/MS to give the title compound as a white solid 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.55 (t, J= 1.5 Hz, 1 H), 8.43 (brs, 1 H), 8.37 (s, 1 H), 8.34 (s, 1 H), 8.23 (dt, J= 7.8 Hz, 1.6 Hz, 1 H), 8.14 (s, 1 H), 7.98 (s, 1 H), 7.73 (dt, J= 7.8 Hz, 1.6 Hz, 1 H), 7.52 (t, J= 7.8 Hz, 1 H), 5.12 (s, 2H), 4.24 (t, J= 6.6 Hz, 2H), 3.53 (t, J= 6.6 Hz, 2H), 3.33 (t, J= 6.8 Hz, 2H), 2.71 (t, J= 6.8 Hz, 2H), 2.05 (quint., J= 6.6 Hz, 2H), 1.93 (quint., J= 6.8 Hz, 2H), 1.80 (quint., J= 6.8 Hz, 2H). HPLC (Condition A): Rt 2.39 min (purity 95.6%). MS (ESI+): 457.5.
Example 43: 2-{4-[2-(3-Pyridin-4-yl-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-1- py rrolidin-1 -yl-ethanone
Figure imgf000172_0001
The title compound was obtained following procedure described for intermediate 5, stepl but starting from 2-{4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-1-pyrrolidin-1- yl-ethanone (intermediate 12, 150 mg; 0.33 mmol; 1.0 eq.) and 4-Pyridineboronic acid (80 mg; 0.65 mmol; 2.0 eq.) as a white solid (15 mg, 11 %). 1 H NMR (300 MHz, DMSO- d6) δ 9.21 (s, 2H), 8.75 (t, J= 1.5 Hz, 1 H), 8.69 (d, J= 6.0 Hz, 2H), 8.50 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 8.38 (s, 1 H), 8.15 (s, 1H), 7.95 (dt, J= 8.0 Hz, 1.5 Hz, 1 H), 7.79 (d, J= 6.0 Hz, 2H), 7.70 (t, J= 8.0 Hz, 1 H), 5.12 (s, 2H), 3.52 (t, J= 6.6 Hz, 2H), 3.32 (m, 2H), 1.93 (quint., J= 6.6 Hz, 2H), 1.80 (quint., J= 6.6 Hz, 2H). HPLC (Condition A): Rt 2.17 min (purity 99.1 %). MS (ESI+): 411.4.
Example 44: 1-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-propan-2-one
Figure imgf000172_0002
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1 -methyl- 1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 75 mg; 0.25 mmol; 1.0 eq.) and 1-Chloro-propan-2-one (59 μΙ; 0.74 mmol; 3.0 eq.) as a white powder (25 mg, 28%). 1 H NMR (300 MHz, DMSO-d6): 9.17 (s, 2H), 8.53 (s, 1 H), 8.34 (s, 1H), 8.25 (s, 1 H), 8.21 (d, J = 8.2 Hz, 1 H), 8.17 (s, 1 H), 7.92 (s, 1 H), 7.70 (d, J = 7.9 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1 H), 5.23 (s, 2H), 3.89 (s, 3H), 2.16 (s, 3H). HPLC (Condition A): Rt 3.08 min (purity 98.3%). MS (ESI+): 359.4, (ESI-): 357.4.
Example 45: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-furan-3- ylmethyl)-1 H-pyrazol-4-yl]-pyrimidine
Figure imgf000173_0001
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 3-Chloromethyl-tetrahydro-furan (39.88 mg; 0.33 mmol; 1.00 eq.) as a beige powder (32 mg, 25%). 1 H NMR (300 MHz, DMSO- d6) δ 9.16 (s, 2H), 8.59 - 8.45 (m, 2H), 8.33 - 8.11 (m, 3H), 7.93 (s, 1 H), 7.77 - 7.66 (m, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 4.17 (d, J = 7.5 Hz, 2H), 3.89 (s, 3H), 3.85 - 3.74 (m, 1 H), 3.74 - 3.60 (m, 2H), 3.52 (dd, J = 8.7, 5.4 Hz, 1 H), 2.85 - 2.68 (m, 1 H), 2.04 - 1.88 (m, 1 H), 1.73 - 1.56 (m, 1 H). HPLC (Condition A): Rt 3.34 min (purity 98.0%). MS (ESI+):387.4.
Example 46: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-oxazol-2-ylmethyl-1 H- pyrazol-4-yl)-pyrimidin
Figure imgf000173_0002
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 2-Chloromethyl-oxazole (39 mg; 0.33 mmol; 1.0 eq) as a beige powder (27 mg, 21 %). 1 H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.57 (d, J = 16.9 Hz, 2H), 8.35 - 8.09 (m, 4H), 7.93 (s, 1 H), 7.72 (d, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 7.26 (s, 1 H), 5.63 (s, 2H), 3.89 (s, 3H). HPLC (Condition A): Rt 3.09 min (purity 98.9%). MS (ESI+):384.4.
Example 47: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-pyridin-2-yl-ethyl)-1 H- py razo l-4-y l]-py rim idine
Figure imgf000174_0001
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 2-(2-Chloro-ethyl)-pyridine (47 mg; 0.33 mmol; 1.0 eq.) as a beige powder (6 mg, 4%). 1 H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.57 - 8.50 (m, 2H), 8.41 (s, 1 H), 8.26 (s, 1 H), 8.24 - 8.18 (m, 1 H), 8.13 (d, J = 0.6 Hz, 1 H), 7.92 (d, J = 0.7 Hz, 1 H), 7.74 - 7.65 (m, 2H), 7.51 (t, J = 7.7 Hz, 1 H), 7.30 - 7.19 (m, 2H), 4.58 (t, J = 7.3 Hz, 2H), 3.89 (s, 3H), 3.36 - 3.27 (m, 2H). HPLC (Condition A): Rt 2.62 min (purity 95.5%). MS (ESI+):408.4.
Example 48: 2-[2-Fluoro-3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl- 1 H-pyrazol-4-yl)-pyrimidine Formate
Figure imgf000174_0002
The title compound was obtained following procedure described for example 24 but starting from tert-butyl 4-[4-(2-iodopyrimidin-5-yl)-1 H-pyrazol-1-yl]piperidine-1- carboxylate (intermediate 6, 249 mg; 0.55 mmol; 1.0 eq.), 3-bromo-2- fluorophenylboronic acid (155 mg; 0.71 mmol; 1.3 eq.) and 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (308 mg; 1.48 mmol; 2.7 eq.) as an orange solid (40 mg, 16%). 1 H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.54 (s, 1 H), 8.29 (s, 1 H), 8.22 (d, J = 2.2 Hz, 1H), 8.17 (s, 1 H), 7.96 (s, 1 H), 7.88 - 7.77 (m, 2H), 7.33 (t, J = 7.7 Hz, 1 H), 4.41 - 4.27 (m, 1 H), 3.91 (s, 3H), 3.22 - 3.10 (m, 2H), 2.82 - 2.67 (m, 2H), 2.15 - 2.01 (m, 2H), 1.99 - 1.79 (m, 2H). HPLC (Condition A): Rt 2.17 min (purity 95.5%). MS (ESI+): 404.5.
Example 49: 2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-acetamide
Figure imgf000175_0001
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 2-Bromo-acetamide (46 mg; 0.33 mmol; 1.0 eq.) as a beige powder (4 mg, 3%). HPLC (Condition A): Rt 2.65 min (purity 97.9%). MS (ESI+):360.4.
Example 50: 2-[4-(2-{3-[1-(2-Amino-ethyl)-1 H-pyrazol-4-yl]-phenyl}-pyrimidin-5-yl)- pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone hydrochloride
Stepl : formation of (2-f4-(3-(5-ri-(2-Oxo-2-pyrrolidin-1-yl-ethyl)- H-pyrazol-4-vn- pyrimidin-2-yl phenyl)-pyrazol-1-vH-ethyl|-carbamic acid tert-butyl ester
Figure imgf000175_0002
The title compound was obtained following procedure described for example 27 but starting from 2-(4-{2-[3-(1 H-Pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-1- pyrrolidin-1-yl-ethanone (intermediate 14, 150 mg; 0.38 mmol; 1.0 eq.) and (2-Bromo- ethyl)-carbamic acid tert-butyl ester (17 mg; 0.08 mmol; 0.2 eq.) as a white solid (70 mg, 34%). 1 H NMR (300 MHz, DMSO-d6) d 9.18 (s, 2H), 8.55 (t, J= 1.5 Hz, 1 H), 8.37 (s, 1 H), 8.24-8.21 (m, 2H), 8.14 (s, 1H), 7.95 (s, 1 H), 7.71 (dt, J= 7.8 Hz, 1.5 Hz, 1 H), 7.52 (t, J= 7.8 Hz, 1 H), 6.99 (t, J= 6.0 Hz, 1 H), 5.12 (s, 2H), 4.18 (t, J= 6.0 Hz, 2H), 3.53 (t, J= 6.6 Hz, 2H), 3.40-3.31 (m, 4H), 1.93 (quint, J= 6.6 Hz, 2H), 1.80 (quint., J= 6.6 Hz, 2H), 1.36 (s, 9H). HPLC (Condition A): Rt 3.58 min (purity 95.0%). MS (ESI+): 543.6. Step 2: Formation of 2-f4-(2-(3-f1-(2-Amino-ethyl)-1 H-pyrazol-4-yll-phenyl)-pyrimidin-5-
Figure imgf000176_0001
The title compound was obtained following procedure described for example 13, step 2 but starting from {2-[4-(3-{5-[1-(2-Oxo-2-pyrrolidin-1-yl-ethyl)-1 H-pyrazol-4-yl]-pyrimidin- 2-yl}-phenyl)-pyrazol-1-yl]-ethyl}-carbamic acid tert-butyl ester (70 mg; 0.13 mmol; 1.0 eq.)
as a yellow solid (57 mg, 86%). 1 H NMR (300 MHz, DMSO-d6) d 9.18 (s, 2H), 8.58 (t, J= 1.6 Hz, 1 H), 8.39-8.38 (m, 2H), 8.24 (dt, J= 7.8 Hz, 1.6 Hz, 1 H), 8.23-8.06 (m, 6H), 7.75 (dt, J= 7.8 Hz, 1.6 Hz, 1 H), 7.54 (t, J= 7.8 Hz, 1 H), 5.13 (s, 2H), 4.44 (t, J= 6.0 Hz, 2H), 3.53 (t, JO 6.7 Hz, 2H), 3.33 (m, 4H), 1.93 (quint. , J= 6.7 Hz, 2H), 1.80 (quint. , J= 6.7 Hz, 2H). HPLC (Condition A): Rt 2.31 min (purity 99.0%). MS (ESI+): 443.5.
Example 51 : 1-(4-Methyl-piperazin-1-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}- razol-1-yl)-ethanone hydrochloride
Figure imgf000176_0002
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.00 eq.) and 1-Methyl-piperazine (55 mg; 0.55 mmol; 2.0 eq.) as a white solid (20 mg, 15%). 1 H NMR (300 MHz, DMSO-d6 + D20) d 9.16 (s, 2H), 8.52 (t, J = 1.6 Hz, 1 H), 8.31 (s, 1 H), 8.25 - 8.18 (m, 2H), 8.15 (d, J = 0.5 Hz, 1 H), 7.91 (d, J = 0.7 Hz, 1 H), 7.76 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.29 (d, J = 11.3 Hz, 2H), 4.52 - 4.29 (m, 1 H), 4.24 - 4.08 (m, 1 H), 3.88 (s, 3H), 3.56 - 3.29 (m, 3H), 3.21 - 2.89 (m, 3H), 2.84 (s, 3H). HPLC (Condition A): Rt 2.36 min 98.4%). MS (ESI+): 443.5
Example 52: 1 -(3-Hydroxy-piperidin-1 -l)-2-(4-{2-[3-(1 -methy 1-1 H-py razol-4-y I)- phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-ethanone
Figure imgf000177_0001
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and [Dimethylamino- ([1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium; hexafluoro phosphate (158.3 mg; 0.42 mmol; 1.50 eq.) as a white solid (75 mg, 61%). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.54 (s, 1 H), 8.37 (d, J = 3.7 Hz, 1 H), 8.31 - 8.20 (m, 2H), 8.14 (s, 1 H), 7.93 (s, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 5.33 - 5.12 (m, 2H), 4.95 (d, J = 4.0 Hz, 1 H), 4.15 - 4.01 (m, 0.6H), 3.90 (s, 3H), 3.74 - 3.62 (m, 1 H), 3.62 - 3.48 (m, 0.6H), 3.48 - 3.37 (m, 1 H), 3.37 - 3.20 (m, 0.4H), 3.20 - 2.99 (m, 0.8H), 2.78 - 2.61 (m, 0.6H), 1.97 - 1.20 (m, 4H). HPLC (Condition A): Rt 2.70 min (purity 97.8%). MS (ESI+): 444.5, mp = 198-200°C.
Example 53: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-pyridin-4-yl-ethyl)-1 H- pyrazol-4-yl]-pyrimidi
Figure imgf000177_0002
A solution of 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 eq.) in dry DMA (1 mL) was added over a suspension of NaH (60% in oil, 28 mg; 1.19 mmol; 3.0 eq.) in dry DMA (2 mL) maintained at 0°C under nitrogen atmosphere. The resulting mixture was stirred for one hour at 0°C then heated at 100°C O/N after the addition of a solution of 14-(2-Bromo- ethyl)-pyridine hydrobromide (159 mg; 0.60 mmol; 1.5 eq.) in DMA (2 mL). Cesium carbonate (388 mg; 1.19 mmol; 3.00eq.) and 4-(2-Bromo-ethyl)-pyridine hydrobromide (159 mg; 0.60 mmol; 1.5 eq.) were added and the reaction mixture was heated again at 100°C O/N. Reaction mixture was then cooled down to RT and quenched with water and extracted with DCM (three times). Combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified by autopreparative LC/MS to give the title compound a white foam (80 mg, 49%).1 H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.56 - 8.50 (m, 1 H), 8.50 - 8.41 (m, 2H), 8.38 (s, 1H), 8.26 (s, 1 H), 8.24 - 8.17 (m, 1 H), 8.15 (s, 1H), 7.92 (s, 1 H), 7.77 - 7.66 (m, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 7.29 - 7.19 (m, 2H), 4.48 (t, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.21 (t, J = 7.0 Hz, 2H). HPLC (Condition A): Rt 2.47 min (purity 99.6%). MS (ESI+):408.4.
Example 54: 2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-N-(tetrahydro-pyran-4- -acetamide
Figure imgf000178_0001
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1 -Methyl- 1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and tetrahydro-pyran-4-ylamine (56 mg; 0.55 mmol; 2.0 eq.) as a white powder (9 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.54 (s, 1 H), 8.43 (s, 1 H), 8.37 - 8.18 (m, 3H), 8.15 (s, 1H), 7.93 (s, 1 H), 7.77 - 7.67 (m, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 5.21 (s, 0.3H), 4.86 (s, 1.7H), 3.98 - 3.69 (m, 6H), 3.46 - 3.26 (m, 2H), 1.82 - 1.66 (m, 2H), 1.53 - 1.30 (m, 2H). HPLC (Condition A): Rt 2.64 min (purity 96.6%). MS (ESI+): 444.3. Eample 55: 2-(4-{2-[3-(1- ethyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-1-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethanone
Figure imgf000179_0001
The title compound was obtained following procedure described for example 25 but starting from 4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and 2-Oxa-6-aza-spiro[3.3]heptane oxalate (105 mg; 0.55 mmol; 2.0 eq.) as a white powder (40 mg, 33%). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.54 (s, 1 H), 8.38 (s, 1 H), 8.27 (s, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1 H), 7.93 (s, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.92 (s, 2H), 4.69 (s, 4H), 4.36 (s, 2H), 4.10 (s, 2H), 3.90 (s, 3H). HPLC (Condition A): Rt 2.50 min (purity 98.3%). MS (ESI+): 442.3.
Example 56: 2-(4-{2-[3-(2- ethyl-thiazol-5-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- 1-pyrrolidin-1-yl-ethanone
Figure imgf000179_0002
The title compound was obtained following procedure described for example 37 but starting from 2-{4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-1-pyrrolidin-1-yl- ethanone (intermediate 12, 200 mg; 0.44 mmol; 1.0 eq.) and 5-Bromo-2-methyl-thiazole (77 mg; 0.44 mmol; 1.0 eq.) as a white solid (30 mg, 16%). 1 H NMR (300 MHz, DMSO- d6) d 9.21 (s, 2H), 8.55 (t, J= 1.5 Hz, 1 H), 8.37-8.34 (m, 2H), 8.14-8.13 (m, 2H), 7.82 (ddd, J= 7.8 Hz, 2.0 Hz, 1.5 Hz, 1 H), 7.60 (t, J= 7.8 Hz, 1 H), 5.12 (s, 2H), 3.53 (t, J= 6.8 Hz, 2H), 3.32 (t, J= 6.8 Hz, 2H), 2.71 (s, 3H), 1.93 (quint., J= 6.8 Hz, 2H), 1.80 (quint., J= 6.8 Hz, 2H). HPLC (Condition A): Rt 3.17 min (purity 97.4%). MS (ESI+): 431.4.
Example 57: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-piperidin-1-yl-ethyl)-1 H- pyrazol-4-yl]-pyrimidne
Figure imgf000180_0001
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1 -methyl- 1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 eq.) and 1-(2-Chloro-ethyl)-piperidine hydrochloride (110 mg; 0.60 mmol; 1.5 eq.) as a white solid (80 mg, 49%). 1 H NMR (300 MHz, DMSO- d6) 5 9.15 (s, 2H), 8.53 (t, J = 1.5 Hz, 1 H), 8.45 (s, 1 H), 8.26 (s, 1 H), 8.25 - 8.17 (m, 1 H), 8.12 (s, 1 H), 7.92 (d, J = 0.6 Hz, 1 H), 7.77 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.27 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 2.71 (t, J = 6.7 Hz, 2H), 2.46 - 2.33 (m, 4H), 1.56 - 1.29 (m, 6H). HPLC (Condition A): Rt 2.59 min (purity 98.1%). MS (ESI+):414.5.
Example 58: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-pyrrolidin-1-yl-ethyl)- 1 H-pyrazol-4-yl]-pyri
Figure imgf000180_0002
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 eq.) and 1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (101 mg; 0.60 mmol; 1.5 eq.) as a beige foam (75 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.53 (t, J = 1.6 Hz, 1H), 8.46 (s, 1 H), 8.26 (s, 1 H), 8.24 - 8.18 (m, 1 H), 8.12 (s, 1 H), 7.92 (d, J = 0.6 Hz, 1 H), 7.77 - 7.68 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.27 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 2.87 (t, J = 6.6 Hz, 2H), 2.50 - 2.40 (m, 4H), 1.73 - 1.58 (m, 4H). MS (ESI+):400.4.
Example 59: 2-[4-(2-{3-[1-(2-Hydroxy-ethyl)-1 H-pyrazol-4-yl]-phenyl}-pyrimidin-5- yl)-pyrazol-1-yl]-1 -pyrrolidin-1-yl-ethanone
Figure imgf000181_0001
The title compound was obtained following procedure described for intermediate 5, stepl but starting from 2-{4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-1-pyrrolidin-1- yl-ethanone (intermediate 12 , 130 mg; 0.28 mmol; 1.0 eq.) and 2-[4-(4,4,5,5- Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethanol (101 mg; 0.42 mmol; 1.5 eq.) as a white solid (45mg, 36%). 1 H NMR (300 MHz, DMSO-d6) d 9.18 (s, 2H), 8.55 (t, J= 1.6 Hz, 1 H), 8.37 (s, 1 H), 8.26 (s, 1H), 8.22 (dt, J= 7.8 Hz, 1.6 Hz, 1 H), 8.14 (d, J= 0.6 Hz, 1 H), 7.95 (d, J= 0.6 Hz, 1 H), 7.74-7.70 (m, 1 H), 7.52 (t, J= 7.8 Hz, 1 H), 5.12 (s, 2H), 4.96 (t, J= 5.6 Hz, 1H), 4.19 (t, J= 5.6 Hz, 2H), 3.79 (q, J= 5.6 Hz, 2H), 3.53 (t, J= 6.6 Hz, 2H), 3.32 (t, J= 6.6 Hz, 2H), 1.91 (quint., J= 6.6 Hz, 2H), 1.80 (quint, J= 6.8 Hz, 2H). HPLC (Condition A): Rt 2.64 min (purity 97.7%). MS (ESI+): 444.4.
Example 60: N-(1-Hydroxymethyl-propyl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-acetamide
Figure imgf000181_0002
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and 2-Amino-butan-1-ol (49 mg; 0.55 mmol; 2.0 eq.) as a white powder (14 mg, 12%). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.43 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.19 (m, 1 H), 8.15 (d, J = 0.6 Hz, 1 H), 8.00 (d, J = 8.5 Hz, 1 H), 7.93 (d, J = 0.7 Hz, 1 H), 7.75 - 7.68 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1H), 4.88 (d, J = 2.0 Hz, 2H), 3.90 (s, 3H), 3.72 - 3.58 (m, 1 H), 3.42 - 3.27 (m, 3H), 1.68 - 1.51 (m, 1 H), 1.42 - 1.25 (m, 1 H), 0.86 (t, J = 7.4 Hz, 3H). HPLC (Condition A): Rt 2.60 min (purity 98.0%).
MS (ESI+): 432.3, (ESI-): 430.2. Example 61 : (3-exo)-8-Methy l-3-(4-{2-[3-(1 -methyl-1 H-py razol-4-yl)-pheny I]- pyrimidin-5-yl}-pyrazol-1-yl)-8-aza-bicyclo[3.2.1]octane
Figure imgf000182_0001
The title compound was obtained following procedure described for example 13, stepi , but starting from 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2] dioxaborolan-2-yl)-pyrimidine (intermediate 15, 150 mg; 0.25 mmol; 1.0 eq.) and (3-exo)- 3-(4-lodo-pyrazol-1-yl)-8-methyl-8-aza-bicyclo[3.2.1]octane (intermediate 16, 79 mg; 0.25 mmol; 1.0 eq.) as a beige foam (45 mg, 43%). 1 H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.57 - 8.47 (m, 2H), 8.27 (s, 1H), 8.24 - 8.19 (m, 1H), 8.13 (s, 1 H), 7.93 (s, 1 H), 7.74 - 7.68 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.57 (tt, J = 11.4, 5.7 Hz, 1 H), 3.89 (s, 3H), 3.37 - 3.24 (m, 2H), 2.33 (s, 3H), 2.24 - 2.10 (m, 2H), 2.10 - 2.00 (m, 2H), 1.96 - 1.84 (m, 2H), 1.80 - 1.69 (m, 2H). HPLC (Condition A): Rt 2.55 min (purity 98.9%). MS (ESI+):426.3.
Example 62: 4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 - yl)-cyclohexanecarboxylic acid
Step 1 : formation of 4-(4-(2-f3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl1-pyrimidin-5-yl)-pyrazol- 1-yP-cyclohexanecarboxylic acid ethyl ester
Figure imgf000182_0002
4-Methanesulfonyloxy-cyclohexanecarboxylic acid ethyl ester (AOKChem Co., Ltd; 689 mg; 2.75 mmol; 1.04 eq.) in DMF (5 ml_) was added in one portion to a suspension of 2- [3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 104 mg; 0.34 mmol; 1.0 eq.) and cesium carbonate (2.35 g; 7.21 mmol; 2.7 eq.) in DMF (10 ml_). The reaction mixture was heated in MW at 120°C for 35 min. It was then poured into water and filtered. The resulting solid was triturated with ACN to give the title compound as a yellow solid (264 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) d 9.16 (s, 2H), 8.57 - 8.46 (m, 2H), 8.26 (s, 1 H), 8.24 - 8.18 (m, 1 H), 8.13 (s, 1 H), 7.92 (s, 1 H), 7.77 - 7.66 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.32 - 3.99 (m, 3H), 3.89 (s, 3H), 2.48 - 2.34 (m, 1 H), 2.23 - 1.48 (m, 8H), 1.27 - 1.14 (m, 3H). MS (ESI+): 457.3.
Step 2: Formation of 4-(4-(2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-pyrimidin-5-yl'}- pyrazol-1 -yl)-cvclohexanecarboxylic acid
Figure imgf000183_0001
A solution of 4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- cyclohexanecarboxylic acid ethyl ester (50 mg; 0.11 mmol; 1.0 eq.) and NaOH (5.00 mL of a 1N solution; 5.0 mmol; 46 eq.) in iPrOH (20 mL) was stirred at RT for 16h. It was then poured into a 1 N solution of HCI and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a cis-trans mixture of the title compound as a yellow solid (30 mg, 59%). 1 H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.57 - 8.47 (m, 2H), 8.27 (s, 1 H), 8.24 - 8.17 (m, 1 H), 8.13 (s, 1 H), 7.92 (s, 1 H), 7.78 - 7.66 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.31 - 4.15 (m, 1 H), 3.89 (s, 3H), 2.66 - 1.45 (m, 9H). HPLC (Condition A): Rt 3.23 min (purity 93.0%). HPLC (Chiralpak IA, EtOH:TFA:THF 90:0.1 :10): Rt 7.23; 10.97 min (purity 30.2: 66.6%); MS (ESI+): 429.2.
Example 63: 2-[3-(1 -Meth -1 H-pyrazol-4-yl)-pheny l]-5-(1 H-py razol-4-yl)-py rimidine
Figure imgf000183_0002
The title compound was obtained following procedure described for example 25, but starting from (4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 eq.) and 2-Methoxy-1-methyl-ethylamine (49 mg; 0.55 mmol; 2.0 eq.) as a white solid (13 mg, 11 %).1 H NMR (300 MHz, DMSO) d 9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.42 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.19 (m, 2H), 8.15 (s, 1 H), 7.93 (s, 1 H), 7.75 - 7.68 (m, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 4.86 (s, 2H), 4.03 - 3.88 (m, 1 H), 3.90 (s, 3H), 3.36 - 3.13 (m, 5H), 1.08 (d, J = 6.8 Hz, 3H). MS (ESI+): 432.3.
Example 64: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1-[2-(1-methyl-pyrrolidin-2- yl)-ethyI]-1 H-pyrazol-4- -pyrimidine
Figure imgf000184_0001
The title compound was obtained following procedure described for example 27, but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 eq.) and 2-(2-Chloro-ethyl)-1-methyl-pyrrolidine hydrochloride (110 mg; 0.60 mmol; 1.5 eq.) as a white solid (75 mg, 465). 1 H NMR (300 MHz, DMSO-d6) 5 9.17 (s, 2H), 8.53 (t, J = 1.6 Hz, 1 H), 8.51 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.19 (m, 1 H), 8.18 - 8.16 (m, 1 H), 7.92 (d, J = 0.7 Hz, 1 H), 7.75 - 7.69 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.39 - 4.11 (m, 2H), 3.90 (s, 3H), 3.29 - 3.16 (m, 2H), 3.12 - 3.04 (m, 1 H), 2.57 (s, 3H), 2.43 - 2.26 (m, 1 H), 2.16 - 1.70 (m, 4H), 1.64 - 1.47 (m, 1 H). HPLC (Condition A): Rt 2.51 min (purity 99.3%). MS (ESI+):414.5.
Example 65: 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-pyrrolidin-3-ylmethyl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of 3-(4-(2-f3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-pyrimidin-5-yl>- pyrazol-1-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester
Figure imgf000184_0002
A solution of 3-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in WO2010100144; 200 mg; 0.64 mmol; 1.0 eq.), cesium carbonate (420 mg; 1.29 mmol; 2.0 eq.) and 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5- (1 H-pyrazol-4-yl)pyrimidine (example 3, 195 mg; 0.64 mmol; 1.0 eq.) was heated at 100°C O/N. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine (three times), dried over magnesium sulfate, filtered and concentrated. Purification by autopreparative LC/MS afforded the title compound as a white foam (179 mg, 57%). MS (ESI+):486.5. Step 2: Formation of 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl1-5-(1-pyrrolidin-3-ylmethyl- 1 H-pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000185_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from 3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 - ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (170 mg; 0.35 mmol; 1.0 eq.) as a yellow powder (145 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ 9.49 - 9.22 (m, 2H), 9.18 (s, 2H), 8.53 (d, J = 3.3 Hz, 2H), 8.27 (s, 1 H), 8.25 - 8.16 (m, 2H), 7.93 (s, 1 H), 7.75 - 7.68 (m, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 4.30 (d, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.34 - 3.07 (m, 3H), 3.07 - 2.90 (m, 1 H), 2.88 - 2.72 (m, 1 H), 2.12 - 1.93 (m, 1 H), 1.79 - 1.61 (m, 1 H). HPLC (Condition A): Rt 2.55 min (purity 97.7%). MS (ESI+): 386.2.
Example 66: 5-(1-Azetidin-3-ylmethyl-1 H-pyrazol-4-yl)-2-[3-(1-methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidine hydrochloride
Step 1 : Formation of 3-(4-{2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-pyrimidin-5-yl}-
Figure imgf000185_0002
A solution of 3-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (Matrix scientific, 200 mg; 0.68 mmol; 1.0 eq.), cesium carbonate (442 mg; 1.36 mmol; 2.0 eq.) and 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 205 mg; 0.68 mmol; 1.0 eq.) in dry DMA (3 mL) was heated at 100°C O/N. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine (three times), dried over magnesium sulfate, filtered and concentrated. The crude was dissolved in DMSO and precipitated by addition of acetonitrile. It was filtered, rinced with acetonitrile and dried under vacuum to give the title compound as a yellow powder (423 mg, quantitative). MS (ESI+): 472.3. Step 2: Formation of 5-(1-Azetidin-3-ylmethyl-1 H-pyrazol-4-ylV2-r3-(1-methyl-1 H- pyrazol-4-yl)-phenyll-pyrimidine hydrochloride
Figure imgf000186_0001
The title compound was obtained following procedure described for example 13, step 2, but starting from 3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- ylmethyl)-azetidine-1-carboxylic acid tert-butyl ester (240 mg; 0.51 mmol; 1.0 eq.) as a yellow foam (55 mg, 26%). 1H NMR (300 MHz, DMSO) δ 9.18 (s, 2H), 9.14 - 8.86 (m, 2H), 8.53 (t, J = 1.7 Hz, 1 H), 8.48 (s, 1 H), 8.26 (s, 1 H), 8.25 - 8.18 (m, 2H), 7.92 (d, J = 0.8 Hz, 1 H), 7.75 - 7.68 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.48 (d, J = 7.1 Hz, 2H), 4.11 - 3.95 (m, 2H), 3.95 - 3.78 (m, 5H), 3.36 - 3.20 (m, 1 H). .HPLC (Condition A): Rt 2.49 min (purity 99.4%). MS (ESI+):372.3.
Example 67: 5-[1-(2,2-Difiuoro-ethyl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidine
Figure imgf000186_0002
The title compound was obtained following procedure described for example 66, step 1 , but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (255 mg; 0.84 mmol; 1.0 eq.) and methanesulfonic acid 2,2-difluoro-ethyl ester (prepared as described in Journal of Organic Chemistry, 74(12), 4547-4553; 2009, 150 mg, 0.84 mmol, 1.0 eq.) as a white solid (140 mg, 45%). NMR (300 MHz, DMSO-d6) δ 9.19(s, 2H), 8.57 - 8.47 (m, 2H), 8.30 - 8.20 (m, 3H), 7.93(d, J = 0.8 Hz, 1 H), 7.76 - 7.69 (m, 1 H), 7.52(t, J = 7.7 Hz, 1 H), 6.44 (tt, J = 54.8, 3.6 Hz, 1 H), 4.73(td, J = 15.3, 3.6
3.90(s, 3H). HPLC (Condition A): Rt 3.46 min (purity 96.4%).
Example 68: 1-Morpholin-4-yl-2-{4-[2-(3-pyridin-4-yl-phenyl)-pyrimidin-5-yl]- py razol-1 -y l}-ethanone
Figure imgf000187_0001
The title compound was obtained following procedure described for intermediate 5, step 1 , but starting from 2-{4-[2-(3-lodo-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-1-morpholin-4- yl-ethanone (intermediate 17, 200 mg; 0.42 mmol; 1.0 eq.) and 4-Pyridineboronic acid (77 mg; 0.63 mmol; 1.5 eq.) as a beige solid (25 mg, 135). 1 H NMR (300 MHz, DMSO- d6) d 9.24 (s, 2H), 8.99 (d, J= 6.8 Hz, 2H), 8.63 (dt, J= 8.0 Hz, 1.5Hz, 1 H), 8.45 (d, J= 6.8 Hz, 2H), 8.41 (s, 1 H), 8.22-8.15 (m, 3H), 7.81 (t, J= 8.0 Hz, 1 H), 5.26 (s, 2H), 3.65- 3.45 (m, 8H). HPLC (Condition A): Rt 2.03 min (purity 98.7%). MS (ESI+): 427.4. Example 69: 2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-{1-[2-(tetrahydro-pyran-4-yl)- ethyl]-1 H-pyrazol-4-yl -pyrimidine
Figure imgf000187_0002
The title compound was obtained following procedure described for example 66, stepl , but starting from 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-yl)pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 4-(2-Bromo-ethyl)-tetrahydropyran (96 mg; 0.50 mmol; 1.5 eq.) as a white foam (57 mg, 42%). 1H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.51 (dd, J = 22.9, 5.9 Hz, 2H), 8.36 - 8.05 (m, 3H), 8.00 - 7.83 (m, 1 H), 7.81 - 7.41 (m, 2H), 11.13 - 11.08 (m, OH), 4.34 - 4.04 (m, 2H), 3.90 (s, 3H), 3.86 - 3.70 (m, 1 H), 3.24 (t, J = 1 .4 Hz, 2H), 1.93 - 0.80 (m, 8H).HPLC (Condition A): Rt 3.58 min (purity 99.7%). MS (ESI+):415.4. Example 70: 2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-(S)-1-pyrrolidin-2- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of (S)-2-(4-{2-r3-(1-Methyl-1 H-pyrazol-4-ylVDhenvn-pyrimidin-5-ylV-
Figure imgf000188_0001
The title compound was obtained following procedure described for example 66, stepl , but starting from (S)-2-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in Organic & Biomolecular Chemistry, 8(16), 3742-3750; 2010, 125 mg; 0.40 mmol; 1.0 eq.) and 2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H- pyrazol-4-yl)pyrimidine (example 3, 146 mg; 0.48 mmol; 1.2 eq.) as a white solid (90 mg, 46%). MS (ESI+):486.3.
Step 2: Formation of 2-r3-(1-Methyl-1 H-pyrazol-4-yl)-phenyll-5-(1-(S)-1-pyrrolidin-2- ylmethyl- H-pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000188_0002
The title compound was obtained following procedure described for example 13, step 2, but starting from (S)-2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (127 mg; 0.26 mmol; 1.0 eq.) as a yellow powder (92 mg, 83%). 1 H NMR (300 MHz, DMSO-d6) δ 9.56 - 9.25 (m, 2H), 9.20 (s, 2H), 8.60(s, 1 H), 8.54(t, J = 1.7 Hz, 1 H), 8.27 (d, J = 2.7 Hz, 2H), 8.22(dt, J = 7.7, 1.4 Hz, 1 H), 7.93(s, 1 H), 7.81 - 7.67 (m, 1 H), 7.52(t, J = 7.7 Hz, 1 H), 4.64 - 4.49 (m, 2H), 4.04 - 3.93 (m, 1 H), 3.90(s, 3H), 3.34 - 3.09 (m, 2H), 2.17 - 1.61 (m, 4H). HPLC (Condition A): Rt 2.53 min (purity 99.6%). MS (ESI+):386.4.
Example 71 : 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-(R)-1-pyrrolidin-2- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride Step 1 : Formation of iR)-2-(4-{2-f3-n-Methyl-1H-pyrazol-4-yl)-phenyl1-pyrimidin-5-yl>- pyrazol-1-ylmethyl -pyrrolidine-1-carboxylic acid tert-butyl ester
Figure imgf000189_0001
The title compound was obtained following procedure described for example 66, stepl , but starting from (R)-2-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in Tetrahedron: Asymmetry, 8(13), 2209-2213; 1997 , 125 mg; 0.40 mmol; 1.0 eq.) and 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4- yl)pyrimidine (example 3, 122 mg; 0.40 mmol; 1.0 eq.) as a white foam (121 mg, 62%). MS (ESI+): MS (ESI+):486.3.
Step 2: Formation of 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenvn-5-(1-(R)-1-pyrrolidin-2- ylmethyl-1 H-pyrazo -4-yl)-pyrimidine hydrochloride
Figure imgf000189_0002
The title compound was obtained following procedure described for example 13, step 2, but starting from (R)-2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (121.00 mg; 0.25mmol; 1.0 eq.) as a yellow powder (87 mg, 78%). 1H NMR (300 MHz, DMSO) δ 9.56 - 9.25 (m, 2H), 9.20 (s, 2H), 8.60 (s, 1 H), 8.54 (t, J = 1.7 Hz, 1 H), 8.27 (d, J = 2.7 Hz, 2H), 8.23 (dt, J = 7.7, 1.4 Hz, 1 H), 7.93 (s, 1 H), 7.81 - 7.67 (m, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 4.64 - 4.49 (m, 2H), 4.04 - 3.93 (m, 1 H), 3.90 (s, 3H), 3.34 - 3.09 (m, 2H), 2.17 - 1.61 (m, 4H). HPLC (Condition A): Rt 2.55 min (purity 99.1 %). MS (ESI+):386.4.
Example 72: 2-[3-(1-Methyl-1 H-[1,2,3]triazol-4-yl)-phenyl]-5-(1 -piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Step 1 : Formation of 4-(4-(2-r3-i1-Trimethylsilanylmethyl-1 H-ri.2.3ltriazol-4-yl)-phenvn- pyrimidin-5-ylVpyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester
Figure imgf000190_0001
A solution of copper sulfate pentahydrate (2.2 mg; 0.01 mmol; 0.04 eq.) in water (0.2 mL) was added to a mixture of 4-{4-[2-(3-Trimethylsilanylethynyl-phenyl)-pyrimidin-5-yl]- pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (intermediate 19, 110 mg; 0.22 mmol; 1.0 eq.), azidomethyl-trimethyl-silane (36 μΙ; 0.24 mmol; 1.1 eq.) and D-(-)- isoascorbic acid sodium salt (9 mg; 0.04 mmol; 0.2 eq.) in Dioxane-1 ,4 (3 mL). The vial was sealed and stirred overnight at 80°C. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica afforded the title compound as a beige solid (60 mg, 49%). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.88 (t, J= 1.6 Hz, 1 H), 8.57 (s, 1 H), 8.54 (s, 1 H), 8.34 (dt, J= 8.0 Hz, 1.6 Hz, 1 H), 8.16 (s, 1 H), 7.96 (dt, J= 8.0 Hz, 1.6 Hz, 1 H), 7.60 (t, J= 8.0 Hz, 1 H), 4.48^.38 (m, 1 H), 4.11-4.03 (m, 4H), 2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H), 0.13 (s, 9H). MS (ESI+): 559.5.
Step 2: Formation of 2-r3-(1-Methyl-1 H-ri .2.3ltriazol-4-yl)-phenvn-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
Figure imgf000190_0002
Tetrabutylammonium fluoride (56 mg; 0.21 mmol; 2.0 eq.) was added to a solution of 4- (4-{2-[3-(1-Trimethylsilanylmethyl-1 H-[1 ,2,3]triazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- yl)-piperidine-1-carboxylic acid tert-butyl ester (60 mg; 0.11 mmol; 1.0 eq.) in THF (1 mL) and the reaction mixture was stirred at RT for 2h. It was then diluted with a saturated solution of NaHC03 and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was dissolved in DCM (1 ml_) and MeOH (MeOH) and HCI/dioxane (0.4 mL of a 4N solution, 1.6 mmol, 15 eq.) was added. The reaction mixture was stirred at RT for 2h, concentrated under reduced pressure and purified by autopreparative LC/Ms to give the title compound as a beige solid (15 mg, 33%). 1 H NMR (300 MHz, DMSO-d6) d 9.22 (s, 2H), 9.11 (brs, 1 H), 8.94-8.81 (m, 2H), 8.67 (s, 1 H), 8.54 (s, 1 H), 8.35 (dt, J= 7.9 Hz, 1.5 Hz, 1 H), 8.22 (s, 1 H), 7.96 (dt, J= 7.9 Hz, 1.5 Hz, 1 H), 7.61 (t, J= 7.9 Hz, 1 H), 4.61-4.52 (m, 1 H), 4.12 (s, 3H), 3.43-3.36 (m, 2H), 3.16-3.06 (m, 2H), 2.28-2.11 (m, 4H). HPLC (Condition A): Rt 2.08 min (purity 98.5%). MS (ESI+): 387.3.
Example 73: 1-(3-Hydroxy-azetidin-1-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-py
Figure imgf000191_0001
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 80 mg; 0.22 mmol; 1.0 eq.) and azetidin-3-ol hydrochloride (36 mg; 0.33 mmol; 1.5 eq.) as a white solid (5 mg, 5%). 1 H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.40 (s, 1 H), 8.27 (s, 1 H), 8.25 - 8.18 (m, 1 H), 8.16 (s, 1 H), 7.93 (d, J = 0.7 Hz, 1 H), 7.77 - 7.67 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 4.95 (s, 2H), 4.58 - 4.46 (m, 1 H), 4.42 - 4.29 (m, 1 H), 4.17 - 4.05 (m, 1H), 3.99 - 3.83 (m, 4H), 3.73 - 3.59 (m, 1 H). HPLC (Condition A): Rt 2.37 min (purity 92.9%). MS (ESI+): 416.2, (ESI-): 414.3, mp = 177-181°C
Example 74: 1-(3-Hydroxy-pyrrolidin-1-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)- pheny l]-pyrimidin-5-y l}-py razol-1 -y l)-ethanone
Figure imgf000191_0002
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 80 mg; 0.22 mmol; 1.0 eq.) and Pyrrolidin-3-ol (29 mg; 0.33 mmol; 1.5 eq.) as
A yellow solid (25 mg, 26%). 1 H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.54 (s, 1 H), 8.39 (s, 1 H), 8.31 - 8.19 (m, 2H), 8.15 (s, 1 H), 7.93 (s, 1 H), 7.72 (d, J = 7.7 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 5.25 - 5.01 (m, 3H), 4.33 (d, J = 29.2 Hz, 1 H), 3.90 (s, 3H), 3.72 - 3.25 (m, 4H), 2.09 - 1.65 (m, 2H). HPLC (Condition A): Rt 2.39 min (purity 99.8%). MS (ESI+): 430.3 (ESI-): 428.1 , mp = 237-238°C
Example 75: 1-t2-(2-Hydroxy-ethyl)-morpholin-4-yl]-2-(4-{2-[3-(1-methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
Figure imgf000192_0001
The title compound was obtained following procedure described for example 25 but starting from (4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- acetic acid (example 8, 80 mg; 0.22 mmol; 1.0 eq.) and 2-Morpholin-2-yl-ethanol (44 mg;
0.33 mmol; 1.5 eq.) as a yellow solid (17 mg, 16%). 1 H NMR (300 MHz, DMSO-d6) δ
9.18 (s, 2H), 8.54 (t, J = 1.6 Hz, 1 H), 8.38 (s, 1 H), 8.31 - 8.12 (m, 3H), 7.93 (d, J = 0.7
Hz, 1 H), 7.78 - 7.66 (m, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 5.43 - 5.28 (m, 1 H), 5.25 - 5.10 (m, 1 H), 4.25 - 4.06 (m, 1 H), 3.94 - 3.74 (m, 4H), 3.62 - 3.31 (m, 6H), 3.27 - 3.12 (m, 1 H),
3.01 - 2.68 (m, 1 H), 1.68 - 1.42 (m, 2H). HPLC (Condition A): Rt 2.48 min (purity 100
%). MS (ESI+): 474.3.
Example 95: Cis-5-{1-[1-(3-Fluoro-tetrahydro-pyran-4-yl)-piperidin-4-yl]-1 H-pyrazol- 4-yl}-2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
Figure imgf000193_0001
The title compound was obtained following procedure described for example 27 but starting from 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidine (example 1 , 165 mg; 0.26 mmol; 1.0 eq.) and 3-Fluoro-tetrahydro-pyran-4- one (Activate scientific; 60.7 mg; 0.51 mmol; 2.0 eq.). The crude was purified by autopreparative LC/MS to afford the pure cis isomer as a white solid (55 mg, 44%). 1 H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.62 -8.49 (m, 2H), 8.26 (s, 1 H), 8.21 (dt, J = 7.8, 1.5 Hz, 1 H), 8.13 (s, 1 H), 7.92 (s, 1 H), 7.71 (dt, J = 7.8, 1.5 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.98 (brd, J = 48 Hz, 1 H), 4.30 - 4.12 (m, 1 H), 4.00 - 3.82 (m, 5H), 3.54 - 3.34 (m, 2H), 3.20 - 3.03 (m, 2H), 2.79 - 2.53 (m, 1 H), 2.47 - 2.35 (m, 2H), 2.15 - 1.79 (m, 5H), 1.66 - 1.56 (m, 1 H). HPLC (Condition A): Rt 2.60 min (purity 100 %). MS (ESI+): 488.4.
Example 121 yrimidin-5-yl}-pyrazol- 1-yl)-cyclohe
Figure imgf000193_0002
Trimethylaluminium (1.50 mL; 3.0 mmol; 5.4 eq.) was added dropwise over 1 min to a solution of dimethylamine (2.50 mL; 5.0 mmol; 9.1 eq.) in DCE (50 mL) at 0°C. After 10 min, 4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- cyclohexanecarboxylic acid ethyl ester (prepared as described in example 62, stepl ; 300 mg; 0.55 mmol; 1.0 eq.) in DCE (50 mL) was added dropwise over 5 min. The reaction solution was stirred for 16 h then a further portion of trimethylaluminium (10 mL; 20 mmol; 36 eq.) was added and the reaction solution refluxed for 4 h. The reaction mixture was then poured into ice-cold MeOH and concentrated under reduced pressure. The residue was redissolved in DCM, washed with 1 N HCI solution, Rochelle's salt solution and brine. Organic phase was finally dried over magnesium sulfate, filtered and concentrated to give the title compounds as a 3:1 mixture of cis and trans 4-(4-{2-[3-(1 - Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid dimethylamide (165 mg; 60%) in the form of a beige solid. HPLC (Chiralpak IC, EtOH:THF 90:10): Rt 6.61 ; 10.38 min (purity 76, 24%); MS (ESI+): 456.4. Example 134: Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-cyclohexanecarbox lic acid dimethylamide
Figure imgf000194_0001
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- cyclohexanecarboxylic acid dimethylamide (example 121 ; 165 mg; 0.33 mmol) was suspended in DMF and filtered to give the title compound as a white solid (50 mg; 20%). 1 H NMR (300 MHz, DMSO) d 9.16 (s, 2H), 8.53 (t, J = 1.6 Hz, 1 H), 8.49 (s, 1 H), 8.26 (s, 1 H), 8.24 - 8.18 (m, 1 H), 8.13 (s, 1 H), 7.92 (d, J = 0.7 Hz, 1 H), 7.74 - 7.67 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.32 - 4.16 (m, 1 H), 3.89 (s, 3H), 3.05 (s, 3H), 2.83 (s, 3H), 2.77 - 2.63 (m, 1 H), 2.20 - 2.06 (m, 2H), 1.97 - 1.77 (m, 4H), 1.67 - 1.48 (m, 2H). HPLC (Chiralpak IC, EtOH HF 90:10): Rt 6.91 min (purity 98.4 %); MS (ESI+): 456.4.
Example 135: Cis-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-cyclohexanecarbox lic acid dimethylamide
Figure imgf000194_0002
The DMF mother liquor obtained in example 134 was concentrated and the reside purified by Chiral-HPLC (Chiralpack IC; EtOH:THF 90:10) to give the title compound as a white solid (9 mg; 3 %). 1 H NMR (300 MHz, DMSO) δ 9.20 (s, 2H), 8.60 - 8.48 (m, 2H), 8.27 (s, 1 H), 8.24 - 8.18 (m, 1 H), 8.15 (s, 1 H), 7.92 (d, J = 0.6 Hz, 1 H), 7.78 - 7.65 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.38 - 4.26 (m, 1 H), 3.89 (s, 3H), 3.03 (s, 3H), 2.89 - 2.83 (m, 1 H), 2.80 (s, 3H), 2.47 - 2.32 (m, 2H), 2.00 - 1.85 (m, 2H), 1.79 - 1.54 (m, 4H). HPLC (Chiralpak IC, EtOH HF 90:10): Rt 10.84 min (purity 99.9 %); MS (ESI+): 456.4. Example 182 : Trans-4-(4- 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimid pyrazol-1 -yl)-cyclohexanol
Figure imgf000195_0001
5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 700 mg; 2.22 mmol; 1.0 eq.), 4,4,5,5,4',4,,5,,5,-Octamethyl-[2,2']bi[[1 ,3,2]dioxaborolanyl] (620 mg; 2.44 mmol; 1.1 eq.), Potassium acetate (327 mg; 3.33 mmol; 1.5 eq.) and trans- Dichlorobis(tricyclohexylphosphine)palladium(ll), 99% (16.4 mg; 0.02 mmol; 0.01 eq.) were flushed with nitrogen for 10 min before the addition of Dioxane-1 ,4 (15 mL). The reaction mixture was then heated at reflux under nitrogen for 4 h. The temperature was reduced to 70°C before the addition of trans-4-(4-lodo-pyrazol-1-yl)-cyclohexanol (intermediate 22; 714 mg; 2.44 mmol; 1.10eq.), potassium carbonate (921 mg; 6.66 mmol; 3.0 eq.), trans-Dichlorobis(tricyclohexylphosphine)palladium(ll), 99% (16.4 mg; 0.02 mmol; 0.01 eq.) and water (5 mL). The new reaction mixture was heated again at 100°C for 30 min. It was allowed to cool to RT and diluted with EtOAc. Organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (THF : EtOAc, 50:50) folllowed by a recrystallisation in THF afforded the tittle compound as an off-white powder (550 mg, 62 %). 1 H NMR (300 MHz, DMSO) δ 9.14 (s, 2H), 6.51 (m, 1 H), 8.48 (s, 1 H), 8.25 (s, 1 H), 8.20 (m, 1 H), 8.11 (s, 1 H), 7.91 (s, 1 H), 7.69 (m, 1 H), 7.50 (t, J = 8.1 Hz, 1H), 4.70 (d, J = 4.2 Hz, 1 H), 4.18 (m, 1 H), 3.88 (s, 3H), 3.50 (m, 1 H), 1.73-2.08 (m, 6H), 1.36 (m, 2H). HPLC (Condition A): Rt 3.21 min (purity 98.6 %). MS (ESI+): 459.4. Example 250: cis-8-(4^2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1 -yl)-1 -aza-spiro[4.5]decan-2-one (first isomer)
Figure imgf000196_0001
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 160 mg; 0.51 mmol; 1.0 eq.) and cis-8-(4-Bromo-pyrazol-1-yl)-1-aza-spiro[4.5]decan- 2-one (intermediate 23; 166 mg; 0.56 mmol; 1.1 eq.). The crude was purified by autopreparative LC/MS to afford the title compound as a white solid (45 mg, 20%). 1 H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.53 (m, 2H), 8.26 (s, 1 H), 8.23 (m, 1 H), 8.13 (s, 1 H), 7.92 (s, 1H), 7.71 (m, 1 H), 7.50 (m, 1 H), 4.20 (m, 1 H), 3.89 (s, 3H), 2.22 (m, 2H), 1.95 (m, 6H), 1.70 (m, 4H). Rt 3.19 min (purity 87.2 %). MS (ESI+): 454.5.
Example 251 : Trans-8-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-1-az -spiro[4.5]decan-2-one (second isomer)
Figure imgf000196_0002
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 200 mg; 0.63 mmol; 1.0 eq.) and trans-8-(4-Bromo-pyrazol-1-yl)-1-aza- spiro[4.5]decan-2-one (intermediate 24; 208 mg; 0.7 mmol; 1.1 eq.). The crude was purified by autopreparative LC/MS to afford the title compound as a white solid (25 mg, 9%). 1 H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.53 (m, 2H), 8.26 (s, 1 H), 8.23 (m, 1 H), 8.13 (s, 1H), 7.92 (s, 1 H), 7.71 (m, 1 H), 7.50 (m, 1 H), 4.20 (m, 1 H), 3.89 (s, 3H), 2.22 (m, 2H), 1.95 (m, 6H), 1.70 (m, 4H). HPLC (Condition A): Rt 3.34 min (purity 100 %). MS (ESI+): 454.5. Example 254: 4-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-cyclohex l]-morpholin-3-one
Figure imgf000197_0001
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 230 mg; 0.73 mmol; 1.0 eq.) and trans-4-[4-(4-lodo-pyrazol-1-yl)-cyclohexyl]- morpholin-3-one (intermediate 26; 274 mg; 0.73 mmol; 1.0 eq.). The crude was purified by recrystallisation in methylisobutylketone. The title compound was obtained as a beige solid (16 mg, 5%). 1 H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.54 (s, 2H), 8.40 - 8.06 (m, 3H), 7.93 (s, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.9 Hz, 1 H), 4.31 (d, J = 39.6 Hz, 2H), 4.05 (s, 2H), 3.95 - 3.71 (m, 5H), 2.20 (d, J = 11.5 Hz, 2H), 2.03 - 1.49 (m, 6H), 1.23 (s, 1 H), 0.84 (t, J = 7.3 Hz, 1 H). HPLC (Condition A): Rt 3.31 min (purity 99.2%). MS (ESI+): 484.4.
Example 255 : 3-[4-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1 -yl)-cyclohexyl]-oxazolidin-2-one
Figure imgf000197_0002
The title compound was obtained following procedure described for example 182 but starting from 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 200 mg; 0.63 mmol; 1.0 eq.) and trans-3-[4-(4-lodo-pyrazol-1-yl)-cyclohexyl]- oxazolidin-2-one (intermediate 27; 231 mg; 0.63 mmol; 1.0 eq.). The crude was triturated in acetonitrile and the suspension filtered and dried under vacuum to afford the title compound as a brown solid (151 mg, 51 %). 1 H NMR (300 MHz, DMSO) δ 9.21 (s, 2H), 8.58 (d, J = 3.6 Hz, 2H), 8.38 - 8.10 (m, 3H), 7.98 (s, 1 H), 7.86 - 7.44 (m, 2H), 4.32 (dd, J = 14.8, 6.5 Hz, 3H), 3.95 (s, 3H), 3.78 - 3.46 (m, 4H), 2.23 (s, 2H), 2.08 - 1.57 (m, 7H). HPLC (Condition A): Rt 3.39 min (purity 97.9%). MS (ESI+): 470.4. Example 258: Cis-1-Hydroxymethyl-4-(4-{2-[3-(1 -methyl-1 H-pyrazoI-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1 - l)-cyclohexanol
Figure imgf000198_0001
The title compound was obtained following procedure described for example 182 but starting from 4-lodo-1-(1-oxa-spiro[2.5]oct-6-yl)-1 H-pyrazole (intermediate 28; 816 mg; 2.68 mmol; 1.0 eq.) and 5-Bromo-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (Intermediate 2; 845 mg; 2.68 mmol; 1.0 eq.) as a yellow solid (6 mg). 1 H NMR (300 MHz, DMSO) δ 9.18 (s, 2H), 8.55 - 8.50 (m, 2H), 8.27 (s, 1 H), 8.24 - 8.19 (m, 1 H), 8.12 (s, 1 H), 7.92 (s, 1 H), 7.74 - 7.68 (m, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.62 (t, J = 5.8 Hz, 1 H), 4.20 - 4.07 (m, 2H), 3.89 (s, 3H), 3.22 (d, J = 5.8 Hz, 2H), 2.21 - 2.05 (m, 2H), 1.93 - 1.82 (m, 2H), 1.58 (d, J = 6.3 Hz, 4H). HPLC (Condition A): Rt 2.92 min (purity 92.3%). MS (ESI+): 431.4.
Example 259: 5-[1-(3,3-Difluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine
Figure imgf000198_0002
To a solution of 4-(4-Bromo-pyrazol-1-yl)-3,3-difluoro-piperidine (intermediate 29; 150 mg; 0.50 mmol; 1.0 eq.) in Dioxane-1 ,4 (12 mL) and Water (3.0 mL) was added Potassium carbonate (141 mg; 0.99 mmol; 2.0 eq.) and 2-[3-(1 -Methyl-1H-pyrazol-4-yl)- phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 30; 221 mg; 0.60 mmol; 1.2 eq.). The reaction mixture was degasified for 15 min and then 1 ,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (20.88 mg; 0.02 mmol; 0.05 eq.) was added. The reaction mixture was then heated at 100° C for 90 min. It was concentrated under reduced pressure, diluted with Water (15 ml_) and extracted with ethylacetate (2 X 25 ml_). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, 9:1) afforded the title compound as a brown solid (24 mg; 11 %). 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.53-8.52 (m, 2H), 8.26 (s, 1 H), 8.23-8.20 (m, 2H), 7.91 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.96-4.86 (m, 1 H), 3.89 (s, 3H), 3.22-3.15 (m, 1 H), 3.08-3.05 (m, 1H), 2.98-2.87 (m, 1 H), 2.72-2.67 (m, 1 H), 2.66-2.59 (m, 1 H), 2.36-2.29 (m, 1 H), 2.08-2.05 (m, 1 H). HPLC (Condition A): Rt 3.00 min (purity 96.8%). MS (ESI+): 422.2.
Example 260: trans-2-Methyl-8-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-py
Figure imgf000199_0001
The title compound was obtained following procedure described for example 164 but starting from trans-8-(4-Bromo-pyrazol-1-yl)-2-methyl-2-aza-spiro[4.5]decan-3-one (Intermediate 33; 250 mg; 0.67 mmol; 1.00 eq.) and 2-[3-(1-Methyl-1 H-pyrazol-4-yl)- phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 30; 298 mg; 0.80 mmol; 1.2 eq.) as a brown solid (158 mf, 49%). 1 H NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 8.54-8.52 (m, 2H), 8.26 (s, 1 H), 8.21 (d, J = 7.9 Hz, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.70 (d, J = 7.7 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 4.25-4.19 (m, 1H), 3.88 (s, 3H), 3.13 (s, 2H), 2.72 (s, 3H), 2.27 (s, 2H), 2.03-1.99 (m, 2H), 1.91-1.83 (m, 2H), 1.76-1.72 (m, 2H), 1.61-1.55 (m, 2H). HPLC (Condition A): Rt 3.64 min (purity 96.6%). MS (ESI+): 468.3.
Example 262: cis-2- ethyl-8-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin- 5-yl}-pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one
Figure imgf000200_0001
The title compound was obtained following procedure described for example 164 but starting from cis-8-(4-Bromo-pyrazol-1-yl)-2-methyl-2-aza-spiro[4.5]decan-3-one (Intermediate 32; 250 mg; 0.56 mmol; 1.0 eq.) and 2-[3-(1-Methyl-1 H-pyrazol-4-yl)- phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 15; 250 mg; 0.67 mmol; 1.2 eq.) as a brown solid (34 mg, 12%). 1H NMR (400MHz, DMSO) δ 9.15 (s, 2H), 8.53-8.51 (m, 2H), 8.25 (s, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 8.13 (s, 1 H), 7.91 (s, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 4.25-4.20 (m, 1 H), 3.88 (s, 3H), 3.29 (s, 2H), 2.74 (s, 3H), 2.13 (s, 2H), 2.01-1.98 (m, 2H), 1.93-1.84 (m, 2H), 1.79-1.76 (m, 2H), 1.59-1.52 (m, 2H). HPLC (Condition A): Rt 3.62 min (purity 94.2%). MS (ESI+): 468.3.
Example 265: cis-3-Fluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine
Figure imgf000200_0002
The title compound was obtained following procedure described for example 164 but starting from 4-(4-Bromo-pyrazol-1-yl)-3-fluoro-piperidine (Intermedaite 37; 200 mg; 0.80 mmol; 1.0 eq.) and 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 15; 296 mg; 0.80 mmol; 1.0 eq.). After Purification of the crude by flash chromatography on silica (DCM:MeOH; 9:1) only the cis isomer was isolated as a brown solid (41 mg, 12%). 1 H NMR (400 MHz, DMSO-d6) 5 9.20 (s, 2H), 8.52-8.50 (m, 2H), 8.25-8.19 (m, 3H), 7.91 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 4.92 (d, J = 52 Hz, 1 H), 4.62-4.51 (m, 1 H), 3.89 (s, 3H), 3.24-3.10 (m, 2H), 2.85 (dd, J = 14, 40 Hz, 1 H), 2.67 (m, 1 H), 2.45 (m, 1 H), 2.23 (m, 1 H), 1.95 (m, 1 H). HPLC (Condition A): Rt 2.85 min (purity 97.6%). MS (ESI+): 404.3.
Example 280: (3aS,7aS)-7a-Hydroxy methy l-5-((R)-4-{2-[3-(1 -methy 1-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-hexahydro-isobenzofuran-3a-ol
(configuration attributed arbitrarily)
Chiral
Figure imgf000201_0001
The title compound was obtained following procedure described for example 164 but starting from cis-5-(4-bromopyrazol-1-yl)-cis-7a-(hydroxymethyl)-1 ,3,4,5,6,7- hexahydroisobenzofuran -3a-ol (intermediate 35; 187 mg; 0.58 mmol; 1.0 eq.) and 2-[3- (1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- pyrimidine (intermediate 15; 269 mg; 0.69 mmol; 1.2 eq.), as an off-white solid (30 mg; 11%). 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.57 (s, 1 H), 8.52 (s, 1 H), 8.25 (s, 1 H), 8.21 (d, J = 7.88 Hz, 1 H), 8.13 (s, 1 H), 7.91 (s, 1 H), 7.70 (d, J = 7.72 Hz, 1 H), 7.49 (t, J = 7.72 Hz, 1 H), 5.20 (s, 1 H), 4.68 (t, J = 5.24 Hz, 1 H), 4.49-4.43 (m, 1 H), 3.89-3.83 (m, 4H), 3.77 (d, J = 8.72 Hz, 1 H), 3.67 (d, J = 7.80 Hz, 1 H), 3.54-3.44 (m, 3H), 2.15 (t, J = 12.72 Hz, 1 H), 2.14-2.03 (m, 1 H), 1.96-1.91 (m, 1 H), 1.88-1.78 (m, 2H), 1.70-1.68 (m, 1 H). HPLC (Condition A): Rt 3.20 min (purity 99.3%). MS (ESI+): 473.2. m.p.: 190.10 - 201.70 ° C.
Example 281 : (3aR,5R,7aR)-7a-Hydroxymethy l-5-(4-{2-[3-(1 -methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-hexahydro-isobenzofuran-3a-ol
(configuration attributed arbitrarily)
Chiral
Figure imgf000201_0002
The title compound was obtained following procedure described for example 164 but starting from cis-5-(4-bromopyrazol-1-yl)-cis-7a-(hydroxymethyl)-1 ,3,4,5,6,7- hexahydroisobenzofuran -3a-ol (intermediate 36; 180 mg; 0.56 mmol; 1.0 eq.) and 2-[3- (1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- pyrimidine (intermediate 15; 259 mg; 0.67 mmol; 1.2 eq.), as an pale yellow solid (80 mg; 29%). 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.57 (s, 1 H), 8.52 (s, 1 H), 8.26 (s, 1 H), 8.21 (d, J = 7.8 Hz, 1 H), 8.13 (s, 1 H), 7.92 (s, 1 H), 7.70 (d, J = 7.6 Hz, 1 H), 7.50 (t, J = 7.7 Hz, 1 H), 5.21 (s, 1 H), 4.68 (d, J = 5.2 Hz, 1 H), 4.45 (t, J = 12.0 Hz, 1 H), 3.89- 3.84 (m, 3H), 3.77 (d, J = 8.8 Hz, 1 H), 3.67 (d, J = 7.9 Hz, 1 H), 3.66-3.51 (m, 1 H), 3.52- 3.49 (m, 2H), 3.46-3.44 (m, 1 H), 2.16 (t, J = 12.8 Hz, 1 H), 2.07-1.97 (m, 2H), 1.92-1.89 (m, 1 H), 1.86-1.78 (m, 1 H), 1.67-1.61 (m, 1 H). HPLC (Condition A): Rt 3.21 min (purity 92.4%). MS (ESI+): 473.2. m.p.: 191.40 - 199.70 ° C.
Example 285: Cis-1-Methyl-8-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yI)-phenyl]-pyrimidin- 5-yl}-pyrazol-1-yl)-1
Figure imgf000202_0001
The title compound was obtained following procedure described for example 164 but starting from 8-(4-Bromo-pyrazol-1-yl)-1-methyl-1-aza-spiro[4.5]decan-2-one (intermediate 38; 130.0 mg; 0.41 mmol; 1.0 eq.)) and 2-[3-(1 -Methyl-1 H-pyrazol-4-yl)- phenyl]-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 15; 171 mg; 0.45 mmol; 1.1 eq.) as Brown Solid ( 35 mg, 17%). 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.53 (d, J = 5.0 Hz, 2H), 8.25 (s, 1 H), 8.21 (d, J = 7.8 Hz, 1H), 8.13 (s, 1 H), 7.91 (s, 1 H), 7.70 (d, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 4.80-4.40 (m, 1 H), 3.88 (s, 3H), 2.66 (s, 3H), 2.32-2.25 (m, 2H), 2.09-2.02 (m, 2H), 1.99-1.91 (m, 6H), 1.53-1.51 (m, 2H). HPLC (max plot) 95.4%; (254nm) 94.2 %; Rt (min) 3.59; MS: (ESI+) 468.0.
Example 286: trans-8-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-py rimidin-5-yl}- pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one
Figure imgf000203_0001
The title compound was obtained following procedure described for example 164 but starting from trans-8-(4-bromo-1 H-pyrazol-1-yl)-2-azaspiro [4.5] decan-3-one (intermediate 30) and trans-2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyi]-5-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 15) as a off white Solid; 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.53 (s, 1H), 8.52-8.51 (m, 1 H), 8.25 (s, 1 H), 8.21 (d, J = 7.9 Hz, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.55 (bs, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 4.24-4.19 (m, 1 H), 3.88 (s, 3H), 3.18 (s, 2H), 2.03-1.98 (m, 4H), 1.90-1.78 (m, 4H), 1.58-1.52 (m, 2H). HPLC (max plot) 98.6%; (254nm) 98.9 %; Rt (min) 3.42; MS: (ESI+) 454.20. m.p.: 255.0 - 258.7 ° C.
Example 287: cis-8-(4-(2-(3-(1 -methyl-1 H-pyrazol-4-y l)phenyl)pyrimidin-5-y l)-1 H- pyrazol-1-yl)-2-azasp
Figure imgf000203_0002
The title compound was obtained following procedure described for example 164 but starting from cis-8-(4-bromo-1 H-pyrazol-1-yl)-2-azaspiro [4.5] decan-3-one (Intermediate 31) and 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 15) as an off white Solid; 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.55 (s, 1 H), 8.53-8.52 (m, 1 H), 8.26 (s, 1 H), 8.21 (d, J = 7.8 Hz, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.56 (bs, 1 H), 7.50 (t, J = 7.8 Hz, 1H), 4.25-4.18 (m, 1 H), 3.88 (s, 3H), 3.02 (s, 2H), 2.18 (s, 2H), 2.03- 1.99 (m, 2H), 1.91-1.85 (m, 2H), 1.81-1.76 (m, 2H), 1.59-1.51 (m, 2H). HPLC (max plot) 98.8 %; (254nm) 99.0 %; Rt (min) 3.44; MS: (ESI+) 454.20. m.p.: 262.00 - 265.80 ° C. Other examples have been synthesized following similar procedures as described above or following procedures well known from those skilled in the art.
Example 291 : enzymatic assays
IRAKI enzymatic assay
IRAKI is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712)) In this assay, IRAK-1 hydrolyses ATP and autophosphorylates.
Measurement of IRAK-1 inhibition is performed in streptavidin coated 384well FlashPlate (PerkinElmer #SMP410A).
His-TEV-IRAK-1 (15ng/well), ATP (1 μΜ, [33P]ATP 0.25pCi/well) and compounds in DMSO (range of concentrations from 20μΜ to 1 nM) or controls (2%DMSO) are incubated for 3 hours at 30°C in assay buffer : Hepes pH7.0 50mM, Fatty acid-free BSA 0.1%, Dithiothreitol DTT 2mM, MgCI2 10mM, EGTA 0.5mM, Triton-X-100 0.01 %. Kinase reaction is stopped by addition of EDTA. Supernatant is discarded, plates are washed three times with 150 mM NaCI and radioactivity is then measured in a Microbeta Trilux reader.
IRAK4 enzymatic assay
IRAK4 is a human purified recombinant enzyme (His-TEV-IRAK1 (194-712) IRAK4 hydrolyses ATP, autophosphorylates and phosphorylates a Serine/Threonine generic peptidic substrate (STK: 61 ST1 BLC from CisBio International based in Bagnols/Ceze FR).
Measurement of IRAK-4 inhibition is performed in streptavidin coated 384well FlashPlate (PerkinElmer #SMP410A). His-TEV-IRAK4 (20ng/well), ATP (2μΜ, [33P]ATP 0.25pCi/well), STK1-biotin peptide (300nM) and compounds in DMSO (range of concentrations from 20μΜ to 1 nM) or controls (2%DMSO) are incubated for 3 hours at 30°C in assay buffer: Hepes pH7.0 50mM, Fatty acid-free BSA 0.1 %, Dithiothreitol DTT 2mM, MgCI2 10mM, EGTA 0.5mM, Tween-20 0.01 %, MnCI2 5mM.
Kinase reaction is stopped by addition of EDTA. Supernatant is discarded, plates are washed three times with 150 mM NaCI and radioactivity is then measured in a Microbeta Trilux reader.
Results are given in the following table:
IRAK4
Ex IC50
(nM)
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 -piperidin-4-yl-
1 1 H-pyrazol-4-yl)-pyrimidine hydrochloride **
5-(1-(piperidin-4-yl)-1 H-pyrazol-4-yl)-2-(3-(pyridin-3-
2 yl)phenyl)pyrimidine .hydrochloride **
2-[3-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-5-(1 H-pyrazol-4-
3 yl)pyrimidine **
2,2,2-Trifluoro-1 -[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
4 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone **
-[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
5 yl}-pyrazol-1 -yl)-piperidin-1 -yl]-ethanone ***
5-[1-(1-Methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-
6 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine **
2-(3-Furan-3-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)-
7 pyrimidine Hydrochloride **
4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
8 pyrazol-1-yl)-acetic acid *
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
9 pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone **
4-[2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
10 yl}-pyrazol-1-yl)-ethyl]-morpholine ** Dimethyl-[2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-ethyl]-amine *
2-[3-(1 -Methy 1-1 H-pyrazol-4-y l)-phenyl]-5-[1 -(tetrahydro- furan-3-yl)-1 H-pyrazol-4-yl]-pyrimidine **
2-(3-lsoxazol-4-yl-phenyl)-5-(1-piperidin-4-yl-1 H-pyrazol-4- yl)-pyrimidine hydrochloride **
2-[3-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4- yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride *
2-[3-(1 ,5-Dimethyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4- yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride **
2-{3-[1-(2-Fluoro-1-fluoromethyl-ethyl)-1 H-pyrazol-4-yl]- phenyl}-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine ** hydrochloride
2-(4-{3-[5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]- phenyl}-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone * hydrochloride
5-(1 -Piperidin-4-yl-1 H-pyrazol-4-yl)-2-[3-(1 H-pyrazol-4-yl)- phenylj-pyrimidine hydrochloride ***
5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-[3-(1-propyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine hydrochloride **
2-[3-(1-lsopropyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4- y 1-1 H-pyrazol-4-yl)-pyrimidine hydrochloride **
2-[3-(1-Benzyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl- 1 H-pyrazol-4-yl)-pyrimidine hydrochloride **
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-pyridin-3- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine **
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yi}- pyrazol-1-yl)-ethanol **
2-[3-Fluoro-5-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1- piperidin-4-yl-l H-pyrazol-4-yl)-pyrimidine hydrochloride ** 2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-1-piperidin-1-yl-ethanone *
5-(1-Azetidin-3-yl-1 H-pyrazol-4-yl)-2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine hydrochloride *
5-[1-(3-Methoxy-propyl)-1 H-pyrazol-4-yl]-2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1 -(1-oxetan-3-yl- piperidin-4-yl)-1 H-pyrazol-4-yl]-pyrimidine **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride * trans-5-[1-(3-Fluoro-piperidin-4-yl)- H-pyrazol-4-yl]-2-[3-(1- methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine hydrochloride **
1 , 1 ,1 -Trifluoro-3-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-2- ** ol
5-(1-Methyl-1 H-pyrazol-4-yl)-2-[3-(1-methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidine **
5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-(3-pyridin-4-yl-phenyl)- pyrimidine hydrochloride **
3-(1 -Methyl-1 H-pyrazol-4-yl)-5-[5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidin-2-yl]-phenol Formate **
1-Methoxy-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-propan-2-ol *
1-Methoxy-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-propan-2-ol **
2-(4-{2-[3-(3-Methyl-3H-imidazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone *
N,N-Dimethyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-acetamide **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1 -[1 -(tetrahydro- pyran-4-yl)-piperidin-4-yl]-1 H-pyrazol-4-yl}-pyrimidine *** 1 -(3-Methoxy-azetidin-1 -yl)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
2-(4-{2-[3-(1 -Methyl-1 H-yrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1 -ylmethyl)-morpholine hydrochloride **
2-[4-(2-{3-[1 -(3-Amino-propyl)-1 H-pyrazol-4-yl]-phenyl}- pyrimidin-5-yl)-pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone * hydrochloride
2-{4-[2-(3-Pyridin-4-yl-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}- 1-pyrrolidin-1-yl-ethanone *
1 -(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-propan-2-one **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[ -(tetrahydro- furan-3-ylmethyl)-1 H-pyrazol-4-yl]-pyrimidine **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 -oxazol-2- ylmethyl-1 H-pyrazol-4-yl)-pyrirnidine *
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1 -(2-pyridin-2-yl- ethyl)-1 H-pyrazol-4-yl]-pyrimidine **
2-[2-Fluoro-3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 - piperidin-4-yl-l H-pyrazol-4-yl)-pyrimidine Formate *
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1 -yl)-acetamide *
2-[4-(2-{3-[1-(2-Amino-ethyl)-1 H-pyrazol-4-yl]-phenyl}- pyrimidin-5-y l)-pyrazol- 1 -y I]- 1 -py rrolidi n- 1 -y l-ethanone * hydrochloride
1-(4-Methyl-piperazin-1-yl)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-
4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone ** hydrochloride
1-(3-Hydroxy-piperidin-1-l)-2-(4-{2-[3-(1-methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1 -(2-pyridin-4-yl- ethyl)-1 H-pyrazol-4-yl]-pyrimidine *** 2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yI)-N-(tetrahydro-pyran-4-yl)-acetamide **
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-1-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethanone **
2-(4-{2-[3-(2-Methyl-thiazol-5-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone **
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-piperidin-1- yl-ethyl)-1 H-pyrazol-4-yl]-pyrimidne **
2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-pyrrolidin-1- yl-ethyl)-1 H-pyrazol-4-yl]-pyrimidine **
2-[4-(2-{3-[1 -(2-Hydroxy-ethy l)-1 H-pyrazol-4-yl]-pheny I}- pyrimidin-5-yl)-pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone *
N-(1 -Hydroxymethy l-propyl)-2-(4-{2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-acetamide *
(3-exo)-8-Methy l-3-(4-{2-[3-(1 -methyl-1 H-py razol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-8-aza- *** bicyclo[3.2.1]octane
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1 -yl)-cyclohexanecarboxylic acid **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 H-pyrazol-4-yl)- pyrimidine **
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1-[2-(1-methyl- pyrrolidin-2-yl)-ethyl]-1 H-pyrazol-4-yl}-pyrimidine **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-pyrrolidin-3- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride **
5-(1-Azetidin-3-ylmethyl-1 H-pyrazol-4-yl)-2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine hydrochloride **
5-[1-(2,2-DifIuoro-ethyl)-1 H-pyrazol-4-yl]-2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine ** 1-Morpholin-4-yl-2-{4-[2-(3-pyridin-4-yl-phenyl)-pyrimidin-5- yl]-pyrazol-1-yl}-ethanone *
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-pheny l]-5-{1 -[2-(tetrahydro- pyran-4-yl)-ethyl]-1 H-pyrazol-4-yl}-pyrimidine **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-(S)-1-pyrrolidin- 2-ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride *
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-(R)-1-pyrrolidin- 2-ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride *
2-[3-(1 -Methyl-1 H-[1 , 2,3]triazol-4-yl)-phenyl]-5-(1-piperidin- 4-yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride *
1-(3-Hydroxy-azetidin-1-yl)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
1-(3-Hydroxy-pyrrolidin-1-yl)-2-(4-{2-[3-(1-methyi-1 H- pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
1 -[2-(2-Hydroxy-ethyl)-morpholin-4-yl]-2-(4-{2-[3-(1 -methyl-
1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ** ethanone
5-[1-(1-Methanesulfonyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-2- [3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine **
1-Azetidin-1-yl-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
1-Morpholin-4-yl-2-{4-[2-(3-oxazol-5-yl-phenyl)-pyrimidin-5- y l]-pyrazol-1 -y l}-ethanone **
1-Morpholin-4-yl-2-(4-{2-[3-(1 H-[1 ,2,3]triazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-ethanone *
1-(2-Methyl-morpholin-4-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
1-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-2-(4-{2-[3-(1-methyl-
1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ** ethanone
N-(2-Hydroxy-1 ,1-dimethyl-ethyl)-2-(4-{2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-acetamide * 3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-pheny l]-pyrimidin-5-yl}-
83 pyrazol-1-yl)-1-morpholin-4-yl-propan-1-one *
3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
84 pyrazol-1 -yl)-1 -pyrrolidin-1 -yl-propan-1 -one *
N,N-Dimethyl-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
85 pyrimidin-5-yl}-pyrazol-1-yl)-propionamide **
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-pheny l]-pyrimidin-5-y I}-
86 pyrazol-1-yl)-1-(2-oxa-7-aza-spiro[3.5]non-7-yl)-ethanone **
1-[2-(2-Methoxy-ethyl)-morpholin-4-yl]-2-(4-{2-[3-(1-methyl-
87 1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)- **
ethanone
1-(3-Methoxymethyl-piperidin-1-yl)-2-(4-{2-[3-(1 -methyl-1 H-
88 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1 -[2-(2-methyl-
89 pyridin-3-yl)-ethyl]-1 H-pyrazol-4-yl}-pyrinnidine **
1 -(3-Methoxy-pyrrolidin-1-yl)-2-(4-{2-[3-(1 -methyl-1 H-
90 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
N-Methyl-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
91 pyrimidin-5-yl}-pyrazol-1-yl)-N-(tetrahydro-pyran-4-yl)- **
acetamide
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
92 pyrazol-1 -y l)-1 -(1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1 ]hept-5-y I- **
ethanone
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
93 pyrazol-1-yl)-1-[1 ,4]oxazepan-4-yl-ethanone **
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
94 pyrazol-1-yl)-1-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-ethanone **
Cis-5-{1 -[1 -(3-Fluoro-tetrahydro-pyran-4-y l)-piperidin-4-y I]-
95 1 H-pyrazol-4-yl}-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- **
pyrimidine
5-{1 -[2-(3,4-Dimethoxy-phenyl)-ethyl]-1 H-pyrazol-4-yl}-2-[3-
96 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine ** 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro- pyran-4-yl)-1 H-pyrazol-4-yl]-pyrimidine **
5-[1-(2-Methoxy-ethyl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidine **
N,N-Dimethyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-propionamide *
1 -(3-Methoxy-azetidin-1 -yl)-3-(4-{2-[3-(1 -methy 1-1 H-pyrazol- 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-propan-1-one *
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-1-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propan-1- * one
1-(4-Methyl-piperazin-1-yl)-3-(4-{2-[3-(1-methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrinnidin-5-yl}-pyrazol-1-yl)-propan-1-one *
2-(4-{2-[3-(1-Methy!-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-1-morpholin-4-yl-propan-1-one *
[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-piperidin-1-yl]-(tetrahydro-furan-3-yl)- ** methanone
2-Methoxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone **
2-Hydroxy-1 -[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-y l)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone **
[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-piperidin-1-yl]-(tetrahydro-pyran-4-yl)- ** methanone
[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-piperidin-1-yl]-(tetrahydro-pyran-2-yl)- ** methanone
3-Methoxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-1-one **
(1 R,5S)-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-8-aza-bicyclo[3.2.1]octane **
2-Ethoxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1 -yi)-piperidin-1 -yl]-ethanone ** 5-{1-[1-(3-Ethoxy-2,2-dimethyl-cyclobutyl)-piperidin-4-yl]-1 H- pyrazol-4-yl}-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- ** pyrimidine
1 -Methyl-4-[4-(4-{2-[3-(1 -methyl-1 H-py razol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-piperidine-1-carbonyl]- ** pyrrolidin-2-one
3,3,3-Trifluoro-1-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-1- ** one
3,3,3-Trifluoro-2-hydroxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-
4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]- ** propan-1-one
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((R)-1-pyrrolidin-3- yl-1 H-pyrazol-4-yl)-pyrimidine **
3-[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-py razol-1 -yl)-piperidine-1 -carbonyl]-cyclobutanone **
1 ,1 ,1-Trifluoro-3-[(1R,5S)-3-(4-{2-[3-(1 -methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-8-aza- ** bicyclo[3.2.1]oct-8-yl]-propan-2-ol
1-[(1 R,5S)-3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]- ** ethanone
(3-Hydroxy-cyclobutyl)-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]- ** methanone
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide ***
5-{1-[1-((S)-3-Methoxy-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 H-pyrazol-4-yl}-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- ** pyrimidine
[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-py razol-1 -yl)-piperidin-1 -y l]-((S)-1 -methy l-pyrrolidin-2-y I)- ** methanone
(S)-2-Amino-3-methy 1-1 -[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-butan- **
1-one
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((S)-1 -pyrrol idin-3- yl-1 H-pyrazol-4-yl)-pyrimidine ** 1 -[(S)-3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-phenyl]- pyrimidin-5-yl}-pyrazol-1 -yl)-pyrrolidin-1-yl]-ethanone **
1-(3-Hydroxy-8-aza-bicyc!o[3.2.1]oct-8-yl)-2-(4-{2-[3-(1 - methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- ** yl)-ethanone
1 -(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-2-(4-{2-[3-(1- methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- *■* yl)-ethanone
3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- py razol- 1 -y l)-d i hy d ro-f u ra n-2-o ne **
1 -[(R)-3-(4-{2-[3-(1 -Methyl-1 H-py razol-4-y l)-pheny I]- pyrimidin-5-yl}-pyrazol-1 -yl)-pyrrolidin-1-yl]-ethanone
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1-[2-(tetrahydro- furan-3-yl)-ethyl]-1 H-pyrazol-4-yl}-pyrimidine **
3-[2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl)-pyrazol-1-yl)-ethyl]-dihydro-furan-2-one **
9-lsopropyl-3-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-9-aza-bicyclo[3.3.1]nonane **
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-pheny I]- pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid *** dimethylamide
Cis-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin- 5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid ** dimethylamide
4-(3-{5-[1 -(Tetrahydro-pyran-4-yl)-1 H-pyrazol-4-yl]- pyrimidin-2-yl}-phenyl)-pyridin-2-ylamine **
4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1- (tetrahydro-pyran-4-yl)-1 H-pyrazole-3-carboxylic acid amide *
3-Methyl-5-(3-{5-[1 -(tetrahydro-pyran-4-yl)-1 H-pyrazol-4-yl]- pyrimidin-2-yl}-phenyl)-pyridazine **
2-[3-(2-Methyl-pyridin-4-yl)-phenyl]-5-[1 -(tetrahydro-pyran-4- yl)-1 H-pyrazol-4-yl]-pyrimidine ** 4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1-
140 (tetrahydrc-pyran-4-yl)-1 H-pyrazole-3-carboxylic acid *
2-[3-(1-Methyi-1 H-pyrazol-4-yl)-phenyl]-5-(1-oxetan-3-yl-1 H-
141 pyrazol-4-yl)-pyrimidine **
Exo-9- ethy l-3-(4-{2-[3-(1 -methy 1-1 H-py razol-4-y!)-pheny I]-
142 pyrimidin-5-yl}-pyrazol-1-yl)-9-aza-bicyclo[3.3.1]nonane **
Trans- 4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
143 pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid ***
methylamide
1 -Methyl-4-{2-[3-(1 -methy 1-1 H-pyrazol-4-y l)-phenyl]-
144 pyrimidin-5-yl}-1 H-pyrazole-3-carboxylic acid methylamide *
N-Methyl-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
145 pyrimidin-5-yl}-pyrazol-1-yl)-N-oxetan-3-yl-acetamide **
1-(3-Methoxymethyl-morpholin-4-yl)-2-(4-{2-[3-(1-methyl-
146 1 H-pyrazol-4-y l)-phenyl]-pyrimidin-5-y l}-py razol-1 -y I)- **
ethanone
1-(3-Methyl-morpholin-4-yl)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-
147 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone **
1-((1 R,4R)-5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-(4-
148 {2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- *
pyrazol-1 -yl)-ethanone
N,N-Dimethyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
149 pyrimidin-5-yl}-pyrazol-1-yl)-isobutyramide **
2-Methyl-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-y l)-pheny I]-
150 pyrimidin-5-yl}-pyrazol-1-yl)-1-morpholin-4-yl-propan-1-one *
[4-(3-{5-[1 -(Tetrahydro-pyran-4-yl)-1 H-pyrazol-4-yl]-
151 pyrimidin-2-yl}-phenyl)-pyridin-2-yl]-methanol **
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-pheny I]-
152 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (2- ***
methoxy-ethyl)-methyl-amide
(3-Hydroxy-azetidin-1-yl)-[4-{2-[3-(1-methyl-1 H-pyrazol-4-
153 yl)-phenyl]-pyrimidin-5-yl}-1-(tetrahydro-pyran-4-yl)-1 H- *
pyrazol-3-yl]-methanone
4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1-
154 (tetrahydro-pyran-4-yl)-1 H-pyrazole-3-carboxylic acid (2- *
hydroxy-ethyl)-amide (1 -Methy l-4-{2-[3-(1 -methyi-1 H-pyrazol-4-y l)-pheny I]-
155 pyrimidin-5-yl}-1 H-pyrazol-3-yl)-methanol *
4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
156 pyrazol-1 -yl)-cyclohexylamine **
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
157 pyrazol-1-yl)-cyclobutanecarboxylic acid methylamide **
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
158 pyrazol-1-yl)-cyclobutanecarboxylic acid dimethylamide **
Trans-4-(4-{2-[3-(1 -Methy 1-1 H-py razol-4-y l)-phenyl]-
159 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (2- ***
methoxy-ethyl)-amide
Trans-(4-Methy l-piperazin-1-yl)-[4-(4-{2-[3-(1 -methy 1-1 H-
160 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ***
cyclohexyl]-methanone
Cis-N-[4-(4-{2-[3-(1 -Methyl- 1 H-pyrazol-4-yl)-phenyl]-
161 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-acetamide ***
Trans-[4-(4-{2-[3-(1 -Methy 1-1 H-py razol-4-y l)-pheny I]-
162 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-morpholin-4-yl- ***
methanone
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid **
163
((R)-1-hydroxymethyl-2-methyl-propyl)-amide
Trans-4-(4-{2-[3-(1 -Methyl- 1 H-pyrazol-4-yl)-phenyl]-
164 pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid **
((R)-1-hydroxymethyl-2-methyl-propyl)-amide
[4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1-
165 (tetrahydro-pyran-4-yl)-1 H-pyrazol-3-yl]-methanol nd
Cis-3-Methoxy-N-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-y I)-
166 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]- **
propionamide
5-{1-[1-((3S,4S)-3-Fluoro-tetrahydro-pyran-4-yl)-piperidin-4-
167 yl]-1 H-pyrazol-4-yl}-2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]- **
pyrimidine
((R)-3-Methoxy-pyrrolidin-1-yl)-trans-[4-(4-{2-[3-(1-methyl-
168 1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ***
cyclohexyl]-methanone
4-Hydroxy-N-methyl-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
169 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-butyramide * Trans-4-(4-{2-[3-(1-Methy!-1 H-pyrazoI-4-yl)-phenyl]-
170 pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid ***
cyclopropylamide
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
171 pyrazol-1-yl)-cyclohexanecarboxylic acid (2-dimethylamino- ***
ethyl)-amide
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
172 pyrazol-1 -yl)-azepane ***
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid ***
173
isobutyl-amide
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
174 pyrazol-1-yl)-cyclohexanecarboxylic acid isopropylamide **
5-{1-[1-(2-Fluoro-phenyl)-piperidin-4-yl]-1 H-pyrazol-4-yl}-2-
175 [3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine **
5-[1-(1 ,1-Dioxo-hexahydro-1l6-thiopyran-4-yl)-1 H-pyrazol-4-
176 y l]-2-[3-(1 -methyl-1 H-pyrazol-4-y l)-pheny l]-py rimidine **
5-[1 -(1 , 1 -Dioxo-hexahydro-116-thiopy ran-3-y l)-1 H-pyrazol-4-
177 yl]-2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin ***
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
178 pyrazol-1-yl)-cyclohexanecarboxylic acid (2-methoxy-1- ***
methyl-ethyl)-amide
7-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
179 pyrazol-1 -yl)-3-oxa-9-aza-bicyclo[3.3.1 Jnonane *** cis-3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-pheny l]-py rimidin-
180 5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid methylamide ** trans-3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid **
181
methylamide
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
182 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanol ***
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((R)-1-piperidin-3-
183 yl-1 H-pyrazol-4-yl)-pyrimidine ** trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-pheny I]-
184 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (2- ***
hydroxy-ethyl)-amide
trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
185 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (2- ***
hydroxy-ethyl)-methyl-amide
((R)-3-Hydroxy-pyrrolidin-1-yl)-[4-(4-{2-[3-(1 -methyl-1 H-
186 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ***
cyclohexyl]-methanone
trans-4-(4-{2-[3-(6-Methyl-pyridazin-4-yl)-phenyl]-pyrimidin-
187 5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid ***
dimethylamide
trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
188 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (2- **
hydroxy-1-methyl-ethyl)-amide
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
189 pyrazol-1 -yl)-cyclohexanone **
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
190 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (3- ***
hydroxy-propyl -amide
Trans-((S)-3-Methoxy-pyrrolidin-1-yl)-[4-(4-{2-[3-(1-
191 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- ***
yl)-cyclohexyl]-methanone
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid tert-
192 ***
butylamide
exo-1 -[7-(4-{2-[3-(1 -Methyl-1 H-py razol-4-y l)-phenyl]-
193 pyrimidin-5-yl}-pyrazol-1-yl)-3-oxa-9-aza-bicyclo[3.3.1]non- **
9-yl]-ethanone
cis-cis-9-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
194 pyrimidin-5-yl}-pyrazol-1-yl)-3-oxa-bicyclo[3.3.1]nonane-7- *
carboxylic acid dimethylamide
3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
195 pyrazol-1-yl)-cyclohexanone **
Cis-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-phenyl]-py rimidin-
196 5-yl}-pyrazol-1-yl)-cyclohexanol **
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- ***
197 pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid
ethylamide Trans-4-(4-{2-[3-(1 -Methyl- 1 H-pyrazol-4-yl)-phenyl]- ***
198 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid
((S)-2-hydroxy-1-methyl-ethyl)-amide
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- ***
199 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid
((R)-2-hydroxy-1-methyl-ethyl)-amide
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]- ***
200 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid
isopropyl-methyl-amide
1 -[(3R,4R)-3-Hydroxy-4-(4-{2-[3-(1 -methyl-1 H-py razol-4-yl)-
201 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone **
(stereochemistry attributed arbitrarely)
1 -[(3S ,4S)-3-Hy droxy-4-(4-{2-[3-(1 -methyl- 1 H-pyrazo l-4-y I)-
202 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone **
(stereochemistry attributed arbitrarely)
trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
203 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (2- ***
hydroxy-butyl)-amide
4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
204 pyrazol-1-yl)-cyclohexanecarboxylic acid ethyl-methyl-amide *** trans-((S)-3-Hydroxy-pyrrolidin-1-yl)-[4-(4-{2-[3-(1-methyl-
205 1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ***
cyclohexylj-methanone
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-phenyl]-
206 pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid ***
amide
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1 -(tetrahydro-
207 thiopyran-3-yl)-1 H-pyrazol-4-yl]-pyrimidine ***
Trans-4-[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
208 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-morpholine *** cis-4-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
209 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-morpholine *
N-[2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
210 yl}-pyrazol-1-yl)-ethyl]-methanesulfonamide *
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
211 pyrazol-1 -y l)-cyclopentanol **
3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
212 pyrazol-1-yl)-propane-1 ,2-diol ** trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
213 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxyljc acid (2- ***
hydroxy-1 ,1-dimethyl-ethyl)-amide
3-lsopropoxy-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
214 pyrimidin-5-yl}-pyrazol-1-yl)-propan-1-ol *
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
215 pyrazol-1 -yl)-1-pyridin-2-yl-ethanol **
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-
216 thiophen-3-yl)-1 H-pyrazol-4-yl]-pyrimidine ** trans-5-{1 -[4-(2-Methoxy-ethoxy)-cyclohexyl]-1 H-pyrazol-4-
217 yl}-2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine *** cis-5-{1 -[4-(2-Methoxy-ethoxy)-cyclohexyl]-1 H-py razol-4-yl}-
218 2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine **
5-[1 -(1 ,1 -Dioxo-tetrahydro-1 lambda6-thiophen-3-yl)-1 H-
219 pyrazol-4-yl]-2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]- **
pyrimidine
trans-5-[1-(4-Cyclopropylmethoxy-cyclohexyl)-1 H-pyrazol-4-
220 yl]-2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine ***
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-
221 pyran-3-yl)-1 H-pyrazol-4-yl]-pyrimidine **
6-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
222 pyrazol-1-yl)-spiro[3.3]heptane-2-carboxylic acid **
dimethylamide
1 -[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-pheny l]-pyrimidin-5-
223 yl -pyrazol-1-yl)-azepan-1-yl]-ethanone ** trans-2-Methyl-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-
224 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyloxy]-propan- ***
2-ol
1-[(3S,4S)-3-Hydroxy-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
225 phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-piperidin-1-yl]-ethanone **
1 -[(3R,4R)-3-Hydroxy-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
226 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone **
(Stereochemistry attributed arbitrarely)
trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
227 pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid (2- ***
hydroxy-2-methyl-propyl)-amide trans-4-(4-{2-[3-(1 -Met yl-1 H-py razol-4-y l)-pheny I]-
228 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid (3- ***
hydroxy-butyl)-amide
Trans-4-(4-{2-[3-(2-Methyl-pyridin-4-yl)-phenyl]-pyrimidin-5-
229 yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide ** tra ns-4-(4-{2-[3-( 1 -Methyl-1 H-py razol-4-y l)-pheny I]-
230 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid ***
cyanomethyl-amide
(1 S,4R)-4-[4-[2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-5-
231 yl]pyrazol-1 -yl]cyclopent-2-en-1 -ol **
Trans-dimethyl-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
232 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexylmethyl]- ***
amine
Trans-4-{4-[2-(3-Pyridazin-4-yl-phenyl)-pyrimidin-5-yl]-
233 pyrazol-1-yl}-cyclohexanecarboxylic acid dimethylamide **
Trans-4-(4-{2-[3-(6-Chloro-pyridazin-3-yl)-phenyl]-pyrimidin-
234 5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid *
dimethylamide
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(Trans-1 -oxo-
235 tetrahydro-thiopyran-3-yl)-1 H-pyrazol-4-yl]-pyrimidine **
(racemate; isomery attributed arbitrarely)
2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-phenyl]-5-[1 -(Cis-1 -oxo-
236 tetrahydro-thiopyran-3-yl)-1H-pyrazol-4-yl]-pyrimidine ***
(racemate; isomery attributed arbitrarely)
Trans-4-(4-{2-[3-(6-Methyl-pyridazin-3-yl)-pheriyl]-pyrimidin-
237 5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid *
dimethylamide
Trans-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
238 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-methanol ***
Trans-4-(4-{2-[3-(6-Amino-pyridazin-3-yl)-phenyl]-pyrimidin-
239 5-yl}-pyrazol-1 -yl)-cyclohexanecarboxylic acid **
dimethylamide
5-(3-{5-[1 -((S)-1 , 1 -Dioxo-hexahydro-1 l6-thiopyran-3-y l)-1 H-
240 pyrazol-4-yl]-pyrimidin-2-yl}-phenyl)-3-methyl-pyr!dazine **
(stereochemistry attributed arbitrarely)
5-(3-{5-[1 -((R)-1 , 1 -Dioxo-hexahydro-1 l6-thiopyran-3-yl)-1 H-
241 pyrazol-4-yl]-pyrimidin-2-yl}-phenyl)-3-methyl-pyridazine **
(stereochemistry attributed arbitrarely)
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-phenyl]-
242 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid ***
(2,3-dihydroxy-propyl)-amide 5-[1-((2R,4R)-2-MethyI-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-
243 (1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine formic acid **
((3S,4S)-3,4-Dihydroxy-pyrrolidin-1-yl)-[4-(4-{2-[3-(1-methyl-
244 1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ***
cyclohexylj-methanone
(Trans-3-Hydroxy-4-methoxy-pyrrolidin-1-yl)-[4-Trans-(4-{2-
245 [3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- ***
pyrazol-1-yl)-cyclohexyl]-methanone
5-[1-((2S,4S)-2-Methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-
246 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine *** trans-4-(4-{2-[3-(6-Methyl-pyridazin-4-yl)-phenyl]-pyrimidin-
247 5-yl}-pyrazol-1-yl)-cyclohexanol **
1-[(2S,4S)-2-Methyl-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
248 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone ***
1-[(2R,4R)-2-Methyl-4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-
249 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone ** cis-8-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
250 5-yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-one (first isomer) ***
Cis-8-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
251 5-yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-one (second **
isomer)
Cis-5-[1-(4-Methoxy-cyclohexyl)-1 H-pyrazol-4-yl]-2-[3-(1-
252 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine *** trans- 5-[1-(4-Methoxy-cyclohexyl)-1 H-pyrazol-4-yl]-2-[3-(1-
253 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine ***
4-[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
254 yl}-pyrazol-1-yl)-cyclohexyl]-morpholin-3-one ***
;3-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
255 yl}-pyrazol-1-yl)-cyclohexyl]-oxazolidin-2-one **
Trans-[4-(4-{2-[3-(6-Methyl-pyridazin-4-yl)-phenyl]-pyrimidin-
256 5-yl}-pyrazol-1-yl)-cyclohexyl]-methanol ***
3-[cis-3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
257 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-oxazolidin-2-one *** Cis-1-Hydroxymethyl-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
258 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanol ***
5-[1-(3,3-Difluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-
259 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine ** trans-2-Methy l-8-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-2-aza-spiro[4.5]decan-
260 ***
3-one
((S)-2-Hydroxymethyl-morpholin-4-yl)-[4-((S)-4-{2-[3-(1-
261 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- ***
yl)-cyclohexyl]-methanone
cis-2-Methy l-8-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
262 pyrimidin-5-yl}-pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one ***
Cis-1 -[3-Fluoro-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-y I)-
263 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone ***
5-[1-(1 ,9-Dioxa-spiro[5.5]undec-4-yl)-1 H-pyrazol-4-yl]-2-[3-
264 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine ** cis-3-Fluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-
265 1 H-pyrazol-4-yl)-phenyl]-pyrimidine **
((R)-2-Hydroxymethyl-morpholin-4-yl)-[4-((S)-4-{2-[3-(1-
266 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1- ***
yl)-cyclohexyl]-methanone
5-[1-(1 ,9-Dioxa-spiro[5.5]undec-4-yl)-1 H-pyrazol-4-yl]-2-[3-
267 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine ***
5-[(R)-1-(1-Methanesulfonyl-piperidin-3-yl)-1 H-pyrazol-4-yl]-
268 2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine ***
1 -[3-((R)-4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
269 pyrimidin-5-yl}-pyrazol-1 -yl)-piperidin-1 -yl]-ethanone ***
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1 -[1-(tetrahydro-
270 pyran-3-yl)-piperidin-4-yl]- H-pyrazol-4-yl}^pyrimidine ***
4-[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
271 yl]-pyrazol-1-yl)-tetrahydro-pyran-3-ylmethyl]-morpholine * 5-[(R)-1-(1-Methanesulfonyl-piperidin-3-yl)-1 H-pyrazol-4-yl]-
272 2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine *** trans, cis-9-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
273 pyrimidin-5-yl}-pyrazol-1-yl)-3-oxa-bicyclo[3.3.1]nonane-7- **
carboxylic acid dimethylamide
1-[3-((R)-4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
274 pyrinnidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone ***
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1 -[1 -(3-methyl-
275 tetrahydro-pyran-4-yl)-piperidin-4-yl]-1 H-pyrazol-4-yl}- ***
pyrimidine
[9-(4-{2-[3-(1 -Methyl-1 H-py razol-4-yl)-phenyl]-py rimidin-5-
276 yl}-pyrazol-1-yl)-3-oxa-bicyclo[3.3.1]non-7-yl]-methanol **
Trans-2-[4-(-4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
277 pyrimidin-5-yl}-py razol-1 -yl)-cyclohexy loxy]-ethanol ***
(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-trans-[4-(-4-{2-
278 [3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- ***
pyrazol-1 -yl)-cyclohexyl]-methanone hydrobromide
5-[1 -(Cis-3-Methanesulfonyl-cyclohexyl)-1 H-pyrazol-4-yl]-2-
279 [3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (isomery ***
attributed arbitrarely)
(3aS,7aS)-7a-Hydroxymethyl-5-((R)-4-{2-[3-(1-methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ***
280
hexahydro-isobenzofuran-3a-ol (configuration attributed
arbitrarily)
(3aR>5R,7aR)-7a-Hydroxymethyl-5-(4-{2-[3-(1-methyl-1 H- **
281 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- hexahydro-isobenzofuran-3a-ol (configuration attributed
5-[1-(trans-3-Methanesulfonyl-cyclohexyl)-1 H-pyrazol-4-yl]-
282 2-[3-(1-methyi-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (isomery **
attributed arbitrarely)
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((S)-1-piperidin-3-
283 yl-1 H-pyrazol-4-yl)-pyrimidine ***
1 -[3,3-Difluoro-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
284 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone ***
1 -Methy l-8-(4-{2-[3-(1 -methyl-1 H-py razol-4-y l)-pheny I]-
285 pyrimidin-5-yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-one *** trans-8-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-
286 pyrimidin-5-yl}-pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one *** cis-8-(4-(2-(3-(1 -methyl-1 H-pyrazol-4-y l)pheny l)pyrimidin-5-
287 yl)-1 H-pyrazol-1-yl)-2-azaspiro[4.5]decan-3-one *** imino(methyl)(3-(4-(2-(3-(1 -methyl-1 H-pyrazol-4- l)phenyl)pyrimidin-5-yl)-1 H-pyrazol-1 -yl)cyclohexyl)-A6- ***
288 y
sulfanone
2-trans-[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
289 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexylamino]-ethano ***
Trans-3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-
290 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanol **
4-(3-Methyl-4-{2-[3-(1 -methyl-1 H-pyrazol-4-y l)-phenyl]-
291 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanol **
4-(4-{2-[2-Fluoro-5-(1 -methyl-1 H-pyrazo†-4-yl)-phenyl]-
292 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanol **
*: 1 μΜ < IC50 < 5 μΜ
**: 0.1 μΜ < IC50 < 1 μ
***: ICso < 0.1 μΜ
n.d: not determined
Example 293: Preparation of a pharmaceutical formulation
Formulation 1 - Tablets
A compound of formula (I) is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound according to the invention per tablet) in a tablet press.
Formulation 2 - Capsules
A compound of formula (I) is admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound according to the invention per capsule). Formulation 3 - Liquid
A compound of formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL. Formulation 4 - Tablets
A compound of formula (I) is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound according to the invention) in a tablet press.
Formulation 5 - Injection
A compound of formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.

Claims

Claims
1. A compound of Formula (I)
Figure imgf000227_0001
wherein
R denotes absent or denotes A or Q-Het,
Z denotes a group
Figure imgf000227_0002
wherein
X denotes O, S or N,
Y denotes C or N,
T denotes C or N, or
Z denotes a pyridine or a pyridazine group, Ra is absent or denotes OR3, CF3, Hal, N02,
Rb is absent or denotes one of the groups selected from A and COHet, denotes H, Het, Q-Het, Cyc, A or OA,
Het denotes a 4-9 membered monocyclic ring or a fused, spiro or bridged bicyclic ring, which is saturated, unsaturated, or aromatic, which contains 1 to 3 heteroatoms independently selected from N, O, S and a group CO, SO or S02, and wherein 1 or 2 H atoms may be replaced by A, OA, COA, CN, Hal, N02, OR3, SOA and/or S02A,
Cyc denotes a 4-8 saturated carbocyclic ring optionally containing a group SO, S02, CO, and optionally substituted once or twice by a group selected from CO(NR3)2, and COHet, OR3, Het1, A, CH2Het1, NH2, NHCOA, OCH2Cyc1, S02A and/or -SA(=NH)(=0),
Q denotes a linear or branched alkylene, having 1 to 6 carbon atoms wherein 1-5 H atoms may be replaced by a groupe independently selected from OR3, Hal, N(R3)2, and wherein 1 or 2 CH2 groups may be replaced by a group
independently selected from CO, SO, S02 and NR3, or Q denotes a 4-8- membered bivalent heterocyclic ring, which is saturated, unsaturated or aromatic and which contains 1 to 3 heteroatoms independently selected from N, O and S,
A denotes a linear or branched alkyl having 1 to 10 carbon atoms wherein 1 to 7 H atoms may be replaced by a group independently selected from -OR3, Hal, NHS02A, S02A, SOA, N(R3)2, and wherein 1 , 2 or 3 non-adjacent -CH2- groups may be replaced by a group independently selected from -CO-, NR3 and/or -0-,
Hal denotes F, CI, Br or I,
R3 denotes H or d-Ce-alkyl wherein 1 H atom may be replaced by a group selected from OH, O-d-Ce-alkyl, and Hal,
Het1 denotes a five- or six membered saturated monocyclic heterocycle which
contains 1-3 N- and/or O-atoms, which optionally is monosubstituted by A,
Cyc1 denotes cycloalkyl with 3-7 atoms,
and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios.
2. A compound of Formula (I) as defined in claim 1 wherein Z denotes one of the following groups:
Figure imgf000229_0001
3. A compound of Formula (I) according to claim 1 wherein the group Z-R1 denotes one of the following groups:
Figure imgf000229_0002
Figure imgf000230_0001
A compounds of Formula (I) according to claims 1 or 2 wherein R2 denotes of the following groups:
Figure imgf000230_0002
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
5. A compounds according to Formula (I), as defined in claims 1 to 4 wherein Rb is selected from one of the following groups:
Figure imgf000240_0001
A compound of Formula (I) according to claims 1 to 3 wherein the compound selected from the following group
Ex
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H-
1 pyrazol-4-yl)-pyrimidine hydrochloride
5-(1 -(piperidin-4-yl)-1 H-pyrazol-4-yl)-2-(3-(pyridin-3-
2 yl)phenyl)pyrimidine .hydrochloride
2-[3-(1-methyl-1 H-pyrazol-4-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrimidine
3
2,2,2-Trifluoro-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-pheny!]-
4 pyrimidin-5-yl}-pyrazol-1-yl)-p!peridin-1-yl]-ethanone
-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
5 pyrazol-1-yl)-piperidin-1-yl]-ethanone
5-[1-(1-Methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H-
6 pyrazol-4-yl)-phenyl]-pyrimidine
2-(3-Furan-3-yl-phenyl)-5-(1 -piperidin-4-yl-1 H-pyrazol-4-yl)-
7 pyrimidine Hydrochloride 4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 - yl)-acetic acid
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1 -y l)-1 -pyrrolidin-1 -y l-ethanone
4-[2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1 -y l)-ethy l]-morpholine
Dimethyl-[2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-ethyl]-amine
2-[3-(1 -Methy 1-1 H-pyrazol-4-y l)-pheny l]-5-[1 -(tetrahydro-f uran-3-yl)- 1 H-pyrazol-4-yl]-pyrimidine
2-(3-lsoxazol-4-yl-phenyi)-5-(1-piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidine hydrochloride
2-[3-(1 ,3-Dimethyl-l H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
2-[3-(1 ,5-Dimethyl- H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
2-{3-[1-(2-Fluoro-1-fluoromethyl-ethyl)-1 H-pyrazol-4-yl]-phenyl}-5-(1- piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
2-(4-{3-[5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]-phenyl}- pyrazol-1-yl)-1 -pyrrolidin-1 -yl-ethanone hydrochloride
5-(1 -Piperidin-4-yl-1 H-pyrazol-4-yl)-2-[3-(1 H-pyrazol-4-yl)-phenyl]- pyrimidine hydrochloride
5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-[3-(1-propyl-1 H-pyrazol-4-yl)- phenylj-pyrimidine hydrochloride
2-[3-(1 -lsopropyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 -piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
2-[3-(1 -Benzyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 -piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-pyridin-3-ylmethyl-1 H- pyrazol-4-yl)-pyrimidine 2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1-yl)-ethanol
2-[3-Fluoro-5-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl- 1 H-pyrazol-4-yl)-pyrimidine hydrochloride
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1 -y l)-1 -piperidin-1 -y l-ethanone
5-(1-Azetidin-3-yl-1 H-pyrazol-4-yl)-2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidine hydrochloride
5-[1 -(3-Methoxy-propy l)-1 H-py razol-4-yl]-2-[3-(1 -methyl-1 H-py razol- 4-yi)-phenyl]-pyrimidine
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(1-oxetan-3-yl-piperidin- 4-yl)-1 H-pyrazol-4-yl]-pyrimidine
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 -pi peridin-4-ylmethyl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride trans-5-[1 -(3-Fluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1 -methyl- 1 H-pyrazol-4-yl)-phenyl]-pyrimidine hydrochloride
1 ,1 ,1-Trifluoro-3-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-2-ol
5-(1-Methyl-1 H-pyrazol-4-yl)-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidine
5-(1-Piperidin-4-yl-1 H-pyrazol-4-yl)-2-(3-pyridin-4-yl-phenyl)- pyrimidine hydrochloride
3-(1 -Methyl-1 H-pyrazol-4-yl)-5-[5-(1 -piperidin-4-yl-1 H-pyrazol-4-yl)- pyrimidin-2-yl]-phenol Formate
1-Methoxy-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-propan-2-ol
1-Methoxy-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-propan-2-ol
2-(4-{2-[3-(3-Methyl-3H-imidazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone N,N-Dimethyl-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-acetamide
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1-[1-(tetrahydro-pyran-4- yl)-piperidin-4-yl]-1H-pyrazol-4-yl}-pyrimidine
1 -(3-Methoxy-azetidin-1-yl)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
2-(4-{2-[3-(1 -Methyl-1 H-yrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 - ylmethyl)-morpholine hydrochloride
2-[4-(2-{3-[1-(3-Amino-propyl)-1 H-pyrazol-4-yl]-phenyl}-pyrimidin-5- yl)-pyrazol-1 -yl]-1 -py rrolidin-1 -yl-ethanone hydrochloride
2-{4-[2-(3-Pyridin-4-yl-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-1- pyrrolidin-1 -yl-ethanone
1-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1-yl)-propan-2-one
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-furan-3- ylmethyl)-1H-pyrazol-4-yl]-pyrimidine
2-[3-(1 -Methy!-1 H-py razol-4-y l)-phenyl]-5-(1 -oxazol-2-ylmethy 1-1 H- pyrazol-4-yl)-pyrimidine
2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-phenyl]-5-[1 -(2-pyridin-2-y l-ethy l)-1 H- pyrazol-4-yl]-pyrimidine
2-[2-Fluoro-3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl- 1 H-pyrazol-4-yl)-pyrimidine Formate
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1-yl)-acetamide
2-[4-(2-{3-[1-(2-Amino-ethyl)-1 H-pyrazol-4-yl]-phenyl}-pyrimidin-5-yl)- pyrazol-1 -yl]-1 -py rrolidin-1 -yl-ethanone hydrochloride
1-(4-Methyl-piperazin-1-yl)-2-(4-{2-[3-(1 -methyl-1 H-py razol-4-yl)- phenyl]-pyrimidin-5-y!}-pyrazol-1-yl)-ethanone hydrochloride
1 -(3-Hydroxy-piperidin-1 -l)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-pyridin-4-yl-ethyl)-1 H- pyrazol-4-yl]-pyrimidine
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-y!}-pyrazol- 1-yl)-N-(tetrahydro-pyran-4-yl)-acetamide
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1-yl)-1-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethanone
2-(4-{2-[3-(2-Methyl-thiazol-5-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- 1-pyrrolidin-1-y!-ethanone
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-piperidin-1-yl-ethyl)- 1 H-pyrazol-4-yl]-pyrimidne
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(2-pyrrolidin-1-yl-ethyl)- 1 H-pyrazol-4-yl]-pyrimidine
2-[4-(2-{3-[1-(2-Hydroxy-ethyl)-1 H-pyrazol-4-yl]-phenyl}-pyrimidin-5- yl)-pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone
N-(1-Hydroxymethyl-propyl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-acetamide
(3-exo)-8-Methyl-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-8-aza-bicyclo[3.2.1]octane
4-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1-yl)-cyclohexanecarboxylic acid
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 H-pyrazol-4-yl)- pyrimidine
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1 -[2-(1-methyl-pyrrolidin- 2-yl)-ethyl]-1 H-pyrazol-4-yl}-pyrimidine
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-pyrrolidin-3-ylmethyl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
5-(1-Azetidin-3-ylmethyl-1 H-pyrazol-4-yl)-2-[3-(1 -methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrimidine hydrochloride
5-[1-(2,2-Difluoro-ethyl)-1 H-pyrazol-4-yl]-2-[3-(1 -methyl-1 H-pyrazol- 4-yl)-phenyl]-pyrimidine 1-Morpholin-4-yl-2-{4-[2-(3-pyridin-4-yl-phenyl)-pyrimidin-5-yl]- pyrazol-1 -yl}-ethanone
2-[3-(1-Methyl-1 H-pyrazol-4-yi)-phenyl]-5-{1-[2-(tetrahydro-pyran-4- yl)-ethyl]-1 H-pyrazol-4-yl}-pyrimidine
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1-(S)-1-pyrrolidin-2- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 -(R)-1 -pyrrolidin-2- ylmethyl-1 H-pyrazol-4-yl)-pyrimidine hydrochloride
2-[3-(1 -Methyl-1 H-[1 ,2,3]triazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1 H- pyrazol-4-yl)-pyrimidine hydrochloride
1-(3-Hydroxy-azetidin-1-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1-(3-Hydroxy-pyrrolidin-1-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1 -[2-(2-Hydroxy-ethyl)-morpholin-4-yl]-2-(4-{2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
5-[1-(1-Methanesulfonyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1- methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
1-Azetidin-1-yl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1-Morpholin-4-yl-2-{4-[2-(3-oxazol-5-yl-phenyl)-pyrimidin-5-yl]- pyrazol-1 -yi}-ethanone
1 -Morpholin-4-yi-2-(4-{2-[3-(1 H-[1 ,2,3]triazol-4-yl)-phenyl]-pyrimidin- 5-yl}-pyrazol-1 -y l)-ethanone
1-(2-Methyl-morpholin-4-yl)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)- phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1 -((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-2-(4-{2-[3-(1 -methyl-1 H- pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1-(4,4-dimethyloxazolidin-3-yl)-2-[4-[2-[3-(1-methylpyrazol-4- yl)phenyl]pyrimidin-5-yl]pyrazol-1-yl]ethanone N-(2-Hydroxy-1 ,1-dimethyl-ethyl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-
82a yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-acetamide
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yi}-pyrazol-
83 1 -yl)-1 -morpholin-4-yl-propan-1 -one
3-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
84 1 -yl)-1 -pyrrolidin-1 -yl-propan-1 -one
N,N-Dimethyl-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
85 pyrimidin-5-yl}-pyrazol-1-yl)-propionamide
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
86 1-yl)-1-(2-oxa-7-aza-spiro[3.5]non-7-yl)-ethanone
1-[2-(2-Methoxy-ethyl)-morp olin-4-yl]-2-(4-{2-[3-(1-methyl-1 H-
87 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1-(3-Methoxymethyl-piperidin-1-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-
88 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1 -[2-(2-methyl-pyridin-3-
89 yl)-ethyl]-1H-pyrazol-4-yl}-pyrimidine
1-(3-Methoxy-pyrrolidin-1-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-
90 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
N-Methyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
91 yl}-pyrazol-1-yl)-N-(tetrahydro-pyran-4-yl)-acetamide
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
92 1-yl)-1-(1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-ethanone
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
93 1-yl)-1-[1 ,4]oxazepan-4-yl-ethanone
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
94 1-yl)-1-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-ethanone Cis-5-{1-[1-(3-Fluoro-tetrahydro-pyran-4-yl)-piperidin-4-yl]-1 H-
95 pyrazol-4-yl}-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
5-{1-[2-(3,4-Dimethoxy-phenyl)-ethyl]-1 H-pyrazol-4-yl}-2-[3-(1-
96 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-pyran-4-yl)-
97 1 H-pyrazol-4-yl]-pyrimidine
5-[1 -(2-Methoxy-ethy l)-1 H-pyrazol-4-y l]-2-[3-(1 -methyl-1 H-pyrazol-4-
98 yl)-phenyl]-pyrimidine
N,N-Dimethyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
99 pyrimidin-5-yl}-pyrazol-1-yl)-propionamicle
1-(3-Methoxy-azetidin-1-yl)-3-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
100 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-propan-1-one
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrinnidin-5-yl}-pyrazol-
101 1-yl)-1-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propan-1-one
1-(4-Methyl-piperazin-1-yl)-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-
102 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-propan-1-one
2-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
103 1 -yl)-1 -morpholin-4-yl-propan-1 -one
[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
104 1-yl)-piperidin-1-yl]-(tetrahydro-furan-3-yl)-methanone
2-Methoxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
105 5-yl}-py razol-1 -yl)-piperidin-1 -yl]-ethanone
2-Hydroxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
106 5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone
[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
107 1-yl)-piperidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone
[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin- 5-yl}-pyrazol-
108 1-yl)-piperidin-1-yl]-(tetrahydro-pyran-2-yl)-methanone
3-Methoxy-1-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
109 5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-1-one (1 R,5S)-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
110 pyrazol-1-yl)-8-aza-bicyclo[3.2.1]octane
2-Ethoxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
111 5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone
5-{1-[1-(3-Ethoxy-2,2-dimethyl-cyclobutyl)-piperidin-4-yl]-1 H-pyrazol-
112 4-yl}-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
1-Methyl-4-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
113 yl}-pyrazol-1-yl)-piperidine-1-carbonyl]-pyrrolidin-2-one
3,3,3-Trifluoro-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
114 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-1-one
3,3,3-Trifluoro-2-hydroxy-1-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-
115 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-propan-1-one
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((R)-1-pyrrolidin-3-yl-1 H-
116 pyrazol-4-yl)-pyrimidine
3-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
117 pyrazoI-1-yl)-piperidine-1-carbonyl]-cyclobutanone
1 ,1 ,1-Trifluoro-3-[(1 R,5S)-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-
118 pheny l]-pyrimidin-5-y l}-py razol- -y l)-8-aza-bicyclo[3.2.1 ]oct-8-y I]- propan-2-ol
1 -[(1 R,5S)-3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
119 y l)-pyrazol-1 -yl)-8-aza-bicyclo[3.2.1 ]oct-8-yl]-ethanone
(3-Hydroxy-cyclobutyl)-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
120 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-methanone
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
121 1-yl)-cyclohexanecarboxylic acid dimethylamide
5-{1-[1-((S)-3-Methoxy-tetrahydro-pyran-4-yl)-piperidin-4-yl]-1 H-
122 pyrazo!-4-yl}-2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrinnidine
[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
123 1-yl)-piperidin-1-yl]-((S)-1-methyl-pyrrolidin-2-yl)-methanone
(S)-2-Amino-3-methyl-1 -[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
124 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-butan-1-one 2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((S)-1-pyrrolidin-3-yl-1 H-
125 pyrazol-4-yl)-pyrimidine
1-[(S)-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
126 pyrazol-1 -yl)-pyrrolidin-1 -y l]-ethanone
1-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-2-(4-{2-[3-(1 -methyl-1 H-
127 pyrazol-4-yl)-pheny!]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-2-(4-{2-[3-(1-methyl-1 H-
128 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
129 1 -yl)-dihydro-furan-2-one
1-[(R)-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-y])-phenyl]-pyrimidin-5-yl}- pyrazol-1 -y l)-py rrolidin-1 -yl]-ethanone
130
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1-[2-(tetrahydro-furan-3-
131 yl)-ethyl]-1H-pyrazol-4-yl}-pyrimidine
3-[2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-pheny!]-pyrimidin-5-yl}-
132 pyrazo!-1-yl)-ethyl]-dihydro-furan-2-one
9-lsopropyl-3-(4-{2-[3-(1-methyl-1 H-pyrazo!-4-yl)-phenyl]-pyrimidin-5-
133 yl -pyrazol-1-yl)-9-aza-bicyclo[3.3.1]nonane
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
134 pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide
Cis-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
135 pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide
4-(3-{5-[1-(Tetrahydro-pyran-4-yl)-1 H-pyrazol-4-yl]-pyrimidin-2-yl}-
136 phenyl)-pyridin-2-ylamine
4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1 -
137 (tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid amide
3-Methyl-5-(3-{5-[1-(tetrahydro-pyran-4-yl)-1 H-pyrazol-4-yl]-
138 pyrimidin-2-yl}-phenyl)-pyridazine 2-[3-(2-Methyl-pyridin-4-yl)-phenyl]-5-[1-(tetrahydro-pyran-4-yl)-1 H-
139 pyrazol-4-yl]-pyrimidine
4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1 -
140 (tetrahydro-pyran-4-yl)-1 H-pyrazole-3-carboxylic acid
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-(1 -oxetan-3-yl-1 H-pyrazol-
141 4-yl)-pyrimidine
Exo-9-Methyl-3-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
142 5-yl}-pyrazol-1-yl)-9-aza-bicyclo[3.3.1]nonane
Trans- 4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
143 pyrazol-1-yl)-cyclohexanecarboxylic acid methylamide
1 -Methyl-4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl>-
144 1 H-pyrazole-3-carboxylic acid methylamide
N-Methyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
145 yl}-pyrazol-1-yl)-N-oxetan-3-yl-acetamide
1-(3-Methoxymethyl-morpholin-4-yl)-2-(4-{2-[3-(1-methyl-1 H-pyrazol-
146 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone
1 -(3-Methyl-morpholin-4-yl)-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-
147 phenyl]-pyrimidin-5-yl)~pyrazol-1-yl)-ethanone
1-((1 R,4R)-5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-(4-{2-[3-(1-
148 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- ethanone
N,N-Dimethyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
149 pyrimidin-5-yl}-pyrazol-1-yl)-isobutyramide
2-Methyl-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
150 yl}-pyrazol-1-yl)-1-morpholin-4-yl-propan-1-one
[4-(3-{5-[1-(Tetrahydro-pyran-4-yl)-1 H-pyrazol-4-yl]-pyrimidin-2-yl}-
151 phenyl)-pyridin-2-yl]-methanol
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
152 pyrazol-1 -yl)-cyclohexanecarboxylic acid (2-methoxy-ethyl)-methyl- amide
(3-Hydroxy-azetidin-1 -yl)-[4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
153 pyrimidin-5-yl}-1-(tetrahydro-pyran-4-yl)- H-pyrazol-3-yl]-methanone 4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1-
154 (tetrahydro-pyran-4-yl)-1 H-pyrazole-3-carboxylic acid (2-hydroxy- ethyl)-amide
(1-Methyl-4-{2-[3-(1-methy!-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
155 1 H-pyrazol-3-yl)-methanol
4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
156 1 -yl)-cyclohexylamine
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
157 1-yl)-cyclobutanecarboxylic acid methylamide
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
158 1-yl)-cyclobutanecarboxylic acid dimethy!amide
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
159 pyrazol-1-yl)-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide
Trans-(4-Methyl-piperazin-1-yl)-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-
160 yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-methanone
Cis-N-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
161 pyrazol-1-yl)-cyclohexyl]-acetamide
Trans-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
162 pyrazol-1-yl)-cyclohexyl]-morpholin-4-yl-methanone
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
163 pyrazol-1-yl)-cyclohexanecarboxylic acid ((R)-1-hydroxymethyl-2- methyl-propyl)-amide
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
164 pyrazol-1-yl)-cyclohexanecarboxylic acid ((R)-1-hydroxymethyl-2- methyl-propyl)-amide
[4-{2-[3-(1-Methyi-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-1-
165 (tetrahydro-pyran-4-yl)-1 H-pyrazol-3-yl]-methanol
Cis-3-Methoxy-N-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
166 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-propionamide
5-{1-[1-((3S,4S)-3-Fluoro-tetrahydro-pyran-4-yl)-piperidin-4-yl]-1 H-
167 pyrazol-4-yl}-2-[3-(1-methyl-1 l-l-pyrazol-4-yl)-phenyl]-pyrimidine
((R)-3-Methoxy-pyrrolidin-1 -yl)-trans-[4-(4-{2-[3-(1 -methyl-1 H-
168 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]- methanone 4-Hydroxy-N-methyl-2-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
169 pyrimidin-5-yl}-pyrazol-1 -yl)-butyramide
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
170 pyrazol-1-yl)-cyclohexanecarboxylic acid cyclopropylamide
4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-pheny!]-pyrimidin-5-yl}-pyrazol-
171 1-yl)-cyclohexanecarboxylic acid (2-dimethylamino-ethyl)-amide
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
172 1-yl)-azepane
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
173 pyrazol-1 -yl)-cyclohexanecarboxylic acid isobutyl-amide
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
174 1-yl)-cyclohexanecarboxylic acid isopropylamide
5-{1-[1-(2-Fluoro-phenyl)-piperidin-4-yl]-1 H-pyrazol-4-yl}-2-[3-(1-
175 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
5-[1 -(1 , 1 -Dioxo-hexahydro-1 l6-thiopyran-4-y l)-1 H-pyrazol-4-yl]-2-[3-
176 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
5-[1-(1 ,1 -Dioxo-hexahydro-1 l6-thiopyran-3-yl)-1 H-pyrazol-4-yl]-2-[3-
177 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin
4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyi]-pyrimidin-5-yl}-pyrazol-
178 1-yl)-cyclohexanecarboxylic acid (2-methoxy-1 -methyl-ethyl)-amide
7-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
179 1 -y l)-3-oxa-9-aza-bicyclo[3.3.1 Jnonane cis-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
180 pyrazol-1 -yl)-cyclohexanecarboxylic acid methylamide trans-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
181 pyrazol-1 -yl)-cyclohexanecarboxylic acid methylamide
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
182 pyrazol-1 -yl)-cyclohexanol
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((R)-1-piperidin-3-yl-1 H-
183 pyrazol-4-yl)-pyrimidine trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
184 pyrazol-1-yl)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-amide trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
185 pyrazol-1 -yl)-cyclohexanecarboxylic acid (2-hydroxy-ethyl)-methy I- amide
((R)-3-Hydroxy-pyrrolidin-1-yl)-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-
186 phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-methanone trans-4-(4-{2-[3-(6-Methyl-pyridazin-4-yl)-phenyl]-pyrimidin-5-yl}-
187 pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
188 pyrazol-1 -yl)-cyclohexanecarboxylic acid (2-hydroxy-1 -methy l-ethyl)- amide
4-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
189 1 -y l)-cyclohexanone
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
190 pyrazol-1-yl)-cyclohexanecarboxylic acid (3-hydroxy-propyl)-amide
Trans-((S)-3-Methoxy-pyrrolidin-1-yl)-[4-(4-{2-[3-(1-methyl-
191 1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]- methanone
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
192 pyrazol-1-yl)-cyclohexanecarboxylic acid tert-butylamide exo-1-[7-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
193 pyrazol-1-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-9-yl]-ethanone cis-cis-9-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
194 pyrazol-1-yl)-3-oxa-bicyclo[3.3.1]nonane-7-carboxylic acid
dimethylamide
3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
195 1 -y l)-cyclohexanone
Cis-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
196 pyrazol-1-yl)-cyclohexanol
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
197 pyrazol-1-yl)-cyclohexanecarboxylic acid ethylamide
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
198 pyrazol-1-yl)-cyclohexanecarboxylic acid ((S)-2-hydroxy-1 -methy I- ethyl)-amide Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
199 pyrazol-1-yl)-cyclohexanecarboxylic acid ((R)-2-hydroxy-1-methyl- ethyl)-amide
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
200 pyrazol-1-yl)-cyclohexanecarboxylic acid isopropyl-methyl-amide
1-[(3R,4R)-3-Hydroxy-4-(4-{2-[3-(1-methyl-1 H-pyrazo!-4-yl)-phenyl]-
201 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone
(stereochemistry attributed arbitrarely)
1 -[(3S,4S)-3-Hydroxy-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
202 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone
(stereochemistry attributed arbitrarely)
trans-4-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
203 pyrazol-1 -yl)-cyclohexanecarboxylic acid (2-hydroxy-butyl)-amide
4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidi n-5-yl}-py razol-
204 1-yl)-cyclohexanecarboxylic acid ethyl-methyl-amide trans-((S)-3-Hydroxy-pyrrolidin-1 -yl)-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-
205 4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]-methanone
Trans-4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
206 pyrazol-1-yl)-cyclohexanecarboxylic acid amide
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-thiopyran-3-
207 yl)-1 H-pyrazol-4-yl]-pyrimidine
Trans-4-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
208 yl}-pyrazol-1-yl)-cyclohexyl]-morpholine cis-4-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
209 pyrazol-1-yl)-cyclohexyl]-morpholine
N-[2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
210 pyrazol-1-yl)-ethyl]-methanesulfonamide
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
211 1-yl)-cyclopentanol
3-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
212 1-yl)-propane-1 ,2-diol trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
213 pyrazol-1-yl)-cyclohexanecarboxylic acid (2-hydroxy-1 ,1-dimethyl- ethyl)-amide 3-lsopropoxy-2-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-
214 5-ylJ-pyrazol-1-yl)-propan-1-ol
2-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
215 1 -yl)-1 -pyridin-2-y l-ethanol
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1-(tetrahydro-thiophen-3-
216 yl)-1 H-pyrazol-4-ylj-pyrimidine trans-5-{1-[4-(2-Methoxy-ethoxy)-cyclohexyl]-1 H-pyrazol-4-yl}-2-[3-
217 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine cis-5-{1 -[4-(2-Methoxy-ethoxy)-cyclohexyl]-1 H-pyrazol-4-yl}-2-[3-(1 -
218 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
5-[1-(1 ,1-Dioxo-tetrahydro-1 lambda6-thiophen-3-yl)-1 H-pyrazol-4-yl]-
219 2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine trans-5-[1-(4-Cyclopropylmethoxy-cyclohexyl)-1 H-pyrazol-4-yl]-2-[3-
220 (1 -methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1 -(tetrahydro-pyran-3-yl)-
221 1 H-pyrazol-4-yl]-pyrimidine
6-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-
222 1-yl)-spiro[3.3]heptane-2-carboxylic acid dimethylamide
1 -[4-(4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
223 pyrazol-1-yl)-azepan-1-yl]-ethanone trans-2-Methyl-1-[4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
224 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyloxy]-propan-2-ol
1 -[(3S,4S)-3-Hydroxy-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-y l)-pheny I]-
225 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone
1 -[(3R,4R)-3-Hydroxy-4-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-
226 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone
(Stereochemistry attributed arbitrarely)
trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
227 pyrazol-1-yl)-cyclohexanecarboxylic acid (2-hydroxy-2-methyl- propyl)-amide
trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
228 pyrazol-1-yl)-cyclohexanecarboxylic acid (3-hydroxy-butyl)-amide Trans-4-(4-{2-[3-(2-Methyl-pyridin-4-yl)-phenyl]-pyriiTiiclin-5-yl}-
229 pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
230 pyrazol-1-yl)-cyclohexanecarboxylic acid cyanomethyl-amide
(1 S,4R)-4-[4-[2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-5-
231 yl]pyrazol-1-yl]cyclopent-2-en-1-ol
Trans-dimethyl-[4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
232 pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexylmethyl]-amine
Trans-4-{4-[2-(3-Pyridazin-4-yl-phenyl)-pyrimidin-5-yl]-pyrazol-1-yl}-
233 cyclohexanecarboxylic acid dimethylamide
Trans-4-(4-{2-[3-(6-Chloro-pyridazin-3-yl)-phenyl]-pyrimidin-5-yl}-
234 pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide
2-[3-(1 -Methyl-1 H-pyrazol-4-y l)-pheny l]-5-[1 -(Trans-1 -oxo-tetrahydro-
235 thiopyran-3-yl)-1 H-pyrazol-4-yl]-pyrimidine (racemate; isomery
attributed arbitrarely)
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-[1 -(Cis-1-oxo-tetrahydro-
236 thiopyran-3-yl)-1 H-pyrazol-4-yl]-pyrimidine (racemate; isomery
attributed arbitrarely)
Trans-4-(4-{2-[3-(6-Methyl-pyridazin-3-yl)-phenyl]-pyrimidin-5-yl}-
237 pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide
Trans-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
238 pyrazol-1-yl)-cyclohexyl]-methanol
Trans-4-(4-{2-[3-(6-Amino-pyridazin-3-yl)-phenyl]-pyrimidin-5-yl}-
239 pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide
5-(3-{5-[1-((S)-1 ,1-Dioxo-hexahydro-1 l6-thiopyran-3-yl)-1H-pyrazol-4-
240 yl]-pyrimidin-2-yl}-phenyl)-3-methyl-pyridazine (stereochemistry
attributed arbitrarely)
5-(3-{5-[1 -((R)-1 , 1 -Dioxo-hexahydro-116-thiopy ran-3-yl)-1 H-pyrazol-
241 4-yl]-pyrimidin-2-yl}-phenyl)-3-methyl-pyridazine (stereochemistry attributed arbitrarely)
Trans-4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
242 pyrazol-1 -yl)-cyclohexanecarboxylic acid (2,3-dihydroxy-propyl)- amide
5-[1-((2R,4R)-2-Methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-
243 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine formic acid ((3S,4S)-3,4-Dihydroxy-pyrrolidin-1 -yl)-[4-(4-{2-[3-(1-methyl-1 H-
244 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]- methanone
(Trans-3-Hydroxy-4-methoxy-pyrrolidin-1-yl)-[4-Trans-(4-{2-[3-(1 -
245 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- cyclohexyl]-methanone
5-[1-((2S,4S)-2-Methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1 -
246 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine trans-4-(4-{2-[3-(6-Methyl-pyridazin-4-yl)-phenyl]-pyrimidin-5-yl}-
247 pyrazol-1-yl)-cyclohexanol
1 -[(2S,4S)-2-Methyl-4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
248 pyrimidin-5-yl}-pyrazol-1 -yl)-piperidin-1-yl]-ethanone
1-[(2R,4R)-2-Methyl-4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
249 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone cis-8-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
250 pyrazol-1 -yl)-1-aza-spiro[4.5]decan-2-one (first isomer)
Cis-8-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
251 pyrazol-1 -yl)-1-aza-spiro[4.5]decan-2-one (second isomer)
Cis-5-[1-(4-Methoxy-cyclohexyl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H-
252 pyrazol-4-yl)-phenyl]-pyrimidine trans-5-[1 -(4-Methoxy-cyclohexyl)-1 H-pyrazol-4-yl]-2-[3-(1 -methy I-
253 1 H-pyrazol-4-yl)-phenyl]-pyrimidine
4-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
254 pyrazol-1-yl)-cyclohexyl]-morpholin-3-one
;3-[4-(4-{2-[3-(1- ethyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
255 pyrazol-1 -yl)-cyclohexyl]-oxazolidin-2-one
Trans-[4-(4-{2-[3-(6-Methyl-pyridazin-4-yl)-phenyl]-pyrimidin-5-yl}-
256 pyrazol-1 -yl)-cyclohexyl]-methanol
3-[cis-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
257 pyrazol-1-yl)-cyclohexyl]-oxazolidin-2-one
Cis-1-Hydroxymethyl-4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-
258 pyrimidin-5-yl}-pyrazol-1 -yl)-cyclohexanol 5-[1-(3,3-Difluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-1 H-
259 pyrazol-4-yl)-phenyl]-pyrimidine trans-2-Methyl-8-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyi]-
260 pyrimidin-5-yl}-pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one
((S)-2-Hydroxymethyl-morpholin-4-yl)-[4-((S)-4-{2-[3-(1-methyl-1 H-
261 pyrazol-4-yl)-phenylj-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]- methanone
cis-2-Methyl-8-(4-{2-[3-(1-methyl-1 H-pyrazoi-4-yl)-phenyl]-pyrimidin-
262 5-yl}-pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one
Cis-1-[3-Fluoro-4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-p enyl]-
263 pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1-yl]-ethanone
5-[1-(1 ,9-Dioxa-spiro[5.5]undec-4-yl)-1 H-pyrazol-4-y!]-2-[3-(1-methyl-
264 1 H-pyrazol-4-yl)-phenyl]-pyrimidine cis-3-Fluoro-piperidin-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1 -methyl- 1 H-
265 pyrazol-4-yl)-phenyl]-pyrimidine
((R)-2-Hydroxymethyl-morpholin-4-yl)-[4-((S)-4-{2-[3-(1-methyl-1 H-
266 pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexyl]- methanone
5-[1-(1 ,9-Dioxa-spiro[5.5]undec-4-yl)-1 H-pyrazol-4-yl]-2-[3-(1-methyl-
267 1 H-pyrazol-4-yl)-phenyl]-pyrimidine
5-[(R)-1-(1-Methanesulfonyl-piperidin-3-yl)-1 H-pyrazol-4-yl]-2-[3-(1-
268 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine
1-[3-((R)-4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
269 pyrazol-1-yl)-piperidin-1-yl]-ethanone
2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1-[1-(tetrahydro-pyran-3-
270 yl)-piperidin-4-yl]-1 H-pyrazol-4-yl}-pyrimidine
^^-.(^-[S-CI-Methyl-I H-pyrazol^-y -pheny -pyrimidin-S-yl}-
271 pyrazol-1-yl)-tetrahydro-pyran-3-ylmethyl]-morpholine
5-[(R)-1-(1- ethanesulfonyl-piperidin-3-yl)-1 H-pyrazol-4-yl]-2-[3-(1 -
272 methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine trans, cis-9-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
273 yl}-pyrazol-1-yl)-3-oxa-bicyclo[3.3.1]nonane-7-carboxylic acid
dimethylamide 1 -[3-((R)-4-{2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1 -yl)-piperidin-1-yl]-ethanone
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-{1 -[1 -(3-methyl-tetrahydro- pyran-4-yl)-piperidin-4-yl]-1 H-pyrazol-4-yl}-pyrimidine
[9-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol- 1 -yl)-3-oxa-bicyclo[3:3.1 ]non-7-yl]-methanol
Trans-2-[4-(-4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-cyclohexyloxy]-ethanol
(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-trans-[4-(-4-{2-[3-(1- methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)- cyclohexyl]-methanone hydrobromide
5-[1-(Cis-3-Methanesulfonyl-cyclohexyl)-1 H-pyrazol-4-yl]-2-[3-(1 - methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (isomery attributed arbitrarely)
(3aS,7aS)-7a-Hydroxymethyl-5-((R)-4-{2-[3-(1-methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-hexahydro-isobenzofuran-3a- ol (configuration attributed arbitrarily)
(3aR,5R,7aR)-7a-Hydroxymethyl-5-(4-{2-[3-(1-methyl-1 H-pyrazol-4- yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1 -yl)-hexahydro-isobenzofuran-3a- ol (configuration attributed arbitrarily)
5-[1-(trans-3-Methanesulfonyl-cyclohexyl)-1 H-pyrazol-4-yl]-2-[3-(1 - methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidine (isomery attributed arbitrarely)
2-[3-(1 -Methyl-1 H-pyrazol-4-yl)-phenyl]-5-((S)-1-piperidin-3-yl-1 H- pyrazol-4-yl)-pyrimidine
1-[3,3-Difluoro-4-(4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]- pyrimidin-5-yl}-pyrazol-1-yl)-piperidin-1 -yl]-ethanone
1 -Methy l-8-(4-{2-[3-(1 -methyl-1 H-pyrazol-4-y l)-phenyl]-pyrimidin-5- yl}-pyrazol-1-yl)-1-aza-spiro[4.5]decan-2-one trans-8-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}- pyrazol-1-yl)-2-aza-spiro[4.5]decan-3-one cis-8-(4-(2-(3-(1-methyl-1 H-pyrazol-4-yl)phenyl)pyrimidin-5-yl)-1 H- pyrazol-1 -yl)-2-azaspiro[4.5]decan-3-one imino(methyl)(3-(4-(2-(3-(1 -methyl-1 H-pyrazol-4-yl)phenyl)pyrimidin- 5-yl)-1 H-pyrazol-1-yl)cyclohexyl)-A6-sulfanone 2-trans-[4-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
289 pyrazol-1-yl)-cyclohexylamino]-ethano
Trans-3-(4-{2-[3-(1-Methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-
290 pyrazol-1-yl)-cyclohexanol
4-(3-Methyl-4-{2-[3-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-pyrimidin-5-
291 yl}-pyrazol-1 -yl)-cyclohexanol
4-(4-{2-[2-Fluoro-5-(1-methyl-1 H-pyrazol-4-yt)-phenyl]-pyrimidin-5-
292 yl}-pyrazol-1 -yl)-cyclohexanol
7. A compound of Formula (I) as defined in claims 1 to 6 and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios, for use as a medicament.
8. A compound according to claim 1 for use in the treatment or prevention of inflammatory disease, autoimmune disorder, cancer or multiple sclerosis and related disorders.
9. A compound according to claim 8 wherein the autoimmune disease is selected from the group consisting of Asthma, Rheumatoid arthritis, Acute disseminated encephalomyelitis (ADEM), Addison's disease, Alopecia areata, Ankylosing spondylitis, Antiphospholipid antibody syndrome (APS), Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Bullous pemphigoid, Behcet's disease, Coeliac disease, Anti-transglutaminase, Chagas disease, Chronic obstructive pulmonary disease, Crohns Disease, Dermatomyositis, Diabetes mellitus type 1 , Endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, Hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, Idiopathic thrombocytopenic purpura, Interstitial cystitis, Lupus erythematosus, Mixed Connective Tissue Disease, Morphea, Multiple sclerosis (MS), Myasthenia gravis, Narcolepsy, Neuromyotonia, Pemphigus vulgaris, Pernicious anaemia, Psoriasis, Psoriatic Arthritis, Polymyositis, Primary biliary cirrhosis, Rheumatoid arthritis, Schizophrenia, Scleroderma, Sjogren's syndrome, Stiff person syndrome, Systemic sclerosis, Temporal arteritis, Ulcerative Colitis, Vasculitis, Vitiligo, Wegener's granulomatosis
10. A compound of claim 8 wherein the disease is selected from rheumathoid arthritis, lupus nephritis, systemic lupus erythematosus.
11. A compound of Formula (I) according to claim 1 for the prevention and/or treatment of the diseases associated to IRAK overexpression.
12. A kit consisting of separate packs of :
(a) an effective amount of a compound of the formula (I) and/or pharmaceutically usable derivatives, solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios, and
(b) an effective amount of a further medicament active ingredient.
13. A Pharmaceutical compositions containing at least one of the compounds of Formula (I) according to any one of claims 1 to 6.
14. A pharmaceutical composition according to claim 13 which additionally contains at least one further medicament used in the treatment of inflammatory diseases or immune disorders or immunomodulating agent.
15. A process for producing compounds of Formula (I) according to claims 1 to 6, comprising the step of reacting a compound of Formula (II)
Figure imgf000261_0001
(I")
Wherein X denotes Hal or a triflate group and wherein R1, Ra and Z are as defined in claim 1 , With a compound of Formula (III)
Figure imgf000262_0001
(III)
Wherein R is H or a d-Cg-alkyl group, and wherein Rb and R2 are as defined in claim 1.
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