HK1210778B - Pyrimidine pyrazolyl derivatives - Google Patents

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 associated with IRAK overexpression such as rheumatoid arthritis, systemic lupus erythematosus or lupus nephritis.

Background

Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play a key role in all aspects of eukaryotic cell physiology.

In particular, protein kinases and lipid kinases are involved in signaling events that control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. Generally, protein kinases are divided into two groups: one group preferentially phosphorylates tyrosine residues and the other group preferentially phosphorylates 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), such as kinases involved in the control of adaptive and innate immune responses (organization). Kinase targets of particular interest are members of the IRAK family.

Interleukin-1 receptor-associated kinase (IRAK) is critically involved in the regulation of intracellular signaling networks that control inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7). IRAK is expressed in many cell types and can mediate signaling from a variety of cellular receptors including toll-like receptors (TLRs). IRAK4 is believed to be an initial protein kinase that is activated downstream of interleukin-1 (IL-1) receptors and all toll-like receptors (TLRs) except TLR3, and triggers a signal in the innate immune system via rapid activation of IRAK1 and slow activation of IRAK 2. IRAK1 was originally identified by biochemical purification of IL-1 dependent kinase activity co-immunoprecipitated with IL-11 type receptors (Cao et al, 1996. Science 271(5252): 1128-31). IRAK2 was identified by searching for sequences homologous to IRAK1 in the human Expressed Sequence Tag (EST) database (Muzio et al, 1997. Science 278(5343): 1612-5). IRAK3 (also known as IRAKM) was identified using murine EST sequences encoding polypeptides significantly homologous to IRAK1 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 search of IRAK-like sequences and PCR universal cDNA libraries (Li et al, 2002. Proc. Natl. Acad. Sci. USA 99 (8): 5567-.

Mice expressing catalytically inactive mutants of IRAK4, but not the wild-type kinase, were completely resistant to septic shock triggered by several TLR agonists and were compromised in their response to IL-1. Children lacking IRAK4 activity due to genetic defects suffer from repeated infections caused by pyogenic bacteria. IRAK-dependent TLRs and IL-1R appear to be extremely important for immunity in children against some pyogenic bacteria, but play a redundant role in protective immunity in adults against most infections. Therefore, IRAK4 inhibitors may be used to treat 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). Effective IRAK4 inhibitors have been developed (Buckley et al, 2008. Bioorg Med Chem Lett. 18 (12): 3656-60). IRAK1 is essential for TLR 7-mediated and TLR 9-mediated activation of IRF7 and production of interferon-alpha (IFN- α), suggesting that IRAK1 inhibitors may be useful in the treatment of Systemic Lupus Erythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays a role in pro-inflammatory cytokine production. Therefore, IRAK2 inhibitors may be useful in inflammatory diseases.

Summary of The Invention

According to one aspect of the invention, there is provided a compound of formula (I).

According to another aspect of the present invention there is provided a compound of formula (I) which is suitable for the treatment and/or prevention of IRAK-related disorders.

According to another aspect of the present invention there is provided a compound capable of modulating, in particular inhibiting, the activity or function of IRAK in a disease state in a mammal, in particular in a human.

According to another aspect of the present invention, there is provided a method of treating and/or preventing a condition selected from the group consisting of: autoimmune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multi-organ injury, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases, and ischemic conditions.

According to another aspect, the present invention provides compounds of formula (I) which are selective for IRAK-4 and/or IRAK-1 over other isoforms.

According to another aspect of the invention, there is provided a kit or kit comprising at least one compound of formula (I), preferably in combination with an immunomodulator. Preferably the kit consists of the following separate packets:

(a) an effective amount of said compound of formula (I) and/or pharmaceutically useful derivatives, solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios, and

(b) an effective amount of another pharmaceutically active ingredient.

According to another aspect of the invention, methods of synthesizing compounds of formula (I) and related formulae are provided.

Detailed Description

In one embodiment, the present invention provides a compound of formula (I),

wherein:

R¹represents the absence or represents A or Q-Het,

z represents a group:，

wherein:

x represents O, S or N, and X represents O, S or N,

y represents C or N, and Y represents C or N,

t represents C or N, or

Z represents a pyridine or pyridazine group,

R^ais absent OR represents OR³、CF₃、Hal、NO₂，

R^bAbsent or represents one of the groups selected from A and COhet,

R²represents H, Het, Q-Het, Cyc, A or OA,

het represents a 4-9 membered monocyclic ring or a fused, spiro or bridged bicyclic ring which is saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O, S and the groups CO, SO or SO₂And wherein 1 or 2H atoms may be replaced by A, OA, COA, CN, Hal, NO₂、OR³SOA and/or SO₂The substitution of A is carried out, and the substitution of A,

cyc denotes a 4-to 8-membered saturated carbocyclic ring which optionally contains the groups SO, SO₂CO and optionally selected from CO (NR)³)₂And COhet, OR³、Het¹、A、CH₂Het¹、NH₂、NHCOA、OCH₂Cyc¹、SO₂The group of a and/or-SA (= NH) (= O) is substituted once or twice,

q represents a linear or branched alkylene group having 1 to 6 carbon atomsWherein 1-5H atoms can be independently selected from OR³、Hal、N(R³)₂And wherein 1 or 2 CH₂The radicals may be independently selected from CO, SO₂And NR³Or Q represents a 4-8 membered divalent heterocyclic ring which is saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O and S,

a represents a linear OR branched alkyl group having 1 to 10 carbon atoms, wherein 1 to 7H atoms may be independently selected from-OR³、Hal、NHSO₂A、SO₂A、SOA、N(R³)₂And wherein 1,2 or 3 are not adjacent-CH₂The radicals-may be independently selected from-CO-, NR³And/or a group replacement of-O-,

hal represents F, Cl, Br or I,

R³represents H or C₁-C₆Alkyl, in which 1H atom may be chosen from OH, O-C₁-C₆-a radical replacement of alkyl and Hal,

Het¹represents a 5-or 6-membered saturated monocyclic heterocycle which contains 1 to 3N-and/or O-atoms and which is optionally mono-substituted by A,

Cyc¹represents a cycloalkyl group having 3 to 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, for example in CO (NR)³)₂R in (1)³It may independently take any of the values given in the respective definitions.

In the compounds of formula (I) and related formulae, Z may represent a groupWherein X is O, S or N and T is C orN。

Alternatively, Z is selected from the following specific groups:

。

z in formula (I) and related formulae preferably represents a group selected from pyridazine, pyrazole and 4-pyridine.

R in formula (I) and related formulae¹Preferably represents a straight-chain or branched C₁-C₆-an alkyl group.

Or, the group Z-R in formula (I) and related formulae¹Selected from the following groups:

in a particular embodiment, the radicals R in the formula (I) and the related formulae²Represents piperidine or the group Cyc as defined above.

Or, the radicals R in the formula (I) and the related formulae²Preferably selected from the following groups:

the group R in formula (I) and related formulae^bPreferably represents H.

Alternatively, R^bMay represent a C group selected from COhet or linear or branched₁-C₆-alkyl radicals in which 1H atom may be chosen from NR³OR OR³And wherein 1 CH₂The group may be replaced by a group CO.

More specifically, R in formula (I) and related formulae^bMay be selected from the following groups:

het in formula (I) and related formulae preferably represents a saturated 4-6 membered monocyclic ring containing 1 heteroatom selected from nitrogen, wherein 1H atom may be selected from COC₁-C₆Radical replacement of alkyl and oxacyclohexane.

Alternatively, Het in formula (I) and related formulae represents a 4-9 membered spiro or bridged bicyclic ring containing 1-2 heteroatoms selected from nitrogen and oxygen and optionally mono-substituted by a group A.

More preferably Het represents a piperidine group wherein 1 or 2H atoms may independently be selected from A, OA, COA, CN, Hal, NO₂、OR³SOA and SO₂Group replacement of A.

Cyc¹Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The compounds of the present invention also include compounds of formula (Ia)

Wherein T represents a group NCOA, wherein A is as defined above, or T represents a group which may be CON (R)³)₂A substituted carbon atom, wherein R³As defined above, and wherein R in formula (Ia)¹As defined above.

Most preferred are the following compounds:

abbreviations in the above tables: ex is an example; max plot is the maximum point; min is min.

In another embodiment, the most preferred compounds are piperidines as examples 5, 30, 259, 263, 265, and 284.

In another embodiment, the most preferred compounds are the amides and spiroamides as examples 121, 233, 234, 278, 250, 251, 260, 262, 285, 286, and 287.

In another embodiment, the most preferred compounds are the sulfonyl compounds (sulfonyl) as examples 279 and 288; and cyclic amides: 254 and 255; and the spiro ether from example 267.

“C₁-C₆Alkyl (C)₁-C₆Alkyl) "or" C₁-C₆Alkyl (C)₁-C₆-alkyl group) "means a straight or branched alkyl chain having 1 to 6 carbon atoms.

“C₁-C₆-alkyl "or" C₁-C₃Alkyl "may also include halo-alkyl. Halo-alkyl groups contain 1 to 10 halogen atoms, preferably 1 to 3 halogen atoms. Halo-alkyl radicals, e.g. containing the group-CF₃、-CHF₂or-CH₂F。

A represents an alkyl group, unbranched (linear) or branched, having 1,2,3,4, 5,6,7, 8, 9 or 10C atoms. A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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 represents alkyl having 1,2,3,4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1, 1-trifluoroethyl.

Further, A preferably represents CH₂OCH₃、OCH₂CH₂OCH₃、CH₂OH、CH₂NH₂、NHCH₂CH₂OH、CH₂CH₂OH、CH₂NHCH₂Or NHCH₂CH₃。

Hal preferably represents Cl or F.

R³Preferably represents H or CH₃。.

Q is preferably absent or preferably represents NR³COCH₂、CH₂CONR³、COCH(CH₃)、CH(CH₃)CO、COCH₂CH₂、CH₂CH₂CO、CH₂、CH₂CH₂、CH₂CO、COCH₂、CH(OH)CH₂、CH₂CH(OH)、CO-C(CH₃)₂Or (CH)₃)₂C-CO。

"leaving group" means a chemical moiety that can be removed or replaced by another chemical group.

In the present specification, the term leaving group preferably denotes Cl, Br, I or a reaction-modified OH group, such as an activated ester, an onium imidazole (imidazolide) or an alkylsulfonyloxy group having 1 to 6 carbon atoms, preferably a methylsulfonyloxy or trifluoromethylsulfonyloxy group, or an arylsulfonyloxy group having 6 to 10 carbon atoms, preferably a phenyl-or p-tolylsulfonyloxy group.

Groups of this type which are used in typical acylation reactions for activating carboxyl groups are described in the literature (for example in the authoritative works, such as Houben-Weyl, Methoden der organischen chemistry [ Methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart).

The activated ester is advantageously formed in situ, for example by addition of HOBt or N-hydroxysuccinimide.

Cyclic alkyl (cycloalkyl) preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Het, irrespective of further substitution, for example denotes 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, preferably furthermore 1,2, 3-triazol-1-, -4-or-5-yl, optionally substituted phenyl, optionally, 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-benzo-2, 1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 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-benzothiadiazol-4-, -5-yl or 2,1, 3-benzooxadiazol-5-yl, azabicyclo [3.2.1] octyl or dibenzofuranyl. The heterocyclic group may also be partially or fully hydrogenated.

Het therefore, irrespective of further substitution, may 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-dioxolan-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-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-dioxanyl 1, 3-dioxanyl-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-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-quinolinyl, 1,2,3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 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- (difluoromethylenedioxy) phenyl, 2, 3-dihydrobenzofuran-5-or-6-yl, 2,3- (2-oxymethylenedioxy) 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-1H-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 represents isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyridazinyl, triazolyl, pyridyl, pyrazolyl or furyl, each of which is unsubstituted or substituted by methyl, Hal, NH₂、CH₂COHet²And/or benzyl mono-or di-substitution.

Z very particularly preferably represents 1-methyl-1H-pyrazol-4-yl or 6-methyl-pyridazin-4-yl.

Het¹

Het²Preferably represents piperidinyl or pyrrolidinyl.

R²Preferably H, Het, Q-Het, Cyc or A.

The present invention preferably relates to compounds of the formula (I)

(I)

Wherein:

R¹in the absence of the presence of the agent,

z represents isoxazolyl, imidazolyl, thiazolyl, oxazolyl, pyridazinyl, triazolyl, pyridyl, pyrazolyl or furanyl, each of which is unsubstituted or substituted by A, Hal, N (R)³)₂、CH₂COHet²And/or benzyl mono-or di-substituted,

R^ain the absence or representation of Hal, or,

R^bis absent or represents CONH₂、COOH、CONHA、COHet¹Or CH₂OH，

R²Represents H, Het, Q-Het, Cyc, A, OA, CH₂COOH、NHA、NA₂、CH₂CONH₂、CH₂CONHA, CH (A) CONHA or NR³SO₂A，

Or represents phenyl optionally mono-or disubstituted by OA,

het represents tetrahydrothiopyranyl, 2-oxa-6-aza-spiro [3.3]Heptyl, 2-oxa (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, piperidinyl, furanyl, pyrrolidinyl, morpholinyl, 1, 9-dioxa-spiro [5.5]Undecyl, 2, 5-diaza-bicyclo [2.2.1]Heptyl, 3-oxa-bicyclo [3.3.1]Nonyl, tetrahydrothienyl, 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 CON (R)³)₂、A、COA、(CH₂)_nHet¹、Hal、Ar¹、(CH₂)_nOH、(CH₂)_nOA、Cyc¹、COCyc¹、SO₂A、COHet¹And/or = O mono-, di-or tri-substituted,

cyc represents cyclohexyl, spiro [3.3]]Heptyl, cyclopentyl or cyclopentenyl, each of which is unsubstituted or A, OCH₂Cyc¹、CONHCH₂CN、NHCOA、(CH₂)_nCONHA、(CH₂)_nCONA₂、COOH、NH₂、COHet¹、CONHCyc¹、CONHHet¹、SO₂A、CH₂OH、=O、Het¹And/or SR³(= O) (= NH) mono-or di-substitution,

q is absent or represents NR³COCH₂、CH₂CONR³、COCH(CH₃)、CH(CH₃)CO、COCH₂CH₂、CH₂CH₂CO、CH₂、CH₂CH₂、CH₂CO、COCH₂、CH(OH)CH₂、CH₂CH(OH)、CO-C(CH₃)₂Or (CH)₃)₂C-CO，

A represents a linear OR branched alkyl group having 1 to 10 carbon atoms, wherein 1 to 7H atoms may be independently selected from-OR³、Hal、NHSO₂A、SO₂A、SOA、N(R³)₂And wherein 1,2 or 3 are not adjacent-CH₂The radicals-may be independently selected from-CO-, NR³And/or a group replacement of-O-,

hal represents F, Cl, Br or I,

Ar¹represents phenyl optionally substituted by Hal,

R³represents H or C₁-C₆Alkyl, in which 1H atom may be chosen from OH, O-C₁-C₆-a radical replacement of alkyl and Hal,

Het¹represents 2, 5-diaza-bicyclo [2.2.1 ]]Heptyl, piperazinyl, morpholinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl or piperidinyl, each of which is unsubstituted or substituted with CH₂OH, OA, Hal and/or A are mono-or disubstituted,

Het²represents a piperidinyl group or a pyrrolidinyl group,

Cyc¹represents cycloalkyl having 3 to 7 atoms, optionally mono-, di-or trisubstituted by a, = O and/or OH,

n represents 0, 1,2 or 3,

and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in all ratios.

Chemical moieties

The following abbreviations refer to the abbreviations used below:

ac (acetyl), BINAP (2,2' -bis (diphenylphosphino) -1,1' -binaphthyl), dba (dibenzylideneacetone), Bu (butyl), tBu (tert-butyl), DCE (dichloroethane), DCM (dichloromethane), DIEA (diisopropylethylamine), DMA (dimethylacetamide), DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), Dppf (1, 1' -bis (diphenylphosphinoferrocene)), EtOAc (ethyl acetate), EtOH (ethanol), g (g), cHex (cyclohexane), HATU (N- [ (dimethylamino) (3H- [1,2, 3-dimethyl-amino-), (N-methyl-ethyl-N-propyl-dimethyl-acetamide), and its salts]Triazolo [4,5-b]Pyridin-3-yloxy) methylene]-N-methylammonium hexafluorophosphate), HPLC (high performance liquid chromatography), hr (h), LDA (lithium diisopropylamide), LiHMDS (lithium bis (trimethylsilyl) amide), MHz (megahertz), MeOH (methanol), min (min), mL (mL), mmol (millimole), mM (millimole concentration), mp (melting point), MS (mass spectrometry), MW (microwave), NMR (nuclear magnetic resonance), O/N (overnight), PBS (phosphate buffered saline), PPh₃(triphenylphosphine), RT (rt), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), oTol (o-tolyl), UV (ultraviolet).

In general, the compounds of formula (I) and related formulae of the present invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be prepared by standard synthetic techniques. In general, the synthetic route for any single compound of formula (I) and related formulae will depend on the particular substituents of each molecule, and these factors will be understood by those of ordinary skill in the art. The following general methods and procedures, described below in the examples, may be employed to prepare compounds of formula (I) and related formulae. The reaction conditions such as temperature, solvent or co-reagent described in the following schemes are given as examples only and are not limiting. It will be appreciated that where typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are given, other experimental conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reactants and solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures. For all 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.

According to R¹、R²、R^a、R^bAnd the nature of Z, different synthetic schemes may be chosen for the synthesis of the compounds of formula (I). In the methods illustrated in the schemes below, unless otherwise noted, R¹、R²、R^a、R^bAnd Z is as defined above in the description.

As outlined in scheme 1, compounds of formula (I) wherein R¹、R²、R^a、R^bAnd Z is as defined above, by a compound of formula (II) wherein R is¹、R^aAnd Z is as defined above and X is halogen (preferably, bromine or iodine) or trifluoromethylA sulfonate group with a boronic acid or ester of formula (III) wherein R²And R^bAs defined above and R is H or alkyl, by Suzuki-Miyura coupling reaction. General conventions for such couplings are given in the examples below using conditions and methods for performing such couplings that are well known to those skilled in the art (see, e.g., Miyaura, N.; Suzuki, A. chem. Rev. 1995, 95, 2457; Takahiro I. and Toshiaki M., Tetrahedron Lett. 2005, 46, 3573-. In a typical procedure, the aryl halide of formula (II) and the boronic acid or ester of formula (III) are dissolved in a suitable solvent such as THF, toluene, DMF or dioxane, in the presence or absence of water as co-solvent, in the presence or absence of, for example, Cs₂CO₃、K₂CO₃In the presence of a base such as, but not limited to, dichlorobis (triphenylphosphine) palladium (II), Pd (PPh)₃)₄Or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), Pd (OAc)₂、Pd₂(dba)₃、Pd(Cl)₂(PPh₃)₂Or Pd/C over a suitable catalyst, such as, but not limited to, P (C)tBu)₃、P(oTol)₃、PPh₃Heating in the presence or absence of additional ligands of BINAP. The coupling reaction may be carried out at a temperature of about 20 ℃ to about 150 ℃, preferably at about 120 ℃, possibly under microwave irradiation for several minutes to several hours.

Scheme 1

In general, compounds of formula (IIa) can be obtained as outlined in scheme 2, wherein R is¹、R^aAnd Z is as defined above and X is bromine. A compound of formula (IV) wherein R¹And Z is as defined above and R is H or alkyl, with a compound of formula (V) wherein R is as defined above, by Suzuki-Miyaura coupling^aAs defined above, to give a compound of the general formula (VI) wherein R¹、R^aAnd Z is as defined above. A general agreement for such couplings is given in the examples below: in a typical procedure, an aryl halide of the formula (V)And boronic acids or esters of formula (IV) in a suitable solvent such as THF, toluene, DMF or dioxane, in the presence or absence of water as co-solvent, in the presence of, for example, Cs₂CO₃、K₂CO₃In the presence of a base such as, but not limited to, dichlorobis (triphenylphosphine) palladium (II), Pd (PPh)₃)₄Or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), Pd (OAc)₂、Pd₂(dba)₃、Pd(Cl)₂(PPh₃)₂Or Pd/C over a suitable catalyst, such as, but not limited to, P (C)tBu)₃、P(oTol)₃、PPh₃Heating in the presence or absence of additional ligands of BINAP. The coupling reaction may be carried out at a temperature of about 20 ℃ to about 150 ℃, preferably at about 120 ℃, possibly under microwave irradiation for several minutes to several hours.

A compound of formula (VI) wherein R¹、R^aAnd Z is as defined above, may be generated by reaction with a suitable boron source such as, but not limited to, dipinacol diborate, diboronic acid (catecholate), diboronic acid bis (diethyl-D-tartrate), diboronic acid (hexylidene glycol ester), diboronic acid bis (neopentyl glycol ester), preferably dipinacol diboronate, in, for example, but not limited to, 1' -bis (diphenylphosphine) ferrocene dichloropalladium (II), dichlorobis (triphenylphosphine) palladium (II), Pd (PPh)₃)₄、Pd(OAc)₂、Pd₂(dba)₃、Pd(Cl)₂(PPh₃)₂Preferably 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) in which R is converted to the compound of formula (VII) in the presence of a suitable catalyst, in the presence of a suitable base such as, but not limited to, potassium acetate, caesium 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 of about 20 ℃ to about 150 ℃, preferably at about 120 ℃, possibly under microwave irradiation for a few minutes to a few hours¹、R^aAnd Z is as defined above.

Compounds of formula (VII) wherein R¹、R^aAnd Z is as defined above, with 5-bromo-2-iodopyrimidine by Suzuki-MiyauraA coupling reaction to give a compound of formula (IIa) wherein R¹、R^aAnd Z is as defined above. A general agreement for such couplings is given in the examples below: in a typical procedure, 5-bromo-2-iodopyrimidine and boronic acid or ester (xx) are dissolved in a suitable solvent such as THF, toluene or dioxane, in the presence or absence of water as co-solvent, in a solvent such as Cs₂CO₃、K₂CO₃In the presence of a base such as, but not limited to, dichlorobis (triphenylphosphine) palladium (II), Pd (PPh)₃)₄Or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), Pd (OAc)₂、Pd₂(dba)₃、Pd(Cl)₂(PPh₃)₂Or Pd/C over a suitable catalyst, such as, but not limited to, P (C)tBu)₃、P(oTol)₃、PPh₃Heating in the presence or absence of additional ligands of BINAP. The coupling reaction may be carried out at a temperature of about 20 ℃ to about 150 ℃, preferably at about 120 ℃, possibly under microwave irradiation for several minutes to several hours.

Scheme 2

Alternatively, as outlined in scheme 3, compounds of formula (I) wherein R is¹、R²、R^a、R^bAnd Z is as defined above, by a compound of formula (VIII), wherein R¹、R^aAnd Z is as defined above and R is H or alkyl, with a compound of formula (IX) wherein R is²And R^bAs defined above and X is halogen (preferably, bromine or iodine) or a triflate group, by suzuki-miyaura coupling. General conventions for such couplings are given in the examples below using conditions and methods for performing such couplings that are well known to those skilled in the art (see, e.g., Miyaura, N.; Suzuki, A. chem. Rev. 1995, 95, 2457; Takahiro I. and ToshiakiM., Tetrahedron Lett. 2005, 46, 3573-. In a typical procedure, an aryl halide of formula (II) and a boronic acid or ester of formula (III) are reacted, for example, in THFToluene or dioxane in a suitable solvent, in the presence or absence of water as co-solvent, in the presence of, for example, Cs₂CO₃、K₂CO₃In the presence of a base such as, but not limited to, dichlorobis (triphenylphosphine) palladium (II), Pd (PPh)₃)₄Or 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), Pd (OAc)₂、Pd₂(dba)₃、Pd(Cl)₂(PPh₃)₂Or Pd/C over a suitable catalyst, such as, but not limited to, P (C)tBu)₃、P(oTol)₃、PPh₃Heating in the presence or absence of additional ligands of BINAP. The coupling reaction may be carried out at a temperature of about 20 ℃ to about 150 ℃, preferably at about 120 ℃, possibly under microwave irradiation for several minutes to several hours.

A compound of formula (VIII), wherein R¹、R^aAnd Z is as defined above and R is H or alkyl, can be derived from compounds of formula II wherein R is¹、R^aAnd Z is as defined above and X is halogen (preferably bromine or iodine) or a triflate group by reaction with a suitable boron source such as, but not limited to, dipinacol diborate, bis (catecholate) diborate, bis (diethyl-D-tartrate) diborate, bis (hexylidene) glycol diborate, bis (neopentyl glycol) diborate, preferably dipinacol diborate, in a solvent such as, but not limited to, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), dichlorobis (triphenylphosphine) palladium (II), Pd (PPh)₃)₄、Pd(OAc)₂、Pd₂(dba)₃、Pd(Cl)₂(PPh₃)₂Preferably 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), in the presence of a suitable catalyst, 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 of about 20 ℃ to about 150 ℃, preferably at about 120 ℃, possibly under microwave irradiation for a few minutes to a few hours.

Scheme 3

Alternatively, compounds of formula I, wherein R is as described in scheme 4, may be prepared¹、R²、R^a、R^bAnd Z is as defined above. 2-aminopyrimidines of formula (X), wherein X is halogen (preferably, iodine or bromine) or a trifluoromethanesulfonate group, with boronic acid derivatives of formula (III), wherein R²、R^bAs defined above and R is H or alkyl, under Suzuki-Gongpu conditions, as described above, well known to those skilled in the art for such couplings to give compounds of formula (XI) wherein R is²And R^bAs defined above. General conventions for such couplings are given in the examples below using conditions and methods for performing such couplings well known to those skilled in the art. The resulting 2-aminopyridine of formula (XI), wherein R²And R^bAs defined above, it can be converted to 2-iodopyrimidine of formula (XII) by reaction for several hours, for example, with a suitable iodine source such as, but not limited to, diiodomethane, iodine, N-iodosuccinimide, in the presence of an alkyl nitrite such as, but not limited to, tert-butyl nitrite or isoamyl nitrite, in the presence of copper (I) iodide in a suitable solvent such as, but not limited to, THF or dioxane, at a temperature of from about 20 ℃ to about 150 ℃, preferably from about 80 ℃ to 100 ℃. (R-²And R is^bAs defined above.

A compound of formula (XIV) wherein R²、R^aAnd R^bAs defined above, by the compounds of formula (XII) wherein R²And R^bAs defined above, with a boronic acid derivative of formula (XIII) wherein R^aAs defined above and R is H or alkyl, under Suzuki-Gongpu conditions, as described above, well known to those skilled in the art for performing such couplings.

Using similar conditions as described above for the conversion of aromatic or heteroaromatic amines to aromatic or heteroaromatic iodides, for example by reaction with a suitable iodine source such as, but not limited to, diiodomethane, iodine, N-iodosuccinimide, in the presence of, for example, but not limited to, tert-butyl nitrite or vinylidene nitriteThe reaction is carried out in the presence of an alkyl nitrite of isoamyl nitrate, in the presence of copper (I) iodide in a suitable solvent such as, but not limited to THF or dioxane, at a temperature of from about 20 deg.C to about 150 deg.C, preferably from about 80 deg.C to 100 deg.C, for several hours to complete the compound of formula (XIV), wherein R is²、R^aAnd R^bAs defined above, to a compound of formula (XV) wherein R²、R^aAnd R^bTransformation as defined above. Finally, compounds of the formula I, wherein R¹、R²、R^a、R^bAnd Z is as defined above, by the compounds of formula (XV) wherein R²、R^aAnd R^bAs defined above, with a boronic acid derivative of formula (IV) wherein R¹And Z is as defined above and R is H or alkyl, under Suzuki-Gongpu conditions, as described above, known to those skilled in the art for performing such couplings.

Scheme 4

Alternatively, compounds of formula I, wherein R is as described in scheme 5, can be prepared¹、R²、R^a、R^bAnd Z is as defined above. Aryl iodides of the formula (XV) wherein R²、R^aAnd R^bAs defined above, the compounds may be prepared by reaction with suitable diboron derivatives such as, but not limited to, dipinacol diborate, bis (catecholate) diborate, bis (diethyl-D-tartrate), bis (hexylidene glycol) diborate, bis (neopentyl glycol) diborate, preferably dipinacol diborate, as described in, but not limited to, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), dichlorobis (triphenylphosphine) palladium (II), Pd (PPh)₃)₄、Pd(OAc)₂、Pd₂(dba)₃、Pd(Cl)₂(PPh₃)₂Preferably 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), in the presence of a suitable catalyst, 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 suitable base such as, but not limited to, potassium acetateConversion to compounds of formula (XVI) in which R is limited to THF, dioxane, DCE, DMF, preferably THF or dioxane, in the presence of a solvent, possibly under microwave irradiation at a temperature of about 20 ℃ to about 150 ℃, preferably at about 120 ℃, into compounds of formula (XVI), wherein R is²、R^aAnd R is^bAs defined above and R is H or alkyl.

A compound of formula I wherein R¹、R²、R^a、R^bAnd Z is as defined above, by a compound of formula (XVI) wherein R is²、R^aAnd R^bAs defined above and R is H or alkyl, with a compound of formula (XVII) wherein R is¹And Z is as defined above under Suzuki-Gongpu conditions, as described above, known to those skilled in the art for performing such couplings.

Scheme 5

Alternatively, as depicted in scheme 6, compounds of formula (I) wherein R¹、R²、R^a、R^bAnd Z is as defined above, by the compounds of formula (XII) wherein R²And R^bAs defined above, and a compound of formula (VII) wherein R¹、R^aAnd Z is as defined above and R is H or alkyl. The reaction can be carried out using the general conditions described above. General conventions for such couplings are given in the examples below using conditions and methods well known to those skilled in the art for performing such couplings.

Scheme 6

Alternatively, compounds of formula (I), wherein R¹、R²、R^a、R^bAnd Z is as defined above and can be prepared as described in scheme 7A compound of formula (Ia) prepared according to one of the above routes, wherein R¹、R^a、R^bAnd Z is as defined above and R²Is H by reaction with a compound of formula (XVIII) wherein R²As defined above, but is not H and LG is a leaving group such as bromo, chloro, alkylsulfonate, or any other suitable leaving group known to those skilled in the art. General conventions for such conversions are given in the examples below using conditions and methods well known to those skilled in the art. In a typical procedure, a compound of formula (Ia) is reacted with, for example, but not limited to, NaH, K₂CO₃、Cs₂CO₃LDA, LHMDS, preferably NaH, and the compound of formula (XVIII) are treated in a suitable solvent such as THF, dioxane, DMF, DMA at a temperature of-20 ℃ to about 150 ℃ for a time ranging from a few minutes to a few hours.

Alternatively, as depicted in scheme 7, compounds of formula (I) wherein R¹、R²、R^a、R^bAnd Z is as defined above, by a compound of formula (Ib) prepared according to one of the above routes, wherein R¹、R^a、R^bAnd Z is as defined above and R²Is H by reaction with an alcohol of the formula (XIX) in which R is²As defined above, but not H, using conditions well known to those skilled in the art for the Mitsunobu reaction (see, for example, Hughes, D.L. Organic Reactions (New York), 1992, 42, 335-. Typically, the reaction is carried out in, for example, but not limited to, P: (A), (B), (CtBu)₃、PPBu₃、P(oTol)₃、PPh₃In the presence of a phosphine such as, but not limited to, an azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, tetramethyl azadicarboxamide, in a solvent such as THF, dioxane, DCM, DCE, at a temperature of-20 ℃ to about 150 ℃, preferably at room temperature for a period of several minutes to several hours.

Scheme 7

The compounds of the invention may be isolated by crystallization from a suitable solvent or by incorporating solvent molecules by evaporation of a suitable solvent.

Pharmaceutically acceptable anionic salts of compounds of formula (I) containing a basic centre may be prepared in conventional manner. For example, a solution of the free base may be treated with a suitable acid, neat or in a suitable solution, and the resulting salt isolated by filtration or by evaporation of the reaction solvent under vacuum.

The pharmaceutically acceptable cationic salts of the compounds of formula (I) containing an acidic centre can be prepared in a conventional manner. For example, a solution of the free acid may be treated with a suitable base, neat or in a suitable solution, and the resulting salt isolated by filtration or by evaporation of the reaction solvent under vacuum. In some cases, the salt may be prepared by mixing a solution of the acid with a solution of an alkali or alkaline earth metal salt (e.g., sodium ethylhexanoate, magnesium oleate) with a solvent in which the desired alkali or alkaline earth metal salt of the compound of formula (I) precipitates, or may be otherwise isolated by concentration and addition of a non-solvent.

Both types of salts can be formed or interconverted using ion exchange resin techniques.

The reaction time is usually from a few minutes to 14 days, depending on the conditions used. The reaction temperature is between about-30 ℃ and about 140 ℃, usually between-10 ℃ and 90 ℃, especially between about 0 ℃ and 70 ℃.

The compounds of formula (I) and related formulae can furthermore be obtained by liberating the compound of formula (I) from one of its functional derivatives by treatment with a solvolysis or hydrogenolysis agent.

Preferred starting materials for solvolysis or hydrogenolysis are those corresponding to formula I and related formulae but containing the corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those bearing an amino protecting group instead of a H atom bonded to a N atom, in particular those bearing R-N groups, wherein R represents an amino protecting group instead of a HN group; and/or those bearing a hydroxyl protecting group other than the H atom of a hydroxyl group, for example those conforming to formula I, but bearing a-COOR group, wherein R represents a hydroxyl-protecting group other than 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 be selectively cleaved in many cases.

The term "amino protecting group" is known in general terms and relates to a group which is suitable for protecting (blocking) an amino group from a chemical reaction, but which is easily removed after the desired chemical reaction has taken place elsewhere in the molecule. Such radicals are in particular unsubstituted or substituted acyl, aryl, aralkyloxymethyl or aralkyl radicals. Since the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not critical; however, preference is given to those having from 1 to 20, in particular from 1 to 8, carbon atoms. The term "acyl" is to be understood in a broad sense in connection with the process of the invention. These include acyl radicals derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl radicals. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl groups such as benzoyl and tolyl (tolyl); aryloxyalkanoyl, such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("benzyloxycarbonyl"), 4-methoxybenzyloxycarbonyl, and FMOC; and arylsulfonyl groups such as Mtr. Preferred amino protecting groups are BOC and Mtr, in addition CBZ, Fmoc, benzyl and acetyl.

The term "hydroxyl protecting group" is also known in general terms and refers to a group that is suitable for protecting a hydroxyl group from chemical reactions, but is easily removed after the desired chemical reaction is carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, in addition to alkyl groups. The nature and size of the hydroxyl protecting groups are not critical, since they are removed again after the desired chemical reaction or reaction sequence; preference is given to radicals having from 1 to 20, in particular from 1 to 10, carbon atoms. Examples of hydroxy-protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

The compounds of formula I and related formulae are liberated from their functional derivatives depending on the protective group used, for example strong mineral acids such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid, TFA or sulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of additional inert solvents is also possible, but this is not always required. Suitable inert solvents are preferably organic solvents, for example carboxylic acids, such as acetic acid; ethers, such as tetrahydrofuran or dioxane; amides, such as DMF; halogenated hydrocarbons such as dichloromethane; in addition alcohols, such as methanol, ethanol and isopropanol; and water. Also suitable are mixtures of the solvents mentioned above. In the case of no addition of another solvent, TFA is preferably used in excess, and perchloric acid is preferably used as a mixture of acetic acid and 70% perchloric acid in a 9:1 ratio. The reaction temperature for the cleavage is advantageously from about 0 to about 50 deg.C, preferably from 15 to 30 deg.C (room temperature).

The BOC, otput and Mtr groups can be cleaved, for example, preferably using TFA in dichloromethane or using about 3-5N HCl in dioxane at 15-30 ℃, and the FMOC group can be cleaved using dimethylamine, diethylamine or piperidine in about 5-50% solution in DMF at 15-30 ℃.

The hydrogenolytically removable protecting groups (e.g., CBZ, benzyl or release of amidino groups from oxadiazole derivatives thereof) can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (e.g., 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 an amide, such as DMF. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ℃ and a pressure of about 1 and 200 bar, preferably at 20 to 30 ℃ and 1 to 10 bar. Hydrogenolysis of the CBZ group is carried out well at 20-30 ℃ for example on 5-10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF.

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 ether or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or Dimethylformamide (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 said solvents.

The esters can be prepared, for example, using HCl, H₂SO₄(ii) a Or using LiOH, NaOH or KOH in water; water/THF, water/THF/ethanol or water/dioxane at 0-100 ℃.

The free amino group can furthermore be acylated in a conventional manner using acid chlorides or acid anhydrides or alkylated using unsubstituted or substituted alkyl halides, 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 of-60 ℃ to +30 ℃.

Formula (I) and related formulae also encompass optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds. The term "solvate of a compound" is used to indicate the addition of an inert solvent molecule to the compound due to their attractive interaction. Solvates are for example mono-or dihydrate or alcoholates.

The term "pharmaceutically usable derivatives" refers to, for example, salts of compounds of formula I or so-called prodrug compounds.

The term "prodrug derivative" refers to a compound of formula I which has been modified with, for example, an alkyl or acyl group, a sugar or an oligopeptide and which is rapidly cleaved in the organism to form the active compound. Preferably, a "prodrug" of a compound of formula I refers to a derivative compound that is rapidly transformed in vivo, for example by hydrolysis in blood, to yield the parent compound of formula I. A full discussion of the prodrug concept is provided by Higuchi and V.Stella in Pro-drugs as Novel Delivery Systems, volume 14 of the A.C.S. monograph document set, American chemical Society (American chemical Society) (1975). Examples of esters which can be used as prodrugs of compounds containing carboxyl groups can be found on pages 14-21 of E.B. Roche, compiled "Bioreversible Carriers in drug design: Theory and Application", Pergamon Press: New York (1987). These documents, and any other documents mentioned in this specification, are intended to be 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. 115, 61-67 (1995).

Formula (I) and related formulae also encompass mixtures of compounds of formula I, for example mixtures of two diastereomers in a ratio of 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 may be administered in dosage unit form, containing a predetermined amount of active ingredient per dosage unit. Such units may contain, for example, from 0.5mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, depending on the disease state to be treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical preparations may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or sub-dose, or corresponding fraction thereof, of the active ingredient as indicated above. In addition, pharmaceutical formulations of this type may be prepared using methods generally known in the pharmaceutical art.

The pharmaceutical formulation may be adapted for administration by any desired suitable method, for example, 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 may be prepared using all methods known in the medical arts, for example, by combining the active ingredient with one or more excipients or adjuvants.

Pharmaceutical preparations suitable for oral administration may be presented as discrete units, such as capsules or tablets; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component may be combined with inert excipients which are not toxic and which are acceptable for oral administration, such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable small size and mixing it with a similarly comminuted pharmaceutical excipient such as an edible carbohydrate such as starch or mannitol. Flavoring agents, preservatives, dispersing agents and dyes may also be present.

Capsules are produced by preparing a powder mixture as described above and filling shaped capsule shells with it. Glidants and lubricants such as highly disperse silicic acid, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents, such as agar-agar, calcium carbonate or sodium carbonate, may also be added to improve the availability of the medicine after ingestion of the capsule.

In addition, if desired or necessary, suitable binders, lubricants and disintegrants and dyes may also be incorporated into the mixture. Suitable binders include starch; gelatin; natural sugars such as glucose or beta-lactose; sweeteners made from corn; natural and synthetic rubbers such as gum arabic, tragacanth gum, or sodium alginate; a carboxymethyl cellulose; polyethylene glycol; paraffin wax, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets may be formulated, for example, by preparing a powder mix, granulating or press-drying the mix, adding a lubricant and disintegrant, and pressing the entire mixture to give tablets. The powder mixture is prepared by mixing the compound, comminuted in a suitable manner as described above, with a diluent or base and optionally with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution retardant such as a paraffin, an absorption accelerator such as a quaternary salt and/or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting it with a binder such as a paste, starch paste, acadia mucilage or a solution of cellulose or polymeric material and pressing it through a screen. As an alternative to granulation, the powder mixture may be passed through a pelletiser to give non-uniformly shaped pieces which are broken up to form granules. The granules may be lubricated by the addition of stearic acid, stearate, talc or mineral oil to avoid sticking to the tablet casting mould. The lubricated mixture was then compressed to give tablets. The active ingredient can also be combined with free-flowing inert excipients and subsequently directly compressed to give tablets without a granulation or press-drying step. There may be a transparent or opaque protective layer consisting of a shellac blocking layer, a sugar or polymer material layer and a paraffin gloss layer. Dyes may be added to these coatings to enable differentiation between different dosage units.

Oral liquids such as solutions, syrups and elixirs may be prepared in the form of dosage units so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions may be formulated by dispersing the compound in a non-toxic vehicle. Solubilizing agents and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. may also be added.

Dosage unit formulations for oral use may be encapsulated in microcapsules, if desired. The formulations may also be prepared, for example, by coating or embedding the particulate material in a polymer, paraffin, or the like for extended or delayed release.

The compounds of formula (I) and related formulae and salts, solvates and physiologically functional derivatives thereof and other active ingredients may also be administered in the form of liposomal delivery systems, e.g., small unilamellar liposomes, large unilamellar liposomes and multilamellar liposomes. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula (I) and related formulae, and salts, solvates, and physiologically functional derivatives thereof, as well as other active ingredients, can also be delivered using monoclonal antibodies as a single carrier for coupling compound molecules. These compounds can also be coupled to soluble polymers as carriers for targeted drugs. The polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylsuccinimidylphenol, or polyethyleneoxide polylysine substituted with palmitoyl groups. The compounds may furthermore be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphiphilic block copolymers of hydrogels.

Pharmaceutical formulations suitable for transdermal administration may be administered as a separate plaster to be brought into intimate contact with the epidermal extensions of the recipient. Thus, for example, the active ingredient may be delivered from gypsum by iontophoresis as described in the general practice in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues, such as the mouth or skin, the formulation may preferably be administered as a topical ointment or cream. When formulated as an ointment, the active ingredient may be employed with an alkane or water-miscible cream base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water ointment base or a water-in-oil base.

Pharmaceutical formulations suitable for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in the mouth encompass lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical formulations suitable for nasal administration, wherein the carrier material is a solid, comprise a coarse powder having a particle size, for example in the range of 20-500 microns, which is administered by inhalation of snuff, i.e. by rapid inhalation through the nasal passage from a container containing the powder held close to the nose. Suitable formulations for administration as nasal sprays or nasal drops with a liquid as carrier material comprise the active ingredient in water or oil.

Pharmaceutical formulations adapted for administration by inhalation comprise fine particle powders or aerosols, which may be produced by various types of pressurised dispensers, having atomizers, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions containing an antioxidant; a buffering agent; a bacteriostatic agent; and a solute, thereby rendering the formulation isotonic with the blood of the subject to be treated; and aqueous and non-aqueous sterile suspensions which may contain a suspending medium and a thickening agent. These formulations may be administered in single-or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state requiring only the addition of the sterile carrier liquid, for example water for injection purposes, immediately prior to use.

Injectable solutions and suspensions prepared according to the formulation can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the ingredients specifically mentioned above, the formulations may also comprise other agents commonly used in the art for the particular type of formulation; thus, for example, a formulation suitable for oral administration may contain a flavoring agent.

The therapeutically effective amount of the compounds of formula (I) and related formulae and other active ingredients will depend on a number of factors including, for example, the age and weight of the animal, the precise condition and severity of the condition requiring treatment, the nature of the formulation and the method of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of the compound will generally be in the range of 0.1 to 100mg/kg body weight receptor (mammal)/day and particularly typically in the range of 1 to 10mg/kg body weight/day. Thus, the actual daily amount for an adult mammal weighing 70kg is typically 70-700mg, as this amount may be administered as a single dose per day or typically in a series of divided doses (e.g. two, three, four, five or six) per day, such that the total daily dose is the same. An effective amount of a salt or solvate, or physiologically functional derivative thereof, can be determined as a fraction of the effective amount of the compound itself.

The present invention further relates to methods of treating a subject afflicted with an IRAK-related disorder comprising administering to the subject an effective amount of a compound of formula I and related formulae. The present invention preferably relates to methods wherein the IRAK-related disorder is an autoimmune disorder or condition associated with an overactive immune response or cancer. The invention further relates to a method of treating a subject suffering from an immunoregulatory abnormality comprising administering to the subject an amount of a compound of formula (I) and related formulae effective to treat the immunoregulatory abnormality. The present invention preferably relates to a method wherein the dysregulation 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, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, psoriasis, Grave's ophthalmopathy and asthma. The invention further relates to methods wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft versus host disease. The invention further relates to a method wherein the immunoregulatory abnormality is selected from the group consisting of: transplantation of organ or tissue, graft-versus-host disease resulting from transplantation, autoimmune syndrome 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-infection autoimmune diseases including rheumatic fever and post-infection glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, chronic, Uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoplakia, ocular pemphigus, Moren's ulcer, scleritis, Graves ' opthalmopathy, Vogt-Koyanagi-Haradanydrome, sarcoidosis, pollen allergy, reversible obstructive tracheal disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or intractable asthma, late asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular injury due to ischemic disease and thrombus, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, enteropathy associated with thermal burn, abdominal disease, proctitis, gastroenteritis, proctitis, and the like, Mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedo's disease, pure aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoietic failure, osteoporosis, sarcoidosis, fibrosis, idiopathic interstitial pneumonia, Dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic skin diseases, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortosis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, wegener's necrotizing granuloma, Sj foot syndrome (Sj foot syndrome), obesity, eosinophilic fasciitis, gum pathology, periodontal disease (periodontium), alveolar bone lesions, substentia ossea densis, glomerulonephritis, male pattern baldness or alopecia senilis (by preventing hair loss or providing hair sprouting (hair growth) and/or promoting hair production and hair growth), muscle atrophy, pyoderma and heterosis syndrome (Sezary's syndrome), Addison's disease, ischemia reperfusion injury of organs occurring at the time of protection, transplantation or ischemic disease, Endotoxin-shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxopathies caused by lung-oxygen or drugs, lung cancer, emphysema, cataracts, iron dust lung, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, keratine burns, dermatitis erythema multiforme, linear IgA blistering dermatitis and cement dermatitis (cement dermatitis), gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, cancer metastasis and altitude sickness, diseases caused by the release of histamine or leukotriene-C4, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, viral hepatitis, and chronic inflammatory bowel disease, Shock, or hypoxia, B-viral hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "subacute" hepatic failure, potentiation of chemotherapy, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's Disease, trauma, and chronic bacterial infection.

Preferably, the IRAK-related disorder is selected from the group consisting of 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 (Crohn's disease and ulcerative colitis), type D hyperimmunoglobulinemia and periodic fever syndrome, cryptotropin-related periodic syndrome, schnitzler's syndrome, systemic juvenile idiopathic rheumatoid arthritis, adult-onset still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, cancer.

Preferred compounds of formula (I) and related formulae exhibit an IC50 that binds to IRAK of less than about 5 μ Μ, preferably less than about 1 μ Μ and even more preferably less than about 0.100 μ Μ.

Compounds according to formula (I) and related formulae can 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 temperature, time, moles of reagents, solvents, etc.) are given, other experimental conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reactants and solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures.

In general, the synthetic route for any individual compound of formula (I) and related formulae will depend on the availability of the particular substituents and essential intermediates of each molecule; these factors will be further understood by those of ordinary skill in the art.

The compounds of the invention may be isolated in combination with solvent molecules by crystallization by evaporation of an appropriate solvent. Pharmaceutically acceptable acid addition salts of compounds of formula (I) and related formulae containing a basic center can be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, neat or in a suitable solution, and the resulting salt isolated by filtration or by evaporation of the reaction solvent under vacuum. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of the compounds of formula (I) and related formulae containing an acidic center with a suitable base. Both types of salts can be formed or interconverted using ion exchange resin techniques.

If the general synthetic methods of the above-mentioned group are not suitable for obtaining compounds according to formula (I) and/or intermediates necessary for the synthesis of compounds of formula (I), suitable preparation methods known to the person skilled in the art should be used. In general, the synthetic route for any single compound of formula (I) will depend on the particular substituents of each molecule and the availability of the necessary intermediates; these factors will be further understood by those of ordinary skill in the art. For all protection and deprotection methods see Philip j. kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994; and Theodora W. Greene and Peter G.M. Wuts, "Protective Groups in organic Synthesis", Wiley Interscience, third edition, 1999.

In the following, the invention will be illustrated by means of some examples, which are not to be construed as limiting the scope of the invention.

Experimental part

In the following, the invention will be illustrated by means of some examples, which are not to be construed as limiting the scope of the invention.

In general:

the HPLC data provided in the examples described below were obtained as follows:

condition a: column Waters Xbridge^TMC850 mm × 4.6mm, at a flow rate of 2 mL/min; 8 min, gradient H₂O:CH₃CN: TFA, from 100:0:0.1% to 0:100: 0.05%.

UV detection for all cases (maximum points).

The MS data provided in the examples described below were obtained as follows:

mass spectrum: LC/MS Waters ZMD (ESI).

The NMR data provided in the examples described below were obtained as follows:

1H-NMR: bruker DPX-300MHz or Bruker AV-400 MHz.

Unless otherwise reported, the automated preparative LC/MS purification was performed with a 19x 100mm, 5 μ M mass-directed automated purification fraction from Waters equipped with a Sunfire Prep C18 OBD column. All HPLC purifications were performed with ACN/H₂O or ACN/H₂An O/HCOOH (0.1%) gradient was run.

Microwave chemistry was performed on a single mode microwave reactor Emrys ™ Optimier or Initiator ™ Sixty from Biotage.

The compounds of the invention are named according to the standard used in the procedure Autonom.

The compounds of formula (I) can be prepared by a variety of synthetic methods from readily available starting materials using solution phase and solid phase chemistry conventions or mixed solution phase and solid phase conventions. Examples of synthetic routes are described in the examples below. Unless otherwise indicated, compounds of formula (I) and related formulae obtained as racemic mixtures can be separated to provide enantiomerically enriched mixtures or pure enantiomers.

Unless otherwise reported, commercial starting materials used in the following experimental descriptions were purchased from Aldrich or Sigma or ABCR. SPE cartridges were purchased from 1ST and used according to the supplier's recommendations.

Intermediate 1: 1-methyl-4- [3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -1H-pyrazole

To a solution of 4- (3-bromo-phenyl) -1-methyl-1H-pyrazole (Otava, 410mg, 1.7mmol) in dry DMF (10mL) was added dipinacol diborate (525mg, 2.0mmol) and dry KOAc (340mg, 3.4 mmol). After addition of dppf (48mg, 0.09mmol) and (dppf) PdCl_2.CH₂Cl₂Before (71mg, 0.09mmol), the reaction mixture was degassed for 20 minutes. The reaction mixture was then heated at 80 ℃ overnight. It was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (550mg, 92%).¹H NMR (300 MHz, DMSO-d6) 8.24-8.15(s, 1H), 7.89-7.82 (d,J= 0.9 Hz, 1H), 7.82-7.76 (t,J= 1.3 Hz, 1H), 7.73-7.64 (m, 1H), 7.53-7.45 (m, 1H), 7.42-7.29 (m, 1H), 3.89-3.82 (s, 3H), 1.34-1.26 (s, 12H)。

Intermediate 2: 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] pyrimidine

1-methyl-4- [3- (4,4,5, 5-tetramethyl- [1,3,2]dioxaborolan-2-yl) -phenyl]To a solution of-1H-pyrazole (intermediate 1, 5.0g, 17.5mmol) in 1, 4-dioxane (80mL) was added 5-bromo-2-iodo-pyrimidine (6.0g, 21.0mmol) and potassium carbonate (7.3g, 5.25 mmol). The reaction mixture was purged with nitrogen for 30 minutes. Tetrakis (triphenylphosphine) palladium (0) (2.02g, 0.17mmol) was then added and the reaction mixture was heated at 100 ℃ overnight. It was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. Purification by silica flash chromatography (EtOAc/hexanes) afforded the title compound (2.5g, 45%) as a yellow solid.¹H NMR (400 MHz, DMSO-d6): 9.09 (s, 1H),8.49 (t,J= 1.64 Hz, 1H), 8.25 (s, 1H), 8.18 (dd,J= 1.2, 4.74 Hz, 1H),7.90 (d,J= 1.2 Hz, 1H), 7.75-7.73 (m, 1H), 7.52 (t,J= 4.0 Hz,1H), 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) -pyrimidines

Following the 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-. MS (ESI +): 312.0.

Intermediate 4: 3- (5-bromopyrimidin-2-yl) aniline

5-bromo-2-iodo-pyrimidine (9.0 g; 31.6 mmol; 1.0 equiv.), 3-aminophenylboronic acid (4.3 g; 31.6 mmol; 1.0 equiv.), K₂CO₃(17.5g, 126.4mmol, 4.0 equiv.) and Pd (PPh)₃)₄(1.83g, 1.58mmol, 0.05 equiv.) in Water/dioxane (67:135mL)The material was heated at 100 ℃ overnight. The reaction mixture was then diluted with EtOAc and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige solid (7.6g, 96%). HPLC (condition a): rt 1.90 min (purity 78.0%). MS (ESI +) 250.1.

Intermediate 5: 4- {4- [2- (3-iodophenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylic acid tert-butyl ester

Step 1: formation of tert-butyl 4- {4- [2- (3-aminophenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylate

3- (5-Bromopyrimidin-2-yl) aniline (intermediate 4, 220mg, 0.88mmol, 1.0 equiv.), 1- (1-Boc-piperidino) pyrazole-4-boronic acid (389mg, 1.3mmol, 1.5 equiv.), Pd (PPh)₃)₄(51mg, 0.04mmol, 0.05 eq.) and K₂CO₃A mixture of (365mg, 2.6mmol, 3.0 equivalents) in dioxane/water (3.3:1.65mL) was heated at 120 ℃ in a sealed tube at MW for 30 minutes. The reaction mixture was then diluted with EtOAc. The two phases were separated and the aqueous phase was extracted with EtOAc. The 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 as an off-white solid (240mg, 65%).¹H NMR (300 MHz, DMSO-d6) 9.09 (s, 2H), 8.52 (s, 1H), 8.11 (s, 1H), 7.67 (t,J= 2.0 Hz, 1H), 7.57-7.53(m, 1H), 7.14 (t,J= 7.8Hz, 1H), 6.69-6.66 (m,1H), 5.25 (s,2H), 4.46-4.36(m, 1H), 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- [2- (3-iodophenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylate

Isopentyl nitrite (192. mu.l, 1.43mmol, 3.0 equiv.) was added to 4-4- [2- (3-aminophenyl) pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 5, step 1, 200mg, 0.48mmol, 1.0 equiv), copper (I) iodide (91mg, 0.48mmol, 1.0 equiv) and diiodomethane (193 μ l, 2.38mmol, 5.0 equiv) in a solution in dry THF (8.0mL) and the reaction mixture refluxed for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness. Purification by flash chromatography (EtOAc: heptane, gradient from 20:80 to 50:50) afforded the title compound (200mg, 67%) as a white solid.¹H NMR (300 Mz, DMSO-d6) 9.17 (s, 2H), 8.71 (t,J= 1.7Hz, 1H), 8.56 (s, 1H), 8.40-8.37 (m, 1H), 8.15 (s, 1H), 7.90-7.86 (m, 1H),7.35 (t,J= 7.9 Hz,1H), 4.48-4.38 (m,1H), 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 (91.0% purity). MS (ESI +): 532.4.

Intermediate 6: 4- [4- (2-iodopyrimidin-5-yl) -1H-pyrazol-1-yl ] piperidine-1-carboxylic acid tert-butyl ester

Step 1: formation of 4- [4- (2-aminopyrimidin-5-yl) -1H-pyrazol-1-yl ] piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for intermediate 5, step 1, but starting from 2-amino-5-bromopyrimidine (1.28g, 7.36mmol, 1.0 eq.) and 4- [4- (4,4,5, 5-tetramethyl- [1,3, 2-tetramethyl- [1,3]Dioxaborolan-2-yl) -pyrazol-1-yl]Starting from tert-butyl-piperidine-1-carboxylate (2.57g, 6.81mmol, 1.00 eq.) the title compound was obtained as a yellow solid (1.39g, 49%).¹H NMR (300 MHz, DMSO-d6) 8.47 (s, 2H), 8.19 (s, 1H), 7.82 (s, 1H),6.58 (s, 2H), 4.41-4.27 (m, 1H), 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 4- [4- (2-iodopyrimidin-5-yl) -1H-pyrazol-1-yl ] piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for intermediate 5, step 2, but starting from 4- [4- (2-aminopyrimidin-5-yl) -1H-pyrazol-1-yl]Starting from tert-butyl piperidine-1-carboxylate (1.4g, 3.31mmol, 1.0 eq.) the title compound was obtained as a yellow solid (980mg, 61%).¹H NMR (300 MHz, DMSO-d6) 8.84 (s, 2H), 8.52 (s, 1H), 8.09 (s,1H), 4.48-4.32 (m, 1H), 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-yl ] -ethanone

A solution of 1- (bromoacetyl) pyrrolidine (Chemical Diversity Labs; 3.0g, 15.6mmol, 1.2 equivalents) in acetonitrile (15mL) was slowly added to a suspension of pyrazole-4-boronic acid pinacol ester (2.5g, 12.9mmol, 1 equivalent) in acetonitrile and stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was diluted with DCM and washed with water, followed by brine. The separated organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (2.72g, 100%).

Intermediate 8: 1- [ 2-fluoro-1- (fluoromethyl) ethyl ] -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole

To a stirred solution of pyrazole-4-boronic acid pinacol ester (6.6g, 34mmol, 1 eq) in dry THF (150mL) under a nitrogen atmosphere at 0 ℃ was added 1, 3-difluoro-2-propanol (5.1g, 51mmol, 1.5 eq), followed by triphenylphosphine (13.5g, 51mmol, 1.5 eq) and diisopropyl azodicarboxylate (10.5g, 51mmol, 1.5 eq). After this addition, the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc, washed with water (three times), dried over sodium sulfate, filtered, and concentrated. The crude product was redissolved in EtOAc and petroleum ether was added. The resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as an oil (contaminated with triphenylphosphine oxide).

Intermediate 9: trans-3-fluoro-4- [ (methylsulfonyl) oxy ] piperidine-1-carboxylic acid tert-butyl ester

Step 1: formation of trans-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Sodium borohydride (1.53g, 40.5mmol) was added to a stirred solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (omega chem, 8g, 36.8mmol) in dry methanol (100mL) maintained at 0 ℃. The reaction mixture was stirred at the same temperature for 45 minutes, then quenched with dry acetone (20mL) 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 silica flash chromatography (petroleum ether: EtOAc, 80:20) afforded the title compound (4.0g, 50%) as a white solid.¹H NMR (400 MHz, DMSO-d6) 4.61 (ddd,J= 39, 8.6, 3.2 Hz,1H), 3.93 (m,2H), 3.71 (bs, 1H), 3.42(brs, 1H), 3.06-3.00 (m,1H), 1.88-1.83 (m,2H), 1.45 (s, 9H). HPLC (condition a): rt2.7 min (97% purity).

Step 2: formation of cis-3-fluoro-4- [ (methylsulfonyl) oxy ] piperidine-1-carboxylic acid tert-butyl ester

Methanesulfonyl chloride (142. mu.l, 1.84mmol, 1.2 equiv.) is added to a solution of tert-butyl trans-3-fluoro-4-hydroxy-piperidine-1-carboxylate (336mg, 1.53mmol, 1.0 equiv.) in DCM (5mL) and TEA (320. mu.l, 2.3mmol, 1.5 equiv.) maintained at 0 ℃ under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 3 hours. It is poured into NH₄Cl in saturated solution. The phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were washed with saturated NaHCO₃And brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a white solid (432mg, 95%).¹H NMR (300MHz, DMSO) 4.81-4.95 (m, 2H), 4.05 (m,1H), 3.84 (m, 1H), 3.25 (s, 3H), 3.13(m, 1H), 2.94 (m, 1H), 1.84 (m, 2H), 1.38 (s, 9H)。

Intermediate 10: 3-bromo-5- (1-methyl-1H-pyrazol-4-yl) -phenol

1-methyl-4- (4,4, 5)_,5-tetramethyl- [1,3,2]]Dioxaborolan-2-yl) -1H-pyrazole (750mg, 3.6mmol, 1.0 equiv.), 3, 5-dibromo-phenol (4.54g, 18.0mmol, 5.0 equiv.), bis (triphenylphosphine) palladium (II) chloride (253mg, 0.36mmol, 0.1 equiv.), and potassium carbonate (2.49g, 18.02mmol, 5 equiv.) were suspended in DMF (80mL) and water (1 mL). The reaction mixture was then heated at 80 ℃ for 16 hours 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 (337mg, 30%) as a clear oil.¹H NMR (300 MHz, DMSO-d6) 10.01 (brs,1H), 8.14 (s, 1H), 7.83 (d,J= 0.7 Hz, 1H), 6.96 (d,J= 1.7 Hz, 1H), 6.92(dd,J= 2.1, 1.5 Hz, 1H), 6.76 (t,J= 2.0 Hz, 1H), 3.84 (s, 3H)。

Intermediate 11: 2- (3-iodo-phenyl) -5- (1H-pyrazol-4-yl) -pyrimidine

Step 1: formation of 3- [5- (1H-pyrazol-4-yl) -pyrimidin-2-yl ] -phenylamine

Mixing 4- (4,4,5, 5-tetramethyl- [1,3,2]]Dioxaborolan-2-yl) -pyrazole-1-carboxylic acid tert-butyl ester (20.7g, 70.4mmol, 1.0 equiv.), 3- (5-bromo-pyrimidin-2-yl) -phenylamine (intermediate 4, 17.6g, 70.4mmol, 1.0 equiv.), bis (triphenylphosphine) palladium (II) chloride (4.94g, 7.04mmol, 0.10 equiv.), and potassium carbonate (14.6g, 105mmol, 1.5 equiv.) were suspended in dioxane (540mL) and water (273 mL). The reaction mixture was subsequently heated at 90 ℃ for 16 hours. It was filtered through celite and the filtrate was extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting gel was then washed with Et₂Wet milling in O (100 mL). The resulting solid was filtered off and dried under high vacuum to give the title compound as a beige solid (14g, 87%).¹H NMR (300 MHz, DMSO-d6) 13.21 (brs, 1H),9.12 (s, 2H), 8.44 (m, 1H), 8.14 (m, 1H), 7.67 (t,J= 2.0 Hz, 1H), 7.57-7.54(m, 1H), 7.14 (t,J= 7.8 Hz, 1H), 5.25 (s, 2H), 6.68 (ddd,J= 7.8Hz, 2.0Hz, 1.0 Hz, 1H). HPLC (condition a): rt 1.24 min (purity 72.1%). MS (ESI +) 238.2.

Step 2: formation of 2- (3-iodo-phenyl) -5- (1H-pyrazol-4-yl) -pyrimidine

To 3- [5- (1H-pyrazol-4-yl) -pyrimidin-2-yl group]Suspension of-phenylamine (12.6g, 53.2mmol, 1.0 equiv.) in dioxane (500mL) was added diiodomethane (21.6mL, 266mmol,5.0 equiv.), copper (I) iodide (10.1g, 53.2mmol, 1.0 equiv.) and isoamyl nitrite (21.5mL, 159mmol, 3.0 equiv.). The reaction mixture was stirred at 100 ℃ for 2 hours and filtered. The filtrate was held in a flask. The resulting green solid was suspended in dioxane (100mL) and stirred at 100 ℃ 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 (20mL) and pentane (80 mL). The resulting brown solid was filtered and further washed with pentane and dried under high vacuum for several hours to give the title compound as a brown solid (7.0g, 38%).¹H NMR (300 MHz,DMSO-d6) 13.27 (brs, 1H), 9.20 (s, 2H), 8.71 (t,J= 1.5 Hz, 1H), 8.52 (m,1H), 8.39 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.21 (m, 1H), 7.89-7.86 (m, 1H), 7.35(t,J= 8.0 Hz, 1H). HPLC (condition a): rt 3.86 min (purity 67.6%). MS (ESI +): 349.3.

Intermediate 12: 2- {4- [2- (3-iodo-phenyl) -pyrimidin-5-yl ] -pyrazol-1-yl } -1-pyrrolidin-1-yl-ethanone

A solution of cesium carbonate (17.3g, 53mmol, 2.5 equivalents) and 2- (3-iodo-phenyl) -5- (1H-pyrazol-4-yl) -pyrimidine (intermediate 11, 7.4g, 21mmol, 1.0 equivalents) in DMF (150mL) was stirred at room temperature for 30 minutes, after which a solution of 2-bromo-1-pyrrolidin-1-yl-ethanone (Chemical conversion Labs; 4.08g, 21.3mmol, 1.0 equivalents) in DMF (65mL) was added. The reaction mixture was then stirred at room temperature overnight. It was diluted with DCM and washed with water and brine (three times). The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting residue was sonicated in DCM and the resulting solid was filtered, washed with EtOAc and pentane and dried under vacuum to give the title compound as a beige solid (3.70g, 38%).¹H NMR (300 MHz, DMSO-d6) 9.19 (s, 2H), 8.72 (t,J= 1.7 Hz,1H), 8.41-8.38 (m, 2H), 8.14 (d,J= 0.5 Hz, 1H), 7.89 (ddd,J= 7.8 Hz, 1.7Hz, 1.0 Hz, 1H), 7.35 (t,J= 7.8 Hz, 1H), 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-Methanesulfonyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester

Methanesulfonyl chloride (71 μ l, 0.92mmol, 1.0 equiv.) is added to a solution of tert-butyl 2-hydroxymethyl-morpholine-4-carboxylate (200mg, 0.92mmol, 1.0 equiv.) and TEA (190 μ l, 1.38mmol, 1.5 equiv.) in anhydrous DCM (3mL) maintained at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 10% citric acid solution and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown oil (250mg, 92%).¹H NMR (300 MHz, DMSO) 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, 1H), 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

Following the procedure described for intermediate 5, step 1, but starting from 2- {4- [2- (3-iodo-phenyl) -pyrimidin-5-yl]-pyrazol-1-yl } -1-pyrrolidin-1-yl-ethanone (intermediate 12, 1.0g, 2.18mmol, 1.0 equiv.) and 4- (4,4,5, 5-tetramethyl- [1,3,2]Starting from tert-butyl dioxaborolan-2-yl) -pyrazole-1-carboxylate (704mg, 2.4mmol, 1.1 equiv.) the title compound was obtained as an off-white solid (695mg, 80%).¹H NMR (300 MHz, DMSO-d6): 9.15 (s,2H), 8.57-8.56 (m, 1H), 8.37 (s, 1H), 8.21 (dt,J= 8.0 Hz, 1.5 Hz, 1H),8.14-8.13 (m, 3H), 7.75 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.51 (t,J= 8.0 Hz,1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrimidine

Reacting 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Pyrimidine (intermediate 2, 700mg, 2.22mmol, 1.0 equiv.), dipinacol ester (508mg, 2.00mmol, 0.9 equiv.), potassium acetate (436mg, 4.44mmol, 2.0 equiv.), and (dppf) PdCl₂.CH₂Cl₂A mixture of (162mg, 0.22mmol, 0.10 equiv) in 1, 4-dioxane (4mL) was heated at 100 ℃ for 1 hour at MW. The reaction mixture was washed with NaHCO₃The saturated solution was diluted and extracted with EtOAc (three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a dark oil (1g, 89%), which was used in the next step without further purification.¹H NMR (300 MHz, DMSO) 9.03 (s, 2H),8.56 (s, 1H), 8.34-8.18 (m, 2H), 7.92 (s, 1H), 7.76 (d,J= 7.6 Hz, 1H), 7.53(t,J= 7.7 Hz, 1H), 3.89 (s, 3H), .35 (s, 12H)。

Intermediate 16: exo-3- (4-iodo-1H-pyrazol-1-yl) -8-methyl-8-azabicyclo [3.2.1] octane

To a stirred solution of 4-iodopyrazole (50g, 0.257mol) in dry THF (500mL) at 0 deg.C under a nitrogen atmosphere was added Tropine (Tropine) (40)g, 0.283mol), followed by triphenylphosphine (135g, 0.5154mol) and diisopropyl azodicarboxylate (104g, 0.5154 mol). After this addition, the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by flash column chromatography (HCCl)₃MeOH, gradient from 95:5 to 92:8) to afford the title compound as a white crystalline solid (8.5g, 10%).¹H NMR (400 MHz, CDCl₃): 7.50 (s,1H), 7.46 (s, 1H), 4.54 (m, 1H), 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-iodo-phenyl) -pyrimidin-5-yl ] -pyrazol-1-yl } -1-morpholin-4-yl-ethanone

Following the procedure described for intermediate 12, but starting from 2- (3-iodo-phenyl) -5- (1H-pyrazol-4-yl) -pyrimidine (intermediate 11, 850mg, 2.44mmol, 1.0 eq) and 2-chloro-1-morpholin-4-yl-ethanone (599mg, 3.66mmol, 1.5 eq) the title compound was obtained as an off-white solid (730mg, 63%).¹H NMR (300 MHz, DMSO-d6) 9.18(s, 2H), 8.72 (t,J= 1.6 Hz, 1H), 8.41-8.37 (m, 2H), 8.15 (s, 1H), 7.90-7.87(m,H), 7.35 (t,J= 7.8Hz, 1H), 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: 4- {4- [2- (3-iodophenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylic acid tert-butyl ester

Step 1: formation of tert-butyl 4- {4- [2- (3-aminophenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylate

Following the procedure described for intermediate 11, step 1But from 3- (5-bromopyrimidin-2-yl) aniline (intermediate 4, 7.50g, 21mmol, 1.0 eq.) and 4- [4- (4,4,5, 5-tetramethyl- [1,3, 2-d-)]Dioxaborolan-2-yl) -pyrazol-1-yl]Starting from tert-butyl piperidine-1-carboxylate (11.9g, 31.5mmol, 1.5 equivalents), the title compound was obtained as a yellow powder (5g, 51%).¹H NMR (300 MHz, DMSO) 9.09 (s, 2H), 8.52 (s, 1H), 8.12 (s,1H), 7.75-7.49 (m, 2H), 7.23-7.09 (m, 1H), 6.69 (ddd,J= 7.9, 2.5, 1.1 Hz,1H), 5.26 (s, 2H), 4.42 (td,J= 7.3, 3.5 Hz, 1H), 4.05 (dd,J= 13.2, 7.7Hz, 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-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylate

Following the procedure described for intermediate 11, step 2, but starting from 4-4- [2- (3-aminophenyl) pyrimidin-5-yl]Starting from-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (4.50g, 10.70mmol, 1.00 eq) the title compound was obtained as an off-white solid (3.3g, 58%).¹H NMR (300 MHz, DMSO-d6) 9.16 (s, 2H), 8.71 (t,J=1.5 Hz, 1H), 8.56 (s, 1H), 8.38 (dt,J= 7.8 Hz, 1.5 Hz, 1H), 8.15 (s, 1H),7.88 (dt,J= 7.8 Hz, 1.5 Hz, 1H), 7.34 (t,J= 7.8Hz, 1H), 4.46-4.37 (m,1H), 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 (85.8% purity). MS (ESI +): 532.5.

Intermediate 19: 4- {4- [2- (3-trimethylsilylethynyl-phenyl) -pyrimidin-5-yl ] -pyrazol-1-yl } -piperidine-1-carboxylic acid tert-butyl ester

4- {4- [2- (3-iodophenyl) pyrimidin-5-yl]-1H-pyrazol-1-yl } piperidine-1-carboxylic acid tert-butyl ester (intermediate 18, 315mg, 0.59mmol, 1.0 equiv.), ethynyl-trimethyl-silane (83. mu.l, 0.59mmol, 1.0 equiv), (dppf) PdCl₂.CH₂Cl₂A mixture of (26mg, 0.04mmol, 0.06 equiv.), CuI (7mg, 0.04mmol, 0.06 equiv.), and TEA (115. mu.l, 0.89mmol, 1.5 equiv.) in dry THF (3.6mL) and dry DMF (1mL) was heated in a sealed vial at 80 ℃ for 48 hours. The reaction mixture was then diluted with EtOAc and saturated NH₄Cl and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by silica flash chromatography (heptane: EtOAC, gradient from 90:10 to 50:50) afforded the title compound (115mg, 39%) as an off-white solid.¹H NMR (300 MHz, DMSO-d6) 9.17 (s,2H), 8.57 (s, 1H), 8.41-8.38 (m, 1H), 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-iodo-pyrazol-1-yl) -cyclohexanone

Step 1: formation of toluene-4-sulfonic acid 1, 4-dioxa-spiro [4.5] dec-8-yl ester

4-methyl-benzenesulfonyl chloride (5.51g, 29mmol, 1.0 equiv.) was added portionwise to 1, 4-dioxa-spiro [4.5] spiro maintained at 5 ℃ with an ice bath]Decan-8-ol (4.44g, 28mmol, 1.0 equiv.) in anhydrous pyridine (13.5 mL). The reaction mixture was then allowed to warm to room temperature and stirred overnight. It was then quenched by addition of water and diluted with EtOAc. The organic phase was washed with 1N HCl solution, saturated NaHCO₃The solution and brine washes. It was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6.9g of a pale yellow oil. Purification by silica flash chromatography (heptane/EtOAc 60:40) afforded the title compound (4.7g, 52%) as a white powder. HPLC (condition a): rt 4.04 min (purity 100%).MS (ESI+): 330.3。

Step 2: formation of 1- (1, 4-dioxa-spiro [4.5] decan-8-yl) -4-iodo-1H-pyrazole

A mixture of toluene-4-sulfonic acid 1, 4-dioxa-spiro [4.5] dec-8-yl ester (4.47g, 13.9mmol, 1.0 equiv.), 4-iodo-1H-pyrazole (2.69g, 13.9mmol, 1.0 equiv.), and cesium carbonate (6.78g, 20.8mmol, 1.5 equiv.) was heated in DMA (50.0mL) at 100 ℃ for 3 hours. It was then allowed to cool to room temperature, diluted with EtOAc and washed with water and brine. The aqueous phase was back-extracted with EtOAc. The combined organic phases were finally dried over sodium sulfate, filtered and concentrated to give 6.32g of a yellow oil. Recrystallization from iPrOH afforded the title compound (2.81g, 61%) as a white powder. HPLC (condition a): rt3.46 min (purity 100%). MS (ESI +) 335.1.

And step 3: formation of 4- (4-iodo-pyrazol-1-yl) -cyclohexanone

A solution of 1- (1, 4-dioxa-spiro [4.5] dec-8-yl) -4-iodo-1H-pyrazole (2.81g, 8.41mmol, 1.00 eq) and pyridinium p-toluenesulfonate (4.23g, 16.8mmol, 2.0 eq) in acetone (40mL) and water (40mL) was heated at reflux overnight. It was then allowed to cool to room temperature and diluted with EtOAc. The aqueous phase was extracted with EtOAc (twice) and the combined organic phases were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a white powder (2.34g, 96%). HPLC (condition a): rt 2.83 min (purity 99.2%). MS (ESI +) 291.1.

Intermediates 21 and 22: cis-and trans-4- (4-iodo-pyrazol-1-yl) -cyclohexanols

Sodium borohydride (86mg, 2.27mmol, 0.5 equiv.) was added portionwise to a suspension of 4- (4-iodo-pyrazol-1-yl) -cyclohexanone (1.33g, 4.55mmol, 1.0 equiv.) in EtOH (10 mL). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The residue was treated with EtOAc (50mL) and NH₄Washed with saturated aqueous Cl (50 mL). The aqueous phase was back-extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give 1.42g of an oil. Purification by flash chromatography on silica (heptane/EtOAc, gradient from 80:20 to 40:60) afforded the title compound.

First eluting compound: colorless gum (234mg, 18%). Cis-4- (4-iodo-pyrazol-1-yl) -cyclohexanol. HPLC (condition a): rt 2.69 min (purity 99.7%). MS (ESI +): 293.1.

A second eluting compound: white powder (730mg, 55%). Trans-4- (4-iodo-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-spiro [4.5] dec-8-yl) -hydrazinecarboxylic acid tert-butyl ester

A solution of 1-aza-spiro [4.5] decane-2, 8-dione (Chembridge corporation, 800mg, 4.78mmol, 1.0 equiv.) and tert-butyl hydrazinoformate (309mg, 2.34mmol, 1.1 equiv.) in AcOH (5mL) was stirred at room temperature for 5 min. Sodium cyanoborohydride (133mg, 2.13mmol, 1.0 equiv.) was then added and the reaction mixture was stirred at room temperature overnight. It was then diluted with water and basified to pH 9 by addition of 5N NaOH solution. During this addition, the reaction mixture was maintained at 20 ℃ by the 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 (1.0g, 98%), which was used without further purification.

Step 2: formation of 8- (4-bromo-pyrazol-1-yl) -1-aza-spiro [4.5] decan-2-one

Hydrobromic acid (1.04mL, 48 wt% aq. solution, 9.18mmol, 2.0 eq.) was added to a solution of N' - (2-oxo-1-aza-spiro [4.5] decan-8-yl) -hydrazinecarboxylic acid tert-butyl ester (1.30g, 4.59mmol, 1.0 eq.) and 2-bromo-propionaldehyde (865mg, 5.51mmol, 1.2 eq.) in AcOH (13 mL). The reaction mixture was stirred at room temperature for 2 hours. It was then basified to pH 5 by addition of 5N NaOH solution and extracted with DCM (three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by auto-prep LC/MS afforded the title compound as a pure cis-isomer (1.0g, 94%).

Separation by chiral preparative HPLC (Chiralpak IC 250X 4.6mm), EtOH/DEA, afforded two pure isomers (of arbitrary nature).

First eluting isomer (174mg, Rt = 4.68 min): intermediate 23

Second eluting isomer (224mg, Rt = 6.22 min): intermediate 24

Intermediate 25: 2- [4- (4-iodo-pyrazol-1-yl) -cyclohexylamino ] -ethanol

2-amino-ethanol (0.30mL, 4.96mmol, 1.4 equiv.) was added in one portion to a solution of 4- (4-iodo-pyrazol-1-yl) -cyclohexanone (intermediate 20, 1.00g, 3.45mmol, 1.0 equiv.) in EtOH. After 1 hour, the reaction solution was cooled to 0 ℃ and NaBH was added portionwise over 1 minute₄(290mg, 7.67mmol, 2.2 equiv.). After a further hour, the reaction suspension was poured into 1N NaOH solution and extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification using an SCX-2 cartridge afforded the title compound as a white solid (1.00g, 84%).¹H NMR (300MHz, DMSO) 7.94 (s, 1H), 7.49 (s, 1H), 4.47 (brs, 1H), 4.12 (m, 1H), 3.45(m, 2H), 2.60 (t,J= 5.8 Hz, 2H), 2.41 (m, 1H), 2.95 (m, 4H), 1.72 (m, 2H),1.13 (m, 2H)。

Intermediate 26: trans-4- [4- (4-iodo-pyrazol-1-yl) -cyclohexyl ] -morpholin-3-one

Chloro-acetyl chloride (0.25mL, 3.14mmol, 1.1 equiv.) is added dropwise to 2- [4- (4-iodo-pyrazol-1-yl) -cyclohexylamino at-30 ℃ over 2 minutes]Ethanol (intermediate 25, 1.0g, 2.89mmol, 1.0 equiv.) and DIEA (2.00mL, 11.45mmol, 3.96 equiv.) in THF (80.00 mL). The reaction solution was allowed to slowly warm to room temperature and stirred for 16 hours. It was then poured into 1N HCl solution and extracted with DCM. The combined organic phases were washed with saturated NaHCO₃The solution was washed, dried over magnesium sulfate, filtered and concentrated to give 2-chloro-N- (2-hydroxy-ethyl) -N- [4- (4-iodo-pyrazol-1-yl) -cyclohexyl as a brown oil]-an acetamide. The oil was redissolved in THF (30mL, 370mmol, 128 equiv.) and sodium tert-butoxide (2M solution in THF, 30mL, 60.0mmol, 21 equiv.) was added in one portion. The reaction solution was heated at 40 ℃ for 1 hour and then cooled to roomWarmed and poured into 1N HCl solution. It was extracted with DCM (twice). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was taken up in EtOAc and Et₂Wet milling, filtration and drying in sequence gave the title compound as a yellow solid (275mg, 21%).¹H NMR (300 MHz, DMSO) 7.98 (s, 1H), 7.50 (s, 1H),4.40-4.25 (m, 1H), 4.25-4.10 (m, 1H), 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-iodo-pyrazol-1-yl) -cyclohexyl ] -oxazolin-2-one

Di-imidazol-1-yl-methanone (1.32g, 8.14mmol, 2.9 eq) was added in one portion to 2- [4- (4-iodo-pyrazol-1-yl) -cyclohexylamino]Ethanol (intermediate 25, 997mg, 2.83mmol, 1.0 equiv.) and dimethyl-pyridin-4-yl-amine (60mg, 0.49mmol, 0.17 equiv.) in CHCl₃(30 mL). The reaction suspension was heated at 60 ℃ for 20 minutes, then cooled and poured into 1N HCl solution. It was extracted with DCM (twice), the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica flash chromatography (DCM: MeOH, 96:4) followed by wet milling in acetonitrile afforded the title compound (239mg, 23%) as a white solid.¹H NMR (300 MHz, DMSO) 7.96 (d,J= 0.5 Hz, 1H), 7.51 (d,J= 0.5 Hz,1H), 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-iodo-1- (1-oxa-spiro [2.5] oct-6-yl) -1H-pyrazole

Potassium 2-methyl-propan-2-ol (466mg, 4.15mmol, 1.2 equiv.) was added in one portion to a solution of 4- (4-iodo-pyrazol-1-yl) -cyclohexanone (1.02g, 3.50mmol, 1.0 equiv.) and trimethylsulfonium chloride (531mg, 4.13mmol, 1.2 equiv.) in DMSO (50 mL). The reaction mixture was stirred at room temperature for 16 hours. It was then poured into EtOAc. The organic phase was separated and washed with brine (three times), dried over magnesium sulfate, filtered and concentrated to give the title compound as a white solid (813mg, 76%).¹H NMR (300 MHz, DMSO) 8.01 (d,J= 0.5 Hz, 1H), 7.52 (d,J=0.5 Hz, 1H), 4.41-4.26 (m, 1H), 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-hydrazino) -3, 3-difluoro-piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for intermediate 23, step 1, but starting from tert-butyl 3, 3-difluoro-4-oxo-piperidine-1-carboxylate (omega chem, 500mg, 2.06mmol, 1.0 equiv.) the title compound was obtained as a white solid (495mg, 1.40mmol, 68%).¹H NMR (400 MHz, DMSO; 1H) 8.33 (s, 1H), 4.72 (s, 1H), 3.97-3.91 (m,1H), 3.72-3.60 (m,1H), 3.56-3.44 (m,2H), 3.32-3.28 (m,1H), 1.78-1.71 (m,1H), 1.37 (s, 18H). HPLC (condition a): rt 4.75 min (purity 99.5%).

Step 2: formation of 4- (4-bromo-pyrazol-1-yl) -3, 3-difluoro-piperidine

Following the procedure described for intermediate 23, step 2, but starting from tert-butyl 4- (N' -tert-butoxycarbonyl-hydrazino) -3, 3-difluoro-piperidine-1-carboxylate (490mg, 1.39mmol, 1.0 eq) gave the title compound as a yellow solid (152mg, 36%). HPLC (condition a): rt 2.09 min (purity 88.0%). MS (ESI +): 268.0.

Intermediates 30 and 31: cis-and trans-8- (4-bromo-1H-pyrazol-1-yl) -2-azaspiro [4.5] decan-3-one

Step 1: formation of methyl 1, 4-dioxaspiro [4.5] decan-8-ylideneacetate

A solution of methyl (triphenylphosphoranylidene) acetate (13.9g, 41.6mmol) and cyclohexanedione monovinylketal (5g, 32mmol, 1.0 eq.) in dry toluene (50mL) was heated at reflux under a nitrogen atmosphere for 18 h. The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography (petroleum ether: ethyl acetate). The title compound was isolated as a colorless liquid (4g, 60%).¹H NMR (400 MHz, DMSO) 5.7 (s, 1H), 3.88 (s, 1H), 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 [4.5] decan-8-yl ] acetate

1, 4-dioxaspiro [4.5]]A solution of methyl deca-8-ylideneacetate (4g, 18.8mmol) in dry THF (20mL) was treated with nitromethane (1.5mL, 28.3mmol) followed by tert-butylammonium fluoride (18.8mLot, 1M solution in THF, 0.0188 mol). The resulting mixture was stirred under nitrogen at reflux for 18 hours. After cooling to room temperature, the mixture was diluted with water and extracted with MTBE (3 × 100 mL). The combined organic layers were washed with 10% sodium bicarbonate solution (20mL), water (100mL) and brine (50mL), dried over sodium sulfate, filtered and concentrated. By silica flash chromatography (petroleum)Ether: EtOAc) afforded the title compound (2.5g, 49%) as a colorless liquid.¹H NMR (400 MHz, DMSO) 4.7 (s, 2H), 3.94 (s, 4H), 3.69 (s, 3H), 2.57 (s, 2H), 1.74 (m, 8H)。

And step 3: formation of 1, 4-dioxa-10-azadispiro [4.2.4.2] tetradecan-11-one

To [8- (nitromethyl) -1, 4-dioxaspiro [4.5] under nitrogen atmosphere]Decan-8-yl]To a slurry of methyl acetate (1g, 4.7mmol) in methanol (20mL) was added Pd/C (1g, 10%). The reaction mixture was stirred at room temperature at 5kg/cm²H₂Stirred under pressure for 12 hours. After completion, the reaction mixture was filtered through a pad of celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (0.7g, 70%).¹H NMR (400 MHz, DMSO-d₆) 7.46 (s, 1H), 3.83 (s, 4H), 3.00 (s, 2H), 2.00 (s, 2H), 1.56-1.51 (m, 8H)。

And 4, step 4: formation of 2-azaspiro [4.5] decane-3, 8-dione

1, 4-dioxa-10-aza-dispiro [4.2.4.2]]A solution of tetradecan-11-one (10.5g, 49.8mmol) in aqueous HCl (2N, 20mL) was stirred at room temperature for 2 hours. 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. Purification by silica flash chromatography (petroleum ether: EtOAc) afforded the title compound (7.5g, 92%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) 7.58 (m, 1H), 3.15-3.15 (s, 2H), 2.30 (s,4H), 2.28-2.25 (m, 2H), 1.82-1.79 (m, 4H)。

And 5: formation of tert-butyl 2- (3-oxo-2-azaspiro [4.5] decan-8-yl) hydrazinecarboxylate

Following the procedure described for intermediate 23, step 1, but starting from 2-azaspiro [4.5]]Starting with decane-3, 8-dione (3.8g, 22.7mmol), the title compound was obtained as a white solid (4.6g, 72%).¹H NMR (400 MHz, DMSO-d₆) 8.17 (s, 1H), 7.46-7.44 (m, 1H), 4.20 (s, 1H), 2.97-2.93 (m, 2H), 2.64 (bs,1H), 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)。

And 5: formation of 8- (4-bromo-1H-pyrazol-1-yl) -2-azaspiro [4.5] decan-3-one

Following the procedure described for intermediate 23, step 1, but starting from 2- (3-oxo-2-azaspiro [4.5]]Dec-8-yl) hydrazinecarboxylic acid tert-butyl ester (4g, 14.1mmol) to give the title compound as a white solid (2g, 48%).¹H NMR (400MHz, DMSO-d₆) 8.04-8.04 (d, 1H), 7.52-7.50 (m, 2H), 4.15-4.09 (m, 1H), 3.12(s, 1H), 2.98 (s, 1H), 2.12 (s, 1H), 1.98 (s, 1H), 1.88-1.86 (m, 2H), 1.78-1.69 (m, 4H), 1.50-1.45 (m, 2H)。

And 7: separation of isomers of 8- (4-bromo-1H-pyrazol-1-yl) -2-azaspiro [4.5] decan-3-one

The mixture obtained in step 6 was separated by preparative HPLC (Chiralpak AD-H, heptane: IPA: DEA 80:20: 0.1).

First eluting compound: intermediate 30, Rt = 19.32 min

A second eluting compound: intermediate 31, Rt = 22.69 min

。

Intermediates 32 and 33: cis-and trans-8- (4-bromo-1H-pyrazol-1-yl) -2-methyl-2-azaspiro [4.5] decan-3-one

Step 1: formation of 8- (4-bromo-1H-pyrazol-1-yl) -2-methyl-2-azaspiro [4.5] decan-3-one

To 8- (4-bromo-1H-pyrazol-1-yl) -2-azaspiro [4.5] at 0 deg.C]Decan-3-one (mixture of intermediates 30 and 31 obtained in step 5; 4g, 3.4mmol) in DMF (10mL) was added sodium hydride (60%) (0.8g, 0.0116mol) followed by methyl iodide (2.2mL, 14.8 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with water (50mL) and brine (50mL), dried over sodium sulfate, filtered and concentrated. Purification by silica flash chromatography (petroleum ether: ethyl acetate) afforded the title compound (mixture of two isomers) (1.8g, 43%) as a beige solid.¹H NMR (400 MHz, DMSO-d₆) 8.04-8.03 (m, 1H), 7.51-7.50 (m, 1H), 4.16-4.10 (m, 1H), 3.24 (s, 1H), 3.09(s, 1H), 2.70-2.69 (m, 3H), 2.21 (s, 1H), 2.09 (s, 1H), 1.90-1.86 (m, 6H),1.79-1.54 (m, 2H)。

Step 2: isolation of 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: an intermediate 32; rt = 12.87 min

A second eluting compound: an intermediate 33; rt = 13.87 min

。

Intermediate 34: cis-8- (4-bromo-pyrazol-1-yl) -1-methyl-1-aza-spiro [4.5] decan-2-one

Following the procedure described for intermediates 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) the title compound was obtained as a brown gum (130mg, 82%). HPLC (maximum point (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-3 a-ol.

Step 1: formation of methyl 6- (2-tert-butoxycarbonylhydrazino) -cis-7 a-hydroxy-1, 3,4,5,6, 7-hexahydroisobenzofuran-3 a-carboxylate

Following the procedure described for intermediate 23, step 1, but starting from cis-7 a-hydroxy-6-oxo-3, 4,5, 7-tetrahydro-1H-isobenzofuran-3 a-carboxylic acid methyl ester (as described in Synthesis, 2010, 895 p)Preparation described, 1.0g, 4.6mmol) to give the title compound as a brown oil (0.85g, 55%).¹H NMR (400 MHz, DMSO) 12.00 (brs,1H), 8.20 (brs,1H), 4.91 (s, 1H), 4.17-4.10 (m,1H), 4.08-3.58 (m,1H), 3.57(s, 3H), 3.56-3.32 (m,1H), 1.91-1.61 (m, 10H), 1.37 (s, 9H). HPLC (condition a): rt2.40; 2.47 min (purity 11.6, 86.7%). MS (ESI +) 331.2.

Step 2: formation of methyl 6- (4-bromopyrazol-1-yl) -cis-7 a-hydroxy-1, 3,4,5,6, 7-hexahydroisobenzofuran-3 a-carboxylate

Following the procedure described for intermediate 23, step 2, but starting from methyl 6- (2-tert-butoxycarbonylhydrazino) -cis-7 a-hydroxy-1, 3,4,5,6, 7-hexahydroisobenzofuran-3 a-carboxylate (0.8g, 2.4mmol), the title compound was obtained as a colorless oil (0.2g, 24%).¹H NMR (400 MHz, DMSO) 7.48-7.46 (m,2H), 4.55 (m,1H), 4.30-4.24 (m,2H), 4.13-4.08 (m,2H), 3.92(s, 3H), 3.76-3.60 (m,1H), 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.

And step 3: formation of 5- (4-bromopyrazol-1-yl) -cis-7 a- (hydroxymethyl) -1,3,4,5,6, 7-hexahydroisobenzofuran-3 a-ol

Lithium borohydride (2M in THF, 4.13mL in THF, 8.6mmol) was slowly added to a solution of methyl 6- (4-bromopyrazol-1-yl) -cis-7 a-hydroxy-1, 3,4,5,6, 7-hexahydroisobenzofuran-3 a-carboxylate (1.2g, 3.4mmol) in THF (10mL) under a nitrogen atmosphere at 0-5 deg.C over 10 minutes. The reaction mixture was allowed to warm to 25-26 ℃ and stirred for 8 hours. It was then quenched with ice (50g) and acetic acid (5mL) and extracted with DCM (3 times). The combined organic phases were washed with water, brine, dried over sodium sulfate, filtered and concentrated to give the title compound (0.8g) as a pale yellow liquid containing the cis-trans isomer isolated by preparative HPLC (95: 5).

Minor isomer: 50 mg; HPLC (condition a): rt 3.72 min (purity 93.8%).

Major isomers: 0.5 g.¹H NMR (400 MHz; DMSO): 7.47 (s, 2H), 4.48-4.44 (m,1H), 4.22-4.20 (d,J= 11.08 Hz, 1H), 3.99-3.93 (m, 2H), 3.70-3.68 (d,J=8.32 Hz, 1H), 3.54-3.51 (d,J= 10.0Hz, 2H), 2.28-2.10 (m,4H), 2.02-1.95 (m,1H), 1.64-1.59 (m, 1H). HPLC (condition a): rt 2.95 min (purity 99.9%). MS (ESI +): 319.0. The compounds described in the examples were carried out as cis-cis isomers as shown by NOE experiments.

And 4, step 4: enantiomeric separation of cis-5- (4-bromopyrazol-1-yl) -cis-7 a- (hydroxymethyl) -1,3,4,5,6, 7-hexahydroisobenzofuran-3 a-ol

The enantiomer of the main isomer obtained in step 3 was passed through SFC (Lux A2, CO)₂MeOH).

First eluting enantiomer: an intermediate 35; 200 mg; rt = 15.6 min (Chiralcel OD-H, 250 × 4.6mm; 5 μ M; eluent: hexane: IPA: TFA, 90:10: 0.1).

Second eluting enantiomer: an intermediate 36; 200 mg; rt = 16.78 min (Chiralcel OD-H, 250 × 4.6mm; 5 μ M; eluent: 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-hydrazino) -3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for intermediate 23, step 1, but starting from 3-fluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (omega chem; 1.00 g; 4.47 mmol; 1.0 eq.) the title compound was obtained as a white solid (1.0g, 73%). MS (ESI +): 222.2.

Step 2: formation of 4- (4-bromo-pyrazol-1-yl) -3-fluoro-piperidine

Following the 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) the title compound was obtained as a white solid (mixture of cis: trans isomer 7: 3; 600mg, 74%).¹H NMR (400 MHz, DMSO-d6) 8.06 (s, 0.3H), 7.97(s, 0.7H), 7.59 (brs, 1H), 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, 1H), 2.10 (m, 0.7H),1.93-1.82 (m, 2H)。

Example 1: 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) piperidine-1-carboxylate

After adding Pd (PPh)₃)₄(60mg, 0.05mmol) before 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]Pyrimidine (intermediate 2, 160mg, 0.50mmol), 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, 287mg, 0.76mmol) and Na₂CO₃A solution (140mg, 0.12mmol) in dry toluene ethanol (1:1) (5mL) was purged with nitrogen for 30 minutes. The reaction mixture was then heated at 100 ℃ overnight and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica (hexanes: EtOAc) afforded the title compound (230mg, 93%) as a yellow solid.¹H NMR(400 MHz, DMSO-d6): 9.15 (s, 2H), 8.53 (d,J= 8.0 Hz, 2H), 8.25 (s, 1H),8.21 (d,J= 7.76 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.91-7.48 (m, 10H),4.45-4.44 (m, 1H), 4.07-4.04(m, 2H), 3.88 (s, 3H), 2.12 (s, 2H), 2.70 (d,J=3.44 Hz,1H), 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- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

HCl/dioxane (4N solution in dioxane, 10mL) was added slowly to 4- [4- [2- [3- (3-pyridyl) phenyl ] under nitrogen atmosphere at 0 deg.C]Pyrimidin-5-yl]Pyrazol-1-yl]Piperidine-carboxylic acid tert-butyl ester (200mg, 0.63 mmol). After 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether and dried under reduced pressure to give the title compound as a beige solid (32mg, 81%).¹H NMR (400 MHz, DMSO-d₆): 9.19 (s, 3H),8.52 (t,J= 4.0 Hz, 2H), 8.25-8.19 (m, 3H), 7.91-7.89 (m, 1H), 7.72-7.69 (m,1H), 7.51 (t,J= 7.72 Hz,1H), 3.89 (s,3H), 3.41-3.37 (m,2H), 3.11-3.08(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) -1H-pyrazol-4-yl) -2- (3- (pyridin-3-yl) phenyl) pyrimidine hydrochloride

Step 1: formation of 4- {4- [2- (3-pyridin-3-yl-phenyl) -pyrimidin-5-yl ] -pyrazol-1-yl } -piperidine-1-carboxylic acid tert-butyl ester

Following the 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-piperidinyl) pyrazole-4-boronic acid pinacol ester (combi-Blocks), the title compound was obtained as a yellow solid. MS (ESI +): 483.2.

Step 2: formation of 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -2- (3- (pyridin-3-yl) phenyl) pyrimidine hydrochloride

Following the procedure described for example 1, step 2, but starting from 4- {4- [2- (3-pyridin-3-yl-phenyl) -pyrimidin-5-yl]Starting from tert-butyl-pyrazol-1-yl } -piperidine-1-carboxylate, the title compound is obtained as a yellow oil.¹H NMR (400MHz, DMSO-d₆): 9.21-9.18 (m, 2H), 9.00-8.95 (m, 1H), 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,1H), 7.70-7.60(m, 2H), 4.59-4.53 (m,1H), 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

Following the procedure described for intermediate 4 but starting from 5-bromo-2- [3- (1-methyl-1H-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 equivalents) to yield the title compound as an off-white solid (4g, 85%).¹H NMR (300 MHz, DMSO-d6) 13.25 (s, 1H), 9.20 (s, 2H), 8.59-8.40(m, 2H), 8.30-8.11 (m, 3H), 7.93 (d,J= 0.9 Hz, 1H), 7.71 (ddd,J= 7.6,1.8, 1.1 Hz, 1H), 7.51 (t,J= 7.8Hz, 1H), 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-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -piperidin-1-yl ] -ethanone

Trifluoroacetic anhydride (44. mu.l; 0.31 mmol; 1.0 eq.) is added to 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] maintained at 0 DEG C]-5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine (example 1, 200 mg; 0.31 mmol; 1.0 equiv.) in a solution of DCM (3mL) and TEA (130. mu.l; 0.93 mmol; 3.0 equiv.). The reaction mixture was then stirred at room temperature for 3 hours. By adding NaHCO at 0 deg.C₃The saturated solution quenches it. The aqueous phase was extracted with DCM (twice) and the combined organic phases were saturated with NH₄Cl and brine, dried over magnesium sulfate, filtered and concentrated. Purification by auto-prep LC/MS afforded the title compound as a white foam (61mg, 41%).¹H NMR (300 MHz, DMSO-d6) 9.17(s, 2H), 8.61-8.55 (m, 1H), 8.53 (t,J= 1.6 Hz, 1H), 8.29-8.25 (m, 1H), 8.22(dt,J= 7.8, 1.4 Hz, 1H), 8.19-8.16 (m, 1H), 7.93 (d,J= 0.8 Hz, 1H), 7.75-7.68 (m, 1H), 7.52 (t,J= 7.7Hz, 1H), 4.70-4.56 (m,1H), 4.47-4.35(m, 1H),4.06-3.94 (m,1H), 3.89 (s,3H), 3.58-3.42 (m,1H), 3.24-3.10 (m,1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -piperidin-1-yl ] -ethanone

Acetyl chloride (222. mu.l; 3.1 mmol; 2.0 equiv.) is added to 2- [3- (-methyl-1H-pyrazol-4-yl) -phenyl]-5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride (example 1, 655 mg; 1.55 mmol; 1.0 equiv.) and TEA (503. mu.l; 3.88 mmol; 2.5 equiv.) in dry DMF (12mL) and the reaction mixture was stirred at room temperature under nitrogen for 2H. The reaction mixture was diluted with DCM and washed with water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica flash chromatography (DCM: MeOH, gradient from 100:0 to 80:20) afforded the title compound (370mg, 56%) as a white solid.¹H NMR (300 MHz, DMSO-d6) 9.16 (s, 2H), 8.58-8.50 (m, 2H), 8.26 (s, 1H), 8.21 (dt,J= 8.0, 1.5 Hz, 1H), 8.15 (s, 1H),7.92 (s, 1H), 7.71 (dt,J= 8.0, 1.5 Hz, 1H), 7.51 (t,J= 8.0 Hz, 1H), 4.58-4.43 (m, 2H), 4.01-3.83 (m, 4H), 3.29-3.17 (m, 1H), 2.74 (dd,J= 14.1, 9.2Hz, 1H), 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) -1H-pyrazol-4-yl ] -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine

Sodium triacetoxyborohydride (50 mg; 0.24 mmol; 2.0 equiv.) is added to 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]-5- (1-piperidin-4-yl-1H-pyrazol-4-yl) pyrimidine (example 1, 50 mg; 0.12 mmol; 1.0 eq.), formaldehyde (16. mu.l of a 36% aqueous solution; 0.21 mmol; 1.8 eq.) and DIEA (24. mu.l; 0.14 mmol; 1.2 eq.) in DCE (2 mL). The reaction mixture was heated at 50 ℃ for 1 hour. It was subsequently diluted with DCM and poured into NaHCO₃In a saturated solution. 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%).¹H NMR (300 MHz, DMSO-d6) 9.17 (s, 2H), 8.54-8.52 (m, 2H), 8.26(s, 1H), 8.22 (dt,J= 7.8 Hz, 1.5 Hz, 1H), 8.15 (s, 1H), 7.92 (d,J= 1.5Hz, 1H), 7.51 (dt,J= 7.8 Hz, 1.5 Hz, 1H), 7.51 (t,J= 7.8Hz, 1H), 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-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- (4- {2- [3- (3-furyl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) piperidine-1-carboxylate

4-4- [2- (3-iodophenyl) pyrimidin-5-yl before addition of dioxane: water (1.5:0.75mL)]-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 5; 100 mg; 0.19 mmol; 1.0 eq.), furan-3-boronic acid (25 mg; 0.23 mmol; 1.2 eq.), Pd (Ph)₃)₄(11 mg; 0.01 mmol; 0.05 eq.) and potassium carbonate (78 mg; 0.56 mmol; 3.0mmAmount) was flushed with nitrogen. The reaction mixture was heated in MW at 120 ℃ for 30 minutes. It was then diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (three times) and the 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 (92 mg; 100%) as a white solid.¹H NMR (300 MHz, DMSO-d6) 9.17 (s, 2H), 8.57-8.54 (m, 2H), 8.30-8.27 (m,2H), 8.15 (s, 1H), 7.75 (t,J= 1.7 Hz, 1H), 7.78-7.74 (m, 1H), 7.55 (t,J=7.8 Hz, 1H), 7.03 (dd,J= 1.7 Hz, 1.0 Hz,1H), 4.47-4.40 (m,1H), 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-1H-pyrazol-4-yl) -pyrimidine hydrochloride

HCl/dioxane (4N solution in dioxane, 0.76mL, 3.0mmol, 15 equiv.) was added slowly to 4- (4-2- [3- (3-furyl) phenyl) under nitrogen atmosphere at 0 deg.C]pyrimidin-5-yl-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (95 mg; 0.20 mmol; 1.0 eq) in DCM (0.95mL) and MeOH (0.95 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Purification by auto-prep LC/MS afforded the title compound as a white powder (40 mg; 49%).¹H NMR (300 MHz, DMSO-d6) 9.21 (s, 2H), 8.78 (bs, 2H), 8.57(t,J= 1.6 Hz, 1H), 8.52 (s, 1H), 8.31-8.27 (m, 2H), 8.21 (s, 1H), 7.80 (t,J= 1.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.56 (t,J= 7.8Hz, 1H), 7.03-7.02 (m,1H), 4.58-4.52 (m,1H), 3.46-3.38 (m,2H), 3.16-3.06 (m,2H), 2.28-2.11 (m, 4H). HPLC (condition a): rt 3.11 min (purity 99.8%). MS (ESI +): 372.4.

Example 8: 4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from pyrimidine (intermediate 2; 80 mg; 0.25 mmol; 1.0 equivalent) and 1- (ethoxycarbonylmethyl) -1H-pyrazole-4-boronic acid pinacol ester (71 mg; 0.25 mmol; 1.0 equivalent), the title compound was obtained as a white solid (21mg, 23%).¹H NMR(300 MHz, DMSO-d6) 13.22 (s, 1H), 9.18 (s, 2H), 8.54 (s, 1H), 8.44 (s, 1H),8.27 (s, 1H), 8.23 (d,J= 7.8 Hz, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.72 (d,J= 7.8 Hz, 1H), 7.52 (t,J= 7.8Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -1-pyrrolidin-1-yl-ethanone

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 equiv.) and 1-pyrrolidin-1-yl-2- [4- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -pyrazol-1-yl]Starting with ethanone (intermediate 7, 77 mg; 0.25 mmol; 1.0 equiv.) the title compound was obtained as a yellow powder (57 mg; 54%).¹H NMR (300 MHz, DMSO-d6) 9.18(s, 2H), 8.54 (t,J= 1.6 Hz, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.25-8.17 (m,1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.77-7.67 (m, 1H), 7.52 (t,J= 7.7 Hz, 1H),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 (96.3% purity). MS (ESI +): 414.3.

Example 10: 4- [2- (4- {2- [3- (1-ethyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethyl ] -morpholine

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 equiv.) and 1- (2-morpholinoethyl) -1H-pyrazole-4-boronic acid pinacol ester (78 mg; 0.25 mmol; 1.0 equiv.) the title compound was obtained as a white powder (71 mg; 68%).¹H NMR (300MHz, DMSO-d6) 9.16 (s, 2H), 8.53 (t,J= 1.6 Hz, 1H), 8.46 (s, 1H), 8.26(s, 1H), 8.25-8.19 (m, 1H), 8.13 (s, 1H), 7.92 (d,J= 0.6 Hz, 1H), 7.76-7.66(m, 1H), 7.52 (t,J= 7.8 Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethyl ] -amine

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Pyrimidine (intermediate 2, 80 mg; 0.25 mmol; 1.0 equiv.) and dimethyl-2- [4- (4,4,5, 5-tetramethyl- [1,3,2]]Dioxaborolan-2-yl) -pyrazol-1-yl]-BStarting with an amino group (67 mg; 0.25 mmol; 1.0 equivalent), the title compound was obtained as a white solid (69 mg; 73%).¹H NMR (300 MHz, DMSO-d6) 9.16 (s, 2H), 8.53 (t,J= 1.6 Hz, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.25-8.17 (m, 1H), 8.13 (s, 1H),7.92 (d,J= 0.6 Hz, 1H), 7.77-7.66 (m, 1H), 7.52 (t,J= 7.8 Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- [1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl ] -pyrimidine

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Pyrimidine (intermediate 2, 150 mg; 0.48 mmol; 1.0 equiv.) and 1- (tetrahydrofuran-3-yl) -4- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -1H-pyrazole (CombiPhos Catalysts, inc; 126 mg; 0.48 mmol; 1.0 equivalent) to give the title compound as a white solid (113 mg; 64%).¹H NMR (300 MHz,DMSO-d6) 9.18 (s, 2H), 8.53 (s, 2H), 8.34-8.14 (m, 3H), 7.94 (s, 1H), 7.71(d,J= 7.8 Hz, 1H), 7.52 (t,J= 7.7Hz, 1H), 5.15-5.04 (m,1H), 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-isoxazol-4-yl-phenyl) -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- {4- [2- (3-isoxazol-4-ylphenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylate

4-4- [2- (3-iodophenyl) pyrimidin-5-yl before addition of dioxane: water (2.25:1.1mL)]Tert-butyl (1H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5; 150 mg; 0.24 mmol; 1.0 equiv.), 4-isoxazoleboronic acid pinacol ester (47 mg; 0.24 mmol; 1.0 equiv.), bis (triphenylphosphine) palladium (II) chloride (17 mg; 0.02 mmol; 0.10 equiv.) and cesium fluoride (109 mg; 0.72 mmol; 3.0 equiv.) were purged with nitrogen. The reaction mixture was heated in MW at 120 ℃ for 30 minutes. It was then diluted with EtOAc and water. The aqueous phase was extracted with EtOAc and the 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 an off-white solid (70 mg; 62%).¹H NMR (300 MHz, DMSO-d6) 9.60 (s, 1H), 9.27 (s, 1H), 9.17(s, 2H), 8.64 (t,J= 1.5 Hz, 1H), 8.56 (s, 1H), 8.35 (dt,J= 8.0 Hz, 1.5Hz, 1H), 8.16 (s, 1H), 7.87-7.83 (m, 1H), 7.61 (t,J= 8.0 Hz,1H), 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-isoxazol-4-yl-phenyl) -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

A solution of HCl/dioxane (4N solution in dioxane, 0.55mL, 2.2mmol, 15 equivalents) was slowly added to 4-4- [2- (3-isoxazol-4-ylphenyl) pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (70 mg; 0.15 mmol; 1.0 equiv.) in DCM (0.7mL) and MeOH (0.7 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting solid was suspended in DCM (3mL), sonicated, filtered and washedDried under reduced pressure overnight to give the title compound as a yellow solid (60 mg; 99%).¹H NMR (300 MHz, DMSO-d6): 9.61(s, 1H), 9.27 (s, 1H), 9.25-9.21 (m, 3H), 8.98 (brs, 1H), 8.64 (t,J= 1.5Hz, 1H), 8.55 (s, 1H), 8.36 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.22 (s, 1H), 7.86(dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.62 (t,J= 8.0 Hz,1H), 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-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- (4- {2- [3- (1, 3-dimethyl-1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) piperidine-1-carboxylate

Following the 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 equiv.) and 1, 3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (63 mg; 0.28 mmol; 1.0 equiv.) the title compound was obtained as a brown gum (120mg, 85%). HPLC (condition a): rt 4.37 min (purity 89.4%). MS (ESI +): 500.5.

Step 2: formation of 2- [3- (1, 3-dimethyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- (4-2- [3- (1, 3-dimethyl-1H-pyrazol-4-yl) phenyl)]Pyrimidin-5-yl-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (120 mg; 0.24 mmol; 1.0 equivalent) to give the title compound as a brown solid (60 mg; 57%).¹H NMR (300 MHz, DMSO-d6) 9.20 (m,3H), 8.95 (brs, 1H), 8.52 (s, 1H), 8.47-8.46 (m, 1H), 8.25 (dt,J=7.0 Hz,1.8 Hz,1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.60-7.51 (m,2H), 4.60-4.52 (m,1H), 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-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- (4- {2- [3- (1, 5-dimethyl-1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Following the procedure described for example 7, step 1, but starting from 4-4- [2- (3-iodophenyl) pyrimidin-5-yl]Starting from tert-butyl (intermediate 5, 150 mg; 0.28 mmol; 1.0 eq) 1H-pyrazol-1-ylpiperidine-1-carboxylate and 1, 5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (63 mg; 0.28 mmol; 1.0 eq) the title compound was obtained as a beige solid (96mg, 68%).¹H NMR (300 MHz, DMSO-d6) 9.17 (s,2H), 8.54 (s, 1H), 8.41 (s, 1H),8.28-8.25 (m,1H), 8.14 (s, 1H), 7.64 (s, 1H), 7.59-7.54 (m,2H), 4.47-4.37(m, 1H), 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- [3- (1, 5-dimethyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- (4-2- [3- (1, 5-dimethyl-1H-pyrazol-4-yl) phenyl)]pyrimidin-5-yl-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 5; 95 mg; 0.19 mmol; 1.0 equivalent) to give the title compound as a yellow solid (80 mg; 96%).¹H NMR (300 MHz, DMSO-d6) 9.27-9.21 (m,3H), 9.05-8.86 (m,1H), 8.52 (s, 1H), 8.43-8.41 (m,1H), 8.29-8.24 (m,1H), 8.20 (s, 1H), 7.67 (s, 1H), 7.59-7.53 (m,2H), 4.62-4.49 (m,1H), 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-ethyl) -1H-pyrazol-4-yl ] -phenyl } -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: form 4- {4- [2- (3- {1- [ 2-fluoro-1- (fluoromethyl) ethyl ] -1H-pyrazol-4-yl } phenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for example 7, step 1, but starting from 4-4- [2- (3-iodophenyl) pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 5, 150 mg; 0.28 mmol; 1.0 eq.) and 1- [ 2-fluoro-1- (fluoromethyl) ethyl ester]Starting from (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (intermediate 8, 77 mg; 0.28 mmol; 1.0 eq.) the title compound was obtained as a white solid (120mg, 77%).¹H NMR (300 MHz,DMSO-d6): 9.16 (s, 2H), 8.57 (t,J= 1.5 Hz, 1H), 8.55 (s, 1H), 8.48 (s, 1H),8.24 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.76 (dt,J=8.0Hz, 1.5 Hz,1H), 7.52-7.55 (m,1H), 5.08-4.92 (m,3H), 4.88-4.77 (m,2H), 4.47-4.40 (m,1H), 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: form 2- {3- [1- (2-fluoro-1-fluoromethyl-ethyl) -1H-pyrazol-4-yl ] -phenyl } -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Following the procedure described for example 7, step 2, but starting from 4-4- [2- (3-1- [ 2-fluoro-1- (fluoromethyl) ethyl)]-1H-pyrazol-4-ylphenyl) pyrimidin-5-yl]Starting from tert-butyl (120 mg; 0.22 mmol; 1.0 eq.) of-1H-pyrazol-1-ylpiperidine-1-carboxylate, the title compound is obtained as a white amorphous solid (30 mg; 28%).¹H NMR (300 MHz, DMSO-d6) 9.20 (s, 2H), 8.72 (bs, 2H), 8.57 (t,J= 1.5 Hz, 1H), 8.52 (s,H), 8.47(s, 1H), 8.25 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.76(dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.54 (t,J= 8.0 Hz,1H), 5.11-4.92 (m,3H), 4.87-4.77 (m,2H), 4.60-4.52 (m,1H), 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-1H-pyrazol-4-yl) -pyrimidin-2-yl ] -phenyl } -pyrazol-1-yl) -1-pyrrolidin-1-yl-ethanone hydrochloride

Step 1: formation of tert-butyl 4- [4- (2- {3- [1- (2-oxo-2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl ] phenyl } pyrimidin-5-yl) -1H-pyrazol-1-yl ] piperidine-1-carboxylate

Following the procedure described for example 7, step 1, but starting from 4-4- [2- (3-iodophenyl) pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 5, 150 mg; 0.28 mmol; 1.0 equiv.) and 1-pyrrolidin-1-yl-2- [4- (4,4,5, 5-tetramethyl- [1,3,2]Dioxaborolan-2-yl) -pyrazol-1-yl]Starting with ethanone (intermediate 7; 103 mg; 0.34 mmol; 1.2 equiv.) the title compound was obtained as a grey solid (148 mg; 90%).¹H NMR (300 MHz,DMSO-d6) 9.18 (s, 2H), 8.55-8.54 (m, 2H), 8.24-8.21 (m, 2H), 8.15 (s, 1H),7.94 (s, 1H), 7.73 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.52 (t,J= 8.0 Hz, 1H),5.06 (s, 2H), 4.48-4.39 (m, 1H), 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-1H-pyrazol-4-yl) -pyrimidin-2-yl ] -phenyl } -pyrazol-1-yl) -1-pyrrolidin-1-yl-ethanone hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- [4- (2-3- [1- (2-oxo-2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl]Phenyl-pyrimidin-5-yl) -1H-pyrazol-1-yl]Starting from tert-butyl piperidine-1-carboxylate (145 mg; 0.25 mmol; 1.0 equivalent), the title compound was obtained as a yellow solid (85.00 mg; 65.81%).¹H NMR (300MHz, DMSO-d6) 9.20 (s, 2H), 9.12 (m, 1H), 8.86 (m, 1H), 8.55 (t,J= 1.7Hz, 1H), 8.53 (s, 1H), 8.25-8.21 (m, 3H), 7.95 (d,J= 0.8 Hz, 1H), 7.75-7.71(m, 1H), 7.53 (t,J= 8.0 Hz, 1H), 5.06 (s, 2H), 4.61-4.51 (m, 1H), 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= 6.8Hz, 2H)). HPLC (condition a): rt 2.41 pointsClock (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- [3- (1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) piperidine-1-carboxylate

Following the procedure described for example 7, step 1, but starting from 4-4- [2- (3-iodophenyl) pyrimidin-5-yl]Starting from-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (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) the title compound was obtained as an off-white solid (177 mg; 99%).¹H NMR (300 MHz, DMSO) 13.03 (bs, 1H), 9.17 (s,2H), 8.59-8.52 (m, 2H), 8.29 (s, 1H), 8.22 (dt,J= 8.0, 1.5 Hz, 1H), 8.15(s, 1H), 7.96 (s, 1H), 7.75 (dt,J= 8.0, 1.5 Hz, 1H), 7.51 (t,J= 8.0 Hz,1H), 4.51-4.36 (m,1H), 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-1H-pyrazol-4-yl) -2- [3- (1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Following the procedure described for example 7, step 2, but starting from 4- [4- (2-3- [1- (tert-butoxycarbonyl) -1H-pyrazol-4-yl)]Phenyl-pyrimidin-5-yl) -1H-pyrazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (215 mg; 0.38 mmol; 1.0 eq.) to give a white amorphous solidTitle compound of (b) body (50 mg; 33%).¹H NMR (300 MHz, DMSO-d6) 13.05 (brs, 1H), 9.20 (s, 2H), 8.90 (brs, 2H), 8.56 (t,J= 1.7 Hz, 1H), 8.52(s, 1H), 8.30 (brs, 1H), 8.24-8.21 (m, 2H), 7.98 (brs, 1H), 7.76 (dt,J= 7.8Hz, 1.7 Hz, 1H), 7.52 (t,J= 7.8Hz, 1H), 4.62-4.52 (m,1H), 3.47-3.39 (m,2H), 3.15-3.06 (m,2H), 2.29-2.08 (m, 4H). HPLC (condition a): rt2.08 min (purity 100.0%). MS (ESI +): 372.4.

Example 19: 5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -2- [3- (1-propyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- (4- {2- [3- (1-propyl-1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) piperidine-1-carboxylate

Following the procedure described for example 7, step 1, but starting from 4-4- [2- (3-iodophenyl) pyrimidin-5-yl]Starting from tert-butyl (intermediate 5, 200 mg; 0.38 mmol; 1.0 eq.) and 1-propyl-1H-pyrazole-4-boronic acid pinacol ester (89 mg; 0.38 mmol; 1.0 eq.) the title compound was obtained as a beige solid (160mg, 83%).¹H NMR (300 MHz, DMSO-d6) 9.16 (s, 2H), 8.55 (s, 1H), 8.54 (t,J= 1.5 Hz,1H), 8.30 (s, 1H), 8.21 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.15 (s, 1H), 7.93 (s,1H), 7.72 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.51 (t,J= 8.0 Hz, 1H), 4.47-4.38(m, 1H), 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= 7.5Hz, 3H). HPLC (condition a): rt 4.85 min (91.2% purity). MS (ESI +): 514.6.

Step 2: formation of 5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -2- [3- (1-propyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- (4-2- [3- (1-propyl-1H-pyrazol-4-yl) phenyl)]pyrimidin-5-yl-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (160 mg; 0.31 mmol; 1.00 equivalents) to give the title compound as a pale yellow solid (126 mg; 90%).¹H NMR (300 MHz, DMSO-d6) 9.28-9.20(m, 3H), 9.01-8.98 (m, 1H), 8.55-8.53 (m, 2H), 8.31 (s, 1H), 8.23-8.21 (m,2H), 7.94 (s, 1H), 7.73 (dt,J= 7.8 Hz, 1.6 Hz, 1H), 7.51 (t,J= 7.8 Hz,1H), 4.57 (quint.,J= 5.0 Hz, 1H), 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-isopropyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- (4- {2- [3- (1-isopropyl-1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) piperidine-1-carboxylate

Following the procedure described for example 7, step 1, but starting from 4-4- [2- (3-iodophenyl) pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 5; 200 mg; 0.38 mmol; 1.0 eq.) and 1-isopropyl-4- (4,4,5, 5-tetramethyl- [1,3, 2%]Dioxaborolan-2-yl) -1H-pyrazole (98 mg; 0.41 mmol; 1.1 equivalents) to yield the title compound as a yellow solid (153 mg; 79%).¹H NMR (300 MHz, DMSO-d6) 9.18 (s, 2H),8.55-8.53 (m, 2H), 8.34 (s, 1H), 8.21 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.15 (s,1H), 7.92 (s, 1H), 7.73 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.51 (t,J= 8.0 Hz,1H), 4.54 (sept.,J= 6.7 Hz, 1H), 4.47-4.38 (m, 1H), 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-isopropyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- (4-2- [3- (1-isopropyl-1H-pyrazol-4-yl) phenyl)]pyrimidin-5-yl-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (150 mg; 0.29 mmol; 1.0 equivalent) to give the title compound as a yellow solid (95 mg; 72%).¹H NMR (300 MHz, DMSO-d6) 9.26-9.20(m, 3H), 8.99-8.95 (m, 1H), 8.55 (t,J= 1.6 Hz, 1H), 8.53 (s, 1H), 8.34 (s,1H), 8.23-8.21 (m, 2H), 7.93 (s, 1H), 7.73 (dt,J= 7.8 Hz, 1.6 Hz, 1H), 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 (99.0% purity). MS (ESI +) 414.4.

Example 21: 2- [3- (1-benzyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of tert-butyl 4- (4- {2- [3- (1-benzyl-1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) piperidine-1-carboxylate

Following the procedure described for example 7, step 1, but starting from 4-4- [2- (3-iodophenyl) pyrimidin-5-yl]Starting from-1H-pyrazol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 5; 200 mg; 0.38 mmol; 1.0 equivalent), 1-benzyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (107 mg; 0.38 mmol; 1.0 equivalent) the title compound was obtained as an off-white solid (165 mg; 78%).¹H NMR (300 MHz, DMSO-d6): 9.18 (s, 2H),8.55-8.53 (m, 2H), 8.44 (s, 1H), 8.21 (dt,J= 7.8 Hz, 1.5 Hz, 1H), 8.15 (s,1H), 7.94 (d,J= 0.8 Hz, 1H), 7.73 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.73 (m,1H), 7.51 (t,J= 8.0 Hz,1H), 7.40-7.28 (m, 5H), 5.37 (s,2H), 4.47-4.39 (m,1H), 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- [3- (1-benzyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- (4-2- [3- (1-benzyl-1H-pyrazol-4-yl) phenyl)]pyrimidin-5-yl-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (165 mg; 0.29 mmol; 1.0 equivalent) to give the title compound as a yellow solid (125 mg; 85%).¹H NMR (300 MHz, DMSO-d6) 9.34-9.30 (m,1H), 9.19 (s, 2H), 9.08-9.05 (m, 1H), 8.57-8.53 (m, 2H), 8.44 (s, 1H), 8.24-8.20 (m, 2H), 7.98 (d,J= 0.8 Hz, 1H), 7.73 (dt,J= 7.8 Hz, 1.5 Hz, 1H),7.52 (t,J= 7.8 Hz, 1H), 7.40-7.27 (m, 5H), 5.38 (s, 2H), 4.57 (quint.,J=5.0 Hz,1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- (1-pyridin-3-ylmethyl-1H-pyrazol-4-yl) -pyrimidine

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting with pyrimidine (intermediate 2, 100 mg; 0.32 mmol; 1.0 eq) and 1- (pyridin-3-ylmethyl) -1H-pyrazole-4-boronic acid pinacol ester (90 mg; 0.32 mmol; 1.0 eq) the title compound was obtained as a white solid (14 mg; 12%).¹H NMR(300 MHz, DMSO-d6) 9.17 (s, 2H), 8.60 (s, 2H), 8.56-8.49 (m, 2H), 8.30-8.17(m, 3H), 7.92 (s, 1H), 7.72 (d,J= 7.7 Hz, 2H), 7.52 (t,J= 7.7 Hz, 1H),7.41 (dd,J= 7.9, 4.8 Hz,1H), 5.48 (s,2H), 3.89 (s, 3H). HPLC (condition a): rt2.33 min (purity 100%). MS (ESI +): 394.3.

Example 23: 2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanol

Step 1: formation of 5- [1- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -1H-pyrazol-4-yl ] -2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] pyrimidine

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] pyrimidine (intermediate 2; 100 mg; 0.32 mmol; 1.0 equivalent) and 1- (tetrahydro-furan-3-yl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (112 mg; 0.32 mmol; 1.0 equivalent), the title compound was obtained as a beige oil (116mg, 79%). MS (ESI +): 461.4.

Step 2: formation of 2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanol

Following the procedure described for example 13, step 2, but starting from 5- [1- (2- { [ tert-butyl (dimethyl) silyl)]Oxy } ethyl) -1H-pyrazol-4-yl]-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting with pyrimidine (116 mg; 0.25 mmol; 1.0 equivalent), the title compound was obtained as a white powder (59 mg; 68%).¹H NMR (300 MHz,DMSO-d6) 9.17 (s, 2H), 8.53 (t,J= 1.6 Hz, 1H), 8.44 (s, 1H), 8.27 (s,1H), 8.25-8.18 (m, 1H), 8.15 (d,J= 0.5 Hz, 1H), 7.93 (d,J= 0.7 Hz, 1H),7.76-7.66 (m, 1H), 7.52 (t,J= 7.8 Hz, 1H), 4.99 (brs, 1H), 4.21 (t,J= 5.5Hz, 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. Melting point = 234-.

Example 24: 2- [ 3-fluoro-5- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

4- [4- (2-iodopyrimidin-5-yl) -1H-pyrazol-1-yl]Tert-butyl piperidine-1-carboxylate (intermediate 6; 104 mg; 0.23 mmol; 1.0 equiv.), 3-bromo-5-fluorophenylboronic acid (527 mg; 2.41 mmol; 1.1 equiv.), bis (triphenylphosphine) palladium (II) chloride (14 mg; 0.02 mmol; 0.09 equiv.), and cesium fluoride (272 mg; 1.79 mmol; 1.0 equiv.) were suspended in DMF (4mL) and water (1 mL). The reaction mixture was then heated in MW at 100 ℃ for 30 minutes. To this was added 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.37 g; 6.58 mmol; 3.0 equiv.) and bis (triphenylphosphine) palladium (II) chloride (80 mg; 0.11 mmol; 0.05 equiv.)The reaction suspension was added and heating was continued for another 30 minutes. After cooling, the reaction mixture was filtered through celite, then poured into 1N HCl solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting crude material was purified by silica flash chromatography (DCM: MeOH, gradient from 95:5 to 50: 50). The pure residue was redissolved in HCl/dioxane (4mL of 1N solution; 16 mmol; 70 equivalents) and MeOH (4mL) and the resulting solution was stirred at room temperature for 1 hour. It was then concentrated and wet-milled with acetonitrile. The solid was finally filtered and dried in vacuo to give the title compound as an orange solid (0.72 g; 69%).¹H NMR (300 MHz, DMSO) 9.22 (s, 2H), 9.16 (br, 1H), 8.92 (br, 1H), 8.55 (s,1H), 8.38 (t,J= 1.4 Hz, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 8.00 (d,J= 0.7Hz, 1H), 7.95-7.86 (m,1H), 7.66-7.57 (m,1H), 4.58-4.46 (m,1H), 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): rt2.60 min (purity 92.6%). MS (ESI +): 404.5.

Example 25: 2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -1-piperidin-1-yl-ethanone

Reacting (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Pyrimidin-5-yl } -1H-pyrazol-1-yl) acetic acid (example 9, 110 mg; 0.31 mmol; 1.0 equivalent), piperidine (52 mg; 0.61 mmol; 2.0 equiv), HATU (174 mg; 0.46 mmol; 1.50 equivalents) and DIEA (152 μ Ι; 0.92 mmol; 3.0 equiv.) in DMF (2mL) was stirred at 50 ℃ overnight. The reaction mixture was poured into water and extracted with DCM (three times). The combined organic phases are subsequently concentrated under reduced pressure and the residue is recrystallized from MeOH/ether. The resulting solid was filtered and dried under reduced pressure to give the title compound as a white solid (20mg, 15%).¹H NMR (300 MHz, DMSO) 9.18 (s, 2H), 8.54 (t,J=1.6 Hz, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.25-8.19 (m, 1H), 8.14 (s, 1H),7.93 (s, 1H), 7.77-7.66 (m, 1H), 7.52 (t,J= 7.8Hz, 1H), 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-1H-pyrazol-4-yl) -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Step 1: formation of tert-butyl 3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] pyrimidin-5-yl } -1H-pyrazol-1-yl) azetidine-1-carboxylate

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-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) gave the title compound 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-1H-pyrazol-4-yl) -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Pyrimidin-5-yl } -1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester (150 mg; 0.32 mmol; 1.0 equivalent) to give the title compound as a white solid(3mg，3%)。¹H NMR (300 MHz, DMSO-d6) 9.36(brs, 2H), 9.20 (s, 2H), 8.64 (s, 1H), 8.54 (t,J= 1.6 Hz, 1H), 8.38 (s,1H), 8.30-8.18 (m, 2H), 7.93 (d,J= 0.7 Hz, 1H), 7.72 (d,J= 8.1 Hz, 1H),7.52 (t,J= 7.8Hz, 1H), 5.59-5.38 (m,1H), 4.49-4.21 (m,4H), 3.90(s, 3H). HPLC (condition a): rt 2.23 min (98.6% purity). MS (ESI +): 358.3.

Example 27: 5- [1- (3-methoxy-propyl) -1H-pyrazol-4-yl ] -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine

2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]A solution of-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 130 mg; 0.43 mmol; 1.0 eq) in dry DMF (1mL) was added to a suspension of NaH (60% in oil, 21 mg; 0.86 mmol; 2.0 eq) in dry DMF (1mL) maintained at 0 ℃ under a nitrogen atmosphere. After addition of a solution of 1-chloro-3-methoxypropane (47 mg; 0.43 mmol; 1.0 eq.) in DMF (2mL), the resulting mixture was stirred at 0 ℃ for 1h, then heated at 100 ℃ overnight. The reaction mixture was then cooled to room temperature, quenched with water and extracted with EtOAc (three times). The combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting solid was dried under reduced pressure at 60 ℃ overnight to give the title compound as a beige powder (165 mg; 75%).¹H NMR (300 MHz, DMSO-d6) 9.16 (s, 2H), 8.58-8.49 (m, 1H), 8.46 (s, 1H), 8.30-8.17 (m, 2H), 8.17-8.11 (m, 1H), 7.96-7.89 (m, 1H), 7.75-7.68 (m, 1H), 7.51 (t,J= 7.8 Hz, 1H),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): rt3.34 min (purity 97.1%). MS (ESI +): 375.5.

Example 28: 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- [1- (1-oxetan-3-yl-piperidin-4-yl) -1H-pyrazol-4-yl ] -pyrimidine

Sodium triacetoxyborohydride (0.13 g; 0.62 mmol; 2.0 equiv.) is slowly added to 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]In a solution of-5- (1-piperidin-4-yl-1H-pyrazol-4-yl) pyrimidine (example 1, 200 mg; 0.31 mmol; 1.0 eq.), DIEA (53. mu.l; 0.31 mmol; 1.0 eq.) and 3-oxetanone (oxetanone) (39. mu.l; 0.62 mmol; 2.0 eq.) in DCE (4 mL). The reaction mixture was then stirred at 50 ℃ for 3 hours. It was then quenched by the addition of water. The aqueous phase was basified to pH 12 and extracted with EtOAc (three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige powder (100mg, 73%).¹H NMR (300 MHz, DMSO-d6) 9.17 (s, 2H), 8.59-8.50 (m, 2H), 8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.18-8.1 1 (m, 1H), 7.96-7.89 (m, 1H), 7.77-7.66 (m, 1H), 7.52 (t,J= 7.7 Hz,1H), 4.56 (t,J= 6.5 Hz, 2H), 4.46 (t,J= 6.1 Hz,2H), 4.23 (s, 1H), 3.90(s, 3H), 3.51-3.40 (m,1H), 2.87-2.73 (m,2H), 2.17-1.90 (m, 6H). HPLC (condition a): rt 2.49 min (97.2% purity). MS (ESI +): 442.5.

Example 29: 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of 4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-ylmethyl) -piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for example 27, but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-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), the title compound was obtained as an off-white powder (200mg, 81%). HPLC (condition a): rt 4.44 min (97.2% purity). MS (ESI +): 500.5.

Step 2: formation of 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-ylmethyl) -piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.40 mmol; 1.0 equivalent) to give the title compound as a yellow powder (160mg, 92%).¹H NMR (300 MHz, DMSO-d6) 9.17(s, 2H), 9.10-8.96 (m, 1H), 8.84-8.68 (m, 1H), 8.53 (t,J= 1.6 Hz, 1H), 8.49(s, 1H), 8.27 (s, 1H), 8.25-8.16 (m, 2H), 7.93 (d,J= 0.7 Hz, 1H), 7.75-7.68(m, 1H), 7.52 (t,J= 7.8Hz, 1H), 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,1H), 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- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for example 27, but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-pyrazol-4-yl) pyrimidine (example 3, 150 mg; 0.50 mmol; 1.0 eq) and tert-butyl 3-fluoro-4- [ (methylsulfonyl) oxy ] piperidine-1-carboxylate (intermediate 9; 147 mg; 0.50 mmol; 1.0 eq) the title compound was obtained as an off-white solid (110mg, 44%). HPLC (condition a): rt 4.53 min (purity 87.5%). MS (ESI +): 504.4.

Step 2: formation of trans-5- [1- (3-fluoro-piperidin-4-yl) -1H-pyrazol-4-yl ] -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from trans-3-fluoro-4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (320 mg; 0.64 mmol; 1.0 equivalent) to yield the title compound. After the first precipitation, the title compound was purified by auto-prep LC/MS to afford a white foam (67mg, 24%).¹H NMR (300 MHz, DMSO-d6) 9.87 (brs, 1H), 9.63(brs, 1H), 9.21 (s, 2H), 8.55 (d,J= 8.1 Hz, 2H), 8.35-8.17 (m, 3H), 7.93(s, 1H), 7.72 (d,J= 7.8 Hz, 1H), 7.52 (t,J= 7.7Hz, 1H), 5.38-5.08 (m,1H), 4.89-4.72 (m,1H), 3.90(s, 3H), 3.79-3.64 (m,1H), 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 (98.4% purity). MS (ESI +): 404.3.

Example 31: 1,1, 1-trifluoro-3- [4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -piperidin-1-yl ] -propan-2-ol

1, 2-epoxy-3, 3, 3-trifluoropropane (84 mg; 0.72 mmol; 2.4 equivalents) was added to 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]-5- (1-piperidin-4-yl-1H-pyrazol-4-yl) pyrimidine (example 1, 200 mg; 0.31 mmol; 1.0 eq.) and DIEA (53. mu.l; 0.31 mmol; 1.0 eq.) in DMF (4 mL). The reaction mixture was stirred at 50 ℃ overnight. It was then diluted with water and extracted with EtOAc (three times). The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica flash chromatography (DCM: EtOAc, gradient from 40:60 to 0:100) afforded the title compound as a beige powder (56mg, 36%).¹H NMR (300 MHz, DMSO-d6) 9.17 (s, 2H),8.59-8.49 (m, 2H), 8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.14 (s, 1H), 7.93 (s,1H), 7.75-7.67 (m, 1H), 7.52 (t,J= 7.7Hz, 1H), 6.24-6.13 (m,1H), 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 (98.4% purity). MS (ESI +): 498.4.

Example 32: 5- (1-methyl-1H-pyrazol-4-yl) -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Pyrimidine (intermediate 2, 100 mg; 0.32 mmol; 1.0 equiv.) and 1-methyl-4- (4,4,5, 5-tetramethyl- [1,3,2]]Dioxaborolan-2-yl) -1H-pyrazole (99 mg; 0.48 mmol; 1.5 equivalents) to yield the title compound as a white powder (56 mg; 55%).¹H NMR (300 MHz, DMSO-d6) 9.15 (s, 2H), 8.53 (t,J= 1.6 Hz,1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.24-8.16 (m, 1H), 8.12 (d,J= 0.7 Hz, 1H),7.92 (d,J= 0.7 Hz, 1H), 7.76-7.66 (m, 1H), 7.51 (t,J= 7.8Hz, 1H), 3.92(s, 3H), 3.90(s, 3H). HPLC (condition a): rt 2.86 min (97.4% purity). MS (ESI +): 317.3, mp = 199-.

Example 33: 5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -2- (3-pyridin-4-yl-phenyl) -pyrimidine hydrochloride

Step 1: formation of 4- {4- [2- (3-pyridin-4-yl-phenyl) -pyrimidin-5-yl ] -pyrazol-1-yl } -piperidine-1-carboxylic acid tert-butyl ester

Following the procedure described for example 7, step 1, but starting from tert-butyl 4- {4- [2- (3-iodophenyl) pyrimidin-5-yl ] -1H-pyrazol-1-yl } piperidine-1-carboxylate (intermediate 5, 200 mg; 0.38 mmol; 1.0 equiv.) and 4-pyridineboronic acid (93 mg; 0.75 mmol; 2.0 equiv.), the title compound was obtained as a yellow solid (121mg, 67%). HPLC (condition a): rt3.31 min (purity 99.6%). MS (ESI +): 483.5.

Step 2: formation of 5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -2- (3-pyridin-4-yl-phenyl) -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 4- {4- [2- (3-pyridin-4-yl-phenyl) -pyrimidin-5-yl]Starting from tert-butyl-pyrazol-1-yl } -piperidine-1-carboxylate (120 mg; 0.25 mmol; 1.0 eq.) the title compound was obtained as an off-white solid (100mg, 97%).¹H NMR (300 MHz, DMSO-d6) d 9.41-9.26 (m, 1H), 9.25(s, 2H), 9.20-9.10 (m, 1H), 8.99 (d,J= 6.8 Hz, 2H), 8.89 (t,J= 1.5 Hz,1H), 8.62 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.57 (s, 1H), 8.44 (d,J= 6.8 Hz,2H), 8.23 (s, 1H), 8.18-8.14 (m, 1H), 7.81 (t,J= 8.0 Hz,1H), 4.61-4.52 (m,1H), 3.42-3.37 (m,2H), 3.16-3.04 (m,2H), 2.29-2.17 (m, 4H). HPLC (condition a): rt1.69 min (purity 99.2%). MS (ESI +): 383.3.

Example 34: 3- (1-methyl-1H-pyrazol-4-yl) -5- [5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidin-2-yl ] -phenol formate salt

3-bromo-5- (1-methyl-1H-pyrazol-4-yl) -phenol (337 mg; 1.09 mmol; 1.0 equiv.), dipinacol ester (245 mg; 0.96 mmol; 0.9 equiv.), 1-bis (diphenylphosphino) ferrocene dichloropalladium (II) (98 mg; 0.13 mmol; 0.12 equiv.), and potassium acetate (432 mg; 4.40 mmol; 4.0 equiv.) were suspended in 1, 4-dioxane (8 mL). The reaction suspension was degassed with argon and heated at 80 ℃ for 30 min at MW. Another portion of the dipinacinate dipinacol ester (108 mg; 0.43 mmol; 0.4 equiv.) is added and heating is repeated (30 min at 80 ℃ in MW). Adding 4- [4- (2-iodopyrimidin-5-yl) -1H-pyrazol-1-yl group in one step]Tert-butyl piperidine-1-carboxylate (intermediate 6, 265 mg; 0.58 mmol; 0.53 equiv.), bis (triphenylphosphine) palladium (II) chloride (100 mg; 0.14 mmol; 0.13 equiv.) and potassium carbonate (446 mg; 3.23 mmol; 3.0 equiv.) and the reaction solution was diluted with water (3mL), degassed with argon and heated again at 100 ℃ for 30 min at MW. The reaction mixture was cooled to room temperature and diluted with DCM. It was filtered through celite. The organic phase was washed successively with 1N HCl solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica (N-heptane: EtOAc, gradient from 95:5 to 75:25) and then redissolved in MeOH and HCl/dioxane (10mL of 4N solution; 40 mmol; 37 equivalents). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Purification by auto-prep LC/MS afforded the title compound as a white foam (11mg, 4%).¹H NMR (300 MHz, DMSO-d6) 9.67 (s, 1H),9.16 (s, 2H), 8.50 (s, 1H), 8.18 (d,J= 4.1 Hz, 2H), 8.00 (t,J= 1.5 Hz,1H), 7.83 (d,J= 0.7Hz, 1H), 7.71-7.67 (m,1H), 7.10-7.05 (m,1H), 4.62-4.48 (m,1H), 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 (91.2% purity). MS (ESI +): 402.5.

Example 35: 1-methoxy-3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -propan-2-ol

Following the procedure described for example 7, step 1, but starting from 5-bromo-2- [3- (1-methyl-1H-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 (as in Bioorganic)&The preparation described in Medicinalchemistry Letters, 18(19), 5299-; 134 mg; 0.48 mmol; 1.5 equivalents) to yield the title compound as a white solid (27mg, 22%).¹H NMR (300 MHz, DMSO-d6) 9.17(s, 2H), 8.53 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.22 (d,J= 8.0 Hz, 1H),8.15 (s, 1H), 7.93 (s, 1H), 7.71 (d,J= 7.9 Hz, 1H), 7.52 (t,J= 7.8 Hz,1H), 5.24 (d,J= 5.2 Hz, 1H), 4.25 (dd,J= 13.3, 3.6Hz, 1H), 4.15-3.95 (m,2H), 3.90(s, 3H), 3.40-3.23 (m, 5H). HPLC (condition a): rt 2.68 min (96.6% purity). MS (ESI +) 391.3.

Example 36: 2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -1-morpholin-4-yl-ethanone

Following the procedure described for example 25, but starting from 4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 equivalent) and morpholine (24 mg; 0.28 mmol; 1.0 equivalent) to yield the title compound as a white solid (45mg, 38%).¹H NMR (300 MHz, DMSO-d6) 9.18 (s, 2H), 8.54 (t,J= 1.6 Hz, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.25-8.18(m, 1H), 8.15 (s, 1H), 7.93 (d,J= 0.6 Hz, 1H), 7.77-7.67 (m, 1H), 7.52 (t,J= 7.8Hz, 1H), 5.26 (s,2H), 3.90(s, 3H), 3.71-3.42 (m, 8H). HPLC (condition a): rt2.60 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- [3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanone

2- {4- [2- (3-iodo-phenyl) -pyrimidin-5-yl]-pyrazol-1-yl } -1-pyrrolidin-1-yl-ethanone (intermediate 12, 700 mg; 1.52 mmol; 1.0 equiv.), dipinacol ester (426 mg; 1.68 mmol; 1.10 equiv.), and (dppf) PdCl₂.CH₂Cl₂A mixture of (111 mg; 0.15 mmol; 0.1 equiv.) and potassium acetate (449 mg; 4.57 mmol; 3.0 equiv.) in THF (15mL) and DMF (5mL) was heated at 100 deg.C for 2 hours at MW.

The reaction mixture solution was used as it was in the next step.

Step 2: formation of 2- (4- {2- [3- (3-methyl-3H-imidazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -1-pyrrolidin-1-yl-ethanone

1-pyrrolidine-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 (4mL of the solution obtained in step 1), 5-bromo-1-methyl-1H-imidazole (35 mg; 0.22 mmol; 1.0 equivalent), Pd (Ph)₃)₄A mixture of (13 mg; 0.01 mmol; 0.05 equiv.) and potassium carbonate (90 mg; 0.65 mmol; 3.0 equiv.) in water (0.73mL) was heated at 120 ℃ for 30 minutes at MW. The addition of 5-bromo-1-methyl-1H-imidazole (35 mg; 0.22 mmol; 1.0 equiv.) and heating at 120 ℃ for 30 minutes must be repeated twice to complete the reaction. The reaction mixture was then diluted with water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica flash chromatography (DCM: MeOH, gradient from 100:0 to 80:20) gave a black gum, which was redissolved in DCM. Cyclohexane was added to give a brown precipitate, which was filtered and dried under vacuum to give the title compound as an off-white solid (40mg, 44%).¹H NMR (300 MHz, DMSO-d6) d9.20 (s, 2H), 8.47-8.46 (m, 1H), 8.41-8.37 (m, 2H), 8.14 (d,J= 0.6 Hz, 1H),7.76 (s, 1H), 7.68-7.60 (m, 2H), 7.15 (s, 1H), 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= 6.8Hz, 2H). HPLC (condition a): rt 2.21 min (96.2% purity). MS (ESI +) 414.4.

Example 38: Ν, Ν -dimethyl-2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -acetamide

In accordance with the implementationExample 25 describes the procedure but starting from (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]Starting from-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8) and dimethylamine, the title compound was obtained as a white solid (18mg, 47%).¹H NMR (300 MHz, DMSO-d6) 9.18 (s, 2H), 8.54 (t,J= 1.6 Hz,1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.25-8.17 (m, 1H), 8.14 (d,J= 0.6 Hz, 1H),7.93 (d,J= 0.8 Hz, 1H), 7.77-7.66 (m, 1H), 7.52 (t,J= 7.8Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- {1- [1- (tetrahydro-pyran-4-yl) -piperidin-4-yl ] -1H-pyrazol-4-yl } -pyrimidine

Following the procedure described for example 28 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1-piperidin-4-yl-1H-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.) the title compound was obtained as a white powder (25mg, 17%).¹H NMR(300 MHz, DMSO-d6) 9.16 (s, 2H), 8.59-8.49 (m, 2H), 8.27 (s, 1H), 8.20 (dt,J= 8, 3Hz, 1H), 8.13 (s, 1H), 7.93 (d,J= 0.6 Hz, 1H), 7.76-7.66 (m, 1H),7.51 (t,J= 7.7Hz, 1H), 4.25-4.10 (m,1H), 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,1H), 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 (97.6% purity). MS (ESI +): 470.4.

Example 40: 1- (3-methoxy-azetidin-1-yl) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanone

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-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) the title compound was obtained as a white foam (25mg, 21%).¹H NMR (300 MHz, DMSO-d6) 9.18 (s, 2H), 8.56-8.51 (m, 1H),8.40 (s, 1H), 8.27 (s, 1H), 8.25-8.19 (m, 1H), 8.17 (s, 1H), 7.93 (s, 1H),7.75-7.68 (m, 1H), 7.52 (t,J= 7.7 Hz, 1H), 4.97 (s, 2H), 4.40-4.31 (m, 1H),4.30-4.20 (m, 1H), 4.15-3.99 (m, 2H), 3.89 (s, 3H), 3.72 (dd,J=10.3, 3.6Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-ylmethyl) -morpholine hydrochloride

Step 1: formation of 2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-ylmethyl) -morpholine-4-carboxylic acid tert-butyl ester

Following the procedure described for example 27, but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-pyrazol-4-yl) pyrimidine (example 3, 150 mg; 0.50 mmol; 1.0 eq) and tert-butyl 2-methanesulfonyloxymethyl-morpholine-4-carboxylate (intermediate 13, 146 mg; 0.50 mmol; 1.0 eq), the title compound was obtained as a white powder (10mg, 44%). MS (ESI +) 502.3.

Step 2: formation of 2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-ylmethyl) -morpholine hydrochloride

Following the 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 equivalent) to give the title compound as a yellow powder (50mg, 52%).¹H NMR (300 MHz, DMSO-d6) 9.50(brs, 2H), 9.19 (s, 2H), 8.54 (t,J= 1.6 Hz, 1H), 8.44 (s, 1H), 8.30-8.17(m, 3H), 7.93 (d,J= 0.6 Hz, 1H), 7.75-7.67 (m,1H), 7.52 (t,J= 7.8Hz, 1H), 4.48-4.23 (m,2H), 4.23-4.10 (m,1H), 4.05-3.91 (m,1H), 3.90(s, 3H),3.81-3.64 (m,1H), 3.36-3.28 (m,1H), 3.25-3.12 (m,1H), 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) -1H-pyrazol-4-yl ] -phenyl } -pyrimidin-5-yl) -pyrazol-1-yl ] -1-pyrrolidin-1-yl-ethanone hydrochloride

2- (4- {2- [3- (1H-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 (1mL) was added to NaH (60% in oil, 21 mg; 0.86 mmol; 2.0 equiv) in dry DMF (1 mL). After addition of a solution of (3-bromo-propyl) -carbamic acid tert-butyl ester (60 mg; 0.25 mmol; 1.0 eq) in DMF (2mL), the resulting mixture was stirred at 0 ℃ for 1h, followed by heating at 100 ℃ overnight. Subsequently mixing the reactionThe material was cooled to room temperature, quenched with water and extracted with EtOAc (three times). The combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The crude material was redissolved in DCM (1mL) and treated with HCl/dioxane (0.94mL 4N solution; 3.76 mmol; 15.0 equiv). The resulting reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure and purified by auto-prep LC/MS to give the title compound as a white solid.¹H NMR (300 MHz, DMSO-d6) 9.18 (s,2H), 8.55 (t,J= 1.5 Hz, 1H), 8.43 (brs, 1H), 8.37 (s, 1H), 8.34 (s, 1H),8.23 (dt,J= 7.8 Hz, 1.6 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.73 (dt,J=7.8 Hz, 1.6 Hz, 1H), 7.52 (t,J= 7.8 Hz, 1H), 5.12 (s, 2H), 4.24 (t,J= 6.6Hz, 2H), 3.53 (t,J= 6.6 Hz, 2H), 3.33 (t,J= 6.8 Hz, 2H), 2.71 (t,J= 6.8Hz, 2H), 2.05 (quint.,J= 6.6 Hz, 2H), 1.93 (quint.,J= 6.8 Hz, 2H), 1.80(quint.,J= 6.8Hz, 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-pyrrolidin-1-yl-ethanone

Following the procedure described for intermediate 5, step 1, but starting from 2- {4- [2- (3-iodo-phenyl) -pyrimidin-5-yl]Starting from-pyrazol-1-yl } -1-pyrrolidin-1-yl-ethanone (intermediate 12, 150 mg; 0.33 mmol; 1.0 equiv.) and 4-pyridineboronic acid (80 mg; 0.65 mmol; 2.0 equiv.), the title compound was obtained as a white solid (15mg, 11%).¹H NMR (300MHz, DMSO-d6) 9.21 (s, 2H), 8.75 (t,J= 1.5 Hz, 1H), 8.69 (d,J= 6.0 Hz,2H), 8.50 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.95 (dt,J= 8.0 Hz, 1.5 Hz, 1H), 7.79 (d,J= 6.0 Hz, 2H), 7.70 (t,J= 8.0 Hz, 1H),5.12 (s, 2H), 3.52 (t,J= 6.6 Hz, 2H), 3.32 (m, 2H), 1.93 (quint.,J= 6.6Hz, 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -propan-2-one

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 75 mg; 0.25 mmol; 1.0 eq.) and 1-chloro-propan-2-one (59. mu.l; 0.74 mmol; 3.0 eq.) the title compound was obtained as a white powder (25mg, 28%).¹H NMR (300 MHz, DMSO-d6):9.17 (s, 2H), 8.53 (s, 1H), 8.34 (s, 1H), 8.25 (s, 1H), 8.21 (d,J= 8.2 Hz,1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.70 (d,J= 7.9 Hz, 1H), 7.51 (t,J= 7.5Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- [1- (tetrahydro-furan-3-ylmethyl) -1H-pyrazol-4-yl ] -pyrimidine

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 equivalent) and 3-chloromethyl-tetrahydro-furan (39.88 mg; 0.33 mmol; 1.00 equivalent), the title compound was obtained as an off-white powder (32mg, 25%).¹H NMR (300 MHz,DMSO-d6) 9.16 (s, 2H), 8.59-8.45 (m, 2H), 8.33-8.11 (m, 3H), 7.93 (s, 1H),7.77-7.66 (m, 1H), 7.51 (t,J= 7.7 Hz, 1H), 4.17 (d,J= 7.5 Hz, 2H), 3.89(s, 3H), 3.85-3.74 (m, 1H), 3.74-3.60 (m, 2H), 3.52 (dd,J= 8.7, 5.4 Hz,1H), 2.85-2.68 (m,1H), 2.04-1.88 (m,1H), 1.73-1.56 (m, 1H). HPLC (condition a): rt3.34 min (98.0% purity). MS (ESI +): 387.4.

Example 46: 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-oxazol-2-ylmethyl-1H-pyrazol-4-yl) -pyrimidine

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 equivalent) and 2-chloromethyl-oxazole (39 mg; 0.33 mmol; 1.0 equivalent), the title compound was obtained as an off-white powder (27mg, 21%).¹H NMR (300 MHz, DMSO-d6) 9.19 (s, 2H), 8.57 (d,J= 16.9 Hz, 2H), 8.35-8.09 (m, 4H), 7.93 (s, 1H),7.72 (d,J= 7.4 Hz, 1H), 7.52 (t,J= 7.7Hz, 1H), 7.26 (s, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- [1- (2-pyridin-2-yl-ethyl) -1H-pyrazol-4-yl ] -pyrimidine

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 eq.) and 2- (2-chloro-ethyl) -pir-zineStarting with pyridine (47 mg; 0.33 mmol; 1.0 eq.) the title compound was obtained as an off-white powder (6mg, 4%).¹H NMR (300 MHz,DMSO-d6) 9.12 (s, 2H), 8.57-8.50 (m, 2H), 8.41 (s, 1H), 8.26 (s, 1H), 8.24-8.18 (m, 1H), 8.13 (d,J= 0.6 Hz, 1H), 7.92 (d,J= 0.7 Hz, 1H), 7.74-7.65(m, 2H), 7.51 (t,J= 7.7 Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine formate salt

Following the procedure described for example 24 but starting from 4- [4- (2-iodopyrimidin-5-yl) -1H-pyrazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (intermediate 6, 249 mg; 0.55 mmol; 1.0 equiv.), 3-bromo-2-fluorophenylboronic acid (155 mg; 0.71 mmol; 1.3 equiv.), and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (308 mg; 1.48 mmol; 2.7 equiv.) to give the title compound as an orange solid (40mg, 16%).¹H NMR(300 MHz, DMSO-d6) 9.21 (s, 2H), 8.54 (s, 1H), 8.29 (s, 1H), 8.22 (d,J=2.2 Hz, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.88-7.77 (m, 2H), 7.33 (t,J= 7.7Hz, 1H), 4.41-4.27 (m,1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -acetamide

Following the procedure described for example 27, but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-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) the title compound was obtained as an off-white powder (4mg, 3%). HPLC (condition a): rt 2.65 min (97.9% purity). MS (ESI +) 360.4.

Example 50: 2- [4- (2- {3- [1- (2-amino-ethyl) -1H-pyrazol-4-yl ] -phenyl } -pyrimidin-5-yl) -pyrazol-1-yl ] -1-pyrrolidin-1-yl-ethanone hydrochloride

Step 1: formation of {2- [4- (3- {5- [1- (2-oxo-2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl ] -pyrimidin-2-yl } -phenyl) -pyrazol-1-yl ] -ethyl } -carbamic acid tert-butyl ester

Following the procedure described for example 27, but starting from 2- (4- {2- [3- (1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-yl) -1-pyrrolidin-1-yl-ethanone (intermediate 14, 150 mg; 0.38 mmol; 1.0 equivalent) and (2-bromo-ethyl) -carbamic acid tert-butyl ester (17 mg; 0.08 mmol; 0.2 equivalents) to yield the title compound as a white solid (70mg, 34%).¹H NMR (300 MHz, DMSO-d6) d 9.18 (s, 2H), 8.55 (t,J= 1.5 Hz,1H), 8.37 (s, 1H), 8.24-8.21 (m, 2H), 8.14 (s, 1H), 7.95 (s, 1H), 7.71 (dt,J= 7.8 Hz, 1.5 Hz, 1H), 7.52 (t,J= 7.8 Hz, 1H), 6.99 (t,J= 6.0 Hz, 1H),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- [4- (2- {3- [1- (2-amino-ethyl) -1H-pyrazol-4-yl ] -phenyl } -pyrimidin-5-yl) -pyrazol-1-yl ] -1-pyrrolidin-1-yl-ethanone hydrochloride

Following the procedure described for example 13, step 2, but starting from {2- [4- (3- {5- [1- (2-oxo-2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl [ ] -H]-pyrimidin-2-yl } -phenyl) -pyrazol-1-yl]Starting from tert-butyl-ethyl } -carbamate (70 mg; 0.13 mmol; 1.0 equivalent), the title compound was obtained as a yellow solid (57mg, 86%).¹H NMR (300MHz, DMSO-d6) d 9.18 (s, 2H), 8.58 (t,J= 1.6 Hz, 1H), 8.39-8.38 (m, 2H),8.24 (dt,J= 7.8 Hz, 1.6 Hz, 1H), 8.23-8.06 (m, 6H), 7.75 (dt,J= 7.8 Hz,1.6 Hz, 1H), 7.54 (t,J= 7.8 Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanone hydrochloride

Following the procedure described for example 25, but starting from (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 100 mg; 0.28 mmol; 1.00 equivalents) and 1-methyl-piperazine (55 mg; 0.55 mmol; 2.0 equivalents) to yield the title compound as a white solid (20mg, 15%).¹H NMR (300MHz, DMSO-d6 + D₂O) d 9.16 (s, 2H), 8.52 (t,J= 1.6 Hz, 1H), 8.31 (s, 1H),8.25-8.18 (m, 2H), 8.15 (d,J= 0.5 Hz, 1H), 7.91 (d,J= 0.7 Hz, 1H), 7.76-7.66 (m, 1H), 7.52 (t,J= 7.8 Hz, 1H), 5.29 (d,J= 11.3 Hz,2H), 4.52-4.29(m, 1H), 4.24-4.08 (m,1H), 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% purity). MS (ESI +): 443.5.

Example 52: 1- (3-hydroxy-piperidin-1-yl) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanone

Following the procedure described for example 25, but starting from (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 equivalent) and [ dimethylamino hexafluorophosphate- ([1,2,3]Triazolo [4,5-b]Pyridin-3-yloxy) -methylene]Starting from-dimethyl-ammonium (158.3 mg; 0.42 mmol; 1.50 equivalents), the title compound is obtained as a white solid (75mg, 61%).¹H NMR (300 MHz, DMSO-d6) 9.18 (s, 2H), 8.54 (s, 1H), 8.37 (d,J= 3.7 Hz, 1H), 8.31-8.20 (m, 2H),8.14 (s, 1H), 7.93 (s, 1H), 7.72 (d,J= 7.8 Hz, 1H), 7.52 (t,J= 7.7 Hz,1H), 5.33-5.12 (m, 2H), 4.95 (d,J= 4.0 Hz,1H), 4.15-4.01 (m, 0.6H), 3.90(s, 3H), 3.74-3.62 (m,1H), 3.62-3.48 (m, 0.6H), 3.48-3.37 (m,1H), 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 ℃.

Example 53: 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- [1- (2-pyridin-4-yl-ethyl) -1H-pyrazol-4-yl ] -pyrimidine

2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]A solution of-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 equiv.) in dry DMA (1mL) was added to a suspension of NaH (60%, in oil, 28 mg; 1.19 mmol; 3.0 equiv.) in dry DMA (2mL), maintained at 0 ℃ under a nitrogen atmosphere. After addition of a solution of 14- (2-bromo-ethyl) -pyridine hydrobromide (159 mg; 0.60 mmol; 1.5 eq) in DMA (2mL), the resulting mixture was stirred at 0 ℃ for 1h, then heated at 100 ℃ overnight. Cesium carbonate (388 mg; 1.19 mmol; 3.00 equiv.) and 4- (2-bromo-ethyl) -pyridine hydrobromide (159 mg; 0.60 mmol; 1.5 equiv.) are added and the reaction mixture is heated again at 100 ℃ overnight. The reaction mixture was then cooled to room temperature, quenched with water and extracted with DCM (three times). The combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified by auto-prep LC/MS to give the title compound as a white foam (80mg, 49%).¹H NMR (300 MHz, DMSO-d6) 9.12 (s, 2H),8.56-8.50 (m, 1H), 8.50-8.41 (m, 2H), 8.38 (s, 1H), 8.26 (s, 1H), 8.24-8.17(m, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.77-7.66 (m, 1H), 7.51 (t,J= 7.7 Hz,1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -N- (tetrahydro-pyran-4-yl) -acetamide

Following the procedure described for example 25, but starting from (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 equivalent) and tetrahydro-pyriPyran-4-ylamine (56 mg; 0.55 mmol; 2.0 equivalents) was started to give the title compound as a white powder (9mg, 14%).¹H NMR (300MHz, DMSO-d6) 9.19 (s, 2H), 8.54 (s, 1H), 8.43 (s, 1H), 8.37-8.18 (m, 3H),8.15 (s, 1H), 7.93 (s, 1H), 7.77-7.67 (m, 1H), 7.52 (t,J= 7.7Hz, 1H), 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 (96.6% purity). MS (ESI +): 444.3.

Example 55: 2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -1- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -ethanone

Following the procedure described for example 25, but starting from 4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 equivalent) and 2-oxa-6-aza-spiro [3.3]Heptane oxalate (105 mg; 0.55 mmol; 2.0 equiv.) gave the title compound as a white powder (40mg, 33%).¹H NMR (300 MHz, DMSO-d6) 9.18 (s, 2H), 8.54 (s, 1H), 8.38 (s, 1H),8.27 (s, 1H), 8.22 (d,J= 8.0 Hz, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 7.72 (d,J= 7.9 Hz, 1H), 7.52 (t,J= 7.8Hz, 1H), 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-methyl-thiazol-5-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -1-pyrrolidin-1-yl-ethanone

Following the procedure described for example 37, but starting from 2- {4- [2- (3-iodo-phenyl) -pyrimidin-5-yl]Starting from-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) the title compound was obtained as a white solid (30mg, 16%).¹H NMR (300MHz, DMSO-d6) d 9.21 (s, 2H), 8.55 (t,J= 1.5 Hz, 1H), 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, 1H), 7.60 (t,J=7.8 Hz, 1H), 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= 6.8Hz, 2H). HPLC (condition a): rt 3.17 min (purity 97.4%). MS (ESI +) 431.4.

Example 57: 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- [1- (2-piperidin-1-yl-ethyl) -1H-pyrazol-4-yl ] -pyrimidine

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 equivalent) and 1- (2-chloro-ethyl) -piperidine hydrochloride (110 mg; 0.60 mmol; 1.5 equivalent), the title compound was obtained as a white solid (80mg, 49%).¹H NMR (300MHz, DMSO-d6) 9.15 (s, 2H), 8.53 (t,J= 1.5 Hz, 1H), 8.45 (s, 1H), 8.26(s, 1H), 8.25-8.17 (m, 1H), 8.12 (s, 1H), 7.92 (d,J= 0.6 Hz, 1H), 7.77-7.66(m, 1H), 7.52 (t,J= 7.8 Hz, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- [1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl ] -pyrimidine

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 equivalent) and 1- (2-chloro-ethyl) -pyrrolidine hydrochloride (101 mg; 0.60 mmol; 1.5 equivalent), the title compound was obtained as a beige foam (75mg, 47%).¹H NMR(300 MHz, DMSO-d6) 9.15 (s, 2H), 8.53 (t,J= 1.6 Hz, 1H), 8.46 (s, 1H),8.26 (s, 1H), 8.24-8.18 (m, 1H), 8.12 (s, 1H), 7.92 (d,J= 0.6 Hz, 1H),7.77-7.68 (m, 1H), 7.51 (t,J= 7.8 Hz, 1H), 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) -1H-pyrazol-4-yl ] -phenyl } -pyrimidin-5-yl) -pyrazol-1-yl ] -1-pyrrolidin-1-yl-ethanone

Following the procedure described for intermediate 5, step 1, but starting from 2- {4- [2- (3-iodo-phenyl) -pyrimidin-5-yl]Pyrazol-1-yl } -1-pyrrolidin-1-yl-ethanone (intermediate 12, 130 mg; 0.28 mmol; 1.0 equiv.) and 2- [4- (4,4,5, 5-tetramethyl- [1,3, 2-)]Dioxaborolan-2-yl) -pyrazol-1-yl]Starting from ethanol (101 mg; 0.42 mmol; 1.5 eq.) the title compound is obtained as a white solid (45mg, 36%).¹H NMR (300 MHz, DMSO-d6) d 9.18(s, 2H), 8.55 (t,J= 1.6 Hz, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 8.22 (dt,J=7.8 Hz, 1.6 Hz, 1H), 8.14 (d,J= 0.6 Hz, 1H), 7.95 (d,J= 0.6 Hz, 1H),7.74-7.70 (m, 1H), 7.52 (t,J= 7.8 Hz, 1H), 5.12 (s, 2H), 4.96 (t,J= 5.6Hz, 1H), 4.19 (t,J= 5.6 Hz, 2H), 3.79 (q,J= 5.6 Hz, 2H), 3.53 (t,J= 6.6Hz, 2H), 3.32 (t,J= 6.6 Hz, 2H), 1.91 (quint.,J= 6.6 Hz, 2H), 1.80(quint,J= 6.8Hz, 2H). HPLC (condition a): rt 2.64 min (97.7% purity). MS (ESI +): 444.4.

Example 60: n- (1-hydroxymethyl-propyl) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -acetamide

Following the procedure described for example 25, but starting from (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 100 mg; 0.28 mmol; 1.0 equivalent) and 2-amino-butan-1-ol (49 mg; 0.55 mmol; 2.0 equivalents) to yield the title compound as a white powder (14mg, 12%).¹H NMR (300MHz, DMSO-d6) 9.18 (s, 2H), 8.54 (t,J= 1.6 Hz, 1H), 8.43 (s, 1H), 8.27(s, 1H), 8.25-8.19 (m, 1H), 8.15 (d,J= 0.6 Hz, 1H), 8.00 (d,J= 8.5 Hz,1H), 7.93 (d,J= 0.7 Hz, 1H), 7.75-7.68 (m, 1H), 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, 1H), 3.42-3.27 (m, 3H),1.68-1.51 (m, 1H), 1.42-1.25 (m, 1H), 0.86 (t,J= 7.4 Hz, 3H). HPLC (condition a): rt2.60 min (purity 98.0%). MS (ESI +): 432.3, (ESI-): 430.2.

Example 61: (3-Exo) -8-methyl-3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -8-aza-bicyclo [3.2.1] octane

Following the procedure described for example 13, step 1, but starting from 2- [3- (1-methyl-1H-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 equivalent) and (3-exo) -3- (4-iodo-pyrazol-1-yl) -8-methyl-8-aza-bicyclo [3.2.1]Octane (intermediate 16, 79 mg; 0.25 mmol; 1.0 eq.) gave the title compound as a beige foam (45mg, 43%).¹HNMR (300 MHz, DMSO-d6) 9.15 (s, 2H), 8.57-8.47 (m, 2H), 8.27 (s, 1H), 8.24-8.19 (m, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.74-7.68 (m, 1H), 7.51 (t,J= 7.8Hz, 1H), 4.57 (tt,J11.4, 5.7 Hz,1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid

Step 1: formation of 4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid ethyl ester

4-Methanesulfonyloxy-cyclohexanecarboxylic acid ethyl ester (AOKChem Co., Ltd; 689 mg; 2.75 mmol; 1.04 eq) in DMF (5mL) was added to 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] in one portion]Suspension of-5- (1H-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 ℃ for 35 minutes. It was then poured into water and filtered. The resulting solid was wet milled with ACN to give a mark as a yellow solidThe title compound (264mg, 17%).¹H NMR(300 MHz, DMSO-d6) d 9.16 (s, 2H), 8.57-8.46 (m, 2H), 8.26 (s, 1H), 8.24-8.18(m, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.77-7.66 (m, 1H), 7.51 (t,J= 7.8 Hz,1H), 4.32-3.99 (m, 3H), 3.89 (s, 3H), 2.48-2.34 (m, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid

4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid ethyl ester (50 mg; 0.11 mmol; 1.0 equiv) and NaOH (5.00mL of a 1N solution; 5.0 mmol; 46 equivalents) in iPrOH (20mL) was stirred at room temperature for 16 hours. It was then poured into 1N HCl solution and extracted with EtOAc (twice). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a cis-trans mixture (30mg, 59%) as a yellow solid.¹H NMR (300 MHz, DMSO-d6) 9.17 (s, 2H), 8.57-8.47 (m, 2H),8.27 (s, 1H), 8.24-8.17 (m, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.78-7.66 (m,1H), 7.51 (t,J= 7.8Hz, 1H), 4.31-4.15 (m,1H), 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-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1H-pyrazol-4-yl) -pyrimidine

Following the procedure described for example 25, but from(4- {2- [3- (1-methyl-1H-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 equivalents) to yield the title compound as a white solid (13mg, 11%).¹H NMR(300 MHz, DMSO) d 9.18 (s, 2H), 8.54 (t,J= 1.6 Hz, 1H), 8.42 (s, 1H), 8.27(s, 1H), 8.25-8.19 (m, 2H), 8.15 (s, 1H), 7.93 (s, 1H), 7.75-7.68 (m, 1H),7.52 (t,J= 7.7 Hz, 1H), 4.86 (s, 2H), 4.03-3.88 (m, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- {1- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -1H-pyrazol-4-yl } -pyrimidine

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-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) the title compound was obtained as a white solid (75mg, 465).¹H NMR(300 MHz, DMSO-d6) 9.17 (s, 2H), 8.53 (t,J= 1.6 Hz, 1H), 8.51 (s, 1H),8.27 (s, 1H), 8.25-8.19 (m, 1H), 8.18-8.16 (m, 1H), 7.92 (d,J= 0.7 Hz, 1H),7.75-7.69 (m, 1H), 7.52 (t,J= 7.8Hz, 1H), 4.39-4.11 (m,2H), 3.90(s, 3H),3.29-3.16 (m,2H), 3.12-3.04 (m,1H), 2.57 (s,3H), 2.43-2.26 (m,1H), 2.16-1.70 (m,4H), 1.64-1.47 (m, 1H). HPLC (condition a): rt 2.51 min (99.3% purity). MS (ESI +): 414.5.

Example 65: 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-pyrrolidin-3-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of 3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of 3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in WO 2010100144; 200 mg; 0.64 mmol; 1.0 eq.), cesium carbonate (420 mg; 1.29 mmol; 2.0 eq.) and 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-pyrazol-4-yl) pyrimidine (example 3, 195 mg; 0.64 mmol; 1.0 eq.) was heated at 100 ℃ overnight. The reaction mixture was then diluted with water and extracted with EtOAc (three times). The 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 (179mg, 57%). MS (ESI +): 486.5.

Step 2: formation of 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1-pyrrolidin-3-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (170 mg; 0.35 mmol; 1.0 equivalent) to give the title compound as a yellow powder (145mg, 98%).¹H NMR (300 MHz, DMSO-d6) 9.49-9.22 (m, 2H), 9.18 (s, 2H), 8.53 (d,J= 3.3 Hz, 2H), 8.27 (s, 1H),8.25-8.16 (m, 2H), 7.93 (s, 1H), 7.75-7.68 (m, 1H), 7.52 (t,J= 7.7 Hz, 1H),4.30 (d,J= 7.2 Hz,2H), 3.90(s, 3H), 3.34-3.07 (m,3H), 3.07-2.90 (m,1H), 2.88-2.72 (m,1H), 2.12-1.93 (m,1H), 1.79-1.61 (m, 1H). HPLC (condition a): rt 2.55 min (purity 97.7%)。MS (ESI+): 386.2。

Example 66: 5- (1-azetidin-3-ylmethyl-1H-pyrazol-4-yl) -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Step 1: formation of 3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-4-ylmethyl) -azetidine-1-carboxylic acid tert-butyl ester

A solution of 3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (Matrix scientific, 200 mg; 0.68 mmol; 1.0 equiv.), cesium carbonate (442 mg; 1.36 mmol; 2.0 equiv.), and 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-pyrazol-4-yl) pyrimidine (example 3, 205 mg; 0.68 mmol; 1.0 equiv.) in dry DMA (3mL) was heated at 100 ℃ overnight. The reaction mixture was then diluted with water and extracted with EtOAc (three times). The combined organic phases were washed with brine (three times), dried over magnesium sulfate, filtered and concentrated. The crude material was dissolved in DMSO and precipitated by addition of acetonitrile. It was filtered, washed with acetonitrile and dried under vacuum to give the title compound as a yellow powder (423mg, quantitative). MS (ESI +) 472.3.

Step 2: formation of 5- (1-azetidin-3-ylmethyl-1H-pyrazol-4-yl) -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine hydrochloride

Following the procedure described for example 13, step 2, but starting from 3- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-ylmethyl) -azetidine-1-carboxylic acid tert-butyl ester (240 mg; 0.51 mmol; 1.0 equivalent) to give the title as a yellow foamCompound (55mg, 26%).¹H NMR (300 MHz, DMSO) 9.18 (s, 2H), 9.14-8.86 (m, 2H), 8.53 (t,J= 1.7 Hz, 1H), 8.48 (s, 1H), 8.26(s, 1H), 8.25-8.18 (m, 2H), 7.92 (d,J= 0.8 Hz, 1H), 7.75-7.68 (m, 1H), 7.52(t,J= 7.8 Hz, 1H), 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,1H) HPLC (condition a): rt 2.49 min (purity 99.4%). MS (ESI +): 372.3.

Example 67: 5- [1- (2, 2-difluoro-ethyl) -1H-pyrazol-4-yl ] -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine

Following the procedure described for example 66, step 1, but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-pyrazol-4-yl) pyrimidine (255 mg; 0.84 mmol; 1.0 equivalent) and 2, 2-difluoro-ethyl methanesulfonate (prepared as described in Journal of Organic Chemistry, 74 (12), 4547-4553; 2009, 150mg, 0.84mmol, 1.0 equivalent) gave the title compound as a white solid (140mg, 45%). NMR (300 MHz, DMSO-d6) 9.19(s, 2H), 8.57-8.47 (m,2H), 8.30-8.20 (m,3H), 7.93(d,J= 0.8Hz, 1H), 7.76-7.69 (m, 1H), 7.52 (t,J= 7.7 Hz, 1H), 6.44 (tt,J= 54.8, 3.6Hz, 1H), 4.73 (td,J= 15.3, 3.63.90 (s, 3H). HPLC (condition a): rt3.46 min (96.4% purity).

Example 68: 1-morpholin-4-yl-2- {4- [2- (3-pyridin-4-yl-phenyl) -pyrimidin-5-yl ] -pyrazol-1-yl } -ethanone

Following the procedure described for intermediate 5, step 1, but starting from2- {4- [2- (3-iodo-phenyl) -pyrimidin-5-yl]Starting from-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) the title compound was obtained as an off-white solid (25mg, 135).¹H 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, 1H), 8.45 (d,J= 6.8 Hz, 2H), 8.41 (s, 1H), 8.22-8.15 (m, 3H), 7.81(t,J= 8.0 Hz,1H), 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 ] -1H-pyrazol-4-yl } -pyrimidine

Following the procedure described for example 66, step 1, but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl]Starting from-5- (1H-pyrazol-4-yl) pyrimidine (example 3, 100 mg; 0.33 mmol; 1.0 equivalent) and 4- (2-bromo-ethyl) -tetrahydropyran (96 mg; 0.50 mmol; 1.5 equivalent), the title compound was obtained as a white foam (57mg, 42%).¹H NMR(300 MHz, DMSO) 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, 1H), 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, 1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- (1- (S) -1-pyrrolidin-2-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of (S) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

Chirality

Following the procedure described for example 66, step 1, but starting from (S) -tert-butyl 2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylate (prepared as described in Organic & Biomolecular Chemistry, 8 (16), 3742-membered 3750; 2010, 125 mg; 0.40 mmol; 1.0 equivalent) and 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-pyrazol-4-yl) pyrimidine (example 3, 146 mg; 0.48 mmol; 1.2 equivalents), the title compound was obtained as a white solid (90mg, 46%). MS (ESI +): 486.3.

Step 2: formation of 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1- (S) -1-pyrrolidin-2-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Chirality

Following the procedure described for example 13, step 2, but starting from (S) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (127 mg; 0.26 mmol; 1.0 equivalent) to give the title compound as a yellow powder (92mg, 83%).¹H NMR (300 MHz, DMSO-d6) 9.56-9.25 (m, 2H), 9.20 (s, 2H), 8.60(s, 1H), 8.54(t,J= 1.7 Hz, 1H), 8.27(d,J= 2.7 Hz, 2H), 8.22(dt,J= 7.7, 1.4 Hz, 1H), 7.93(s, 1H), 7.81-7.67(m, 1H), 7.52(t,J= 7.7Hz, 1H), 4.64-4.49 (m,2H), 4.04-3.93 (m,1H), 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-1H-pyrazol-4-yl) -phenyl ] -5- (1- (R) -1-pyrrolidin-2-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of (R) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

Chirality

Following the procedure described for example 66, step 1, but starting from (R) -tert-butyl 2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylate (prepared as described in Tetrahedron: Asymmetry, 8 (13), 2209-2213; 1997, 125 mg; 0.40 mmol; 1.0 equivalent) and 2- [3- (1-methyl-1H-pyrazol-4-yl) phenyl ] -5- (1H-pyrazol-4-yl) pyrimidine (example 3, 122 mg; 0.40 mmol; 1.0 equivalent), the title compound was obtained as a white foam (121mg, 62%). MS (ESI +): MS (ESI +): 486.3.

Step 2: formation of 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -5- (1- (R) -1-pyrrolidin-2-ylmethyl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Chirality

Following the procedure described for example 13, step 2, but starting from (R) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (121.00 mg; 0.25 mmol; 1.0 equivalent) to give the title compound as a yellow powder (87mg, 78%).¹H NMR (300 MHz, DMSO) 9.56-9.25 (m, 2H), 9.20 (s, 2H), 8.60 (s, 1H), 8.54 (t,J= 1.7 Hz, 1H), 8.27(d,J= 2.7 Hz, 2H), 8.23 (dt,J= 7.7, 1.4 Hz, 1H), 7.93 (s, 1H), 7.81-7.67(m, 1H), 7.52 (t,J= 7.7Hz, 1H), 4.64-4.49 (m,2H), 4.04-3.93 (m,1H), 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-1H- [1,2,3] triazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Step 1: formation of 4- (4- {2- [3- (1-trimethylsilylmethyl-1H- [1,2,3] triazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester

A solution of copper sulfate pentahydrate (2.2 mg; 0.01 mmol; 0.04 eq.) in water (0.2mL) was added to 4- {4- [2- (3-trimethylsilylethynyl-phenyl) -pyrimidin-5-yl]-pyrazol-1-yl } -piperidine-1-carboxylic acid tert-butyl ester (intermediate 19, 110 mg; 0.22 mmol; 1.0 equiv.), azidomethyl-trimethyl-silane (36. mu.l; 0.24 mmol; 1.1 equiv.), and D- (-) -erythorbic acid sodium salt (9 mg; 0.04 mmol; 0.2 equiv.) in a mixture in 1, 4-dioxane (3 mL). The vial was sealed and stirred at 80 ℃ overnight. The reaction mixture was then diluted with water and extracted with EtOAc (three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica flash chromatography afforded the title compound as a beige solid (60mg, 49%).¹H NMR (300 MHz, DMSO-d6) 9.18 (s, 2H), 8.88 (t,J=1.6 Hz, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.34 (dt,J= 8.0 Hz, 1.6 Hz, 1H),8.16 (s, 1H), 7.96 (dt,J= 8.0 Hz, 1.6 Hz, 1H), 7.60 (t,J= 8.0 Hz, 1H),4.48^.38 (m, 1H), 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- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -phenyl ] -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine hydrochloride

Tetrabutylammonium fluoride (56 mg; 0.21 mmol; 2.0 equiv.) is added to 4- (4- {2- [3- (1-trimethylsilylmethyl-1H- [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 (1mL) and the reaction mixture was stirred at room temperature for 2 hours. It is subsequently treated with NaHCO₃The saturated solution was diluted and extracted with EtOAc (three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting crude material was dissolved in DCM (1mL) and meoh (meoh) and HCl/dioxane (0.4mL of 4N solution, 1.6mmol, 15 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure and purified by auto-prep LC/MS to give the title compound as a beige solid (15mg, 33%).¹H NMR (300 MHz,DMSO-d6) d 9.22 (s, 2H), 9.11 (brs, 1H), 8.94-8.81 (m, 2H), 8.67 (s, 1H),8.54 (s, 1H), 8.35 (dt,J= 7.9 Hz, 1.5 Hz, 1H), 8.22 (s, 1H), 7.96 (dt,J=7.9 Hz, 1.5 Hz, 1H), 7.61 (t,J= 7.9 Hz,1H), 4.61-4.52 (m,1H), 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): rt2.08 min (purity 98.5%). MS (ESI +) 387.3.

Example 73: 1- (3-hydroxy-azetidin-1-yl) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanone

Following the procedure described for example 25, but starting from (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 80 mg; 0.22 mmol; 1.0 equivalent) and azetidin-3-ol hydrochloride (36 mg; 0.33 mmol; 1.5 equivalents) to yield the title compound as a white solid (5mg, 5%).¹H NMR(300 MHz, DMSO-d6) 9.18 (s, 2H), 8.54 (t,J= 1.6 Hz, 1H), 8.40 (s, 1H),8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.16 (s, 1H), 7.93 (d,J= 0.7 Hz, 1H),7.77-7.67 (m, 1H), 7.52 (t,J= 7.8Hz, 1H), 4.95 (s,2H), 4.58-4.46 (m,1H), 4.42-4.29 (m,1H), 4.17-4.05 (m,1H), 3.99-3.83 (m,4H), 3.73-3.59 (m, 1H). HPLC (condition a): rt 2.37 min (purity 92.9%). MS (ESI +): 416.2, (ESI-): 414.3, mp =177-181 ℃.

Example 74: 1- (3-hydroxy-pyrrolidin-1-yl) -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanone

Following the procedure described for example 25, but starting from (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 80 mg; 0.22 mmol; 1.0 equivalent) and pyrrolidin-3-ol (29 mg; 0.33 mmol; 1.5 equivalents) to yield the title compound as a yellow solid (25mg, 26%).¹H NMR (300 MHz,DMSO-d6) 9.19 (s, 2H), 8.54 (s, 1H), 8.39 (s, 1H), 8.31-8.19 (m, 2H), 8.15(s, 1H), 7.93 (s, 1H), 7.72 (d,J= 7.7 Hz, 1H), 7.52 (t,J= 7.7 Hz, 1H),5.25-5.01 (m, 3H), 4.33 (d,J= 29.2 Hz,1H), 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 ℃.

Example 75: 1- [2- (2-hydroxy-ethyl) -morpholin-4-yl ] -2- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -ethanone

Following the procedure described for example 25, but starting from (4- {2- [3- (1-methyl-1H-pyrazine)Azol-4-yl) -phenyl]-pyrimidin-5-yl } -pyrazol-1-yl) -acetic acid (example 8, 80 mg; 0.22 mmol; 1.0 equivalent) and 2-morpholin-2-yl-ethanol (44 mg; 0.33 mmol; 1.5 equivalents) to yield the title compound as a yellow solid (17mg, 16%).¹H NMR (300MHz, DMSO-d6) 9.18 (s, 2H), 8.54 (t,J= 1.6 Hz, 1H), 8.38 (s, 1H), 8.31-8.12 (m, 3H), 7.93 (d,J= 0.7 Hz, 1H), 7.78-7.66 (m, 1H), 7.52 (t,J= 7.8Hz, 1H), 5.43-5.28 (m,1H), 5.25-5.10 (m,1H), 4.25-4.06 (m,1H), 3.94-3.74(m, 4H), 3.62-3.31 (m, 6H), 3.27-3.12 (m,1H), 3.01-2.68 (m,1H), 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 ] -1H-pyrazol-4-yl } -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine

Following the procedure described for example 27 but starting from 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]Starting from-5- (1-piperidin-4-yl-1H-pyrazol-4-yl) -pyrimidine (example 1, 165 mg; 0.26 mmol; 1.0 eq.) and 3-fluoro-tetrahydro-pyran-4-one (active scientific; 60.7 mg; 0.51 mmol; 2.0 eq.) the title compound is obtained. The crude material was purified by auto-prep LC/MS to afford pure cis-isomer as a white solid (55mg, 44%).¹H NMR (300MHz, DMSO) 9.16 (s, 2H), 8.62-8.49 (m, 2H), 8.26 (s, 1H), 8.21 (dt,J=7.8, 1.5 Hz, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.71 (dt,J= 7.8, 1.5 Hz, 1H),7.51 (t,J= 7.8 Hz, 1H), 4.98 (brd,J= 48 Hz,1H), 4.30-4.12 (m,1H), 4.00-3.82 (m, 5H), 3.54-3.34 (m,2H), 3.20-3.03 (m,2H), 2.79-2.53 (m,1H), 2.47-2.35 (m,2H), 2.15-1.79 (m, 5H), 1.66-1.56 (m, 1H). HPLC (condition a): rt2.60 min (purity 100%). MS (ESI +): 488.4.

Example 121: 4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid dimethylamide

Trimethylaluminum (1.50 mL; 3.0 mmol; 5.4 equiv.) is added dropwise to a solution of dimethylamine (2.50 mL; 5.0 mmol; 9.1 equiv.) in DCE (50mL) over 1 minute at 0 ℃. After 10 min, ethyl 4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylate (prepared as described in example 62, step 1; 300 mg; 0.55 mmol; 1.0 equiv.) in DCE (50mL) was added dropwise over 5 min. The reaction solution was stirred for 16 hours, then another portion of trimethylaluminum (10 mL; 20 mmol; 36 equivalents) was added and the reaction solution was refluxed for 4 hours. The reaction mixture was then poured into ice-cold MeOH and concentrated under reduced pressure. The residue was redissolved in DCM and washed with 1N HCl solution, Rochelle's salt solution and brine. The organic phase was finally dried over magnesium sulfate, filtered and concentrated to give the title compound as a 3:1 mixture of cis and trans-4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid dimethylamide as a beige solid (165 mg; 60%). HPLC (Chiralpak IC, EtOH: THF 90:10) Rt 6.61 min; 10.38 min (76% purity, 24%); MS (ESI +): 456.4.

Example 134: trans-4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid dimethylamide

4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl)]-pyrimidin-5-yl } -pyrazoles-1-yl) -cyclohexanecarboxylic acid dimethylamide (example 121; 165 mg; 0.33mmol) was suspended in DMF and filtered to give the title compound as a white solid (50 mg; 20%).¹H NMR (300 MHz, DMSO) d 9.16 (s, 2H), 8.53 (t,J= 1.6Hz, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 8.24-8.18 (m, 1H), 8.13 (s, 1H), 7.92(d,J= 0.7 Hz, 1H), 7.74-7.67 (m, 1H), 7.51 (t,J= 7.8Hz, 1H), 4.32-4.16(m, 1H), 3.89 (s,3H), 3.05 (s,3H), 2.83 (s,3H), 2.77-2.63 (m,1H), 2.20-2.06 (m,2H), 1.97-1.77 (m,4H), 1.67-1.48 (m, 2H). HPLC (Chiralpak IC, EtOH: THF 90:10): Rt 6.91 min (98.4% purity); MS (ESI +): 456.4.

Example 135: cis-4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanecarboxylic acid dimethylamide

The DMF mother liquor obtained in example 134 was concentrated and the residue was purified by chiral-HPLC (ChiralpackIC; EtOH: THF 90:10) to give the title compound as a white solid (9 mg; 3%).¹H NMR (300 MHz,DMSO) 9.20 (s, 2H), 8.60-8.48 (m, 2H), 8.27 (s, 1H), 8.24-8.18 (m, 1H),8.15 (s, 1H), 7.92 (d,J= 0.6 Hz, 1H), 7.78-7.65 (m, 1H), 7.51 (t,J= 7.8Hz, 1H), 4.38-4.26 (m,1H), 3.89 (s,3H), 3.03 (s,3H), 2.89-2.83 (m,1H), 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: THF 90:10): Rt 10.84 min (purity 99.9%); MS (ESI +): 456.4.

Example 182: trans-4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanol

5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] before addition of 1, 4-dioxane (15mL)]Pyrimidine (intermediate 2; 700 mg; 2.22 mmol; 1.0 eq), 4,5,5,4',4',5',5' -octamethyl- [2,2']Bis [ [1,3,2]]Dioxaborolan radical](bi[[1,3,2]dioxaborolanyl) (620 mg; 2.44 mmol; 1.1 equiv), potassium acetate (327 mg; 3.33 mmol; 1.5 equivalents) and trans-dichlorobis (tricyclohexylphosphine) palladium (II), 99% (16.4 mg; 0.02 mmol; 0.01 eq) was flushed with nitrogen for 10 minutes. The reaction mixture was then heated under nitrogen at reflux for 4 hours. After addition of trans-4- (4-iodo-pyrazol-1-yl) -cyclohexanol (intermediate 22; 714 mg; 2.44 mmol; 1.10 eq), potassium carbonate (921 mg; 6.66 mmol; 3.0 eq), trans-dichlorobis (tricyclohexylphosphine) palladium (II) [99%, 16.4 mg; 0.02 mmol; 0.01 eq) and water (5mL), the temperature was reduced to 70 ℃. The new reaction mixture was heated again at 100 ℃ for 30 minutes. It was allowed to cool to rt and diluted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica flash chromatography (THF: EtOAc, 50:50) followed by recrystallization in THF afforded the title compound as an off-white powder (550mg, 62%).¹H NMR (300 MHz, DMSO) 9.14 (s, 2H), 6.51 (m, 1H), 8.48(s, 1H), 8.25 (s, 1H), 8.20 (m, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.69 (m,1H), 7.50 (t,J= 8.1 Hz, 1H), 4.70 (d,J= 4.2 Hz,1H), 4.18 (m,1H), 3.88(s, 3H), 3.50 (m,1H), 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)

According to the principle ofExample 182 the procedure described but starting from 5-bromo-2- [3- (1-methyl-1H-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 equiv.) to give the title compound. The crude material was purified by auto-prep LC/MS to provide the title compound as a white solid (45mg, 20%).¹H NMR (300 MHz, DMSO) 9.16 (s,2H), 8.53 (m,2H), 8.26 (s, 1H), 8.23 (m,1H), 8.13 (s, 1H),7.92 (s, 1H), 7.71 (m,1H), 7.50 (m,1H), 4.20 (m,1H), 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-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -1-aza-spiro [4.5] decan-2-one (second isomer)

Following the procedure described for example 182, but starting from 5-bromo-2- [3- (1-methyl-1H-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 equiv.) to give the title compound. The crude material was purified by auto-prep LC/MS to provide the title compound as a white solid (25mg, 9%).¹H NMR (300 MHz, DMSO) 9.16 (s,2H), 8.53 (m,2H), 8.26 (s, 1H), 8.23 (m,1H), 8.13 (s, 1H),7.92 (s, 1H), 7.71 (m,1H), 7.50 (m,1H), 4.20 (m,1H), 3.89 (s,3H), 2.22(m, 2H), 1.95 (m, 6H), 1.70 (m, 4H). HPLC (condition a): rt3.34 min (purity 100%). MS (ESI +) 454.5.

Example 254: 4- [4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexyl ] -morpholin-3-one

Following the procedure described for example 182, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]Pyrimidine (intermediate 2; 230 mg; 0.73 mmol; 1.0 equiv.) and trans-4- [4- (4-iodo-pyrazol-1-yl) -cyclohexyl]Starting from morpholin-3-one (intermediate 26; 274 mg; 0.73 mmol; 1.0 eq.) the title compound is obtained. The crude material was purified by recrystallization from methyl isobutyl ketone. The title compound was obtained as a beige solid (16mg, 5%).¹H NMR (300 MHz,DMSO)9.16 (s, 2H), 8.54 (s, 2H), 8.40-8.06 (m, 3H), 7.93 (s, 1H), 7.71 (d,J= 7.9 Hz, 1H), 7.52 (t,J= 7.9 Hz, 1H), 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, 1H), 0.84 (t,J= 7.3 Hz, 1H). HPLC (condition a): rt3.31 min (purity 99.2%). MS (ESI +): 484.4.

Example 255: 3- [4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexyl ] -oxazolidin-2-one

Following the procedure described for example 182, but starting from 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]Pyrimidine (intermediate 2; 200 mg; 0.63 mmol; 1.0 equiv.) and trans-3- [4- (4-iodo-pyrazol-1-yl) -cyclohexyl]Starting with oxazolidin-2-one (intermediate 27; 231mg, 0.63 mmol; 1.0 equivalent) the title compound is obtained. The crude material was wet-milled in acetonitrile and the suspension was filtered and dried under vacuum to give the title compound as a brown solid (151mg, 51%).¹HNMR (300 MHz, DMSO) 9.21 (s, 2H), 8.58 (d,J= 3.6 Hz, 2H), 8.38-8.10 (m,3H), 7.98 (s, 1H), 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): rt3.39 min (97.9% purity). MS (ESI +): 470.4.

Example 258: cis-1-hydroxymethyl-4- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -cyclohexanol

Following the procedure described for example 182, but starting from 4-iodo-1- (1-oxa-spiro [2.5]]Oct-6-yl) -1H-pyrazole (intermediate 28; 816 mg; 2.68 mmol; 1.0 equivalent) and 5-bromo-2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]Starting from pyrimidine (intermediate 2; 845 mg; 2.68 mmol; 1.0 eq.) the title compound is obtained as a yellow solid (6 mg).¹H NMR(300 MHz, DMSO) 9.18 (s, 2H), 8.55-8.50 (m, 2H), 8.27 (s, 1H), 8.24-8.19(m, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.74-7.68 (m, 1H), 7.51 (t,J= 7.8 Hz,1H), 4.62 (t,J= 5.8 Hz, 1H), 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) -1H-pyrazol-4-yl ] -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine

To a solution of 4- (4-bromo-pyrazol-1-yl) -3, 3-difluoro-piperidine (intermediate 29; 150 mg; 0.50 mmol; 1.0 equiv.) in 1, 4-dioxane (12mL) and water (3.0mL) was added potassium carbonate (141 mg; 0.99 mmol; 2.0 equiv.) and 2- [3- (1-methyl-pyrazol-1-yl) -piperidine-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 equivalents). The reaction mixture was degassed for 15 min and then 1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (20.88 mg; 0.02 mmol; 0.05 eq.) was added]Dichloropalladium (II) the reaction mixture was then heated at 100 ℃ for 90 minutes, concentrated under reduced pressure, diluted with water (15mL) and extracted with ethyl acetate (2 × 25mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated, purified by silica flash chromatography (DCM: MeOH, 9:1) to afford the title compound as a brown solid (24 mg; 11%).¹H NMR (400MHz, DMSO-d6) 9.21 (s, 2H), 8.53-8.52 (m, 2H), 8.26 (s, 1H), 8.23-8.20 (m,2H), 7.91 (s, 1H), 7.71 (d,J= 8.1 Hz, 1H), 7.51 (t,J= 7.8Hz, 1H), 4.96-4.86 (m,1H), 3.89 (s,3H), 3.22-3.15 (m,1H), 3.08-3.05 (m,1H), 2.98-2.87(m, 1H), 2.72-2.67 (m,1H), 2.66-2.59 (m,1H), 2.36-2.29 (m,1H), 2.08-2.05(m, 1H). HPLC (condition a): rt 3.00 min (96.8% purity). MS (ESI +): 422.2.

Example 260: trans-2-methyl-8- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -2-aza-spiro [4.5] decan-2-one

Following the 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 equiv.) 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; 298 mg; 0.80 mmol; 1.2 equivalents) to yield the title compound as a brown solid (158mf, 49%).¹H NMR (400 MHz,DMSO) 9.15 (s, 2H), 8.54-8.52 (m, 2H), 8.26 (s, 1H), 8.21 (d,J= 7.9 Hz,1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.70 (d,J= 7.7 Hz, 1H), 7.50 (t,J= 7.8Hz, 1H), 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 (96.6% purity). MS (ESI +): 468.3.

Example 262: cis-2-methyl-8- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -2-aza-spiro [4.5] decan-3-one

Following the 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 equiv.) and 2- [3- (1-methyl-1H-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 equivalents) to yield the title compound as a brown solid (34mg, 12%).¹H NMR (400 MHz,DMSO) 9.15 (s, 2H), 8.53-8.51 (m, 2H), 8.25 (s, 1H), 8.21 (d,J= 8.0 Hz,1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.70 (d,J= 7.9 Hz, 1H), 7.50 (t,J= 7.8Hz, 1H), 4.25-4.20 (m,1H), 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) -1H-pyrazol-4-yl ] -2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidine

Following the procedure described for example 164 but starting from 4- (4-bromo-pyrazol-1-yl) -3-fluoro-piperidine (intermediate 37; 200 mg; 0.80 mmol; 1.0 equivalent) and 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -phenyl]-5- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -pyrimidine (intermediate 15; 296 mg; 0.80 mmol; 1.0 equivalent) to yield the title compound. After purification of the crude material by silica flash chromatography (DCM: MeOH; 9:1), only the cis-isomer (41mg, 12%) was isolated as a brown solid.¹H NMR (400 MHz, DMSO-d6) 9.20 (s, 2H), 8.52-8.50 (m, 2H), 8.25-8.19 (m, 3H), 7.91 (s, 1H), 7.70 (d,J= 7.8 Hz, 1H), 7.51(t,J= 7.7 Hz, 1H), 4.92 (d,J= 52 Hz, 1H), 4.62-4.51 (m, 1H), 3.89 (s,3H), 3.24-3.10 (m, 2H), 2.85 (dd,J= 14, 40 Hz,1H), 2.67 (m,1H), 2.45 (m,1H), 2.23 (m,1H), 1.95 (m, 1H). HPLC (condition a): rt 2.85 min (97.6% purity). MS (ESI +): 404.3.

Example 280: (3aS,7aS) -7 a-hydroxymethyl-5- ((R) -4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -hexahydro-isobenzofuran-3 a-ol

(Arbitrary structural Attribute)

Chirality

The procedure described for example 164 was followed except for using cis-5- (4-bromopyrazol-1-yl) -cis-7 a- (hydroxymethyl) -1,3,4,5,6, 7-hexahydroisobenzofuran-3 a-ol (intermediate 35; 187 mg; 0.58 mmol; 1.0 eq.) and 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -n-ol]-5- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -pyrimidine (intermediate 15; 269 mg; 0.69 mmol; 1.2 equivalents) to give the title compound as an off-white solid (30 mg; 11%).¹H NMR (400 MHz, DMSO-d6) 9.16 (s, 2H), 8.57 (s, 1H), 8.52 (s, 1H),8.25 (s, 1H), 8.21 (d,J= 7.88 Hz, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.70 (d,J= 7.72 Hz, 1H), 7.49 (t,J= 7.72 Hz, 1H), 5.20 (s, 1H), 4.68 (t,J= 5.24Hz, 1H), 4.49-4.43 (m, 1H), 3.89-3.83 (m, 4H), 3.77 (d,J= 8.72 Hz, 1H),3.67 (d,J= 7.80 Hz, 1H), 3.54-3.44 (m, 3H), 2.15 (t,J= 12.72 Hz,1H), 2.14-2.03 (m,1H), 1.96-1.91 (m,1H), 1.88-1.78 (m,2H), 1.70-1.68 (m, 1H). HPLC (condition a): rt 3.20 min (purity 99.3%). MS (ESI +): 473.2. Melting point: 190.10-201.70 ℃.

Example 281: (3aR,5R,7aR) -7 a-hydroxymethyl-5- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -hexahydro-isobenzofuran-3 a-ol

(Arbitrary structural Attribute)

Chirality

The procedure described for example 164 was followed except for using cis-5- (4-bromopyrazol-1-yl) -cis-7 a- (hydroxymethyl) -1,3,4,5,6, 7-hexahydroisobenzofuran-3 a-ol (intermediate 36; 180 mg; 0.56 mmol; 1.0 eq.) and 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -n-ol]-5- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -pyrimidine (intermediate 15; 259mg of sodium benzoate; 0.67 mmol; 1.2 equivalents) to give the title compound as a pale yellow solid (80 mg; 29%).¹H NMR (400 MHz, DMSO-d6) 9.16 (s, 2H), 8.57 (s, 1H), 8.52 (s, 1H),8.26 (s, 1H), 8.21 (d,J= 7.8 Hz, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.70 (d,J= 7.6 Hz, 1H), 7.50 (t,J= 7.7 Hz, 1H), 5.21 (s, 1H), 4.68 (d,J= 5.2 Hz,1H), 4.45 (t,J= 12.0 Hz, 1H), 3.89-3.84 (m, 3H), 3.77 (d,J= 8.8 Hz, 1H),3.67 (d,J= 7.9 Hz, 1H), 3.66-3.51 (m, 1H), 3.52-3.49 (m, 2H), 3.46-3.44 (m,1H), 2.16 (t,J= 12.8 Hz, 1H), 2.07-1.97 (m, 2H), 1.92-1.89 (m, 1H), 1.86-1.78 (m, 1H), 1.67-1.61 (m, 1 H). HPLC (condition a): rt 3.21 min (purity 92.4%). MS (ESI +): 473.2. Melting point: 191.40-199.70 ℃.

Example 285: cis-1-methyl-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

Following the 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 equiv.) and 2- [3- (1-methyl-1H-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 equivalents) to yield the title compound as a brown solid (35mg, 17%).¹H NMR (400 MHz,DMSO-d6) 9.16 (s, 2H), 8.53 (d,J= 5.0 Hz, 2H), 8.25 (s, 1H), 8.21 (d,J=7.8 Hz, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.70 (d,J= 7.6 Hz, 1H), 7.51 (t,J= 7.8Hz, 1H), 4.80-4.40 (m,1H), 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 (maximum point) 95.4%, (254nm) 94.2%, (Rt (min) 3.59%, MS (ESI +) 468.0.

Example 286: trans-8- (4- {2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -pyrimidin-5-yl } -pyrazol-1-yl) -2-aza-spiro [4.5] decan-3-one

Following the procedure described for example 164 but starting from trans-8- (4-bromo-1H-pyrazol-1-yl) -2-azaspiro [4.5]Decan-3-one (intermediate 30) and trans-2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-5- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -pyrimidine (intermediate 15) to give the title compound as an off-white solid.¹H NMR (400 MHz, DMSO-d6)9.15 (s, 2H), 8.53 (s, 1H), 8.52-8.51 (m, 1H),8.25 (s, 1H), 8.21 (d,J= 7.9 Hz, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.70 (d,J= 7.8 Hz, 1H), 7.55 (bs, 1H), 7.50 (t,J= 7.8Hz, 1H), 4.24-4.19 (m,1H), 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 (maximum point) 98.6%, (254nm) 98.9%, (Rt (min) 3.42%, MS (ESI +) 454.20. Melting point: 255.0-258.7 ℃.

Example 287: cis-8- (4- (2- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrimidin-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [4.5] decan-3-one

Following the procedure described for example 164 but starting from cis-8- (4-bromo-1H-pyrazol-1-yl) -2-azaspiro [4.5]Decan-3-one (intermediate 31) and 2- [3- (1-methyl-1H-pyrazol-4-yl) -phenyl]-5- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -pyrimidine (intermediate 15) to give the title compound as an off-white solid.¹H NMR (400 MHz, DMSO-d6) 9.15 (s, 2H), 8.55 (s, 1H), 8.53-8.52 (m, 1H),8.26 (s, 1H), 8.21 (d,J= 7.8 Hz, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.70 (d,J= 7.8 Hz, 1H), 7.56 (bs, 1H), 7.50 (t,J= 7.8Hz, 1H), 4.25-4.18 (m,1H), 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 (maximum point) 98.8%, (254nm) 99.0%, (Rt (min) 3.44%, MS (ESI +) 454.20. Melting point: 262.00-265.80 ℃.

Other examples have been synthesized following procedures similar to those described above or following procedures well known to those skilled in the art.

Example 291: enzyme assay

IRAK1 enzyme assay

IRAK1 is a human purified recombinase (His-TEV-IRAK1 (194-712)).

In this assay, IRAK-1 hydrolyzes ATP and is autophosphorylated.

The assay for IRAK-1 inhibition was performed in streptavidin-coated 384-well FlashPlate (Perkinelmer # SMP 410A).

His-TEV-IRAK-1 (15 ng/well), ATP (1 μm, [ 2]³³P]ATP 0.25 μ Ci/well) and compound in DMSO (concentration range 20 μ Μ -1nM) or control (2% DMSO) at 30 ℃ in assay buffer: hepes pH7.050mM, fatty acid-free BSA 0.1%, dithiothreitol DTT 2mM, MgCl₂10mM, EGTA 0.5mM, Triton-X-1000.01% for 3 hours. The kinase reaction was stopped by the addition of EDTA. The supernatant was discarded, the plate was washed three times with 150mM NaCl, and the radioactivity was subsequently measured in a Microbeta Trilux reader.

IRAK4 enzyme assay

IRAK4 is a human purified recombinase (His-TEV-IRAK1 (194-712)).

IRAK4 hydrolyzes ATP, autophosphorylates and phosphorylates serine/threonine universal peptide substrates (STK: 61 ST1BLC, obtained from CisBio International base in Bagnols/Ceze FR).

Measurement of IRAK-4 inhibition was performed in streptavidin-coated 384-well FlashPlate (PerkinElmer # SMP 410A). His-TEV-IRAK4 (20 ng/well), ATP (2 μm, [ 2]³³P]ATP 0.25 μ Ci/well), STK 1-biotin peptide (300nM) and compound in DMSO (concentration range 20 μ Μ -1nM) or control (2% DMSO) at 30 ℃ in assay buffer: hepes pH7.050mM, fatty acid-free BSA 0.1%, dithiothreitol DTT 2mM, MgCl₂10mM、EGTA 0.5mM、Tween-20 0.01%，MnCl₂Incubate for 3 hours in 5 mM.

The kinase reaction was stopped by the addition of EDTA. The supernatant was discarded, the plate was washed three times with 150mM NaCl, and the radioactivity was subsequently measured in a Microbeta Trilux reader.

The results are given in the table below.

。

Example 293: preparation of pharmaceutical preparations

Formulation 1-tablet

The compound of formula (I) is mixed with a dry gelatin binder in a weight ratio of approximately 1:2 as a dry powder. A minor amount of magnesium stearate was added as a lubricant. The mixture is shaped in a tablet press to 240-270mg tablets (80-90mg of active compound according to the invention per tablet).

Preparation 2-capsule

The compound of formula (I) is mixed with a starch diluent in a weight ratio of approximately 1:1 as a dry powder. The mixture was filled into 250mg capsules (125mg active compound of the invention per capsule).

Formulation 3-liquid agent

Compound of formula (I) (1250mg), sucrose (1.75g) and xanthan gum (4mg) were blended, passed through a No. 10 mesh u.s. sieve and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50mg) in water. Sodium benzoate (10mg), flavours and colouring agents were diluted with water and added under stirring. Sufficient water was then added to generate a total volume of 5 mL.

Formulation 4-tablet

The compound of formula (I) is mixed with a dry gelatin binder in a weight ratio of approximately 1:2 as a dry powder. A minor amount of magnesium stearate was added as a lubricant. The mixture is shaped in a tablet press into 450-900mg tablets (150-300mg of the active compound according to the invention).

Preparation 5-injection

The compound of formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.

Claims (15)

1. A compound of the formula (I),

wherein:

R¹represents the absence or represents A or Q-Het,

z represents a group:，

wherein:

x represents O, S or N, and X represents O, S or N,

y represents C or N, and Y represents C or N,

t represents C or N, or

Z represents a pyridine or pyridazine group,

R^ais absent OR represents OR³、CF₃、Hal、NO₂，

R^bAbsent or represents one of the groups selected from A and COhet,

R²represents H, Het, Q-Het, Cyc, A or OA,

het represents a 4-9 membered monocyclic ring or a fused, spiro or bridged bicyclic ring which is saturated, unsaturated or aromatic and which contains 1-3 radicals independently selected from N, O, S and the groups CO, SO or SO₂And wherein 1 or 2H atoms may be replaced by A, OA, COA, CN, Hal, NO₂、OR³SOA and/or SO₂The substitution of A is carried out, and the substitution of A,

cyc denotes a 4-to 8-membered saturated carbocyclic ring which optionally contains the groups SO, SO₂CO and optionally selected from CO (NR)³)₂And COhet, OR³、Het¹、A、CH₂Het¹、NH₂、NHCOA、OCH₂Cyc¹、SO₂The group of a and/or-SA (= NH) (= O) is substituted once or twice,

q represents a linear OR branched alkylene group having 1 to 6 carbon atoms, wherein 1 to 5H atoms may be independently selected from OR³、Hal、N(R³)₂And wherein 1 or 2 CH₂The radicals may be independently selected from CO, SO₂And NR³Or Q represents a 4-8 membered divalent heterocyclic ring which is saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O and S,

a represents a linear OR branched alkyl group having 1 to 10 carbon atoms, wherein 1 to 7H atoms may be independently selected from-OR³、Hal、NHSO₂A、SO₂A、SOA、N(R³)₂And wherein 1,2 or 3 are not adjacent-CH₂The radicals-may be independently selected from-CO-, NR³And/or-a group replacement of-O-,

hal represents F, Cl, Br or I,

R³represents H or C₁-C₆Alkyl, in which 1H atom may be chosen from OH, O-C₁-C₆The radical replacement of alkyl and Hal,

Het¹represents a 5-or 6-membered saturated monocyclic heterocycle which contains 1 to 3N-and/or O-atoms and which is optionally mono-substituted by A,

Cyc¹represents a cycloalkyl group having 3 to 7 atoms,

and pharmaceutically acceptable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.

2. A compound of formula (I) as defined in claim 1 wherein Z represents one of the following groups:

。

3. a compound of formula (I) according to claim 1, wherein the group Z-R¹Represents one of the following groups:

。

4. a compound of formula (I) according to claim 1 or 2, wherein R²Represents one of the following groups:

。

5. a compound of formula (I) according to any one of claims 1 to 3, wherein R^bOne selected from the following groups:

。

6. a compound of formula (I) according to any one of claims 1 to 3, wherein the compound is selected from:

。

7. use of a compound of formula (I) as defined in any one of claims 1 to 6, and pharmaceutically acceptable tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios, for the manufacture of a medicament.

8. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment or prevention of inflammatory diseases, autoimmune disorders, cancer or multiple sclerosis and related disorders.

9. The use according to claim 8, wherein the autoimmune disease is selected from the group consisting of asthma, rheumatoid arthritis, acute disseminated encephalomyelitis, Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, Behcet's disease, celiac disease, anti-transglutaminase, Chagas ' disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves ' disease, Guilin-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, mixed connective tissue disease, scleroderma, multiple sclerosis, myasthenia gravis, lupus erythematosus, mixed connective tissue disease, scleroderma, multiple sclerosis, and autoimmune diseases, Narcolepsy, neuromuscular stiffness, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, scurvy syndrome, stiff man syndrome, systemic sclerosis, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, wegener's necrotizing granuloma.

10. Use according to claim 8, wherein the disease is selected from rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus.

11. Use of a compound of formula (I) according to claim 1 for the preparation of a medicament for the prevention and/or treatment of diseases associated with IRAK overexpression.

12. A kit consisting of the following separate packets:

(a) an effective amount of said compound of formula (I) and/or pharmaceutically useful salts and stereoisomers thereof, including mixtures thereof in all ratios, and

(b) an effective amount of another pharmaceutically active ingredient.

13. Pharmaceutical composition containing at least one compound of formula (I) according to any one of claims 1 to 6.

14. The pharmaceutical composition according to claim 13, additionally comprising at least one additional drug or immunomodulator for use in the treatment of inflammatory diseases or immune disorders.

15. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6, comprising the steps of: reacting a compound of formula (II)

Wherein X represents Hal or trifluoromethanesulfonate and wherein R¹、R^aAnd Z is as defined in claim 1, with a compound of the formula (III),

wherein R is H or C₁-C₆-alkyl, and wherein R^bAnd R²As defined in claim 1.