HK1186178A

HK1186178A - Derivatives of pyrazolophenyl-benzenesulfonamide compounds and use thereof as antitumor agents

Info

Publication number: HK1186178A
Application number: HK13113619.9A
Authority: HK
Inventors: Maurizio Pulici; Chiara Marchionni; Gabriella Traquandi; Alessandra Scolaro; Daniele Donati
Original assignee: Nerviano Medical Sciences S.R.L.
Priority date: 2010-08-03
Filing date: 2011-08-02
Publication date: 2014-03-07

Description

Derivatives of pyrazolophenylbenzenesulfonamide compounds and their use as antitumor agents

Technical Field

The present invention relates to certain substituted pyrazolophenylbenzenesulfonamide compounds that act as modulators of protein kinase activity. The compounds of the invention are therefore useful for the treatment of diseases which are caused by a deregulated protein kinase activity. The invention also provides processes for preparing these compounds, pharmaceutical compositions containing these compounds and methods of treating diseases using the pharmaceutical compositions containing these compounds.

Background

The classical Ras, Raf, MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase), ERK (extracellular signal-regulated kinase) channels play a key role in the regulation of a variety of cellular functions associated with the cellular environment, including cell proliferation, differentiation, survival, immortalization and angiogenesis (detailed in Peyssonnaux and Eychene, Biology of the cell, 2001, 93, 3-62).

In this channel, Raf family members are recruited to the plasma membrane upon binding to Guanosine Triphosphate (GTP) carried on Ras, resulting in phosphorylation and activation of Raf proteins. Activated Raf subsequently phosphorylates and activates MEK, which in turn phosphorylates and activates ERK. ERK, upon activation, translocates from the cytoplasm into the nucleus, causing phosphorylation and modulation of the activity of transcription factors such as Elk-1 and Myc. The Ras/Raf/MEK/ERK channel has been reported to contribute to the tumorigenic phenotype by: induce immortalization, growth independent of growth factors, insensitivity to growth inhibitory signals, ability to invade and metastasize, stimulate angiogenesis and inhibit apoptosis (reviewed in Kolch et al, exp. Rev. mol. Med. 2002, 25 April, http:// www.expertreviews. org/02004386h. htm). Indeed, ERK phosphorylation is enhanced in approximately 30% of all human tumors (Hoshino et al, Oncogene, 1999, 18, 813-822). This may be the result of overexpression and/or mutation of key members of the channel.

Three Raf serine/threonine protein kinase isoforms have been reported: Raf-1/c-Raf, [ beta ] -Raf and A-Raf (for review see Mercer and Pritchad, Biochim. Biophys. Acta, 2003, 1653, 25-40), whose genes are thought to originate from gene replication. All three Raf genes are expressed in most tissues, but differ: c-Raf is ubiquitously expressed at high levels, whereas high levels of [ beta ] -Raf are present in neuronal tissue, and A-Ref is in urogenital tissue.

Highly homologous Raf family members have overlapping but distinct biochemical activities and biological functions (Hagemann and Rapp, expt. Cell res. 1999, 253, 34-46). Expression of all three Raf genes is essential for normal murine development, but both c-Raf and B-Raf are essential for completion of pregnancy. [ beta ] -Raf-/-mice died at E12.5 due to vascular bleeding caused by increased endothelial apoptosis (Wojnowski et al, Nature Genet, 1997, 16, 293-. B-Raf has been reported to be a major isoform involved in cell proliferation and a major target for oncogenic Ras.

Activation of 5 somatic missense mutations has been identified as predominantly [ β ] -Raf, which occurs at a frequency of 66% in malignant cutaneous melanoma (Davies et al, Nature, 2002, 417, 949-. The most common mutation in [ β ] -Raf (80%) is the substitution of glutamic acid for valine at position 600. These mutations increase basic kinase activity of B-Raf and are thought to decouple Raf/MEK/ERK signaling from upstream proliferative driving forces (including Ras and growth factor receptor activation), resulting in constitutive activation of ERK. The mutated B-Raf proteins are transformed in NIH3T3 cells (Davies et al, Nature, 2002, 15417, 949-954) and melanocytes (Wellbrock et al, Cancer Res., 2004, 64, 2338-2342) and have also been shown to be critical for the viability and transformation of melanoma cells (Hingorani et al, Cancer Res., 2003, 63, 5198-5202). As a key driving force of the Raf/MEK/ERK signaling cascade, [ beta ] -Raf represents a likely point of intervention in tumors that depend on this pathway.

Substituted pyrazole derivatives for the treatment of cytokine mediated diseases such as inflammation and arthritis are disclosed in WO 98/52940 and WO 00/31063 (belonging to g.d. search & Co.). In WO 03/055860 (belonging to Cancer Research Institute) and WO 07/105058 (belonging to Pfizer Inc.) hydroxyarylpyrazole derivatives for the treatment of Cancer are disclosed. Pyrimidylpyrazole derivatives for the treatment of hyperproliferative diseases, such as cancer, are disclosed in WO 07/24843 (belonging to Smithkline Beecham Corporation). In WO 2010/010154 3, 4-diaryl pyrazole derivatives are disclosed for the treatment of diseases associated with a dysregulated protein activity, such as cancer. Despite these advances, there remains a need for effective drugs for the disease.

SUMMARY

It has now been identified that a new class of protein kinase inhibitors has a higher activity than has been achieved in the prior art. These compounds were found to prevent proliferation of human tumor cells at very low concentrations, thereby maximizing antitumor efficacy while reducing the risk of side effects associated with the administration of higher doses of the drug. The novel compound has a structure shown as a formula (I)

Wherein:

m is an integer from 0 to 6;

r1 is hydrogen, trichloromethyl, trifluoromethyl, halogen, cyano, OH, OR5, NR6R7, NR8COR9, COOH, COOR10, CONR11R12, OR is optionally substituted and is selected from linear OR branched (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkenyl, heterocyclyl, aryl and heteroaryl groups;

wherein R5 and R10 are each independently optionally substituted selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

r6, R7, R8, R9, R11 and R12 are identical or different and are each independently hydrogen or are selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl, or R6 and R7, R8 and R9 and R11 and R12 together with the nitrogen atom to which they are bound may form an optionally substituted heterocyclyl or heteroaryl group, which optionally contains one additional heteroatom or heteroatom group selected from S, O, N or NH;

r2 and R3 are each independently hydrogen, halogen, trifluoromethyl, trichloromethyl, cyano, nitro, OR13, OR are selected from straight OR branched (C)₁-C₈) Alkyl and (C)₃-C₈) CycloalkanesOptionally substituted group of (i) wherein:

r13 is selected from straight or branched chain (C)₁-C₈) Alkyl and (C)₃-C₈) Optionally substituted groups of cycloalkyl;

r4 is a heteroaryl group selected from

Wherein R14 is hydrogen or is selected from linear or branched (C)₁-C₈) Alkyl and (C)₃-C₈) Optionally substituted groups of cycloalkyl;

x is CH or N;

r15 is hydrogen, selected from linear or branched (C)₁-C₈) Alkyl and (C)₃-C₈) Optionally substituted cycloalkyl groups, halogen, cyano, NR16R17, CONR18R19, COOR20, OR20, SR20 OR SO₂R20, wherein

R16 and R17 are independently hydrogen or are selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl; or R16 and R17 may form together with the nitrogen atom to which they are bound an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH; or R16 is hydrogen and R17 is COR21, wherein:

r21 is OR22, NR23R24 OR an optionally substituted group selected from: straight or branched chain (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkenyl, heterocyclyl, aryl and heteroaryl, wherein:

r22 is selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl;

r23 and R24 are each independently selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl, or R23 and R24 may together with the nitrogen atom to which they are bound form an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH;

r18 and R19 are independently hydrogen or are selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl; or R18 and R19 may form together with the nitrogen atom to which they are bound an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH;

r20 is selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl;

and pharmaceutically acceptable salts thereof, with the exception of N- [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -2, 5-difluoro-benzenesulfonamide.

In some embodiments, R1 is trichloromethyl, trifluoromethyl, halogen, cyano, OH, OR5, NR6R7, NR8COR9, COOH, COOR10, CONR11R12, OR is an optionally substituted group selected from: straight or branched chain (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkenyl, heterocyclyl, aryl and heteroaryl, wherein:

r5 and R10 are each independently selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl;

r6, R7, R8, R9, R11 and R12 are the same or different and are each independently hydrogen or selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl, or R6 and R7, R8 and R9 and R11 and R12 together with the nitrogen atom to which they are bound may form an optionally substituted heterocyclyl or heteroaryl group, optionally containing one further heteroatom or heteroatom group selected from S, O, N or NH.

In some embodiments, R4 is heteroaryl selected from

。

In some embodiments, R15 is hydrogen, optionally substituted, selected from linear or branched (C)₁-C₈) Alkyl and (C)₃-C₈) Cycloalkyl, halogen, cyano, NR16R17, CONR18R19, OR20, SR20 and SO₂R20, wherein: r16 and R17 are independently hydrogen or are selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl; or R16 and R17 may form together with the nitrogen atom to which they are bound an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH; OR R16 is hydrogen, R17 is COR21, wherein R21 is OR22, NR23R24 OR is selected from linear OR branched (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Optionally substituted groups of cycloalkenyl, heterocyclyl, aryl and heteroaryl, wherein: r22 is optionally substituted and is selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups; r23 and R24 are each independently optionally substituted and selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups, or R23 and R24 may together with the nitrogen atom to which they are bound form an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH; r18 and R19 are independently hydrogen or optionally substituted selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups; or R18 and R19 may form together with the nitrogen atom to which they are bound a 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH; r20 is optionally substituted and is selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups; and pharmaceutically acceptable salts thereof.

Detailed Description

The following definitions apply unless otherwise indicated. When referring to the compounds of formula (I) as such and any pharmaceutical compositions thereof or any therapeutic treatment comprising them, the present invention includes all isomers, tautomers, hydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxides and pharmaceutically acceptable salts of the compounds of the present invention. A metabolite of a compound of formula (I) is any compound to which the same compound of formula (I) is converted in vivo, for example, upon administration to a mammal in need thereof. Generally, but not representing a limiting example, upon administration of a compound of formula (I), the same derivative may be converted into a plurality of compounds, including for example more soluble derivatives, such as hydroxylated derivatives which are easily excreted. Thus, any of these hydroxylated derivatives may be considered a metabolite of the compound of formula (I), depending on the metabolic pathway that takes place.

A prodrug is any covalently bonded compound that releases the active parent drug corresponding to formula (I) in vivo. N-oxides are compounds of formula (I) wherein the nitrogen is bound to the oxygen by a coordinate bond. If chiral centers or other forms of isomeric centers are present in the compounds of the present invention, all forms of the one or more isomers, including enantiomers and diastereomers, are included in the present invention. Compounds containing chiral centers may be used in the form of racemic mixtures, enantiomerically enriched mixtures, or the racemic mixtures may be separated by well-known techniques to use the individual enantiomers alone. If the compound has an unsaturated carbon-carbon double bond, both the cis (Z) and trans (E) isomers are within the scope of the present invention. If a compound can exist in tautomeric forms, each form is contemplated to be included within the invention, whether they exist in equilibrium or in a form that is preferred. If a compound can exist in other tautomeric forms, such as keto-enol tautomers, each tautomeric form is included within the scope of the invention whether they exist predominantly in equilibrium or in one form.

The term "straight or branched C₁-C₈Alkyl "refers to any such group, including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

The term "C₃-C₈Cycloalkyl ", unless otherwise specified, refers to a 3-8 membered all carbon monocyclic ring, which may contain one or more double bonds, but which does not have a completely conjugated pi-electron system. Examples of cycloalkyl groups are, without limitation, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene and cyclohexadiene.

The term "heterocyclyl" refers to a 3-8 membered saturated or partially saturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. The heterocyclyl ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Examples of heterocyclyl groups include, but are not limited to, pyrans, pyrrolidines, pyrrolines, imidazolines, imidazolidines, pyrazolidines, pyrazolines, thiazolines, thiazolidines, dihydrofurans, tetrahydrofurans, 1, 3-dioxolanes, piperidines, piperazines, morpholines, quinuclidines, and the like.

The term "C₂-C₈(or C)₃-C₈) Alkenyl "means an aliphatic C group containing at least one carbon-carbon double bond₂-C₈(or C)₃-C₈) A hydrocarbon chain, which may be straight or branched. Typical examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-or 2-butenyl, and the like.

The term "C₂-C₈(or C)₃-C₈) Alkynyl "refers to an aliphatic C group containing at least one carbon-carbon triple bond₂-C₈(or C)₃-C₈) A hydrocarbon chain, which may be straight or branched. Typical examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-or 2-butynyl, and the like.

The term "aryl" refers to mono-, bi-or polycyclic hydrocarbons having 1 to 4 ring systems, which may optionally be further fused or linked to one another by single bonds, wherein at least one carbocyclic ring is "aromatic", wherein the term "aromatic" refers to a completely conjugated pi-electron bond system. Non-limiting examples of such aryl groups include phenyl, alpha-or beta-naphthyl, and biphenyl groups.

The term "heteroaryl" refers to aromatic heterocycles, typically 5-8 membered heterocycles, containing 1-3 heteroatoms selected from N, O or S. The heteroaryl ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenylpyrrolyl, furyl, phenylfuryl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolyl, benzimidazolyl, quinolinyl, isoquinolinyl, 1,2, 3-triazolyl, 1-phenyl-1, 2, 3-triazolyl, 2, 3-dihydroindolyl, 2, 3-dihydrobenzofuryl, 2, 3-dihydrobenzothienyl, benzopyranyl, 2, 3-dihydrobenzoxazinyl, 2, 3-dihydroquinoxalinyl, and the like.

Unless otherwise specified, any of the above R1, R2, R3, R4 groups may be optionally substituted in any free position thereof with one or more groups (e.g., 1-6 groups) independently selected from: halogen, nitro, oxo (= O), cyano, C₁-C₈Alkyl, polyfluoroalkyl, polyfluoroalkoxy, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, C₃-C₈Cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxy-carbonyl, heterocycloalkyloxycarbonyl-amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, and cycloalkylcarbonyl, Heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonic acid, and alkylphosphonic acid. Each of the above substituents may in turn be further substituted by one or more of the above groups as appropriate. In some embodiments, when R1, R2, R3, or R4 is substituted with one or more of the above groups, each of the above groups present is unsubstituted or is selected from halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄Haloalkyl, C₁-C₄Halogenoalkoxy, CN, CONR'₂、COOR’、OH、-NR’₂and-S (O)_qUp to 3 groups of R 'are substituted, wherein q is 0-2, and each R' is independently H or C₁-C₄An alkyl group.

The term halogen atom refers to a fluorine, chlorine, bromine or iodine atom. The term cyano refers to the group-CN. The term nitro means-NO₂A group. The term polyfluorinated alkyl or polyfluorinated alkoxy refers to any of the above straight or branched chain C substituted with more than one fluorine atom₁-C₈Alkyl or alkoxy groups including, but not limited to, trifluoromethyl, trifluoroethyl, 1,1,1,3,3, 3-hexafluoropropyl, trifluoromethoxy, and the like. The term hydroxyalkyl refers to any of the above C bearing a hydroxyl group₁-C₈Alkyl groups including, but not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

The term "therapeutically effective amount" of a compound of formula (I) as used herein refers to an amount effective to modulate the activity of a protein kinase. Accordingly, the compounds of formula (I) are useful in the treatment of diseases caused by deregulated protein kinase activity.

As used herein, "patient" refers to an individual in need of treatment for diseases and disease states affected by modulation of protein kinase activity, or having or at recognized risk of developing one or more of the diseases or disease states described herein, as diagnosed by an attending physician or clinician. The identification of those patients in need of treatment for the disease states identified herein is well within the ability and knowledge of those skilled in the art. Those in need of such treatment are readily identified by clinicians skilled in the art based on clinical trials, physical examination, and medical/family history. Patients include warm-blooded animals, such as mammals, for example, in need of modulation of protein kinase activity. It goes without saying that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and humans are examples of animals within the meaning of the term. From the foregoing, it will be apparent to those skilled in the art that any radical with a name of compound nounGroups, such as arylamino, must be interpreted in the usual manner from the part from which the word is derived, for example as amino further substituted by aryl, where aryl is as defined above. Also, any terms such as alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkoxycarbonyl and the like are intended to belong to this group, where alkyl, alkoxy, aryl, C₃-C₈Cycloalkyl and heterocyclyl moieties are as defined above.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic or organic acids, for example with nitric, hydrochloric, hydrobromic, sulphuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, fumaric, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, isethionic and salicylic acids. Pharmaceutically acceptable salts of the compounds of formula (I) also include salts with inorganic or organic bases such as hydroxides, carbonates or bicarbonates of alkali or alkaline earth metals, especially sodium, potassium, calcium, ammonium or magnesium, acyclic or cyclic amines (preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine) and the like.

In some embodiments, m is an integer from 0 to 3. In some embodiments, m is 0, 1, or 2. In some embodiments, R1 is trifluoromethyl, halogen, cyano, OR5, NR6R7, COOR10, CONR11R12, OR is optionally substituted selected from (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl and heterocyclyl groups. In some embodiments, R1 is optionally substituted and is selected from (C)₃-C₈) Cycloalkyl or heterocyclyl groups. In some embodiments, R2 and R3 are independently selected from hydrogen and halogen. In some embodiments, when R4 is

Time of flight

R14 is hydrogen; or when R4 is

Time of flight

R15 is hydrogen, halogen or NH₂。

In some embodiments, the compounds of formula (I) include any one or more of the following:

1) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-isopropyl-piperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

2) N- {3- [1- (1-cyclopropyl-piperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-benzenesulfonamide

3) N- {3- [4- (2-amino-pyrimidin-4-yl) -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

4) N- {3- [4- (2-amino-pyridin-4-yl) -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

5) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methyl-piperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

6) N- {3- [4- (2-amino-pyrimidin-4-yl) -1- (1-methyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

7) 2, 5-difluoro-N- { 2-fluoro-3- [1- (2-fluoroethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

8) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methyl-piperidin-4-yl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

9) 2, 5-difluoro-N- [ 2-fluoro-3- (1-isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -benzenesulfonamide

10) N- {3- [4- (2-amino-pyrimidin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

11) N- {3- [4- (2-amino-pyrimidin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

12) N- {3- [4- (2-amino-pyridin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

13) N- {3- [4- (2-amino-pyridin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

14) N- {3- [4- (2-amino-pyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

15) N- {3- [4- (2-amino-pyrimidin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

16) 2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

17) N- {3- [4- (2-amino-pyridin-4-yl) -1-cyclopentyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

18) N- {3- [4- (2-amino-pyrimidin-4-yl) -1- (1-cyclopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

19) N- {3- [4- (2-amino-pyrimidin-4-yl) -1- (1-isopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

20) N- {3- [4- (2-amino-pyridin-4-yl) -1-oxetan-3-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

21) 2, 5-difluoro-N- [ 2-fluoro-3- (1-oxetan-3-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl } -benzenesulfonamide

22) N- (3- {4- [2- (2-amino-pyrimidin-4-ylamino) -pyrimidin-4-yl ] -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide, and

23) n- {3- [4- (2-amino-pyridin-4-yl) -1- (1-cyclopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

24) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

25) N- {3- [1- (4, 4-Difluorocyclohexyl) -4- (pyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

26) N- {4- [3(3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide

27) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

28) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

29) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-methylpyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

30) N- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } -2-methylpropanamide; and

31) n- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide.

In some embodiments, the compounds of formula (I) include any one or more of the following compounds:

1) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-isopropylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

2) N- {3- [1- (1-cyclopropylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

18) N- {3- [4- (2-amino-pyrimidin-4-yl) -1- (1-isopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

19) 2, 5-difluoro-N- [ 2-fluoro-3- (1-oxetan-3-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl } -benzenesulfonamide

20) N- (3- {4- [2- (2-amino-pyrimidin-4-ylamino) -pyrimidin-4-yl ] -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

21) N- {3- [4- (2-amino-pyridin-4-yl) -1- (1-cyclopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

22) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

23) N- {3- [1- (4, 4-Difluorocyclohexyl) -4- (pyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

24) N- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide

25) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

26) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

27) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-methylpyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

28) N- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } -2-methylpropanamide; and

29) n- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide.

2) N- {3- [1- (1-cyclopropyl-piperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

19) N- {3- [4- (2-amino-pyrimidin-4-yl) -1- (1-isopropylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

23) n- {3- [4- (2-amino-pyridin-4-yl) -1- (1-cyclopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide.

20) N- (3- {4- [2- (2-amino-pyrimidin-4-ylamino) -pyrimidin-4-yl ] -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide, and

21) n- {3- [4- (2-amino-pyridin-4-yl) -1- (1-cyclopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide.

In some embodiments disclosed are compounds of formula ICompound (I) wherein each is substituted straight or branched chain (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkenyl, heterocyclyl, aryl and heteroaryl groups are substituted with up to 4 substituents selected from the group consisting of: halogen, nitro, oxo (=0), cyano, C₁-C₈Straight or branched chain alkyl, polyfluoroalkyl, polyfluoroalkoxy, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, C₃-C₈Cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl, heterocyclylalkoxycarbonyl-amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyloxy, heterocyclylcarbonyl-amino, arylcarbonyloxy, heterocyclylcarbonyloxy, ureido, alkylamino, dialkylamino, arylaminocarbonyl, heterocyclylcarbonylamino, alkoxycarbonyl, Heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonic acid, and alkylphosphonic acid.

In some embodiments are disclosed compounds of formula I, wherein each is substituted straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with up to 4 substituents selected from the group consisting of: halogen, nitro, oxo (=0), cyano, C₁-C₈Straight or branched chain alkyl, polyfluoroalkylPolyfluoroalkoxy group, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, hydroxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, C₃-C₈Cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl, heterocyclylalkoxycarbonyl-amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyloxy, heterocyclylcarbonyl-amino, arylcarbonyloxy, heterocyclylcarbonyloxy, ureido, alkylamino, dialkylamino, arylaminocarbonyl, heterocyclylcarbonylamino, alkoxycarbonyl, Heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonic acid, and alkylphosphonic acid.

In a preferred embodiment, compounds of formula I are disclosed wherein each is substituted straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with up to 4 substituents selected from the group consisting of: halogen, nitro, oxo (=0), cyano, C₁-C₄Straight or branched alkyl, C₁-C₄Straight or branched alkoxy, C₁-C₄Haloalkyl, C₁-C₄Halogenoalkoxy, hydroxy, CONR'₂、COOR’、-NR’₂and-S (O)_qR ', wherein q is 0-2, each R' is independently H or C₁-C₄Straight or branched chain alkyl.

In one aspect of the invention, a method of preparing a pyrazolophenylbenzenesulfonamide compound represented by formula (I) by a procedure consisting of standard synthetic transformations is disclosed.

In another aspect, there is disclosed a method for the treatment of a disease caused by and/or associated with dysregulated protein kinase activity, in particular of the RAF family, the PLK family, the different isoforms of protein kinase C, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora A, Aurora B, Aurora C, Bub-1, Chk1, Chk2, HER2, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, P13K, weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, the Cdk/cyclin kinase family, especially the RAF family, which comprises administering to a mammal in need thereof an effective amount of a pyrazolo-phenylsulfonamide compound represented by formula (I) as defined above. In one embodiment, a method of treating a disease caused by and/or associated with dysregulation of protein kinase activity selected from the group consisting of cancer, cell proliferative disorders, viral infections, autoimmune diseases, and neurodegenerative disorders is disclosed.

In another aspect, a method of treating a specific type of cancer is disclosed, including but not limited to: cancers such as bladder, breast, colon, kidney, liver, lung (including small cell lung), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematologic lymphoid tumors including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematological tumors of the myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia; mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytomas, neuroblastomas, gliomas, and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, and kaposi's sarcoma.

In one embodiment, a method of treating a particular cell proliferative disorder is disclosed, including but not limited to: benign prostate hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-operative stenosis and restenosis. In one embodiment, a method of treating viral infections, particularly preventing the development of AIDS in HIV-infected individuals, is disclosed. In addition, the methods provide for inhibition of tumor angiogenesis and metastasis, and treatment of organ transplant rejection and host versus graft disease.

In one embodiment, the method further comprises administering to the mammal in need of treatment a treatment regimen of radiation or chemotherapy in combination with at least one cytostatic or cytotoxic agent. Additionally, disclosed is a method of inhibiting the activity of a RAF family protein in vitro comprising contacting the protein with an effective amount of a compound of formula (I).

In one aspect, pharmaceutical compositions are disclosed comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent. In one embodiment, pharmaceutical compositions are disclosed comprising compounds of formula (I) in combination with known anticancer agents, examples of which are: cytostatic or cytotoxic agents, antibiotic-type drugs, alkylating agents, antimetabolites, hormonal drugs, immunological drugs, interferon-type drugs, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (e.g., angiogenesis inhibitors), farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like. Additionally, a product or kit is disclosed which comprises a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

In another aspect, there is disclosed a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined for use as a medicament. Furthermore, the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament having anti-tumour activity is disclosed. Also disclosed are compounds of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in any of the above methods.

In one aspect, a process for the preparation of a compound of formula (I) as defined above is disclosed, using reaction routes and synthetic schemes described below, using readily available starting materials and techniques in the art. The preparation of certain embodiments is described in the following examples, but one of ordinary skill in the art will recognize that the preparation methods described can be readily modified to prepare other embodiments. For example, synthesis of non-exemplified compounds can be accomplished by variations apparent to those skilled in the art, such as appropriate protection of interfering groups, replacement of other suitable reagents known in the art, or routine modification of reaction conditions. Alternatively, it will be appreciated that other reactions mentioned herein or known in the art are suitable for the preparation of other compounds.

If the pyrazole ring carries a protecting group, for example PG2 as defined in the examples below, this protecting group can be attached to any of the nitrogen atoms of the pyrazole ring to form isomeric compounds of the formulae IIa and IIb. The isomeric compounds are included unless otherwise indicated, since the position of the protecting group is not relevant to the preparation of the compounds of formula (I).

Unless otherwise indicated, when a compound of formula (II) is represented by only one of the regioisomeric forms of the following formula (IIa) or (IIb), the remaining one is still considered to be included within the meaning of the formula.

Thus, when R29 has the meaning of PG2 as defined in the examples below, this group can be attached to any of the nitrogen atoms of the pyrazole ring to form isomeric compounds of the general formulae IIc and IId. Unless otherwise indicated, these isomeric compounds are contemplated to be included. The position of the protecting group is independent of the method of preparation of the compound of formula (I) provided.

Unless otherwise indicated, when a compound of formula (II) is represented by only one of the regioisomeric forms of the following formula (IIc) or (IId), the remaining one is still considered to be included within the meaning of the formula.

The compounds of formula (I) can be prepared according to the general synthesis methods described in Process A and Process B below.

The intermediate compounds of the formulae 1 and 9 are prepared according to the process C shown below starting from the compound of the formula 14.

Intermediate compounds of formula 14A and 14B were prepared according to method D shown below, starting from the compound of formula 20.

The intermediate compound of formula 2 prepared according to method a and method B can be further converted to another compound of formula 2 according to method D and method F below.

One of ordinary skill in the art will appreciate that any transformation according to these methods may require alteration of standards, such as protection of interfering groups, replacement with other suitable reagents known in the art, or routine modification of reaction conditions.

Method A

In the above scheme of process a, Hal is a halogen atom, such as iodine or bromine; r29 is- (CH)₂)_mR1 or PG₂Wherein m and R1 are as defined above, PG₂Suitable protecting groups are pyrazole rings, for example p-methoxybenzyl, tetrahydropyranyl, trityl or silyl derivatives, such as trimethylsilylethoxymethyl (SEM) and 2-trimethylsilylethanesulfonyl (SES). In one embodiment, the protecting group is tetrahydropyranyl. PG (Picture experts group)₁Suitable protecting groups are aniline or sulfonamide, such as t-Butyloxycarbonyl (BOC), benzyloxycarbonyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), and the like, acetyl, ethoxycarbonyl, and the like; r30 is hydrogen or a group SO₂Ph (R2) (R3), wherein R2 and R3 are as defined above. M is B (OH)₂、B(OAlk)₂、Sn(Alk)₃、Al(Alk)₂ZnHal, MgHal or ZrCp₂Hal. M' is B (OAlK)₂Or Sn (alk)₃. L' is a group which functions as a leaving group, such as a halogen atom, a tosylate group or a triflate group. R4 is also as defined above.

With respect to the synthetic method described in method a for preparing the compound of formula (I): in step "a", the compound of formula 1 may be converted to the compound of formula 2 by performing any cross-coupling reaction suitable for carbon-carbon bond formation. Such reactions are well known in the art and include coupling with suitable organometallic reagents (e.g., organoboron, organotin, organozinc, organoaluminum or organozirconium compounds, etc.). Alternatively, in step "b" the compound of formula 1 is converted to an organometallic derivative of formula 3, for example a boron-pyrazole derivative, which in turn is cross-coupled in step "c" with a suitable electrophile according to the conditions of step "a" to form the compound of formula 2. When R29 is PG2 in the compound of formula 2, such protecting group is removed according to step "d" to form the compound of formula 4A, and such compound of formula 4A is combined in step "eThe conversion of the compound reverts to the compound of formula 2 wherein R29 is- (CH)₂) mR 1. Such groups are generally introduced by reaction with the appropriate formula L- (CH)₂) mR1 alkylating agent is subjected to an N-alkylation reaction, wherein L is OH or a group which can act as a leaving group, such as a halogen atom, a tosylate group, a mesylate group or a triflate group, or L is a group-B (OH)₂. This alkylation will produce a mixture of regioisomers from which the desired isomer is purified using known methods, such as silica gel chromatography or preparative HPLC. In step "f", a compound of formula 2 (wherein R29 is- (CH)₂) mR1, R30 is SO₂Ph (R2) (R3)) is converted to the compound of formula (I) by removal of the protecting group PG 1. Alternatively, when R29 is- (CH) in the compound of formula 2₂) When mR1 and R30 are hydrogen, the protecting group is removed according to step "g" to give the compound of formula 5A which is converted to the compound of formula (I) in step "h" by reaction with a suitable sulfonyl chloride.

According to process A, step "a", a compound of formula 1 is cross-coupled with a suitable organometallic compound of the general formula R4M, for example, an organoboron compound (Suzuki reaction), an organotin compound (Still reaction), an organozinc, organoaluminum or organozirconium compound (Negishi reaction), etc. These reactions are well known to those of ordinary skill in the art. In one synthetic method, in the presence of a palladium-based catalyst (e.g., palladium tetrakistriphenylphosphine) and a suitable base (e.g., Cs)₂CO₃、Na₂CO₃、K₂CO₃、Rb₂CO₃NaOH, CsF, etc.) using a suitable aryl or heteroaryl boronate. Such reactions can be carried out in a solvent (e.g., N-dimethylformamide, dimethylsulfoxide, water, dimethoxyethane, 1, 4-dioxane, tetrahydrofuran, and the like, and mixtures thereof) at a temperature ranging from about 20 ℃ to reflux for about 30 minutes to about 24 hours.

Following step "b" of method A, the compound of formula 1 can be converted to a suitable organometallic derivative of formula 3, such as organoboron, organotin, and the like. In one embodiment, organometallic compounds are used. TheThe organometallic compound may be an organoboron compound obtained by: a compound of formula 1 is reacted with a suitable boron compound, such as pinacol ester diboronate, pinacol borane, and the like, over a suitable palladium catalyst (e.g., palladium acetate (Pd (OAc))₂) 1, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (Pd (dppf) Cl₂·CH₂Cl₂) Or Pd (CH)₃CN)₂Cl₂) And a suitable base (e.g., KOAc, triethylamine, etc.) in a solvent (e.g., N-dimethylformamide, dimethylsulfoxide, dimethoxyethane, 1, 4-dioxane, tetrahydrofuran, toluene, etc.), at a temperature of from about 20 ℃ to reflux temperature, and for a reaction time of from about 30 minutes to about 24 hours.

According to method A, step "c", an organometallic derivative of formula 3 is reacted with a suitable electrophile of formula R4L' (e.g., an aryl halide or triflate, mesylate or tosylate) in a palladium-based or nickel-based catalyst (e.g., palladium tetrakistriphenylphosphine) and a suitable base (e.g., Cs)₂CO₃、K₂CO₃、Rb₂CO₃NaOH, CsF, etc.) to give the compound of formula 2. Such reactions can be carried out in solvents such as N, N-dimethylformamide, dimethylsulfoxide, water, dimethoxyethane, 1, 4-dioxane, tetrahydrofuran, and the like, and mixtures thereof, at temperatures from about 20 ℃ to reflux for about 30 minutes to about 24 hours.

According to step "d" of method A (when R29 is PG)₂When this step is employed), the protecting group PG₂Depending on the nature of the protecting group, removal of (A) can be accomplished in a variety of ways. For example, when PG₂When it is a tetrahydropyranyl group, the conversion of the compound of formula 2 to the compound of formula 4A may be carried out using an acid (e.g. p-toluenesulphonic acid or hydrochloric acid in methanol or ethanol). When the protecting group is p-methoxybenzyl or trityl, the conversion of the compound of formula 2 to the compound of formula 4A may be carried out using a strong acid (e.g. trifluoroacetic acid) in a suitable co-solvent (e.g. dichloromethane) at from 20 ℃ to reflux or higher (provided that the reaction is carried outShould be carried out in a sealed tube and heated with, for example, a microwave oven) for 30 minutes to about 24 hours.

According to process A, step "e", N-unsubstituted pyrazoles of formula 4A are reacted with compounds of formula 2 (wherein R29 is- (CH)₂) mR 1) can be transformed with the formula L- (CH)₂) The mR1 compound. When L is OH, well-known Mitsunobu conditions can be employed, in which case the reaction can be carried out with a dialkyl azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) in the presence of a trialkylphosphine or triarylphosphine, preferably triphenylphosphine, in a suitable solvent (e.g., tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, or acetonitrile). When L is a group capable of acting as a leaving group (optionally upon activation), such as a halogen atom, a tosylate group, a mesylate group, a triflate group, etc., the conversion reaction may be carried out with a suitable base (e.g., NaH, K)₂CO₃、Cs₂CO₃NaOH, 1, 8-diazabicyclo [5.4.0 ]]-undec-7-ene (DBU), lithium bis (trimethylsilyl) amide (LiHMDS), etc.) in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, methanol, ethanol, isopropanol, acetonitrile, acetic acid, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, etc.). The reaction can be carried out at a temperature ranging from about 0 ℃ to reflux for about 30 minutes to about 48 hours. When L is a boronic acid group-B (OH)₂When the reaction is carried out in the presence of a base (e.g., Na)₂CO₃、K₂CO₃、Cs₂CO₃Etc.), copper salts (e.g., Cu (OAc)₂) And other copper ligands (e.g., [2, 2']Bipyridyl) is used. The reaction is carried out in a suitable solvent (e.g., dichloroethane, dichloromethane, etc.) at a temperature of from about 0 deg.C to reflux temperature for a reaction time of from about 30 minutes to about 48 hours. The compound of formula 2 thus obtained may be isolated and purified by silica gel chromatography or preparative HPLC, if desired.

According to step "f" of method A (when R29 is- (CH)₂) mR1 and R30 are SO₂This step is taken at Ph (R2) (R3), removal of the protecting group PG1 to give the compound of formula (I) can be accomplished in a variety of ways, depending on the nature of the protecting group. For example, when PG₁When it is an acetyl group or an ethoxycarbonyl group, the protecting group can be removed under basic conditions using, for example, a base such as triethylamine or N, N-Diisopropylethylamine (DIPEA) in methanol or ethanol, or an aqueous solution of an inorganic base such as sodium carbonate or potassium, sodium hydroxide or potassium hydroxide, or the like. Such reactions may be carried out at temperatures from about 0 ℃ to reflux for about 30 minutes to about 48 hours. When PG is used₁In the case of a group such as BOC, MOM, MEM, etc., the deprotection reaction can be carried out under acidic conditions using, for example, hydrochloric acid in a solvent (e.g., 1, 4-dioxane, dimethoxyethane, etc.), or trichloroacetic acid in a solvent (e.g., water, dichloromethane, etc.). The reaction may be carried out at a temperature of from about 0 ℃ to reflux for about 30 minutes to about 48 hours. When the group is benzyloxycarbonyl, the deprotection reaction can be carried out using H in the presence of a suitable hydrogenation catalyst₂And (4) finishing. The hydrogenation catalyst is typically a metal, most commonly palladium, which may be used as such or supported on carbon in a suitable solvent such as tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, methanol, ethyl acetate and mixtures thereof.

According to method A, step "g" (when R29 is- (CH)₂) This procedure is used when mR1 and R30 are hydrogen), the protecting group PG is removed₁The preparation of the compound of formula 5A to give may be carried out in various ways depending on the nature of the protecting group, as described in step "f" of method a.

According to process a, step "h", the compound of formula 5A can be converted to the compound of formula (I) by reaction with a suitable sulfonyl chloride in the presence of a suitable base (e.g., pyridine, N-methylmorpholine or DIPEA) in a suitable solvent (e.g., pyridine, dichloromethane or tetrahydrofuran), at a temperature of from about 0 ℃ to reflux temperature, for a period of from about 1 hour to about 7 days.

Method B

In the above schemes, m, R1, R2, R3, R4, R29, R30 and PG₁And R15' is R15 as defined above, but excluding halogen.

With respect to the synthetic methods described in method B for preparing compounds of formula IB: in step "a", the compound of formula 1 is subjected to a Sonogashira type reaction with trimethylsilylacetylene to form an intermediate of formula 6. The latter desilylation in step "b" followed by hydration of the intermediate alkyne in step "c" affords the compound of formula 8. Alternatively, the compound of formula 1 is converted to the compound of formula 8 in step "d" by a two-step reaction sequence involving cross-coupling with a suitable enol ether or organometallic derivative of an enol ether, followed by hydrolysis of the enol ether intermediate.

The compound of formula 8 may also be prepared according to step "e" by acylating the compound of formula 9 under classical Friedel-Crafts conditions. In step "f", the compound of formula 8 is converted to an enaminone derivative of formula 10, which is condensed in step "g" with a suitable guanidine or amidine derivative or an S-alkylisothiourea derivative to form the compound of formula 2B. When R29 in the compound of formula 2B is PG₂When the protecting group is removed according to step "h", a compound of formula 4B is formed, and such a compound of formula 4B is converted back to a compound of formula 2B in step "i", wherein R29 is- (CH)₂) mR 1. This group is generally introduced by using a suitable alkylating agent L- (CH)₂) mR1, wherein L is as defined above. The latter reaction will form a mixture of regioisomers from which the desired isomer is purified by known methods, such as silica gel chromatography or preparative HPLC. In step "k", a compound of formula 2B (wherein R29 is- (CH)₂) mR1 and R30 are SO₂Ph (R2) (R3)) by removing the protecting group PG₁Conversion to the compound of formula (I) BA compound (I) is provided. Alternatively, when R29 is- (CH) in the compound of formula 2B₂) When mR1 and R30 are hydrogen, removal of the protecting group according to step "j" affords compounds of formula 5B which are converted to compounds of formula (I) B in step "l" by reaction with a suitable sulfonyl chloride.

According to process B, step "a", the compound of formula 1 is reacted with trimethylsilylacetylene in the presence of a suitable palladium catalyst (e.g., bis (triphenylphosphino) palladium (II) dichloride (PdCl)₂(PPh₃)₂) Tetrakis (triphenylphosphine) palladium (Pd (PPh)₃)₄) Etc.) and a suitable copper catalyst (e.g., CuI). The reaction is carried out in the presence of a suitable base (e.g., triethylamine, diethylamine, diisopropylamine, etc.), optionally in the presence of a phosphine ligand (e.g., triphenylphosphine). The reaction is typically carried out at a temperature of from about-20 ℃ to reflux for about 30 minutes to about 48 hours.

According to step "B" of Process B, the trimethylsilyl group is dissolved in a solvent (e.g., methanol, ethanol, etc.) using a base (e.g., KOH, NaOH, K)₂CO₃) Removing, or dissolving in solvent (such as tetrahydrofuran, dimethoxyethane, N-dimethylformamide, etc.) with appropriate fluoride salt (such as KF, N-Bu)₄NF) is removed.

According to step "c" of Process B, the alkyne of formula 7 is hydrated to form the compound of formula 8 using, for example, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, mercuric trifluoromethanesulfonate (Hg (OTf)₂）、NaHSO₃Etc. in a suitable aqueous solvent (e.g., acetonitrile, 1, 4-dioxane, ethanol, etc.).

Following step "d" of Process B, the compound of formula 1 is cross-coupled with a suitable organometallic derivative of an enol ether (e.g., 1-ethoxyvinyltri-n-butyltin), followed by hydrolysis of the enol ether intermediate. The cross-coupling is carried out in the presence of a suitable palladium catalyst (e.g., tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃）、Pd(OAc)₂、PdCl₂(PPh₃)₂、Pd(PPh₃)₄Etc.) and a suitable base (E.g., triethylamine, diethylamine, diisopropylamine, or CsF, etc.), optionally in the presence of a phosphine ligand (e.g., triphenylphosphine, tritolylphosphine, etc.). The enol ethers formed are typically hydrolyzed under acidic conditions using, for example, hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like, in a suitable aqueous solvent (e.g., acetonitrile, 1, 4-dioxane, ethanol, and the like).

According to step "e" of process B, compounds of formula 8 can be prepared starting from compounds of formula 9 by reaction with a suitable electrophile, such as acetyl chloride or acetic anhydride, in the presence of a suitable Lewis acid, such as aluminum trichloride, stannic chloride, etc. Such reactions are typically carried out in a solvent (e.g., carbon disulfide, methylene chloride, ethylene dichloride, carbon tetrachloride, etc.) at a temperature of about-70 ℃ to reflux.

The synthesis of the enaminone derivative of formula 10 according to step "f" of method B is accomplished using N, N-dimethylformamide dialkyl alcohol, e.g., N-dimethylformamide dimethyl acetal, N-dimethylformamide di-tert-butanol, etc., in a suitable solvent, e.g., tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, etc., at a temperature of about 0 ℃ to reflux for about 30 minutes to about 24 hours.

According to step "g" of process B, the condensation reaction of a compound of formula 10 with a compound of formula 13 to form a compound of formula 2B is carried out using a solvent (e.g., N-dimethylformamide, N-dimethylacetamide, water, tetrahydrofuran, 1, 4-dioxane, dimethoxyethane, acetonitrile, ethanol, isopropanol, and mixtures thereof), optionally in a suitable base (e.g., sodium ethoxide, sodium methoxide, K)₂CO₃NaOH, DBU, etc.) at a temperature of from about 20 ℃ to reflux for about 30 minutes to about 48 hours.

The conversion of the compound of formula 2B to the compound of formula 4B is accomplished according to step "h" of method B, as described in step "d" of method a.

The conversion of the compound of formula 4B to another compound of formula 2B is accomplished according to step "i" of method B, as described in step "e" of method a.

The conversion of the compound of formula 2B to the compound of formula (I) B is accomplished according to step "k" of method B, as described in step "f" of method a.

The conversion of the compound of formula 2B to the compound of formula 5B is accomplished according to step "j" of method B, as described in step "g" of method a.

The conversion of the compound of formula 5B to the compound of formula (I) B is accomplished according to step "l" of method B, as described in step "h" of method a.

In the general synthetic procedure, intermediate compounds of general formulae 1 and 9 are prepared starting from the compound of formula 14 according to procedure C shown below.

Method C

In the above schemes, m, R1, R29, R30, PG₁、PG₂L and M are as defined above.

With respect to the synthetic methods described in method C for preparing compounds of general formulae 1 and 9: in step "a", the compound of formula 14 is converted to the compound of formula 9 by cross-coupling reaction with a suitable organometallic derivative of formula 19. According to step "h", compound 9 is halogenated to give the compound of formula 1. According to step "b", the compound of formula 14 is converted to the compound of formula 15 by a two-step reaction sequence involving cross-coupling with a suitable organometallic derivative of an enol ether followed by hydrolysis of the enol ether intermediate. In step "c", the compound of formula 15 is converted to an enaminone derivative of formula 16 which is condensed with hydrazine in step "d" to form the pyrazole of formula 17. The pyrazoles may also be prepared from compounds of formula 9 (when R29 is PG)₂When) removing the protection according to step "eGroup PG₂To obtain the compound. In step "f", the compound of formula 17 is converted back to the compound of formula 9, wherein R29 is- (CH)₂) mR 1. Such groups are generally introduced by using a suitable alkylating agent L- (CH)₂) mR1 is N-alkylated, wherein L is as defined above. The latter reaction will produce a mixture of regioisomers from which the desired isomer is purified by known methods such as silica gel chromatography or preparative HPLC. Compound 17 is halogenated according to step "g" to provide a compound of formula 18. The latter can also be prepared according to step "i" from a compound of formula 1 (when R29 is PG)₂When) removal of the protecting group PG₂Thus obtaining the product. In step "k", the compound of formula 18 is converted back to the compound of formula 1, wherein R29 is- (CH)₂) mR 1. The introduction of such groups is generally carried out by using a suitable alkylating agent L- (CH)₂) mR1 is N-alkylated, wherein L is as defined above. The latter reaction will produce a mixture of regioisomers from which the desired isomer is purified using known methods such as silica gel chromatography or preparative HPLC.

Following step "a" of method C, the compound of formula 14 is cross-coupled with an organometallic derivative of formula 19, such as an organoboron compound. Such reactions are well known to those of ordinary skill in the art. When using suitable pyrazolyl boronic acid ester derivatives, the reaction can be carried out over a palladium-based catalyst (e.g., Pd (PPh)₃)₄) And a suitable base (e.g., Cs)₂CO₃、K₂CO₃、Rb₂CO₃NaOH, CsF, etc.). Such reactions can be carried out in a solvent (e.g., N-dimethylformamide, dimethylsulfoxide, water, dimethoxyethane, 1, 4-dioxane, tetrahydrofuran, and the like, and mixtures thereof) at a temperature of from about 20 ℃ to reflux for about 30 minutes to about 24 hours.

Following step "b" of Process C, the compound of formula 14 is cross-coupled with a suitable organometallic derivative of an enol ether (e.g., 1-ethoxyvinyltri-n-butyltin), followed by hydrolysis of the enol ether intermediate. Cross-coupling reaction over a suitable palladium catalyst (e.g., Pd)₂(dba)₃、Pd(OAc)₂、PdCl₂(PPh₃)₂、Pd(PPh₃)₄Etc.) and a suitable base (e.g., triethylamine, diethylamine, diisopropylamine, or CsF, etc.), optionally in the presence of a phosphine ligand, e.g., triphenylphosphine, trimethylphosphine, etc. The hydrolysis of the enol ether formed is generally carried out under acidic conditions (e.g., using hydrochloric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like) in a suitable aqueous solvent (e.g., acetonitrile, 1, 4-dioxane, ethanol, and the like).

Following step "C" of method C, the conversion of the compound of formula 15 to the compound of formula 16 is accomplished as described in step "f" of method B.

According to process C, step "d", the conversion of the compound of formula 16 to the compound of formula 17 is accomplished using hydrazine in a suitable solvent (e.g., tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, methanol, ethanol, acetonitrile, acetic acid, N-dimethylformamide, and mixtures thereof) at a temperature of from about 0 ℃ to reflux for about 20 minutes to about 24 hours.

According to step "e" of method C, the conversion of the compound of formula 9 to the compound of formula 17 is accomplished as described in step "d" of method A.

According to step "f" of method C, the conversion of a compound of formula 17 to another compound of formula 9 is accomplished as described in step "e" of method A.

Following step "g" of method C, the conversion of the compound of formula 17 to the compound of formula 18 can be accomplished using a variety of halogenating agents. In one embodiment, the compound of formula 17 is brominated using, for example, N-bromosuccinimide in a solvent (e.g., acetonitrile, toluene, dichloromethane, or water, etc.) at a temperature from about-20 ℃ to reflux for about 30 minutes to about 48 hours.

According to step "h" of method C, the conversion of the compound of formula 9 to the compound of formula 1 is accomplished as described in step "g" of method C.

The conversion of the compound of formula 1 to the compound of formula 18 according to step "i" of method C is accomplished as described in step "d" of method A.

The conversion of a compound of formula 18 to another compound of formula 1 according to step "k" of method C is accomplished as described in step "e" of method a.

In the general synthetic procedure, intermediate compounds of general formulae 14A and 14B can be prepared starting from the compound of formula 20 according to method D shown below.

Method D

In the above scheme, PG₁R2 and R3 are as defined above.

With respect to the synthetic method of the compound of formula 14 described in preparation D: the compound of formula 20 is protected in step "a" to give the compound of formula 14A. The compound of formula 20 is reacted with a suitable sulfonyl chloride in step "B" to give a compound of formula 21, which is protected with a suitable protecting group in step "c" to give a compound of formula 14B.

Protection of the aniline derivative of formula 20 according to step "a" of method D can be accomplished in a variety of ways well known to those skilled in the art, depending on the nature of the protecting group. For example, the protection can be performed with di-tert-butyl dicarbonate or benzyloxycarbonyl chloride in a solvent (e.g., dichloromethane, tetrahydrofuran, pyridine, etc.), optionally in the presence of a suitable base (e.g., triethylamine, DIPEA, etc.), at a reaction temperature of about 20 ℃ to reflux temperature, and for a reaction time of about 30 minutes to about 24 hours.

Following process D, step "b", the compound of formula 20 can be converted to the compound of formula 21 by reaction with a suitable sulfonyl chloride in a suitable solvent (e.g., pyridine, dichloromethane, or tetrahydrofuran) in the presence of a suitable base (e.g., pyridine, N-methylmorpholine, DIPEA, or ethylamine) at a temperature from about 0 ℃ to reflux for about 1 hour to about 7 days. This reaction can be carried out using a variety of solvents (e.g., dichloromethane, toluene, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, or acetonitrile) at temperatures from about 0 ℃ to reflux for about 30 minutes to about 24 hours.

Protection of the compounds of formula 21 according to step "c" of process D may be accomplished in a variety of ways well known to those skilled in the art, depending on the nature of the protecting group. For example, protection may be performed using, for example, chlorinated MEMs or chlorinated MOM reagents, which may also be prepared in situ. These reactions are typically carried out in a solvent (e.g., tetrahydrofuran, dichloromethane, etc.) in the presence of a proton scavenger (e.g., DIPEA) at a temperature from about 0 ℃ to reflux for about 1 hour to about 7 days. Such a protection may be carried out using a reagent such as acetyl chloride or ethoxycarbonyl chloride in a solvent such as tetrahydrofuran, dichloromethane, or the like in the presence of a proton scavenger such as DIPEA at a temperature from about 0 ℃ to reflux for about 1 hour to about 7 days.

The compounds of formula 2 prepared according to methods a and B may be further converted to other compounds of formula 2 following methods well known to those skilled in the art.

A compound of formula 2 prepared according to process A wherein R30 is SO₂Ph (R2) (R3), R4 is a group of formula IV wherein X represents a group CH, R15 is hydrogen (compound of formula 2A) or R15 is halogen (compound of formula 2C), which can be further converted to another compound of formula 2 according to procedures well known to those skilled in the art. For example, these compounds can be converted to another compound of formula 2D, 2E, 2F, and 2G following procedure E shown below.

Method E

In the above schemes, R2, R3, R16, R17, R18, R19, R29, PG₁And Hal is as defined above.

With respect to the synthetic methods described in method E for preparing compounds of formulae 2D, 2E, 2F, and 2G: in step "a", the pyridine nitrogen of the compound of formula 2A is oxidized to the N-oxide derivative of formula 22. In steps "b", "c" and "d", the latter are reacted with a suitable electrophile, such as, for example, toluenesulfonic anhydride, in a suitable nucleophile, such as, for example, a secondary amine (NHR16R17), a primary amine (NH)₂R16) or a cyanide source (CN)^-) In the presence of (a) or subsequent treatment therewith, to give compounds of formulae 2F, 2G and 2D, respectively. Alternatively, the compound of formula 2C is reacted with a suitable nucleophile such as a secondary amine (NHR16R17) or a primary amine (NH) in steps "b 1" and "C1", respectively₂R16) to give compounds of formulae 2F and 2G, respectively. Optionally in step "e", when R16 represents tert-butyl, benzyl or the like, this group may be removed by treatment with, for example, an acid or under reducing conditions to give a compound of formula 1 (a). In step "f", the compound of formula 2D may be further hydrolyzed to another compound of formula 2E. The latter is then condensed in step "g" with a suitable amine to form the compound of formula 21.

Following step "a" of method E, the oxidation of the pyridine nitrogen may be carried out with an oxidizing agent well known to those skilled in the art, for example, hydrogen peroxide in a solvent such as acetic acid and the like, or m-chloroperbenzoic acid in a solvent such as dichloromethane, acetone, tetrahydrofuran and the like, at a temperature from about 0 ℃ to reflux for about 30 minutes to about 48 hours.

Following steps "b" and "c" of method E, the conversion of the compound of formula 22 to the compounds of formulae 2F and 2G is accomplished by activating the pyridine N-oxide and reacting with a secondary or primary amine. Activation is usually with a suitable electrophile, such as oxalyl chloride, trifluoromethanesulfonyl chloride, tosyl chloride, phosphoryl chloride (POCl)₃) Benzoyl chloride, acetic anhydride, toluene sulfonic anhydride, etc., in a solvent (e.g., dichloromethane, tetrahydrofuran, acetonitrile, toluene, trifluoromethylbenzene, etc.). Toluene sulfonic anhydride is used in trifluoromethylbenzene in some embodiments. The reaction is typically carried out in the presence of a secondary or primary amine and may be at a temperature of from about 20 ℃ to refluxAnd is carried out at a temperature of about 30 minutes to about 48 hours.

Following step "D" of method E, the conversion of the compound of formula 22 to the compound of formula 2D is accomplished by activating pyridine N-oxide and reacting with a cyanating agent. The activation is usually carried out with suitable electrophiles, for example oxalyl chloride, trifluoromethanesulfonyl chloride, tosyl chloride, phosphoryl chloride (POCl)₃) Benzoyl chloride, acetic anhydride, toluene sulfonic anhydride, etc., in a solvent (e.g., dichloromethane, tetrahydrofuran, acetonitrile, toluene, trifluoromethylbenzene, etc.). In some embodiments, toluene sulfonic anhydride is used in the trifluoromethyl benzene. The reaction may be carried out in the presence of a cyanating agent (e.g., trimethylsilyl cyanide) and may be carried out at a temperature of from about 20 ℃ to reflux for about 30 minutes to about 48 hours.

According to steps "b 1" and "C1" of method E, the conversion of a compound of formula 2C to a compound of formula 2F and 2G is achieved by reacting it with a secondary or primary amine in a solvent (e.g., N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, dichloromethane, tetrahydrofuran, 1, 4-dioxane, ethanol, etc.), optionally in a suitable base such as K₂CO₃NaOH or triethylamine at a reaction temperature of about 20 ℃ to reflux temperature for a reaction time of about 30 minutes to about 48 hours.

According to process step "E" of process E, when primary amines such as tert-butylamine or benzylamine are used in process step "c" or step "c 1" of process E, the alkyl residues of these amines can be removed to give compounds of formula (I) A. The reaction is typically carried out with a strong acid (e.g., trifluoroacetic acid), optionally in the presence of a suitable co-solvent, such as dichloromethane or water, at a temperature of from about 20 ℃ to reflux temperature, and for a reaction time of from about 30 minutes to about 48 hours. Alternatively, the reaction is carried out using reducing conditions, e.g. using H in the presence of a suitable hydrogenation catalyst₂. The hydrogenation catalyst is typically a metal, such as palladium, either on its own or on carbon, in a suitable solvent such as tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, methanol, ethyl acetate andin a mixture thereof.

Following step "f" of method E, the compound of formula 2D is converted to a carbonic acid derivative of formula 2E. This reaction may be carried out under basic or acidic conditions using, for example, aqueous sodium hydroxide or hydrochloric acid or the like at a temperature from about 0 ℃ to reflux for a suitable time, for example from about 30 minutes to about 96 hours.

Following procedure "g" of method E, the compound of formula 2E is converted to the amide of formula 21 by condensation with a suitable amine. It is obvious to the skilled person that this reaction can be carried out in a variety of ways and operating conditions well known in the art of carboxamide preparation. For example, the reaction may be carried out in the presence of a coupling agent such as 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TBTU), 1, 3-dicyclohexylcarbodiimide, 1, 3-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N-cyclohexylcarbodiimide-N '-propoxymethylpolystyrene or N-cyclohexylcarbodiimide-N' -methylpolystyrene in a suitable solvent (e.g., dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1, 4-dioxane, acetonitrile, toluene or N, N-dimethylformamide) at a temperature of about-10 ℃ to reflux for a suitable time, for example from about 30 minutes to about 96 hours. The reaction may optionally be carried out in the presence of a suitable catalyst, such as 4-dimethylaminopyridine, or in the presence of other coupling agents, such as N-hydroxybenzotriazole. Alternatively, the same reaction can also be carried out, for example, by a mixed anhydride method using an alkyl chloroformate (e.g., ethyl chloroformate, isobutyl chloroformate, or isopropyl chloroformate) in the presence of a tertiary base (e.g., triethylamine, DIPEA, or pyridine) in a suitable solvent (e.g., toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, diethyl ether, 1, 4-dioxane, or N, N-dimethylformamide) at a temperature of about-30 ℃ to room temperature.

The compounds of formula 2 prepared according to methods a and B may be further converted to other compounds of formula 2 according to procedures well known to those skilled in the art.

For example, when R4 is a group represented by formula IV (where X is a nitrogen atom) and R15 is thiomethyl (a compound of formula 2J) or R15 is halogen (a compound of formula 2M), these compounds can be converted to additional compounds of formulae 2K, 2L, 2N, and 2P according to method F shown below.

Method F

In the above schemes, R2, R3, R16, R17, R29, PG₁And Hal is as defined above.

With respect to the synthetic methods described in preparation F for the compounds of formulae 2K, 2L, 2N and 2P: in step "a", the compound of formula 2J is reacted with an oxidizing agent to produce a sulfonyl derivative of formula 2K, which is then treated with a suitable nucleophile. In step "b", this nucleophile is a secondary amine, giving a compound of formula 2L. In step "c", this nucleophile is a primary amine, giving a compound of formula 2N. In step "d", this nucleophile is an ammonia equivalent, such as ammonium acetate, to give a compound of formula 2P. Alternatively, in steps "b 1", "c 1" and "d 1", the compound of formula 2M is reacted with a suitable nucleophile (e.g., a secondary amine, a primary amine or an ammonia equivalent, such as ammonium acetate) to provide a compound of formula 2L, 2N or 2P, respectively. Optionally in step "e", when R16 represents tert-butyl, benzyl or the like, this group may be removed, for example by treatment with an acid or under reducing conditions, to give a compound of formula 2P.

Following step "a" of process F, oxidation of the thiomethyl group is carried out using an oxidizing agent well known to those skilled in the art, such as oxone, in a suitable solvent (e.g., tetrahydrofuran, 1, 4-dioxane, acetone), optionally in the presence of water as a co-solvent, or in a solvent (e.g., dichloromethane, acetone, tetrahydrofuran, etc.) using m-chloroperbenzoic acid, at a reaction temperature of about 0 ℃ to reflux for a reaction time of about 30 minutes to about 48 hours.

According to steps "b" and "b 1" of method F, the conversion of a compound of formula 2K or 2M to a compound of formula 2L is carried out using a secondary amine of formula R16R17NH in a solvent (e.g., N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, dichloromethane, tetrahydrofuran, 1, 4-dioxane, ethanol, etc.), optionally in a suitable base (e.g., K)₂CO₃NaOH, triethylamine) at a reaction temperature of about 20 ℃ to reflux for a reaction time of about 30 minutes to about 48 hours.

Conversion of a compound of formula 2K or 2M to a compound of formula 2N according to steps "c" and "c 1" of method F in a solvent (e.g., N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, dichloromethane, tetrahydrofuran, 1, 4-dioxane, ethanol, etc.) with a compound of formula R16NH₂Optionally in a suitable base (e.g. K)₂CO₃NaOH, triethylamine) at a reaction temperature of from about 20 ℃ to reflux for a reaction time of from about 30 minutes to about 48 hours.

Formation of compound 2P from compounds of formula 2K or 2M according to steps "d" and "d 1" of method F is accomplished with a solution of ammonia in a suitable solvent (e.g., dichloromethane, ethanol, etc.) or an ammonium salt (e.g., ammonium acetate) in a solvent (e.g., N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, etc.) at a reaction temperature of from about 20 ℃ to reflux for a reaction time of from about 30 minutes to about 48 hours.

When a primary amine such as tert-butylamine or benzylamine is used in step "c" or step "c 1" of method F, according to step "e" of method F, the alkyl residue of these amines can be removed to yield the compound of formula 2P. This reaction can be carried out using a strong acid such as trifluoroacetic acid, optionally in the presence of a suitable co-solvent, such as dichloromethane or water, at a temperature of from about 20 ℃ to reflux for a reaction time of from about 30 minutes to about 48 hours. Alternatively, the reaction is carried out using reducing conditions, for example using H in the presence of a suitable hydrogenation catalyst₂. The hydrogenation catalyst is typically a metal, most commonly palladium in a suitable solvent (e.g. tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, methanol, ethyl acetate and mixtures thereof), either as such or supported on carbon.

When the compounds of formula (I) are prepared according to any variant of the process, the optional functional groups of the starting materials, reagents or intermediates thereof, which may cause undesirable side reactions, need to be suitably protected according to conventional techniques.

The starting materials for these processes include any of the possible variants of the broad disclosure and any of its reactants, which are known compounds and, even if not commercially available per se, may be prepared according to well known methods.

Pharmacology of

Measurement of

In vitro cell proliferation assay

Exponentially growing human melanoma cells A375 (with mutant B-RAF) and human melanoma cells Mewo (with wild type B-Raf) were seeded and humidified at 37 ℃ with 5% CO₂And (4) incubating in atmosphere. After 24 hours, scalar doses of the compound were added to the medium and the cells were cultured for 72 hours. At the end of the treatment, the cells were washed and counted. The cell number was determined using a cellular adenosine triphosphate monitoring system. Cell proliferation was compared to control cells and the concentration that inhibited cell growth by 50% was calculated.

P-MAPK (T202/Y204) ArrayScan assay

A375 human melanoma cells bearing mutated B-RAF were seeded at a density of 1000 cells per well in 384-well polylysine-coated plates (Matrix) containing appropriate media supplemented with 10% FCS in wells and incubated for 16-24 hours. Cells were treated with increasing doses of compound (starting dose 10 μ M, dilution factor 2.5) for 1.5 or2 hours. At the end of the treatment, the cells were fixed with p-formaldehyde 3.7% for 15-30 min, then washed 2 times with D-PBS (80. mu.l/well) and at room temperature withD-PBS containing 0.1% Triton X-100 and 1% BSA (Sigma-Aldrich) was permeabilized for 15 minutes (staining solution). Anti-phosphorus-MAPK (T202/Y204) monoclonal antibody E10(Cell Signaling, cat. # 9106) was added to the staining solution at a dilution of 1:100 and incubated at 37 ℃ for 1 hour. After removing the primary antibody solution, anti-mouse Cy diluted 1:500 in a staining solution containing 2. mu.g/ml DAPI was added^TM2-conjugated (Green) secondary antibody (Amersham). Plates were incubated for 1 hour at 37 ℃, washed 2 times, and then stained red with Cellomics' ArrayScan VT 1(4 fields per well, CytoNucTrans algorithm).

Reported as a final result is the parameter "MEAN _ RingAvglntenCh 2", which measures the MEAN cytoplasmic fluorescence intensity associated with p-MAPK staining.

B-RAF mutations have been identified in most melanomas and most colorectal and papillary thyroid carcinomas, which constitutively activate kinases. The growth of cells with activated B-RAF is closely related to B-RAF activity.

Some compounds of formula (I) were tested. The results are shown in table 1 below. From these results, it is evident that the compound of formula (I) has a significant cell proliferation inhibitory activity, IC on cell line with mutated B-Raf (A375)₅₀Values below 0.030. mu.M are more effective than for cell lines containing wild type B-Raf (Mewo).

In the same table, data obtained in the ArrayScan assay using the compound of formula (I) are also reported, and the results show the ability of the compound of formula (I) to inhibit the signal transduction pathway controlled by B-RAF activation in a375 cell line containing mutated B-RAF. IC (integrated circuit)₅₀Values always below 0.030. mu.M, corresponding to the IC obtained in the proliferation assay on the same cell line₅₀The values are consistent, confirming that the antiproliferative activity of the compounds is due to inhibition of B-RAF activity.

TABLE 1 proliferation and Array Scan data

It should be noted that the reference compound (i.e. the disclaimer compound corresponding to compound No. 60 of WO 2010/010154) had an antiproliferative activity (0.084) at least 4-fold lower than the compound of the invention.

In light of the above, the novel compounds of formula (I) appear to be particularly advantageous in the treatment of diseases caused by dysregulated protein kinase activity, such as cancer.

The compounds disclosed herein can be administered as a single agent, or in combination with known anti-cancer treatments such as radiation or chemotherapy regimens, in combination with, for example, the following: anti-hormonal agents (such as anti-estrogens, anti-androgens, and aromatase inhibitors), topoisomerase I inhibitor topoisomerase II inhibitors, microtubule-targeting agents, platinum-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, farnesyl transferase inhibitors, and hypoxia response (hypoxic response) inhibitors.

If formulated in fixed doses, such combination products employ the presently disclosed compounds in the following dosage ranges and other pharmaceutically active agents in approved dosage ranges.

When a combined preparation is not suitable, the compound of formula (I) may be used in sequence with known anticancer drugs.

The compounds of formula (I) disclosed herein are suitable for administration to mammals, e.g., humans, and may be administered by conventional routes, e.g., oral, intravenous, topical, transmucosal, etc., at dosage levels dependent upon the age, weight, and condition of the patient and the route of administration.

For example, a suitable dose for oral administration of a compound of formula (I) is 1 to 500 mg/Kg. In some embodiments, the dose is 5 to 100 mg/Kg.

The compounds disclosed herein can be administered in a variety of dosage forms, for example, orally in the form of tablets, capsules, sugar-or film-coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenteral administration, for example, intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.

Also disclosed are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, which may be a carrier or diluent.

Pharmaceutical compositions containing the compounds disclosed herein are generally prepared according to conventional methods and administered in a suitable pharmaceutical form.

For example, solid oral dosage forms may contain diluents in combination with the active compound, e.g., lactose, glucose, sucrose, cellulose, corn starch, or potato starch; lubricants, such as silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycol; binding agents, for example starch, acacia, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents, such as starch, alginic acid, alginates or sodium starch glycolate; foaming the mixture; a dye; a sweetener; wetting agents, such as lecithin, polysorbates, lauryl sulfates; and nontoxic and pharmacologically inactive substances generally used in pharmaceutical preparations. These pharmaceutical preparations may be manufactured in a known manner, for example, by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.

Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions.

For example, a syrup may contain sucrose or sucrose containing glycerol and/or mannitol and sorbitol as a carrier.

Suspending agents and emulsions may contain as carrier, for example, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol), and, if desired, a suitable amount of lidocaine hydrochloride.

A solution for intravenous injection or infusion may comprise sterile water as a carrier, or preferably it may be in the form of a sterile, aqueous, isotonic saline solution, or may include propylene glycol as a carrier.

Suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The term "treating" or "treatment" as used herein includes its generally accepted meaning of treating and caring for a patient to prevent, reduce the risk of, inhibit, restrict, lessen, ameliorate, slow, stop, delay or reverse the progression or severity of a given disease state or disease, and arrest and/or treat its existing characteristics, including reducing or alleviating symptoms or complications, or curing or eliminating the disease, disorder or disease state, for the disease, disorder or pathological condition described herein. The methods of the invention include both medical treatment and/or prophylactic treatment, as appropriate.

Experimental part

For any reference to a particular compound of formula (I) disclosed herein, optionally in the form of a pharmaceutically acceptable salt thereof, see experimental section and claims. With respect to the examples below, the compounds were synthesized using the methods described herein or other methods well known in the art.

The abbreviations and abbreviations used herein have the following meanings:

g (g) mg (mg)

ml (ml) mM (millimolar concentration)

μ M (micromolar) mmol (millimole)

h (hour) MHz (megahertz)

mm (millimeter) Hz (Hertz)

M (molarity) min (minutes)

mol (mol) TLC (thin layer chromatography)

r.t. (Room temperature) TEA (triethylamine)

TFA (trifluoroacetic acid) DMF (N, N-dimethylformamide)

DIPEA (N, N-diisopropyl-N-ethylamine) DCM (dichloromethane)

THF (tetrahydrofuran) Hex (hexane)

MeOH (methanol) DMSO (dimethyl sulfoxide)

TIPS (triisopropylsilyl) bs (broad singlet)

TBDMS (dimethyl tert-butylsilyl) BOC (tert-butyloxycarbonyl)

NaH (sodium hydride, 60% in mineral oil) Ac₂O (acetic anhydride)

Dppf (1, 1' -bis (diphenylphosphino) ferrocene) ESI (electrospray ionization)

mCPBA (m-chloroperbenzoic acid) Ac (acetyl)

TBTU (2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate)

RP-HPLC (reverse phase high performance liquid chromatography).

To better illustrate the invention without posing any limitation thereto, the following examples are now given.

As used herein, the symbols and legends used in the methods, protocols, and examples are consistent with those used in the contemporary scientific literature, e.g., the Journal of the American Chemical Society or Journal of Biological Chemistry.

All materials were of the highest grade obtained from commercial suppliers and used without further purification unless otherwise indicated. Anhydrous solvents such as DMF, THF, CH₂Cl₂And toluene from Aldrich Chemical Company. All reactions involving air or moisture sensitive compounds were carried out under nitrogen or argon atmosphere.

General purification and analytical methods

Flash chromatography was performed on silica gel (Merck grade 9395, 60A). HPLC was performed on a Waters × Terra RP 18(4,6 × 50 mm, 3.5 μm) column using a Waters 2790 HPLC system equipped with a 996 Waters PDA detector and a Micromass mod. ZQ single quadrupole mass spectrometer equipped with an Electrospray (ESI) ion source. Mobile phase a was ammonium acetate 5 mM buffer (pH 5.5, containing acetic acid-acetonitrile 95:5) and mobile phase B was water-acetonitrile (5: 95). The gradient was from 10% to 90% B in 8 min, holding 90% B for 2 min. UV detection was performed at 220 nm and 254 nm. The flow rate was 1 mL/min. The injection volume was 10 microliters. Full scan, mass range from 100 to 800 amu. The capillary voltage is 2.5 KV; the source temperature is 120 ℃; the taper hole voltage is 10V. Retention times at 220 nm or 254 nm (HPLC r.t.) are given in minutes. The mass is given in m/z ratio.

If necessary, the compounds were purified by preparative HPLC on a Waters Symmetry C18 (19X 50 mm, 5 um) column or a Waters X Terra RP 18 (30X 150 mm, 5 μm) column, preparative HPLC 600 using Waters equipped with a 996 Waters PDA detector and a Micromass mod. ZMD single quadrupole mass spectrometer (electrospray ionization, positive charge mode). Mobile phase a was water-0.01% trifluoroacetic acid and mobile phase B was acetonitrile. Gradient 10% -90% B8 min, hold 90% B2 min. The flow rate was 20 mL/min. Alternatively, mobile phase A is water-0.1% NH₃And the mobile phase B is acetonitrile. Gradient 10% to 100% B (8 min), hold 100% B for 2 min. The flow rate was 20 mL/min.

1H-NMR spectroscopy was performed on a Mercury VX 400 equipped with a 5 mm dual resonance probe [1H (15N-31P) ID _ PFG Varian ] operating at 400.45 MHz.

Experimental part

Preparation example 1

N- [3- (4-bromo-1H-pyrazol-3-yl) -2-fluoro-phenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 18, wherein Hal = Br; PG₁= methoxymethyl group; r30=2, 5-difluorobenzenesulfonyl group)

Method D, step b

N- (3-bromo-2-fluoro-phenyl) -2, 5-difluoro-benzenesulfonamide

(formula 21, wherein R2, R3= F)

3-bromo-2-fluoroaniline (10 g, 52.63 mmol) was dissolved in DCM (100 mL) under a nitrogen atmosphere. Dried pyridine (6 mL, 73.68 mmol, 1.4 equiv.) and 2, 5-difluorobenzenesulfonyl chloride (7.08 mL, 52.63 mmol, 1 equiv.) were added sequentially and the mixture was stirred at room temperature for 2 hours. It was then diluted with DCM and washed with 0.5N aqueous HCl (3X 80 mL) and brine. The organic layer was washed with Na₂SO₄Dried and evaporated to dryness. The solid was stirred in ether for 30 minutes, then filtered and dried at 40 ℃ under reduced pressure to give 17.8 g N- (3-bromo-2-fluoro-phenyl) -2, 5-difluoro-benzenesulfonamide as a pale yellow solid (92%).

Method D, step C

N- (3-bromo-2-fluoro-phenyl) -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 14B, wherein PG₁= methoxymethyl group; r2, R3= F)

Dissolution of N- (3-bromo-2-fluoro-phenyl) -2, 5-difluoro-benzenesulfonamide (17.8 g, 48.61 mmol) in anhydrous DCM (160 mL) at 0 deg.CDIPEA (12.5 mL, 73 mmol, 1.5 equiv.) and MOMCl (5.7 mL, 73 mmol, 1.5 equiv.) were added sequentially to the solution. The reaction mixture was stirred at 0 ℃ for 10 minutes and then warmed to room temperature. After 2 hours, a saturated ammonium chloride solution was added, and the mixture was stirred at room temperature for 10 minutes. Then diluted with DCM, washed with water and brine, and Na₂SO₄Dried and evaporated to dryness. The residue was treated with hexane and stirred for 30 minutes. The solid was filtered off and dried to yield 18.52 g (93%) of the title compound as a white powder.

Method C, step a

2, 5-difluoro-N- { 2-fluoro-3- [2- (tetrahydro-pyran-2-yl) -2H-pyrazol-3-yl ] phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 9, wherein PG₁= methoxymethyl group; r30=2, 5-difluoro-benzenesulfonyl; r29= tetrahydro-pyran-2-yl)

N- (3-bromo-2-fluoro-phenyl) -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (12 g, 29.25 mmol) was dissolved in 1, 4-dioxane (156 mL), and argon gas was bubbled through the solution for 10 minutes. 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (prepared as described in WO 2010/010154) (10.6 g, 38.03 mmol, 1.3 equivalents) was then added, followed by cesium carbonate (9.5 g, 29.25 mmol, 2 equivalents), 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (Pd (dppf) Cl)₂·CH₂Cl₂) (1.2 g, 1.46 mmol, 0.05 eq.) and water (0.9 mL), the reaction mixture was heated to 100 ℃ and stirred at this temperature for 2 hours. Then adding 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole (4 g, 0.5 eq) and heating was continued for 2 hours. The mixture was then concentrated under reduced pressure, dissolved with AcOEt (200 mL) and filtered through a pad of celite. The filtrate was washed with water and brine, and Na was added₂SO₄Dried and evaporated to dryness. The crude product was purified by silica gel chromatography (cyclohexane/AcOEt 7:3) to yield 18 g of 2, 5-difluoro-N- { 2-fluoro-3- [2- (tetrahydro-pyran-2-yl) -2H-pyrazol-3-yl ] -miscellaneous N-tetrahydropyranyl-pyrazole]Phenyl } -N-methoxymethyl-benzenesulfonamide.

Method C, step e

2, 5-difluoro-N- [ 2-fluoro-3- (2H-pyrazol-3-yl) -phenyl ] -N-methoxymethyl-benzenesulfonamide

(formula 17, wherein PG₁= methoxymethyl group; r30=2, 5-difluoro-benzenesulfonyl)

To crude 2, 5-difluoro-N- { 2-fluoro-3- [2- (tetrahydro-pyran-2-yl) -2H-pyrazol-3-yl]A solution of-phenyl } -N-methoxymethyl-benzenesulfonamide (1.39 g) in MeOH (20 mL) was added to p-toluenesulfonic acid (100 mg), and the solution was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, dissolved in AcOEt (100 mL) and washed with NaHCO₃The organic phase was washed with saturated aqueous solution (2X 50 mL) and brine (50 mL) and dried (Na)₂SO₄) And evaporated to dryness. The crude product was purified by chromatography on silica gel (gradient cyclohexane/AcOEt 6:4 to 1:1) to give 630 mg of 2, 5-difluoro-N- [ 2-fluoro-3- (2H-pyrazol-3-yl) -phenyl ] -N-methyl-tert-butyl ester]-N-methoxymethyl-benzenesulfonamide as a white powder (two-step yield 80%).

Method C, step g

N- [3- (4-bromo-2H-pyrazol-3-yl) -2-fluoro-phenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

To the 2, 5-difluoro-N- [ 2-fluoro-3- (2H-pyrazol-3-yl) -phenyl group under stirring]-N-methoxymethyl-benzenesulfonamide (620 mg, 1.56 mmol) in DCM (15 mL) was added N-bromosuccinimide (277 mg, 1.56 mmol, 1 eq.) and the solution was stirred at room temperature for 1.5 h. The mixture was then diluted with DCM (100 mL) and 10% NaHSO₃Aqueous (2X 30 mL) and brine. Na for organic layer₂SO₄Drying and evaporation to dryness gave 714 mg (96%) of the title compound as a white foam.

Example 1

2, 5-difluoro-N- [ 2-fluoro-3- (1-isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -benzenesulfonamide (compound 9 of Table 1)

(formula I, wherein m = 0; R₁= isopropyl group; r2, R3= F; r4= 4-pyridyl)

Method C, step k

N- [3- (4-bromo-1-isopropyl-3H-pyrazol-3-yl) -2-fluoro-phenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula (1) wherein Hal = Br; PG₁= methoxymethyl group; r29= isopropyl; r30=2, 5-difluoro-benzenesulfonyl)

To N- [3- (4-bromo-1H-pyrazol-3-yl) -2-fluoro-phenyl]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (prepared as described in preparation example 1) (160 mg, 0.336 mmol) in DMF (1 mL) was added cesium carbonate (164 mg, 0.504 mmol) and isopropyl iodide (50 μ L, 0.504 mmol), and the suspension was stirred at 50 ℃ for 3 hours. The mixture was treated with water and AcOEt and the organic layer was washed once more with water and brine, then Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Hex: AcOEt 7:3) to yield 120 mg of the title compound (68% yield).

Following the same procedure, but using the appropriate alkylating reagent, the following intermediates were prepared:

n- [3- (4-bromo-1-ethyl-1H-pyrazol-3-yl) -2-fluoro-phenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= ethyl; r30=2, 5-difluoro-benzenesulfonyl)

。

N- {3- [ 4-bromo-1- (2-methoxy-ethyl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= 2-methoxyethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

N- [3- (4-bromo-1-cyanomethyl-1H-pyrazol-3-yl) -2-fluoro-phenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= cyanomethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

N- {3- [ 4-bromo-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29=2,2, 2-trifluoroethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

(4-bromo-3- {3- [ (2, 5-difluoro-benzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -pyrazol-1-yl) acetic acid ethyl ester

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= 2-ethoxycarbonylmethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

2- (4-bromo-3- {3- [ (2, 5-difluoro-benzenesulfonyl) -methoxymethyl-amino ] -2-fluoro-phenyl } -pyrazol-1-yl) acetamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= 2-acetamido; r30=2, 5-difluorobenzenesulfonyl group)

。

N- {3- [ 4-bromo-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluoro-benzenesulfonyl)

。

N- {3- [ 4-bromo-1- (4, 4-difluoro-cyclohexyl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29=4, 4-difluoro-cyclohex-1-yl; r30=2, 5-difluorobenzenesulfonyl group)

。

Method A, step a

2, 5-difluoro-N- [ 2-fluoro-3- (1-isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 4-pyridyl; PG₁= methoxymethyl group; r29= isopropyl; r30=2, 5-difluorobenzenesulfonyl group)

Argon degassed N- [3- (4-bromo-1-isopropyl-3H-pyrazol-3-yl) -2-fluoro-phenyl group in a microwave tube under argon atmosphere]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (100 mg, 0.193 mmol) in 1, 2-dimethoxyethane: water (9:1, 2 mL) was added 4- (4,4,5, 5-tetramethyl- [1,3,2] ethyl]Dioxaborolan-2-yl) pyridine (59 mg, 0.289 mmol), cesium carbonate (126 mg, 0.386 mmol) and Pd (dppf) Cl₂·CH₂Cl₂(16 mg, 0.0193 mmol). The mixture was heated in a microwave oven at 100 ℃ for 30 minutes and then filtered through a pad of celite. Placing the solution inIn AcOEt, with NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM: MeOH:7N NH)₃MeOH, 97:2:1) to yield 80 mg of the title compound (80% yield).

Following the same procedure, but using appropriately substituted starting materials, the following intermediates were prepared:

2, 5-difluoro-N- { 2-fluoro-3- [1- (2-methoxyethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 4-pyridyl; PG₁= methoxymethyl group; r29= 2-methoxyethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

N- [3- (1-cyanomethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluoro-phenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2, R4= 4-pyridyl; PG₁= methoxymethyl group; r29= cyanomethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 4-pyridyl; PG₁= methoxymethyl group; r29=2,2, 2-trifluoroethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-fluoro-4-pyridyl; PG₁= methoxymethyl group; r29= isopropyl; r30=2, 5-difluorobenzenesulfonyl group)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-fluoro-4-pyridyl; PG₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

。

Method A, step f

(formula I, wherein m = 0; R₁= isopropyl group; r2, R3= F; r4= 4-pyridyl)

Reacting 2, 5-difluoro-N- [ 2-fluoro-3- (1-isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl]N-methoxymethyl-benzenesulfonamide (80 mg, 0.155 mmol) was dissolved in a 9:1 mixture of TFA: water (1.7 mL) and stirred at 60 ℃ for 1.5 hours. The reaction mixture was concentrated under reduced pressure and then with NaHCO₃The saturated solution was dissolved and extracted with AcOEt. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (Hex: AcOEt 2:8) to yield 44 mg of the title compound (60% yield).

Following the same procedure, but using appropriately substituted starting materials, the following compounds were prepared:

2, 5-difluoro-N- { 2-fluoro-3- [1- (2-methoxyethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

(formula I, wherein m =2; R₁= methoxy group; r2, R3= F; r4= 4-pyridyl)

。

N- [3- (1-cyanomethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 1; R₁= cyano; r2, R3= F; r4= 4-pyridyl)

。

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

(formula I, wherein m = 1; R₁= trifluoromethyl; r2, R3= F; r4= 4-pyridyl)

。

2- {3- [3- (2, 5-difluoro-benzenesulfonylamino) -2-fluorophenyl ] -4-pyridin-4-yl-pyrazol-1-yl } -acetamide

(formula I, wherein m = 1; R₁= carboxamide group; r2, R3= F; r4= 4-pyridyl)

。

2- {3- [3- (2, 5-difluoro-benzenesulfonylamino) -2-fluorophenyl ] -4-pyridin-4-yl-pyrazol-1-yl } -N-methylacetamide

(formula I, wherein m = 1; R₁= N-methylcarboxamide group; r2, R3= F; r4= 4-pyridyl)

。

2- {3- [3- (2, 5-difluoro-benzenesulfonylamino) -2-fluorophenyl ] -4-pyridin-4-yl-pyrazol-1-yl } -N, N-dimethylacetamide

(formula I, wherein m = 1; R₁= N, N-dimethylformamido; r2, R3= F; r4= 4-pyridyl)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -phenyl } benzenesulfonamide

(formula I, wherein m = 0; R₁= isopropyl group; r2, R3= F; r4= 2-fluoropyridin-4-yl)

。

N- {3- [1- (4, 4-Difluorocyclohexyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R₁=4, 4-difluorocyclohex-1-yl; r2, R3= F; r4= 4-pyridyl)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

(formula I, wherein m = 0; R₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-fluoropyridin-4-yl)

。

Example 2

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide (compound 5 in table 1)

(formula I, wherein m = 0; R1= 1-methylpiperidin-4-yl; R2, R3= F; R4= 4-pyridyl)

Method C, step k

4- (4-bromo-3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= N-Boc-piperidin-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

To N- [3- (4-bromo-1H-pyrazol-3-yl) -2-fluorophenyl]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (6.69 g, 14.05 mmol) (prepared as described in preparation example 1) in anhydrous DMF (100 mL) cesium carbonate (10.07 g, 30.91 mmol, 2.2 equiv.) and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (7.95 g, 28.46 mmol, 2 equiv.) were added and the suspension was stirred at 60 ℃ for 16 h. The solvent was then concentrated under reduced pressure and the residue was taken up with AcOEt and NaHCO₃Washed with saturated aqueous solution and brine, and then with Na₂SO₄Dried and evaporated to dryness. The crude two regioisomers were chromatographed on silica gel (N-hexane/ethyl acetate 8:2 to 7:3) to give 7.63 g of the desired N1-alkylated regioisomer incorporating an excess of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester. 4- (4-bromo-3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino]Analytical data for tert-butyl-2-fluorophenyl } -pyrazol-1-yl) -piperidine-1-carboxylate include:

。

following the same procedure, but using benzyl 3-iodo-8-azabicyclo [3.2.1] octane-8-carboxylate as the alkylating agent, the following intermediates were prepared:

3- (4-bromo-3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -pyrazol-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= N-benzyloxycarbonyl-8-azabicyclo [3.2.1]Oct-3-yl; r30=2, 5-difluorobenzenesulfonyl group)

。

Method A, step a

4- (3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -4-pyridin-4-yl-pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester

(formula 2, wherein R4= 4-pyridyl; PG₁= methoxymethyl group; r29= N-Boc-piperidin-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

To the residue of 4- (4-bromo-3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino]A solution of tert-butyl-2-fluorophenyl } -pyrazol-1-yl) -piperidine-1-carboxylate (6.71 mmol) in a 10:1 dioxane/water mixture (66 mL) was degassed by bubbling argon for 5 minutes. 4-Pyridylboronic acid pinacol ester (2.06 mg, 10.07 mmol, 1.5 equiv.) was then added, followed by cesium carbonate (4.37 g, 13.42 mmol, 2 equiv.) and Pd (dppf) Cl₂·CH₂Cl₂(547 mg, 0.670 mmol, 0.1 eq.) the mixture was stirred at 100 ℃ for 2 h. The solvent was concentrated under reduced pressure and the residue was dissolved in AcOEt and filtered through a pad of celite. The filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was purified by silica gel chromatography (ethyl acetate/hexane 7:3 to 8:2) to yield 4.0 g of the title compound (43% yield in the last two steps).

Following the same procedure, but using the appropriate starting materials, the following intermediates were prepared:

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -4- (2-fluoropyridin-4-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester

(formula 2, wherein R4= 2-fluoropyridin-4-yl; PG₁= methoxymethyl group; r29= N-Boc-piperidin-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

。

2, 5-difluoro-N- [ 2-fluoro-3- (1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 4-pyridyl; PG₁= methoxymethyl group; r29= piperidin-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

To 4- (3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino group at room temperature under nitrogen]A solution of-2-fluorophenyl } -4-pyridin-4-yl-pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (2.2 g, 3.35 mmol) in anhydrous 1, 4-dioxane (17 mL) was added dropwise to a 4N HCl/1, 4-dioxane solution (17 mL, 67 mmol, 20 equivalents), and the mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, the residue was diluted with DCM and NaHCO₃Saturated aqueous solution, water and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. 1.8 g of the title compound (96%) was obtained and used in the next step without purification.

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 4-pyridyl; PG₁= methoxymethyl group; r29= N-methylpiperidin-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

To 2, 5-difluoro-N- [ 2-fluoro-3- (1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl]Solution of-N-methoxymethyl-benzenesulfonamide (1.8 g, 3.23 mmol) in methanol (20 mL) was added 37% aqueous formaldehyde (0.36 mL, 4.85 mmol, 1.5 equiv.), followed by acetic acid (0.554 mL, 9.69 mmol, 3 equiv.) and cyanoboronSodium hydride (325 mg, 5.17 mmol, 1.6 equiv.) and the mixture was stirred at room temperature for 1 hour. The solvent was then evaporated under reduced pressure and the residue was taken up with AcOEt and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Drying and evaporation to dryness gave 1.62 g (88%) of the title compound, which was used in the next step without any further purification.

Method A, step f

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide (compound 5 of table 1)

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl } -N-methoxymethyl-benzenesulfonamide (1.62 g, 2.83 mmol) was dissolved in a 9:1 TFA/water mixture and stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, then dissolved with AcOEt and then with NaHCO₃Saturated solution and brine wash. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM: MeOH:7M NH)₃In MeOH, 85:10: 5). The pure fractions were treated with diethyl ether, filtered and dried to yield 780 mg (52%) of the title compound as a white solid.

Following the same procedure, but using the appropriate reagents in the reductive amination step or Suzuki coupling, the following compounds were prepared:

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

(formula I, wherein m = 0; R1= 1-methylpiperidin-4-yl; R2, R3= F; R4= 2-fluoropyridin-4-yl)

。

N- {3- [1- (1-cyclopropylpiperidin-4-yl) -4- (2-fluoropyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R₁1-cyclopropylpiperidin-4-yl; r2, R3= F; r4= 2-fluoropyridin-4-yl)

。

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

(formula I, wherein m = 0; R1= 1-methylpiperidin-4-yl; R2, R3= F; R4= 2-methylpyridin-4-yl)

。

N- {3- [4- (2-Chloropyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R1= 1-methylpiperidin-4-yl; R2, R3= F; R4= 2-chloropyridin-4-yl)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-methoxypyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

(formula I, wherein m = 0; R1= 1-methylpiperidin-4-yl; R2, R3= F; R4= 2-methoxypyridin-4-yl)

。

2, 5-difluoro-N- { 2-fluoro-3- [1- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -4- (pyridin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

(formula I, wherein m = 0; R1= 8-methyl-8-azabicyclo [3.2.1] oct-3-yl; R2, R3= F; R4= 4-pyridyl)

。

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-isopropylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide (compound 1)

(formula I, wherein m = 0; R1= 1-isopropylpiperidin-4-yl; R2, R3= F; R4= pyridin-4-yl)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (1-isopropylpiperidin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

(formula I, wherein m = 0; R1= 1-isopropylpiperidin-4-yl; R2, R3= F; R4= 2-fluoropyridin-4-yl)

。

N- {3- [1- (1-cyclopropylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 2)

(formula I, wherein m = 0; R1= 1-cyclopropylpiperidin-4-yl; R2, R3= F; R4= 4-pyridinyl)

。

3- (4- {3- [3- (2, 5-difluorobenzenesulfonylamino) -2-fluorophenyl ] -4-pyridin-4-yl-pyrazol-1-yl } -piperidin-1-yl) -propionic acid ethyl ester

(formula I, wherein m =0, R1=1- (2-ethoxycarbonylethyl) -piperidin-4-yl, R2, R3= F, R4= 4-pyridinyl)

。

3- (4- {3- [3- (2, 5-difluorobenzenesulfonylamino) -2-fluorophenyl ] -4-pyridin-4-ylpyrazol-1-yl } -piperidin-1-yl) -propionic acid methyl ester

(formula I, wherein m =0, R1=1- (2-methoxycarbonylethyl) piperidin-4-yl, R2, R3= F, R4= 4-pyridinyl)

。

2, 5-difluoro-N- [ 2-fluoro-3- (1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -benzenesulfonamide

(formula I, wherein m = 0; R1= piperidin-4-yl; R2, R3= F; R4= 4-pyridyl)

4- (3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl amino group]-2-fluorophenyl } -4-pyridin-4-yl-pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (47 mg, 0.072 mmol) was dissolved in a 9:1 TFA/water mixture (2 mL) and stirred at 70 ℃ for 2 h. The reaction mixture was then concentrated under reduced pressure, dissolved in AcOEt and washed with NaHCO₃Saturated solution and brine wash. Na for organic layer₂SO₄Dried and concentrated to dryness. The crude product was eluted with methanol on a small silica gel column. 12 mg of the title compound are obtained as a white solid.

Example 3

N- {3- [1- (1-acetylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m =0, R1= 1-acetylpiperidin-4-yl; R2, R3= F; R4= 4-pyridinyl)

To 2, 5-difluoro-N- [ 2-fluoro-3- (1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl]A solution of-N-methoxymethyl-benzenesulfonamide (135 mg, 0.242 mol) (prepared as described in example 2) in DCM (2 mL) was added triethylamine (0.040 mL, 0.290 mmol, 1.2 equiv.) followed by acetyl chloride (0.019 mL, 0.266 mmol, 1.1 equiv.), and the solution was stirred at room temperature for 2 hours. The reaction mixture was then diluted with DCM and NaHCO₃Washed with saturated aqueous solution and brine, and then with Na₂SO₄Dried and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH 97:3) to yield 81 mg (56%) of N- {3- [1- (1-acetylpiperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide. This intermediate was then treated with a 9:1 TFA/water mixture (1 mL) and stirred at 60 ℃ for 1.5 h. The reaction mixture was concentrated under reduced pressure, then dissolved with AcOEt and then with NaHCO₃Saturated solution and brine wash. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH 95:5) to give 9 mg of the title compound.

Example 4

N- {3- [4- (2-Aminopyrimidin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-benzenesulfonamide (compound 10 in Table 1)

(formula I, wherein m = 0; R₁= isopropyl group; r2, R3= F; r4= 2-aminopyrimidin-4-yl)

Method A, step b

2, 5-difluoro-N- { 2-fluoro-3- [ 1-isopropyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 3, wherein M' =4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl; PG (Picture experts group)₁= methoxymethyl group; r29= isopropyl; r30=2, 5-difluorobenzenesulfonyl group)

Argon degassed N- [3- (4-bromo-1-isopropyl-3H-pyrazol-3-yl) -2-fluorophenyl in a microwave tube under argon atmosphere]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (see example 1, method C, step k) (295 mg, 0.569 mmol) in toluene (4 mL) 4,4,5, 5-tetramethyl- [1,3,2] was added]Dioxaborolane (728 mg, 569 mmol), TEA (0.2 mL, 1.42 mmol), 2-dicyclohexylphosphino-2 ', 6 ' -dimethoxy-1, 1 ' -biphenyl (35 mg, 0.085 mmol) and bis (acetonitrile) dichloropalladium (II) (PdCl)₂·(CH₃CN)₂) (8 mg, 0.028 mmol). The mixture was heated in a microwave oven at 90 ℃ for 1 hour and then filtered through a pad of celite. The solution was concentrated to dryness and the residue was purified by flash chromatography on silica gel (Hex: AcOEt 7:3) to yield 330 mg of the title compound (quantitative yield).

n- {3- [ 1-Ethyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl benzenesulfonamide

(formula 3, M' =4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl; PG (Picture experts group)₁= methoxymethyl group; r29= ethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

Method A, step c

N- {3- [4- (2-aminopyrimidin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-aminopyrimidin-4-yl; PG₁= methoxymethyl group; r29= isopropyl; r30=2, 5-difluorobenzenesulfonyl group)

Argon degassed 2, 5-difluoro-N- { 2-fluoro-3- [ 1-isopropyl alcohol in a microwave tube under argon atmosphere4- (4,4,5, 5-tetramethyl- [1,3, 2) yl]Dioxaborolan-2-yl) -1H-pyrazol-3-yl]A solution of-phenyl } -N-methoxymethyl-benzenesulfonamide (330 mg, 0.569 mmol) in 1, 2-dimethoxyethane: water (9:1, 6 mL) was added 4-chloropyrimidin-2-ylamine (110 mg, 0.853 mmol), cesium carbonate (371 mg, 1.138 mmol) and Pd (dppf) Cl₂·CH₂Cl₂(46 mg, 0.057 mmol). The mixture was heated in a microwave oven at 100 ℃ for 90 minutes and then filtered through a pad of celite. The filtrate was dissolved with AcOEt and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM: MeOH 97:3) to give 100 mg of the title compound (33% yield).

Following the same procedure, but using the appropriate starting materials and aryl halides, the following compounds were prepared:

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-methylpyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-methylpyridin-4-yl; PG₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-chloropyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-chloropyridin-4-yl; PG₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

。

N- {3- [4- (2-aminopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-aminopyridin-4-yl; PG₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl group)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl } -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl, PG₁= methoxymethyl, R29= ethyl, R30=2, 5-difluorobenzenesulfonyl)

。

Method A, step f

N- {3- [4- (2-Aminopyrimidin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 10 in Table 1)

Mixing N- {3- [4- (2-aminopyrimidin-4-yl) -1-isopropyl-1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (100 mg, 0.188 mmol) was dissolved in a 9:1 mixture of TFA: water (1 mL) and stirred at 60 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure and then saturated NaHCO₃The solution was dissolved and extracted with AcOEt. Is provided withNa for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM: MeOH: acetone, 94:3:3) to give 26 mg of the title compound (28% yield).

Following the same procedure, but using the appropriate starting materials, the following compounds were prepared:

2, 5-difluoro-N- { 2-fluoro-3- [4- (2-methylpyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

(formula I, wherein m = 0; R1= tetrahydro-2H-pyran-4-yl; R2, R3= F; R4= 2-methylpyridin-4-yl)

。

N- {3- [4- (2-Chloropyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R1= tetrahydro-2H-pyran-4-yl; R2, R3= F; R4= 2-chloropyridin-4-yl)

。

N- {3- [4- (6-aminopyrimidin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R1= tetrahydro-2H-pyran-4-yl; R2, R3= F; R4= 6-aminopyrimidin-4-yl)

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

(formula I, wherein m = 0; R1= tetrahydro-2H-pyran-4-yl; R2, R3= F; R4= 7H-pyrrolo [2,3-d ] pyrimidin-4-yl)

。

N- {3- [4- (2-Aminopyrimidin-4-yl) -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 3)

(formula I, wherein m = 1; R1= methyl; R2, R3= F; R4= 2-aminopyrimidin-4-yl)

。

The following by-products were obtained during the synthesis:

n- (3- {4- [2- (2-Aminopyrimidin-4-ylamino) -pyrimidin-4-yl ] -1-ethyl-1H-pyrazol-3-yl } -2-fluorophenyl) -2, 5-difluorobenzenesulfonamide (compound 22)

(formula I, wherein m = 1; R1= methyl; R2, R3= F; R4= 2-aminopyrimidin-4-ylamino) -pyrimidin-4-yl)

。

Example 5

N- {3- [4- (2-Aminopyrimidin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 11)

(formula I, wherein m =2; R₁R2, R3= F; r4= 2-aminopyrimidin-4-yl)

Method C, step h

N- {3- [ 4-bromo-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 1, wherein Hal = Br; PG₁= methoxymethyl group; r29= tetrahydropyran-2-yl; r30=2, 5-difluorobenzenesulfonyl group)

To 2, 5-difluoro-N- { 2-fluoro-3- [2- (tetrahydropyran-2-yl) -2H-pyrazol-3-yl]A solution of-phenyl } -N-methoxymethyl-benzenesulfonamide (4 g, 8.3 mmol) (obtained as described in preparation example 1) in DCM (30 mL) was added N-bromosuccinimide (2.2 g, 12.46 mmol, 1.5 eq.) and the solution was stirred at room temperature for 4 h. The mixture was then diluted with DCM and 10% NaHSO₃Aqueous solution and brine. Is provided withNa for organic layer₂SO₄Drying and evaporation to dryness gave 4.1 g (88%) of N- {3- [ 4-bromo-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl]2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide as a yellow wax (mixture of two regioisomers).

Method A, step b

2, 5-difluoro-N- { 2-fluoro-3- [1- (tetrahydropyran-2-yl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 3, wherein M' =4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl; PG (Picture experts group)₁= methoxymethyl group; r29= tetrahydropyran-2-yl; r30=2, 5-difluorobenzenesulfonyl group)

Placing N- {3- [ 4-bromo-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl in a microwave tube]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (2 g, 3.569 mmol) was dissolved in anhydrous toluene (34 mL), and the solution was degassed by bubbling argon gas through it for 10 minutes. Triethylamine (1.24 mL, 8.92 mmol, 2.5 equivalents) was then added followed by S-Phos (146 mg, 0.1 equivalents), PdCl₂(CH₃CN)₂(46 mg, 0.05 equiv.) and pinacolborane (5.2 mL, 35.69 mmol, 10 equiv.). The tube was sealed and the mixture was irradiated in a microwave oven at 90 ℃ for 30 minutes. The reaction mixture was filtered through a pad of celite and the pad was washed thoroughly with AcOEt. NaHCO for filtrate₃Washed with saturated aqueous solution and brine, and then with Na₂SO₄Dried and evaporated to dryness. The crude product was purified by silica gel chromatography (hexane/ethyl acetate 7:3) to yield 1.9 mg of the desired product contaminated with debrominated by-productsPyrazole boronic acid esters.

Method A, step c

N- {3- [4- (2-aminopyrimidin-4-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-aminopyrimidin-4-yl; PG₁= methoxymethyl group; r29= tetrahydropyran-2-yl; r30=2, 5-difluorobenzenesulfonyl group)

Argon degassed 2, 5-difluoro-N- { 2-fluoro-3- [1- (tetrahydropyran-2-yl) -4- (4,4,5, 5-tetramethyl- [1,3,2] in a microwave tube under argon atmosphere]Dioxaborolan-2-yl) -1H-pyrazol-3-yl]A solution of-phenyl } -N-methoxymethyl-benzenesulfonamide (383 mg, 0.63 mmol) in 1, 2-dimethoxyethane: water 9:1(4 mL) was added 4-chloropyrimidin-2-ylamine (122 mg, 0.94 mmol), cesium carbonate (410 mg, 1.26 mmol) and Pd (dppf) Cl₂·CH₂Cl₂(51 mg, 0.063 mmol). The mixture was heated in a microwave oven at 100 ℃ for 3 hours and then filtered through a pad of celite. The solution was dissolved with DCM and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM: MeOH: acetone, 96:2:2) to give 135 mg of the title compound (37% yield).

Method A, step d

N- {3- [4- (2-aminopyrimidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 4A, whichR4= 2-aminopyrimidin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r30=2, 5-difluorobenzenesulfonyl group)

To the N- {3- [4- (2-aminopyrimidin-4-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl group]To a solution of-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (135 mg, 0.23 mmol) was added p-toluenesulfonic acid monohydrate (90 mg, 0.47 mmol), and the reaction mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved with AcOEt and purified with NaHCO₃Saturated aqueous solution and brine. The residue was not subjected to any further purification (45 mg, yield 40%).

Method A, step e

N- {3- [4- (2-aminopyrimidin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 2-aminopyrimidin-4-yl; PG₁= methoxymethyl group; r29= 2-fluoroethyl; r30=2, 5-difluorobenzenesulfonyl group)

To the N- {3- [4- (2-aminopyrimidin-4-yl) -1H-pyrazol-3-yl group]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (45 mg, 0.091 mmol) in DMF (2 mL) was added cesium carbonate (100 mg, 0.306 mmol) and 1-fluoro-2-iodoethane (54 mg, 0.306 mmol), and the suspension was stirred at 50 ℃ for 1 hour. The mixture was treated with water and DCM. Water for organic layer andwashed with brine 1 more times and then Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM: MeOH: acetone, 94:3:3) to give 36 mg of the title compound (73% yield).

2, 5-difluoro-N- { 2-fluoro-3- [1- (2-fluoroethyl) -4- (1-methoxymethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 1-methoxymethyl-1H-pyrrolo [2,3-b ]]Pyridin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r29= 2-fluoroethyl; r30=2, 5-difluorobenzenesulfonyl group)

。

Method A, step f

(formula I, wherein m = 0; R₁= 2-fluoroethyl; r2, R3= F; r4= 2-aminopyrimidin-4-yl)

Mixing N- {3- [4- (2-aminopyrimidin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (36 mg, 0.067 mmol) was dissolved in a 9:1 mixture of TFA: water (1 mL), and stirred at 100 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure and then with NaHCO₃The saturated solution was dissolved and extracted with AcOEt. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (Hex: AcOEt: EtOH, 4:4:2) to give 16 mg of the title compound (50% yield).

Following the same procedure, but using a suitable alkylating agent and standard functional group interconversion procedures, the following compounds were prepared:

n- {3- [4- (2-aminopyrimidin-4-yl) -1-piperidin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R₁= piperidin-4-yl; r2, R3= F; r4= 2-aminopyrimidin-4-yl)

。

N- {3- [4- (2-Aminopyrimidin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 6)

(formula I, wherein m = 0; R₁1-methylpiperidin-4-yl; r2, R3= F; r4= 2-aminopyrimidin-4-yl)

。

N- {3- [4- (2-Aminopyrimidin-4-yl) -1- (1-isopropylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 19)

(formula I, wherein m = 0; R₁1-isopropylpiperidin-4-yl group; r2, R3= F; r4= 2-aminopyrimidin-4-yl)

。

N- {3- [4- (2-Aminopyrimidin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 15)

(formula I, wherein m = 0; R₁= tetrahydropyran-4-yl; r2, R3= F; r4= 2-aminopyrimidin-4-yl)

。

2, 5-difluoro-N- { 2-fluoro-3- [1- (2-fluoroethyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

(formula I, wherein m =2; R₁= 2-fluoroethyl; r2, R3= F; r4= 1H-pyrrolo [2,3-b]Pyridin-4-yl)

。

Example 6

N- {3- [ 1-Ethyl-4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 1; R1= methyl; R2, R3= F; R4= 1H-pyrrolo [2,3-b ] pyridin-4-yl)

Method A, step c

N- {3- [ 1-ethyl-4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 1H-pyrrolo [2,3-b ]]Pyridin-4-yl, PG₁= methoxymethyl, R29= ethyl, R30=2, 5-difluorobenzenesulfonyl)

In the microwave tube, N- {3- [ 1-ethyl-4- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -1H-pyrazol-3-yl]A solution of-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (prepared as described in example 4) (273 mg, 0.496 mmol) in DME/water (9:1, 5 mL) was degassed by bubbling argon through for 5 minutes. 4-iodo-7-azaindole (121 mg, 0.496 mmol, 1 eq) was then added, followed by cesium carbonate (242 mg, 0.744 mmol, 1.5 eq) and Pd (dppf) Cl₂·CH₂Cl₂(30 mg, 0.037 mmol, 0.075 eq.). The mixture was irradiated in a microwave oven at 100 ℃ for 1 hour, then diluted with AcOEt and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 96:4) to give 220 mg of product. After recrystallization from an AcOEt/Hex mixture, 122 mg (45%) of pure N- {3- [ 1-ethyl-4- (1H-pyrrolo [2,3-b ] are obtained]Pyridin-4-yl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide as a white solid.

Method A, step f

N- {3- [ 1-ethyl-4- (1H-pyrrolo [2,3-b ]]Pyridin-4-yl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (116 mg, 0.214 mmol) was treated with TFA/water 9:1(2 mL) at 55 ℃ for 1 hour. The reaction mixture was then evaporated to dryness, dissolved with AcOEt and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated under reduced pressure. The residue was treated with a 5:1 mixture of Hex/MTBE (2 mL) and stirred for 30 minutes, filtered and dried to give 93 mg (87%) of the title compound as a white solid.

Example 7

N- {3- [4- (2-Aminopyridin-4-yl) -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 4)

(formula I, wherein m = 1; R1= methyl; R2, R3= F; R4= 2-aminopyridin-4-yl)

Method A, step a

N- [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 4-pyridyl, PG₁= methoxymethyl, R29= ethyl; r30=2, 5-difluorobenzenesulfonyl group)

N- [3- (4-bromo-1-ethyl-1H-pyrazol-3-yl) -2-fluorophenyl) into microwave tube]A solution of-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (prepared as described in example 1) (420 mg, 0.833 mmol) in DME/water (9:1, 10 mL) was degassed by bubbling argon through for 5 minutes. 4-Pyridylboronic acid pinacol ester (256 mg, 1.249 mmol, 1.5 equiv.) was added, followed by cesium carbonate (543 mg, 1.666 mmol, 2 equiv.) and Pd (dppf) Cl₂·CH₂Cl₂(68 mg, 0.083 mmol, 0.1 equiv.). The mixture was irradiated in a microwave oven at 100 ℃ for 30 minutes, then filtered through a celite pad, and the pad was thoroughly washed with AcOEt. The filtrate is treated with NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product is purified by chromatography on silica gel (DCM/MeOH 97:3) to yield 370 mg (88%) of N- [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide as a white solid.

Method E, step a

N- {3- [ 1-ethyl-4- (1-oxy-pyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 22, wherein PG₁= methoxymethyl group; r29= ethyl; r2, R3= F)

To N- [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (370 mg, 0.736 mmol) in DCM (5 mL) was added meta-chloroperbenzoic acid (380 mg, 2.209 mmol, 3 equiv.) and the solution was stirred at room temperature for 16 h. M-chloroperbenzoic acid (190 mg, 1.1 mmol, 1.5 equivalents) was added and stirring was continued for 1 hour. The reaction mixture was diluted with DCM and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness to give 413 mg of crude N- {3- [ 1-ethyl-4- (1-oxy-pyridin-4-yl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide, which is used in the next step without purification.

Method E, step c

N- {3- [4- (2-tert-butylamino-pyridin-4-yl) -1-ethyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

(formula 2G, wherein PG₁= methoxymethyl group; r2, R3= F; r16= tert-butyl; r29= ethyl)

The crude N- {3- [ 1-ethyl-4- (1-oxy-pyridin-4-yl) -1H-pyrazol-3-yl group was washed with water]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide(0.736 mmol) was dissolved in a 2:1 mixture of trifluoromethylbenzene/DCM (9 mL) and cooled to 0 ℃. Tert-butylamine (0.387 mL, 3.68 mmol, 5 equiv.) was then added, followed by toluene sulfonic anhydride (480 mg, 1.472 mmol, 2 equiv.) in portions and the mixture stirred at 0 ℃. After multiple additions of tert-butylamine and toluenesulfonic anhydride, the reaction mixture was diluted with DCM and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. After chromatography on silica gel (DCM/MeOH 98:2 to 95:5), 256 mg of N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1-ethyl-1H-pyrazol-3-yl are obtained]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (61% yield in two steps).

Method E, step E

(formula I, wherein m = 1; R1= methyl; R2, R3= F; R4= 2-aminopyridin-4-yl)

N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1-ethyl-1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (250 mg, 0.436 mmol) was treated with TFA/water (9:1, 3 mL) at 70 ℃ for 4.5 hours. The reaction mixture was then evaporated to dryness, dissolved with AcOEt and then NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (DCM: MeOH:7M NH)₃MeOH solution, 90:8:2), then treatment with diethyl ether, filtration and drying give 78 mg of N- {3- [4- (2-aminopyridin-4-yl) -1-ethyl-1H-pir-zineAzol-3-yl]-2-fluorophenyl } -2, 5-difluorobenzenesulfonamide as a white solid.

n- {3- [4- (2-Aminopyridin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 12)

(formula I, wherein m = 0; R1= isopropyl; R2, R3= F; R4= 2-aminopyridin-4-yl)

。

N- {3- [4- (2-butylamino-pyridin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R1= isopropyl; R2, R3= F; R4= 2-butylaminopyridin-4-yl)

。

N- {3- [4- (2-aminopyridin-4-yl) -1-cyclopropyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

(formula I, wherein m = 0; R1= cyclopropyl; R2, R3= F; R4= 2-aminopyridin-4-yl)

。

Example 8

N- {3- [4- (2-Aminopyridin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 13)

(formula I, wherein m =2; R1, R2, R3= F; R4= 2-aminopyridin-4-yl)

Method A, step a

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 2, wherein R4= 4-pyridyl, PG₁= methoxymethyl, R29= tetrahydropyridinePyran-2-yl, R30=2, 5-difluorobenzenesulfonyl)

Argon degassed N- {3- [ 4-bromo-1- (tetrahydropyran-2-yl) -2H-pyrazol-3-yl into a microwave tube]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (900 mg, 1.607 mmol) (prepared as described in example 5) in dimethoxyethane: water (9:1, 11 mL) was added under argon atmosphere 4- (4,4,5, 5-tetramethyl- [ 1.3.2)]Dioxaborolan-2-yl) -pyridine (494 mg, 2.41 mmol), cesium carbonate (1.048 g, 3.214 mmol) and Pd (dppf) Cl₂·CH₂Cl₂(131 mg, 0.16 mmol). The mixture was heated in a microwave oven at 100 ℃ for 45 minutes and then filtered through a pad of celite. The solution was dissolved with AcOEt and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (AcOEt: Hex 9:1) to yield 770 mg of the title compound (85% yield).

Method E, step a

2, 5-difluoro-N- { 2-fluoro-3- [4- (1-oxy-pyridin-4-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

(formula 22, wherein PG₁= methoxymethyl group; r29= tetrahydropyran-2-yl; r2, R3= F)

To 2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl]A solution of-phenyl } -N-methoxymethyl-benzenesulfonamide (770 mg, 1.38 mmol) in DCM (10 mL) was added 3-chloroperbenzoic acid (715 mg, 4.14 mmol) and the reaction was stirred at room temperature overnight. After a further addition of more than 1 equivalent of oxidizing agent and a further 30 minutes, the reaction mixture is concentrated under reduced pressure, dissolved with AcOEt and taken up with NaHCO₃Saturated aqueous solution and brine. This intermediate was used directly in the next step without any further purification.

Method E, step c

N- {3- [4- (2-tert-butylamino-pyridin-4-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2G, wherein PG₁= methoxymethyl group; r2, R3= F; r16= tert-butyl; r29= tetrahydropyran-2-yl

To 2, 5-difluoro-N- { 2-fluoro-3- [4- (1-oxy-pyridin-4-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl]Suspension of-phenyl } -N-methoxymethyl-benzenesulfonamide (1.38 mmol) in trifluorotoluene (20 mL) was added tert-butylamine (728 mL, 6.9 mmol) and the mixture was cooled to 0 ℃. Toluene sulfonic anhydride (900 mg, 2.76 mmol) was added in portions and the reaction was stirred at 0 ℃. After 30 minutes, another portion of the reagent (146. mu.L of tert-butylamine, 225 mg of tosylate) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, dissolved with AcOEt and concentrated with NaHCO₃Saturated aqueous solution and brine. The residue was purified by flash chromatography on silica gel (Hex: AcOEt: EtOH 70:25:5) to give 572 mg of the title compound (66% over 2 steps).

Method A, step d

N- {3- [4- (2-tert-butylamino-pyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl benzenesulfonamide

Formula 4A, wherein R4= 2-tert-butylaminopyridin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r2, R3= F; r30=2, 5-difluorobenzenesulfonyl

To the N- {3- [4- (2-tert-butylaminopyridin-4-yl) -2- (tetrahydropyran-2-yl) -2H-pyrazol-3-yl group]To a solution of-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (572 mg, 0.91 mmol) was added p-toluenesulfonic acid monohydrate (346 g, 1.818 mmol), and the reaction mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved with AcOEt and purified with NaHCO₃Saturated aqueous solution and brine. The residue was not purified any further (420 mg, yield 85%).

Method A, step e

N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 2-tert-butylaminopyridin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r29= 2-fluoroethyl; r30=2, 5-difluorobenzenesulfonyl

To the N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1H-pyrazol-3-yl group]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (100 mg, 0.183 mmol) in DMF (2 mL) was added cesium carbonate (90 mg, 0.275 mmol) and 1-fluoro-2-iodoethane (48 mg, 0.275 mmol), and the suspension was stirred at 50 ℃ for 1 hour. The mixture was treated with water and AcOEt, the organic layer was washed once more with water and brine, then Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Hex: EtOH 8:2) to yield 49 mg of the title compound (45% yield).

n- {3- [4- (2-tert-butylaminopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 2-tert-butylaminopyridin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl

。

Method E, step E

Formula I, wherein m =2; r1, R2, R3= F; r4= 2-aminopyridin-4-yl

N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1- (2-fluoroethyl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (49 mg, 0.082 mmol) was dissolved in a 9:1 mixture of TFA: water (1.4 mL) and stirred at 70 ℃ for 3.5 hours. The reaction mixture was concentrated under reduced pressure and concentrated with NaHCO₃The saturated solution was dissolved and extracted with ethyl acetate. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (Hex: AcOEt: EtOH 4:4:2) to give 26 mg of the title compound (63% yield).

n- {3- [4- (2-Aminopyridin-4-yl) -1-cyclopentyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 17)

Formula I, wherein m = 0; r1= cyclopentyl; r2, R3= F; r4= 2-aminopyridin-4-yl

。

N- {3- [4- (2-aminopyridin-4-yl) -1-cyclohexyl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r1= cyclohexyl; r2, R3= F; r4= 2-aminopyridin-4-yl

。

N- {3- [4- (2-Aminopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 14)

Formula I, wherein m = 0; r1= tetrahydropyran-4-yl; r2, R3= F; r4= 2-aminopyridin-4-yl

。

Example 9

N- {3- [4- (2-aminopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r1= 1-methylpiperidin-4-yl; r2, R3= F; r4= 2-aminopyridin-4-yl

Method E, step a

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -4- (1-oxy-pyridin-4-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester

Formula 22, wherein PG₁= methoxymethyl group; r2, R3= F; r29= 1-tert-butoxycarbonylpiperidin-4-yl

To the 4- (3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino group]To a solution of tert-butyl (2-fluorophenyl) -4-pyridin-4-yl-pyrazol-1-yl) -piperidine-1-carboxylate (1.8 g, 2.737 mmol) (prepared as described in example 2) was added benzoic acid (1.42 g, 8.210 mmol, 3 equiv.) and the solution was stirred at room temperature for 5 hours. M-chloroperbenzoic acid (350 mg, 0.75 eq) was further added and stirring was continued overnight. The reaction mixture was then diluted with DCM and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 95:5) to yield 1.23 g (67%) of 4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) methoxymethylamino ] methyl]-2-fluorophenyl } -4- (1-oxy-pyridin-4-yl) -pyrazol-1-yl]Tert-butyl piperidine-1-carboxylate as a white foam.

Method E, step c

4- (4- (2-tert-butylaminopyridin-4-yl) -3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

Formula 2G, wherein PG₁= methoxymethyl group; r2, R3= F; r16= tert-butyl; r29= 1-tert-butoxycarbonyl-piperidin-4-yl

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino group]-2-fluorophenyl } -4- (1-oxypyridin-4-yl) -pyrazol-1-yl]Tert-butyl-piperidine-1-carboxylate (0.727 mg, 1.079 mmol) was dissolved in trifluoromethylbenzene (5 mL) and cooled to 0 ℃. Tert-butylamine (0.567 mL, 5.395 mmol, 5 equiv.) was added followed by toluene sulfonic anhydride (704 mg, 2.158 mmol, 2 equiv.) and the mixture stirred at 0 ℃. After addition of two more times tert-butylamine (5 eq) and toluene sulfonic anhydride (2 eq), the reaction mixture was diluted with DCM and with NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. After flash chromatography on silica gel (DCM/MeOH 95:5 to 9:1), 574 mg of 4- (4- (2-tert-butylaminopyridin-4-yl) -3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino group are obtained]-tert-butyl 2-fluorophenyl } -pyrazol-1-yl) piperidine-1-carboxylate (73%).

N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1-piperidin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2G, wherein PG₁= methoxymethyl group; r2, R3= F; r16= tert-butyl; r29= piperidin-4-yl

To 4- (4- (2-tert-butylaminopyridin-4-yl) -3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] was added at room temperature under a nitrogen atmosphere]A solution of-2-fluorophenyl } -pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (235 mg, 0.322 mmol) in anhydrous dioxane (1 mL) was added dropwise to a 4N HCl/dioxane solution (1 mL, 4 mmol, 12 equivalents), and the mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure and the residue was diluted with AcOEt and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness to give 220 mg of crude product, which was used in the next step without purification.

N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2G, wherein PG₁= methoxymethyl group; r2, R3= F; r16= tert-butyl; r29= 1-methylpiperidin-4-yl

To the N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1-piperidin-4-yl-1H-pyrazol-3-yl group]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl group-benzenesulfonamide (69 mg, 0.11 mmol) in MeOH (1 mL) was added 37% aqueous formaldehyde (0.013 mL, 0.165 mmol, 1.5 equiv.), followed by acetic acid (0.019 mL, 0.33 mmol, 3 equiv.) and sodium cyanoborohydride (13 mg, 0.176 mmol, 1.6 equiv.), and the mixture was stirred at room temperature for 1 h. The solvent was then evaporated under reduced pressure and the residue was taken up in AcOEt and NaHCO₃Treating with saturated aqueous solution, and separating two phases. The aqueous phase was basified to pH 10 by addition of ammonium hydroxide and extracted with AcOEt. The combined organic layers were washed with brine and Na₂SO₄Dried and evaporated to dryness to give 66 mg of crude product (mixture of MOM protected and deprotected product) which was used in the next step without purification. [ M + H ]]⁺ 643。

Method E, step E

The crude N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl group was purified]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (66 mg, 0.103 mmol) was dissolved in a 9:1 TFA/water mixture (1 mL) and stirred at 60 ℃ for 8 hours. The reaction mixture was concentrated under reduced pressure, then dissolved with AcOEt and then with NaHCO₃The saturated solution was washed with brine, and the organic layer was washed with Na₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM: MeOH:7M NH)₃MeOH solution, 80:15:5) to yield 57 mg of the title compound as a white solid.

Following the same procedure, but using the appropriate reagents in the reductive amination step, the following compounds were prepared:

n- {3- [4- (2-aminopyridin-4-yl) -1- (1-isopropylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r1= 1-isopropylpiperidin-4-yl; r2, R3= F; r4= 2-aminopyridin-4-yl

。

N- {3- [4- (2-aminopyridin-4-yl) -1- (1-ethylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r1= 1-ethylpiperidin-4-yl; r2, R3= F; r4= 2-aminopyridin-4-yl

。

N- {3- [4- (2-Aminopyridin-4-yl) -1- (1-cyclopropylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (compound 23)

Formula I, wherein m = 0; r1= 1-cyclopropylpiperidin-4-yl; r2, R3= F; r4= 2-aminopyridin-4-yl

。

In some cases, the following partially deprotected products were also isolated:

n- {3- [4- (2-tert-butylaminopyridin-4-yl) -1-piperidin-4-yl-1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r1= piperidin-4-yl; r2, R3= F; r4= 2-tert-butylaminopyridin-4-yl

。

N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r1= 1-methylpiperidin-4-yl; r2, R3= F; r4= 2-tert-butylaminopyridin-4-yl

。

Example 10

N- {3- [1- (1-acetylpiperidin-4-yl) -4- (2-aminopyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r1= 1-acetylpiperidin-4-yl; r2, R3= F; r4= 2-aminopyridin-4-yl

N- {3- [1- (1-acetylpiperidin-4-yl) -4- (2-tert-butylaminopyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2G, wherein PG₁= methoxymethyl group; r2, R3= F; r16= tert-butyl; r29= 1-acetylpiperidin-4-yl

To the N- {3- [4- (2-tert-butylaminopyridin-4-yl) -1-piperidin-4-yl-1H-pyrazol-3-yl group]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (100 mg, 0.159 mmol) (prepared as described in example 8) in DCM (1.5 mL) was added triethylamine (0.024 mL, 0.175 mmol, 1.1 equiv.) and acetyl chloride (0.011 mL, 0.159 mmol, 1 equiv.) successively, and the solution was stirred at room temperature for 1 hour. The reaction mixture was then diluted with DCM and washed with water. The aqueous phase was back-extracted with DCM. The combined organic layers were washed with brine and Na₂SO₄Dried and evaporated to dryness. The crude product was purified by flash chromatography (DCM: MeOH:7 NH)₃MeOH 94:5:1) to yield 93 mg (87%) of N- {3- [1- (1-acetylpiperidin-4-yl) -4- (2-tert-butylaminopyridin-4-yl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide.

Method E, step E

Mixing N- {3- [1- (1-acetylpiperidin-4-yl) -4- (2-tert-butylaminopyridin-4-yl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (85 mg, 0.127 mmol) was dissolved in a 9:1 TFA/water mixture (2 mL) and stirred at 60 ℃ for 8 hours. The reaction mixture was decompressedConcentrated and then taken up with DCM and NaHCO₃Saturated solution and brine wash. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH 9:1) to give 63 mg (87%) of the title compound as a white solid.

Example 11

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide (compound 16)

Formula I, wherein m = 0; r1= tetrahydropyran-4-yl; r2, R3= F; r4= 4-pyridinyl

Method A, step d

2, 5-difluoro-N- [ 2-fluoro-3- (4-pyridin-4-yl-2H-pyrazol-3-yl) -phenyl ] -N-methoxymethyl-benzenesulfonamide

Formula 4A, wherein R4= 4-pyridyl; PG (Picture experts group)₁= methoxymethyl group; r30=2, 5-difluorobenzenesulfonyl

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl]-phenyl } -N-methoxymethyl-benzenesulfonamide (950 mg, 1.61 mmol) (prepared as described in example 8) was dissolved in MeOH (10 mL), and p-toluenesulfonic acid monohydrate (700 mg, 3.68 mmol) was added. The solution was heated to reflux for 2h, concentrated under reduced pressure, then taken up in DCM and NaHCO₃Saturated solution and brine wash. Na for organic layer₂SO₄Dried and concentrated to dryness. Flash chromatography of the residue on silicaPurify on gel (cyclohexane/AcOEt from 4:6 to 2:8) to obtain 550 mg (72%) of the title compound as a colorless solid.

Method A, step e

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 4-pyridyl; PG (Picture experts group)₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl

To 2, 5-difluoro-N- [ 2-fluoro-3- (4-pyridin-4-yl-2H-pyrazol-3-yl) -phenyl]-N-methoxymethyl-benzenesulfonamide (190 mg, 0.4 mmol) in DMF (3 mL) was added cesium carbonate (260 mg, 0.8 mmol) and tetrahydropyran-4-yl methanesulfonate (108 mg, 0.6 mmol), and the suspension was stirred at 70 ℃ overnight. The mixture was treated with water and AcOEt. The organic layer was washed once more with water and brine, then Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (AcOEt: Hex 95:5) to yield 60 mg of the title compound (yield 27%). [ M + H ]]⁺ 559。

Method A, step f

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

Formula I, wherein m = 0; r1= tetrahydropyran-4-yl; r2, R3= F; r4= 4-pyridinyl

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl]-phenyl } -N-methoxymethyl-benzenesulfonamide (60 mg, 0.107 mmol) was dissolved in a 9:1 mixture of TFA: water (1 mL) and stirred at 70 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure and then with NaHCO₃The saturated solution was dissolved and extracted with AcOEt. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (AcOEt) to yield 47 mg of the title compound (85% yield).

2, 5-difluoro-N- { 2-fluoro-3- [1- (2-fluoroethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide (compound 7)

Formula I, wherein m =2; r1, R2, R3= F; r4= 4-pyridinyl

。

Example 12

2, 5-difluoro-N- (2-fluoro-3- {1- [2- (4-methylpiperazin-1-yl) -ethyl ] -4-pyridin-4-yl-1H-pyrazol-3-yl } -phenyl) benzenesulfonamide

Formula I, wherein m =2; r1= 4-methylpiperazin-1-yl; r2, R3= F; r4= 4-pyridinyl

Method C, step k

N- (3- { 4-bromo-1- [2- (tetrahydropyran-2-yloxy) -ethyl ] -1H-pyrazol-3-yl } -2-fluorophenyl) -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 1, wherein Hal = Br; PG (Picture experts group)₁= methoxymethyl group; r29=2- (tetrahydropyran-2-yloxy-) ethyl; r30=2, 5-difluorobenzenesulfonyl

Reacting N- [3- (4-bromo-1H-pyrazol-3-yl) -2-fluorophenyl]A solution of-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (346 mg, 0.726 mmol) (prepared as described in preparation example 1) in anhydrous DMF (4 mL) was cooled to 0 ℃ under argon atmosphere and sodium hydride (60% in mineral oil, 87 mg, 2.179 mmol, 3 equiv.) was added. The mixture was stirred at 0 ℃ for 30 minutes, then 2- (2-bromoethoxy) -tetrahydropyran (0.165 mL, 1.089 mmol, 1.5 equiv.) was added dropwise and the mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was then diluted with AcOEt, washed with water and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product is purified by flash chromatography on silica gel (cyclohexane/AcOEt, 55:45) to yield 243 mg (55%) of the desired regioisomer N- (3- { 4-bromo-1- [2- (tetrahydropyran-2-yloxy) -ethyl]-1H-pyrazol-3-yl } -2-fluorophenyl) -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide.

Method A, step a

2, 5-difluoro-N- (2-fluoro-3- { 4-pyridin-4-yl-1- [2- (tetrahydropyran-2-yloxy) -ethyl ] -1H-pyrazol-3-yl } -phenyl) -N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 4-pyridyl; PG (Picture experts group)₁= methoxymethyl group; r29=2- (tetrahydropyran-2-yloxy) ethyl; r30=2, 5-difluorobenzenesulfonyl

Argon degassed N- (3- { 4-bromo-1- [2- (tetrahydropyran-2-yloxy) -ethyl ] in a microwave tube under argon atmosphere]-1H-pyrazol-3-yl } -2-fluorophenyl) -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (233 mg, 0.385 mmol) in 1, 2-dimethoxyethane water (9:1, 4.5 mL) was added 4- (4,4,5, 5-tetramethyl- [1,3, 2-tetramethyl- [1, 4,5,5 ] methyl]Dioxaborolan-2-yl) -pyridine (118 mg, 0.578 mmol, 1.5 equiv.), cesium carbonate (251 mg, 0.770 mmol, 2 equiv.), and Pd (dppf) Cl₂·CH₂Cl₂(31 mg, 0.038 mmol, 0.1 equiv.). The mixture was heated in a microwave oven at 100 ℃ for 30 minutes and then filtered through a celite pad, which was washed thoroughly with AcOEt. NaHCO for filtrate₃Saturated aqueous solution and brine. The organic layer was washed with Na₂SO₄Dried and concentrated to dryness, and the residue purified by flash chromatography on silica gel (DCM/MeOH 97:3) to yield 210 mg (90%) of the title compound.

2, 5-difluoro-N- { 2-fluoro-3- [1- (2-hydroxyethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 4-pyridyl; PG (Picture experts group)₁= methoxymethyl group; r29=2-hydroxyethyl, R30=2, 5-difluorobenzenesulfonyl

To 2, 5-difluoro-N- (2-fluoro-3- { 4-pyridin-4-yl-1- [2- (tetrahydropyran-2-yloxy) ethyl]-1H-pyrazol-3-yl } phenyl) -N-methoxymethyl-benzenesulfonamide (205 mg, 0.340 mmol) in MeOH (2 mL) was added p-toluenesulfonic acid monohydrate (78 mg, 0.408 mmol, 1.2 equiv.), the reaction mixture was stirred at room temperature for 2 hours, then diluted with DCM, and saturated NaHCO₃Aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated to dryness and the crude product (181 mg) was used in the next step without further purification.

2, 5-difluoro-N- (2-fluoro-3- {1- [2- (4-methylpiperazin-1-yl) -ethyl ] -4-pyridin-4-yl-1H-pyrazol-3-yl } -phenyl) -N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 4-pyridyl; PG (Picture experts group)₁= methoxymethyl, R29=2- (4-methylpiperazin-1-yl) -ethyl, R30=2, 5-difluorobenzenesulfonyl

To 2, 5-difluoro-N- { 2-fluoro-3- [1- (2-hydroxyethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl]A solution of-phenyl } -N-methoxymethyl-benzenesulfonamide (177 mg, 0.341 mmol) in anhydrous DCM (2 mL) was added triethylamine (0.047 mL, 0.341 mmol, 1 equiv.), followed by methanesulfonyl chloride (0.034 mL, 0.341 mmol, 1 equiv.), and the mixture was stirred at room temperature for 1 hour. Followed by the addition of N-methylPiperazine (0.040 mL, 1 eq) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was then changed to acetonitrile and the reaction was heated to 80 ℃. After 1 hour, more than 2 equivalents of N-methylpiperazine were added and heating was continued. After addition of more than 2 equivalents of N-methylpiperazine and heating for more than 3 hours, the reaction was diluted with AcOEt and saturated NaHCO₃And (4) washing with an aqueous solution. The aqueous phase was basified to pH 11 and extracted with AcOEt. The combined organic layers were washed with brine and Na₂SO₄Dried and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (DCM: EtOH:7N NH)₃Methanol solution, 90:8:2) to yield 114 mg of the title compound.

2, 5-difluoro-N- (2-fluoro-3- {1- [2- (4-methylpiperazin-1-yl) -ethyl ] -4-pyridin-4-yl-1H-pyrazol-3-yl } -phenyl) -benzenesulfonamide

Formula I, wherein m =2; r₁= 4-methylpiperazin-1-yl; r2, R3= F; r4= 4-pyridinyl

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl]-phenyl } -N-methoxymethyl-benzenesulfonamide (57 mg, 0.095 mmol) was dissolved in a 9:1 mixture of TFA: water (2 mL) and stirred at 60 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure and then with NaHCO₃The saturated solution was treated and extracted with AcOEt. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM: EtOH:7N NH)₃Methanol solution, 80:15:5) to yield 44 mg of the title compound with a small amount of regioisomeric impurities. After crystallization from AcOEt, 33 mg of pure 2, 5-difluoro-N- (2-fluoro-3- {1- [2- (4-methylpiperazin-1-yl) -ethyl ] -ethyl are obtained]-4-pyridin-4-yl-1H-pyrazol-3-yl } -phenyl) -benzenesulfonamide as a white solid.

Following the same procedure, but using the appropriate nucleophile in the nucleophilic substitution reaction, the following compounds were obtained:

2, 5-difluoro-N- { 2-fluoro-3- [1- (2-piperidin-1-yl-ethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

Formula I, wherein m =2; r₁= piperidin-1-yl; r2, R3= F; r4= 4-pyridinyl

。

Example 13

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide (compound 8)

Formula I, wherein m =2; r₁1-methylpiperidin-4-yl; r2, R3= F; r4= 1H-pyrrolo [2,3-b]Pyridin-4-yl

Method A, step b

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester

Formula 3, whichM' =4,4,5, 5-tetramethyl- [1,3,2]Dioxaborolan-2-yl, PG₁= methoxymethyl, R29= 1-tert-butoxycarbonyl, R30=2, 5-difluorobenzenesulfonyl group

Argon degassed 4- (4-bromo-3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino group in a microwave tube under argon atmosphere](iii) -2-fluorophenyl } pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (see example 2, method C, step k) (730 mg, 1.1073 mmol) in toluene (11 mL) 4,4,5, 5-tetramethyl- [1,3,2]Dioxaborolane (1.411 g, 11.07 mmol), TEA (0.385 mL, 2.77 mmol), 2-dicyclohexylphosphino-2 ', 6 ' -dimethoxy-1, 1 ' -biphenyl (46 mg, 0.111 mmol), and bis (acetonitrile) dichloropalladium (II) (14 mg, 0.056 mmol). The mixture was heated in a microwave oven at 90 ℃ for 30 minutes and then filtered through a pad of celite. The solution was concentrated to dryness and the residue was purified by flash chromatography on silica gel (Hex/AcOEt 8:2) to give 354 mg of the title compound (45% yield). [ M + H ]]⁺ 707。

Method A, step c

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] -2-fluorophenyl } -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester

Formula 2, wherein R4= 1H-pyrrolo [2,3-b]Pyridin-4-yl, PG₁= methoxymethyl, R29=2- (4-methylpiperazin-1-yl) ethyl, R30=2, 5-difluorobenzenesulfonyl

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino ] was oriented in a microwave tube]-2-fluorophenyl } -4- (4,4,5, 5-tetramethyl- [1,3, 2)]DioxaborolidinesCyclopent-2-yl) -pyrazol-1-yl]A solution of tert-butyl piperidine-1-carboxylate (354 mg, 0.501 mmol) in a 9:1 mixture of DME/water (5 mL) was degassed by bubbling argon for 5 minutes. 4-iodo-7-azaindole (134 mg, 0.501 mmol, 1 eq) was then added followed by cesium carbonate (325 mg, 1.0 mmol, 2 eq) and Pd (dppf) Cl₂·CH₂Cl₂(82 mg, 0.050 mmol, 0.2 equiv.). The mixture was irradiated in a microwave oven at 90 ℃ for 1 hour, then filtered through a pad of celite and washed with NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was purified by silica gel chromatography (DCM/MeOH 98:2) to give 270 mg of the title compound (35% yield) as a white solid. [ M + H ]]⁺ 697。

2, 5-difluoro-N- { 2-fluoro-3- [ 1-piperidin-4-yl-4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

Formula I, wherein m =2; r₁= piperidin-4-yl; r2, R3= F; r4= 1H-pyrrolo [2,3-b]Pyridin-4-yl

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethyl-amino group]-2-fluorophenyl } -4- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -pyrazol-1-yl]Tert-butyl-piperidine-1-carboxylate (130 mg, 0.187 mmol) was dissolved in a 9:1 TFA/water mixture (1 mL) and stirred at 60 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure, then dissolved in toluene and concentrated to dryness, which was done 3 times. The crude product was used directly in the next step without further purification. [ M + H ]]⁺ 553。

2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

To 2, 5-difluoro-N- { 2-fluoro-3- [ 1-piperidin-4-yl-4- (1H-pyrrolo [2,3-b ]]Pyridin-4-yl) -1H-pyrazol-3-yl]-phenyl } -benzenesulfonamide (103 mg, 0.187 mmol) in MeOH (2 mL) was added 37% aqueous formaldehyde (0.021 mL, 0.281 mmol, 1.5 equiv.), followed by acetic acid (0.032 mL, 0.56 mmol, 3 equiv.) and sodium cyanoborohydride (19 mg, 0.299 mmol, 1.6 equiv.), and the mixture was stirred at room temperature for 2 h. The solvent was then evaporated under reduced pressure and the residue was taken up with AcOEt and NaHCO₃Aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was chromatographed on silica gel (DCM: MeOH: ammonia, 90:10: 1). The thus-obtained substance was treated with diethyl ether and filtered to obtain 16 mg of the title compound (yield in two steps, 15%) as a white solid.

Example 14

N- [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -3-fluorobenzenesulfonamide

Formula I, wherein m = 1; r₁=CH₃(ii) a R2= H; r3= F; r4= 4-pyridinyl

Method C, step a

{ 2-fluoro-3- [2- (tetrahydropyran-2-yl) -2H-pyrazol-3-yl ] -phenyl } -carbamic acid tert-butyl ester

Formula 9, wherein PG₁= tert-butoxycarbonyl, R30= H, R29= tetrahydropyran-2-yl

N-Boc-3-bromo-2-fluoroaniline (300 mg, 1.034 mmol) was dissolved in 9:1 DME/H in a microwave tube₂To the O mixture (12 mL), argon was bubbled through the solution for 10 minutes. 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (prepared as described in WO 2010/010154) (576 mg, 2.071 mmol, 2 equiv.) was then added followed by cesium carbonate (1.0 g, 3 equiv.) and Pd (dppf) Cl₂·CH₂Cl₂(84 mg, 14.6 mmol, 0.1 equiv.) the reaction mixture was irradiated at 100 ℃ for 30 minutes. 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1 eq.) was added and a second microwave cycle was carried out at 100 ℃ for 30 minutes. The mixture was then filtered through a pad of celite, and the pad was washed with AcOEt. The filtrate was washed with water and brine, and Na was added₂SO₄Dried and evaporated to dryness. The crude product was purified by chromatography on silica gel (Hex/AcOEt 8:2) to give 570 mg of { 2-fluoro-3- [2- (tetrahydropyran-2-yl) -2H-pyrazol-3-yl group]-phenyl } -carbamic acid tert-butyl ester, in which N-tetrahydropyranyl-pyrazole is mixed (NMR measurement about 57%).

Method C, step e

[ 2-fluoro-3- (2H-pyrazol-3-yl) -phenyl ] -carbamic acid tert-butyl ester

Formula 17, wherein PG₁= tert-butoxycarbonyl, R30= H

To crude { 2-fluoro-3- [2- (tetrahydropyran-2-yl) -2H-pyrazol-3-yl]-phenyl } -carbamic acid tert-butyl ester (570 mg, containing the maximum theoretical amount of 1.034 mmol) in MeOH (10 mL) p-toluenesulfonic acid (48 mg) was added and the solution stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved with AcOEt (100 mL) and concentrated with NaHCO₃A saturated aqueous solution (2X 50 mL) and brine (50 mL). Na for organic phase₂SO₄Dried and evaporated to dryness to give 400 mg of crude product. [ M + H ]]⁺ 278。

Method C, step g

[3- (4-bromo-2H-pyrazol-3-yl) -2-fluorophenyl ] -carbamic acid tert-butyl ester

Formula 18, wherein Hal = Br, PG₁= tert-butoxycarbonyl, R30= H

To [ 2-fluoro-3- (2H-pyrazol-3-yl) -phenyl group under stirring]A solution of tert-butyl carbamate (400 mg, containing maximum theoretical amount 1.034 mmol) in DCM (5 mL) was added N-bromosuccinimide (160 mg, 0.9 mmol) and the solution was stirred at room temperature for 16 h. After additional NBS (16 mg) and stirring for more than 1 hour, the mixture was diluted with DCM (50 mL) and 10% NaHSO₃Aqueous (2X 10 mL) and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (cyclohexane/AcOEt, 8:2 to 7:3) to yield 310 mg of the title compound (84% yield in three steps).

Method C, step k

[3- (4-bromo-1-ethyl-1H-pyrazol-3-yl) -2-fluorophenyl ] -carbamic acid tert-butyl ester

Formula 1, wherein Hal = Br, PG₁= tert-butoxycarbonyl, R30= H, R29= ethyl

Reacting [3- (4-bromo-2H-pyrazol-3-yl) -2-fluorophenyl]Tert-butyl carbamate (305 mg, 0.856 mmol) is dissolved in DCM (4.5 mL), 32% aqueous NaOH (4.5 mL) is added, followed by ethyl iodide (0.076 mL, 0.942 mmol, 1.1 equiv.) and tetrabutylammonium bromide (28 mg, 0.086 mmol, 0.1 equiv.), and the biphasic mixture is stirred vigorously at room temperature for 1 hour. An additional 26 mg of tetrabutylammonium bromide was added followed by 0.030 mL of ethyl iodide and the reaction mixture was stirred for an additional 3 hours. The mixture was then diluted with DCM and water and the two phases separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with water and brine, and Na₂SO₄Dried and evaporated to dryness. Flash chromatography on silica gel (cyclohexane/AcOEt 9:1) separated the two regioisomers, yielding 153 mg of N1-alkylated product (46%) (N- [3- (4-bromo-1-ethyl-1H-pyrazol-3-yl) -2-fluorophenyl)]2, 5-difluoro-N-methoxymethyl-benzenesulfonamide and 78 mg of N2-alkylation product.

Method A, step a

[3- (1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -carbamic acid tert-butyl ester

Formula 2, wherein R4= 4-pyridyl, PG₁= tert-butoxycarbonyl, R30= H, R29= ethyl

Argon degassed (N- [3- (4-bromo-1-ethyl-1H-pyrazol-3-yl) -2-fluorophenyl) in a microwave tube under argon atmosphere]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (153 mg, 0.398 mmol) in 1, 2-dimethoxyethane: water (9:1, 4 mL) was added 4- (4,4,5, 5-tetramethyl- [1,3,2] ethyl]Dioxaborolan-2-yl) -pyridine (122 mg, 0.597 mmol, 1.5 equiv.), cesium carbonate (260 mg, 0.798 mmol, 2 equiv.), and Pd (dppf) Cl₂·CH₂Cl₂(33 mg, 0.040 mmol, 0.1 equiv.). The mixture was heated in a microwave oven at 100 ℃ for 30 minutes and then filtered through a pad of celite. The filtrate was dissolved with AcOEt and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was used directly in the next reaction without any further purification. [ M + H ]]⁺ 383。

Method A, step g

3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenylamine

Formula 5A, wherein m = 1; r₁= methyl group; r4= 4-pyridinyl

To [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl]-solution of tert-butyl carbamate (200 mg, 0.523 mmol) in DCM (3 mL) was added 2 mL of trifluoroacetic acid and the mixture was stirred at room temperature for 2 h. The mixture was then evaporated to dryness and the residue was taken up in DCM and NaHCO₃Saturated aqueous solution and brine. Na for organic layer₂SO₄Dried and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 98:2) to yield 86 mg of the title compound (77% over 2 steps).

Method A, step h

Formula I, wherein m =2, R₁R2= H; r3= F; r4= 4-pyridinyl

To a solution of 3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenylamine (40 mg, 0.142 mmol) in anhydrous pyridine (2 mL) was added 3-fluorobenzenesulfonyl chloride (0.018 mL, 1 eq) at 0 ℃, and the mixture was stirred at 0 ℃ for 1 hour, then diluted with DCM, washed with 0.5N aqueous HCl (3 × 80 mL) and brine. Na for organic layer₂SO₄Dried and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 98:2) to give 30 mg of the title compound as a white powder.

Following the same procedure, using the appropriate sulfonyl chloride, the following compounds were also prepared:

n- [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -2-fluorobenzenesulfonamide

Formula I, wherein m =2, R₁R3= H, R2= F, R4= 4-pyridyl

。

Example 15

2, 5-difluoro-N- [ 2-fluoro-3- (4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -benzenesulfonamide

Formula I, wherein m = 0; r₁= H; r2, R3= F; r4= 4-pyridinyl

Method A, step f

2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl]-phenyl } -N-methoxymethyl-benzenesulfonamide (2.86 g, 5.102 mmol) (see example 8, method A, step a) was dissolved in a 9:1 TFA/water mixture (15 mL) and stirred at 60 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure, then dissolved with AcOEt and then with NaHCO₃Saturated solution and brine wash. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH 95:5) to give 936 mg of the title compound as a white solid (43% yield).

Example 16

2, 5-difluoro-N- [ 2-fluoro-3- (1-oxetan-3-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -benzenesulfonamide (compound 21)

Formula I, wherein m = 0; r1= oxetan-3-yl; r2, R3= F; r4= 4-pyridinyl

Method C, step k

2, 5-dioxo-N- [ 2-fluoro-3- (4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl]A solution of benzenesulfonamide (200 mg, 0.465 mmol), prepared as described in example 15, in anhydrous DMF (4 mL) was added to sodium hydride (60% mineral oil) (46 mg, 1.162 mmol, 2.5 eq) which had previously been washed with n-hexane under an argon atmosphere and cooled to 0 ℃. After stirring at 0 ℃ for 40 min, the freshly prepared 3-oxetanyl triflate (144 mg, 0.689 mmol, 1.5 eq) in dry DMF (1 mL) was added and the mixture stirred at 0 ℃ for 1 h. Then, sodium hydride (40 mg) and 3-oxetanyl trifluoromethanesulfonate (40 mg) were added thereto, and the reaction mixture was warmed to room temperature overnight. The reaction mixture was then diluted with water and ethyl acetate. The aqueous phase was brought to pH 4-5 with 2N hydrochloric acid and extracted with ethyl acetate. Na for organic phase₂SO₄Dried and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (ethyl acetate: n-hexane, 7:3) to give 24 mg of the title compound as a white solid.

During this synthesis, the following by-products were also separated: 2, 5-difluoro-N- { 2-fluoro-3- [1- (oxetan-2-yl) -4- (pyridin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

Formula I, wherein m = 0; r1= oxetan-2-yl; r2, R3= F; r4= 4-pyridinyl

。

Following the same procedure, but using the appropriate alkylating agent, the following compounds were prepared:

2, 5-difluoro-N- { 2-fluoro-3- [1- (3-methyloxetan-3-ylmethyl) -4-piperidin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide

Formula I, wherein m = 1; r1= 3-methylcyclobut-3-yl; r2, R3= F; r4= 4-pyridinyl

。

2, 5-difluoro-N- { 2-fluoro-3- [4- (pyridin-4-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide

Formula I wherein m =1, R1= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 4-pyridinyl

。

Example 17

N- [3- (1-cyclopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r₁= cyclopropyl; r2, R3= F; r4= 4-pyridinyl

Method A, step e

N- [3- (1-cyclopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl ] -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 4-pyridyl, PG₁= methoxymethyl, R29= cyclopropyl, R30=2, 5-difluorobenzenesulfonyl group

Reacting 2, 5-difluoro-N- [ 2-fluoro-3- (4-pyridin-4-yl-2H-pyrazol-3-yl) -phenyl]-N-methoxymethyl-benzenesulfonamide (300 mg, 0.632 mmol) (see example 11, method A, step d), cyclopropylboronic acid (131 mg, 1.32 mmol, 2.5 equiv.) and sodium carbonate (162 mg, 1.32 mmol, 2.5 equiv.) were suspended in dichloroethane (6 mL) at room temperature and stirred. To this suspension was added copper (II) acetate (138 mg, 0.758 mmol, 1.2 equiv.) and [2,2 'dropwise']Bipyridine (115 mg, 0.758 mmol, 1.2 eq) was warmed to a solution of 70 ℃ in dichloroethane (8.5 mL). The mixture was stirred at 70 ℃ for 3 hours. After cooling, the reaction mixture was diluted with DCM and NH₄Saturated Cl solution and brine wash. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:1.5) to give 290 mg of the title compound (89% yield).

Method A, step f

Formula I, wherein m = 0; r₁= cyclopropyl; r2, R3= F; r4= 4-pyridinyl

Reacting N- [3- (1-cyclopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluorophenyl]-2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (71 mg, 0.138 mmol) was dissolved in a 9:1 mixture of TFA: water (1 mL) and stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure and then with NaHCO₃The saturated solution was dissolved and extracted with DCM. Na for organic layer₂SO₄Dried and concentrated to dryness. The residue was treated with ether and filtered to give 64 mg of the title compound (yield 99%).

Example 18

N- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide

Formula I, wherein m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-acetylaminopyridin-4-yl

To N- {3- [4- (2-aminopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl at 0 DEG C]-2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (65 mg, 0.123 mmol) (prepared as described in example 8) in DCM (1 mL) was added acetyl chloride (0.030 mL, 0.369 mmol) and triethylamine (0.068 mL, 0.492 mmol, 4 equiv.) and the reaction was stirred at room temperature for 2 h. The reaction mixture was then diluted with DCM, washed once with water and then with brine. The reaction mixture was concentrated under reduced pressure and the crude peracetylated product was dissolved with MeOH (1 mL) and treated with 1N NaOH (0.5 mL) to hydrolyze the two unwanted acetyl groups. After 1 hour at room temperature the reaction mixture was concentrated under reduced pressure and dissolved with AcOEt and NaHCO₃Saturated aqueous solution and brine. The residue is purified by flash chromatography on silica gel (DCM: MeOH: NH)₃A 7N solution in methanol, 98:1:1) to yield 49 mg of the title compound (61% yield).

Following the same procedure, but using the appropriate acylating agent, the following compounds were prepared:

n- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } -2-methylpropanamide

Formula I, wherein m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-methylpropionamidopyridin-4-yl

。

Following the same procedure, but starting from N- {3- [4- (2-aminopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide (prepared as described in example 9), the following compounds are prepared:

n- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide

Formula I, wherein m = 0; r₁1-methylpiperidin-4-yl; r2, R3= F; r4= 2-acetamidopyridin-4-yl

。

Example 19

N- {3- [4- (2-cyanopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-cyanopyridin-4-yl

Method A, step b

2, 5-difluoro-N- { 2-fluoro-3- [1- (tetrahydropyran-4-yl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazol-3-yl ] -phenyl } -N-methoxymethyl-benzenesulfonamide

Formula 3, wherein M' =4,4,5, 5-tetramethyl- [1,3,2]Dioxaborolan-2-yl; PG (Picture experts group)₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl

Placing N- {3- [ 4-bromo-1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl in a microwave tube]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (590 mg, 1.053 mmol) (prepared as described in example 1) was dissolved in dry toluene (10 mL), and the solution was degassed by passing argon through for 5 minutes. Triethylamine (0.367 mL, 2.633 mmol, 2.5 equiv.) was then added followed by S-Phos (43 mg, 0.105 mmol, 0.1 equiv.), PdCl₂(CH₃CN)₂(14 mg, 0.053 mmol, 0.05 equiv.) and pinacolborane (1.5 mL, 10.53 mmol, 10 equiv.). The vial was sealed and the mixture was irradiated in a microwave oven at 90 ℃ for 30 minutes. Then another portion of S-Phos (43 mg) and PdCl was added₂(CH₃CN)₂(14 mg), the mixture was subjected to a second microwave cycle. Then, the mixture was filtered through a celite pad, and the pad was thoroughly washed with ethyl acetate. The filtrate was washed with water and brine, dried over sodium sulfate andthe mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel (n-hexane/AcOEt 7:3) to give 890 mg of the title product containing debrominated by-product impurities. The product was used directly in the next step without further purification.

Method A, step c

N- {3- [4- (2-cyanopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide

Formula 2, wherein R4= 2-cyanopyridin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r29= tetrahydropyran-4-yl; r30=2, 5-difluorobenzenesulfonyl

In a microwave tube to 2, 5-difluoro-N- { 2-fluoro-3- [1- (tetrahydropyran-4-yl) -4- (4,4,5, 5-tetramethyl- [1,3, 2-]Dioxaborolan-2-yl) -1H-pyrazol-3-yl]-phenyl } -N-methoxymethyl-benzenesulfonamide (420 mg, 0.691 mmol) in DME/H₂The solution in O9: 1(10 mL) was degassed by bubbling argon for 5 minutes. 4-bromo-2-cyanopyridine (252 mg, 1.383 mmol, 2 equiv.) was then added, followed by cesium carbonate (563 mg, 1.728 mmol, 2.5 equiv.) and Pd (dppf) Cl₂·CH₂Cl₂(56 mg, 0.069 mmol, 0.1 equiv.). The mixture was irradiated in a microwave oven at 100 ℃ for 30 minutes and then partitioned between ethyl acetate and NaHCO₃In a saturated aqueous solution, the two phases are separated and the organic layer is again treated with NaHCO₃Washed with saturated aqueous solution and then with brine. The combined organic layers were washed with Na₂SO₄Dried and evaporated to dryness. The crude product was purified by chromatography on silica gel (gradient cyclohexane/ethyl acetate, 1:1 to 1:2) to give 210 mg of the title compound (52% yield) as a white solid.

Method A, step f

To the N- {3- [4- (2-cyanopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl group]A solution of-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (60 mg, 0.103 mmol) in dioxane (2 mL) was added concentrated hydrochloric acid (0.5 mL), and the mixture was stirred at room temperature overnight. After two more additions of concentrated hydrochloric acid (0.5 mL each) and stirring for more than 5 hours, the reaction mixture was diluted with water, neutralized with 32% NaOH and then extracted with ethyl acetate. The combined organic layers were washed with brine and Na₂SO₄Dried and concentrated under reduced pressure. The title product was obtained as well as 4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl]Amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl]1:1 mixtures of pyridine-2-carboxamides. The two products were separated by flash chromatography on silica gel (gradient cyclohexane/AcOEt 2:8 to pure AcOEt) to give 21 mg of the title compound and 15 mg of 4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl]Amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl]Pyridine-2-carboxamide as a white solid.

4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridine-2-carboxamide

The compound of the formula I is shown in the specification,wherein m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-carboxamidopyridin-4-yl

。

Example 20

4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridine-2-carboxylic acid methyl ester

Formula I, m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-methoxycarbonylpyridin-4-yl

N- {3- [4- (2-cyanopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl in a Pirex nutsche]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (140 mg, 0.240 mmol) (prepared as described in example 19) was dissolved in methanol (2.5 mL), and 4N hydrochloric acid/dioxane solution (2 mL) was added. The sealed tube was heated at 80 ℃ for 30 hours, and then the solvent was evaporated under reduced pressure. After chromatography on silica gel (gradient DCM/MeOH 98:2 to 90:10), 130 mg of the MOM-protected and deprotected methyl ester mixture are obtained. 40 mg of this mixture was treated with a 9:1 trifluoroacetic acid/water mixture (1 mL)And heated at 70 ℃ for 50 minutes to achieve complete deprotection. The solvent was evaporated to dryness, the residue was taken up in ethyl acetate and NaHCO₃Saturated aqueous solution and brine. The crude product was chromatographed on silica gel (DCM/MeOH 97:3) and triturated with ether to give 25 mg of the title compound as a white solid.

Example 21

4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl ] pyridine-2-carboxamide

Formula I, wherein m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-carboxamidopyridin-4-yl

Method A, step c

4- (4- (2-cyanopyridin-4-yl) -3- {3- [ (2, 5-difluorobenzenesulfonyl) methoxymethylamino ] -2-fluorophenyl } -pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester

Formula 2, wherein R4= 2-cyanopyridin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r29= N-tert-butoxycarbonylpiperidin-4-yl; r30=2, 5-difluorobenzenesulfonyl

4- [3- {3- [ (2, 5-difluorobenzenesulfonyl) methoxymethylamino ] was aligned in a microwave tube]-2-fluorophenyl } -4- (4,4,5, 5-tetramethyl)-[1,3,2]Dioxaborolan-2-yl) -pyrazol-1-yl]Tert-butyl piperidine-1-carboxylate (0.708 mmol) (prepared as described in example 13) in DME/H₂The solution in O9: 1(10 mL) was degassed by bubbling argon for 5 min, then 4-bromo-2-cyanopyridine (259 mg, 1.416 mmol, 2 equiv.) was added, followed by cesium carbonate (577 mg, 1.770 mmol, 2.5 equiv.) and Pd (dppf) Cl₂·CH₂Cl₂(58 mg, 0.071 mmol, 0.1 equiv.). The mixture was irradiated in a microwave oven at 100 ℃ for 30 minutes and then partitioned between ethyl acetate and saturated NaHCO₃In aqueous solution. The phases were separated and the organic layer was again treated with NaHCO₃Washed with saturated aqueous solution and then with brine. The combined organic layers were washed with Na₂SO₄Dried and evaporated to dryness. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1) to yield 425 mg of the title compound.

N- {3- [4- (2-cyanopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl benzene sulfonamide

Formula 2, wherein R4= 2-cyanopyridin-4-yl; PG (Picture experts group)₁= methoxymethyl group; r29= 1-methylpiperidin-4-yl; r30=2, 5-difluorobenzenesulfonyl

To the solution of 4- (4- (2-cyanopyridin-4-yl) -3- {3- [ (2, 5-difluorobenzenesulfonyl) -methoxymethylamino ] in]To tert-butyl-2-fluorophenyl } -pyrazol-1-yl) -piperidine-1-carboxylate (420 mg, 0.615 mmol) was added dropwise a 4N HCl/dioxane solution (3 mL, 12 mmol), and the mixture was stirred at room temperature for 45 minutes. The solvent was concentrated under reduced pressure and the residue was dissolved with DCM and evaporated to dryness a total of 3 times. The residue was dissolved in MeOH (6 mL), and 37% aqueous formaldehyde solution (A)0.070 mL, 0.923 mmol, 1.5 equiv.), followed by acetic acid (0.106 mL, 1.845 mmol, 3 equiv.) and sodium cyanoborohydride (73 mg, 0.984 mmol, 1.6 equiv.) are added and the mixture is stirred at room temperature for 1 hour. The solvent was then evaporated under reduced pressure and the residue was taken up in AcOEt and NaHCO₃Treating with saturated aqueous solution, and separating two phases. NaHCO for organic phase₃Washed with saturated aqueous solution and brine, and then with Na₂SO₄Dried and evaporated to dryness. The crude product was purified by chromatography on silica gel (DCM: MeOH:7N NH)₃Methanol solution, 95:4:1 to 93:6:1) to yield 140 mg of the title product.

Method E, Steps f and g

Mixing N- {3- [4- (2-cyanopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (68 mg, 0.114 mmol) was dissolved in a 9:1 trifluoroacetic acid/water mixture (2 mL) and stirred at 70 ℃ for 7 hours. The solvent was evaporated to dryness and the residue was dissolved in toluene and evaporated to dryness a total of 2 times. The crude product was dissolved in dry DMF (2 mL) under argon, DIPEA (0.060 mL, 0.342 mmol, 3 equiv) was added followed by ammonium acetate (93 mg, 1.206 mmol, 10 equiv) and TBTU (60 mg, 0.187 mmol, 1.6 equiv), and the mixture was stirred at room temperature overnight. Then diluted with water and ethyl acetate and the two phases separated. NaHCO for aqueous phase₃The saturated aqueous solution was diluted and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and Na₂SO₄Dried and concentrated to dryness. The crude product was purified by chromatography on silica gel (DCM: MeOH:7N NH)₃Methanol solution, 90:10:1 to 85:15:1) to yield 18 mg of the title compound as a white solid.

Example 22

4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] -N-methylpyridine-2-carboxamide

Formula I, wherein m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4=2- (N-methylcarboxamido) pyridin-4-yl

N- {3- [4- (2-cyanopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl in a Pirex nutsche]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (140 mg, 0.240 mmol) (prepared as described in example 19) was dissolved in methanol (2.5 mL), and 4N HCl/dioxane (2 mL) was added. The sealed tube was heated at 80 ℃ for 30 h, then the solvent was evaporated under reduced pressure to give 130 mg of a mixture of MOM protected and deprotected methyl esters after chromatography on silica gel (gradient DCM/MeOH 98:2 to 90: 10). 85 mg of this mixture was dissolved in ethanol (1 mL) and treated with 33% methylamine in ethanol (1.5 mL) at 70 ℃ for 5 minutes. The solvent was evaporated to dryness and the residue treated with a 9:1 trifluoroacetic acid/water mixture (1 mL) and heated at 60 ℃ for 40 min. The solvent was evaporated to dryness, the residue was taken up in ethyl acetate and NaHCO was used₃Saturated aqueous solutionAnd brine washing. The crude product was purified by chromatography on silica gel (DCM/MeOH, 97:3) and wet-milled with diethyl ether to give 56 mg of the title compound as a white solid.

Following the same procedure, but starting from N- {3- [4- (2-cyanopyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (prepared as described in example 21), the following compounds were prepared:

4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl ] -N-methylpyridine-2-carboxamide

Formula I, wherein m = 0; r₁1-methylpiperidin-4-yl; r2, R3= F; r4=2- (N-methylcarboxamido) pyridin-4-yl

。

Example 23

2, 5-difluoro-N- (2-fluoro-3- {4- [2- (methylamino) pyridin-4-yl ] -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl } phenyl) benzenesulfonamide

Of the formula I, whereinm=0；R₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-methylaminopyridin-4-yl

To N- {3- [4- (2-aminopyridin-4-yl) -1- (tetrahydropyran-4-yl) -1H-pyrazol-3-yl group at room temperature]-2-fluorophenyl } -2, 5-difluoro-N-methoxymethyl-benzenesulfonamide (55 mg, 0.095 mmol) (prepared as described in example 4) in MeOH (1 mL) glacial acetic acid (0.011 mL, 0.2 mmol), formaldehyde (37% in water, 0.008 mL, 0.1 mmol), and sodium cyanoborohydride (7 mg, 0.11 mmol) were added and the reaction stirred at room temperature for 1 h. All these reagents were added a second time in the same amounts and the reaction mixture was stirred for more than one hour. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in a 9:1 mixture of TFA: water (1.5 mL) and stirred at 70 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure, then dissolved with 1N NaOH and extracted with AcOEt. The organic layer was washed with brine and Na₂SO₄Dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH/7N NH)₃Methanol solution, 96:3:1) to yield 3 mg of 2, 5-difluoro-N- (2-fluoro-3- {4- [2- (methylamino) pyridin-4-yl)]-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl } phenyl) benzenesulfonamide (yield 6%) and 29 mg of N- (3- {4- [2- (dimethylamino) pyridin-4-yl)]-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl } -2-fluorophenyl) -2, 5-difluorobenzenesulfonamide (yield 54%).

N- (3- {4- [2- (dimethylamino) pyridin-4-yl ] -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl } -2-fluorophenyl) -2, 5-difluorobenzenesulfonamide

Formula I, wherein m = 0; r₁= tetrahydro-2H-pyran-4-yl; r2, R3= F; r4= 2-dimethylaminopyridin-4-yl

Claims

1. A compound of formula (I)

Wherein:

m is an integer from 0 to 6;

r1 is hydrogen, trichloromethyl, trifluoromethyl, halogen, cyano, OH, OR5, NR6R7, NR8COR9, COOH, COOR10, CONR11R12, OR is optionally substituted and selected from linear OR branchedIs (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkenyl, heterocyclyl, aryl and heteroaryl groups;

r2 and R3 are each independently hydrogen, halogen, trifluoromethyl, trichloromethyl, cyano, nitro, OR13, OR are optionally substituted from linear OR branched (C)₁-C₈) Alkyl and (C)₃-C₈) A radical of cycloalkyl, wherein:

r13 is optionally substituted and is selected from straight or branched chain (C)₁-C₈) Alkyl and (C)₃-C₈) A group of cycloalkyl groups;

r4 is a heteroaryl group selected from

Wherein R14 is hydrogen or is optionally substituted selected from straight or branched chain (C)₁-C₈) Alkyl and (C)₃-C₈) A group of cycloalkyl groups;

x is CH or N;

r15 is hydrogen, optionally substituted, selected from linear or branched (C)₁-C₈) Alkyl and (C)₃-C₈) A cycloalkyl group,Halogen, cyano, NR16R17, CONR18R19, COOR20, OR20, SR20 OR SO₂R20, wherein

R16 and R17 are independently hydrogen or optionally substituted selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups; or R16 and R17 may form together with the nitrogen atom to which they are bound an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH; or R16 is hydrogen and R17 is COR21, wherein:

r22 is optionally substituted and is selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

r23 and R24 are each independently optionally substituted and selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups, or R23 and R24 may together with the nitrogen atom to which they are bound form an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH;

r18 and R19 are independently hydrogen or optionally substituted selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups; or R18 and R19 may form together with the nitrogen atom to which they are bound an optionally substituted 3-8 membered heterocyclyl or heteroaryl group, optionally containing one additional heteroatom or heteroatom group selected from S, O, N or NH;

r20 is optionally substituted and is selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

and pharmaceutically acceptable salts thereof, with the exception of N- [3- (1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -2-fluoro-phenyl ] -2, 5-difluoro-benzenesulfonamide.

2. A compound of formula (I)

Wherein:

m is an integer from 0 to 6;

r1 is trichloromethyl, trifluoromethyl, halogen, cyano, OH, OR5, NR6N7, NR8COR9, COOH, COOR10, CONR11R12 OR is optionally substituted from linear OR branched (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl, (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkenyl, heterocyclyl, aryl and heteroaryl groups;

wherein R5 and R10 are each independently an optionally substituted group selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl;

r6, R7, R8, R9, R11 and R12 are the same or different and are each independently hydrogen or are selected from linear or branched (C)₁-C₈) Alkyl, (C)₃-C₈) Optionally substituted groups of cycloalkyl, heterocyclyl, aryl and heteroaryl, or R6 and R7, R8 and R9 and R11 and R12 together with the nitrogen atom to which they are bound may form an optionally substituted heterocyclyl or heteroaryl group, which optionally contains one additional heteroatom or heteroatom group selected from S, O, N or NH;

r2 and R3 are each independently of the other hydrogen, halogen, trifluoromethyl, trichloromethyl, cyano, nitro, OR13, OR are optionally substituted from the group consisting of straight-chain OR branched (C)₁-C₈) Alkyl and (C)₃-C₈) A radical of cycloalkyl, wherein:

r4 is a heteroaryl group selected from:

x is CH or N;

r15 is hydrogen, optionally substituted, selected from linear or branched (C)₁-C₈) Alkyl and (C)₃-C₈) Cycloalkyl, halogen, cyano, NR16R17, CONR18R19, OR20, SR20 OR SO₂R20, wherein

R16 and R17 are independently hydrogen or optionally substituted selected from straight or branched chain (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl, heterocyclyl, aryl and heteroaryl groups; or R16 and R17 may form together with the nitrogen atom to which they are bound an optionally substituted 3-8 membered heterocyclyl or heteroaryl group containing one additional heteroatom or heteroatom group selected from S, O, N or NH; or R16 is hydrogen and R17 is COR21, wherein:

3. A compound according to any one of claims 1 and 2, wherein m is an integer from 0 to 3.

4. A compound according to any one of claims 1 and 2, wherein m is 0, 1 or 2.

5. The compound according to any one of claims 1 to 4, wherein R1 is selected from the group consisting of: trifluoromethyl, halogen, cyano, OR5, NR6R7, COOR10, CONR11R12, OR optionally substituted from (C)₁-C₈) Alkyl, (C)₃-C₈) Cycloalkyl or heterocyclyl groups.

6. The compound according to any one of claims 1 to 5, wherein R1 is optionally substituted selected from (C)₃-C₈) Cycloalkyl or heterocyclic ringsRadical of (a).

7. A compound according to claim 1, wherein R1 is hydrogen.

8. A compound according to any one of claims 1 to 7, wherein R2 and R3 are independently selected from hydrogen and halogen.

9. The compound according to any one of claims 1 to 8, wherein R4 has structure (III) and R14 is hydrogen, or R4 has structure (IV)

And R15 is selected from hydrogen, halogen or NH₂。

10. The compound according to any one of claims 1 to 8, wherein R4 has structure (V), R14 is hydrogen and X is N, or R4 has structure (VI)

And R15 is selected from hydrogen, halogen or NH₂。

11. A compound selected from:

1) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-isopropyl-piperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide;

2) n- {3- [1- (1-cyclopropyl-piperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

3) n- {3- [4- (2-amino-pyrimidin-4-yl) -1-ethyl-1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

4) n- {3- [4- (2-amino-pyridin-4-yl) -1-ethyl-1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

5) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methyl-piperidin-4-yl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide;

6) n- {3- [4- (2-amino-pyrimidin-4-yl) -1- (1-methyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

7) 2, 5-difluoro-N- { 2-fluoro-3- [1- (2-fluoro-ethyl) -4-pyridin-4-yl-1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide;

8) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methyl-piperidin-4-yl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide;

9) 2, 5-difluoro-N- [ 2-fluoro-3- (1-isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl ] -benzenesulfonamide;

10) n- {3- [4- (2-amino-pyrimidin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

11) n- {3- [4- (2-amino-pyrimidin-4-yl) -1- (2-fluoro-ethyl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

12) n- {3- [4- (2-amino-pyridin-4-yl) -1-isopropyl-1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

13) n- {3- [4- (2-amino-pyridin-4-yl) -1- (2-fluoro-ethyl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

14) n- {3- [4- (2-amino-pyridin-4-yl) -1- (tetrahydro-pyran-4-yl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

15) n- {3- [4- (2-amino-pyrimidin-4-yl) -1- (tetrahydro-pyran-4-yl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

16) 2, 5-difluoro-N- { 2-fluoro-3- [ 4-pyridin-4-yl-1- (tetrahydro-pyran-4-yl) -1H-pyrazol-3-yl ] -phenyl } -benzenesulfonamide;

17) n- {3- [4- (2-amino-pyridin-4-yl) -1-cyclopentyl-1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

18) n- {3- [4- (2-amino-pyrimidin-4-yl) -1- (1-isopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

19) 2, 5-difluoro-N- [ 2-fluoro-3- (1-oxetan-3-yl-4-pyridin-4-yl-1H-pyrazol-3-yl) -phenyl } -benzenesulfonamide;

20) n- (3- {4- [2- (2-amino-pyrimidin-4-ylamino) -pyrimidin-4-yl ] -1-ethyl-1H-pyrazol-3-yl } -2-fluoro-phenyl) -2, 5-difluoro-benzenesulfonamide;

21) n- {3- [4- (2-amino-pyridin-4-yl) -1- (1-cyclopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide;

22) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide;

23) n- {3- [1- (4, 4-difluorocyclohexyl) -4- (pyridin-4-yl) -1H-pyrazol-3-yl ] -2-fluorophenyl } -2, 5-difluorobenzenesulfonamide;

24) n- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide;

25) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-fluoropyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide;

26) 2, 5-difluoro-N- { 2-fluoro-3- [1- (1-methylpiperidin-4-yl) -4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide;

27) 2, 5-difluoro-N- { 2-fluoro-3- [4- (2-methylpyridin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl ] phenyl } benzenesulfonamide;

28) n- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } -2-methylpropanamide;

29) n- {4- [3- (3- { [ (2, 5-difluorophenyl) sulfonyl ] amino } -2-fluorophenyl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-yl } acetamide;

and pharmaceutically acceptable salts thereof.

12. A compound according to claim 11, selected from:

20) n- (3- {4- [2- (2-amino-pyrimidin-4-ylamino) -pyrimidin-4-yl ] -1-ethyl-1H-pyrazol-3-yl } -2-fluorophenyl) -2, 5-difluoro-benzenesulfonamide; and

21) n- {3- [4- (2-amino-pyridin-4-yl) -1- (1-cyclopropyl-piperidin-4-yl) -1H-pyrazol-3-yl ] -2-fluoro-phenyl } -2, 5-difluoro-benzenesulfonamide.

13. A compound according to claim 1, selected from:

20) n- (3- {4- [2- (2-amino-pyrimidin-4-ylamino) -pyrimidin-4-yl ] -1-ethyl-1H-pyrazol-3-yl } -2-fluoro-phenyl) -2, 5-difluoro-benzenesulfonamide; and

14. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 and 2, characterized in that it comprises the following steps:

a) reacting a compound of formula 1

Wherein

Hal is a halogen atom, R29 is- (CH)₂)_mR1 or PG₂Wherein m and R1 are as defined in claim 1, and PG₂Are suitable protecting groups for the pyrazole ring,

PG₁is a suitable protecting group for aniline or sulfonamide, and

r30 is hydrogen or a group SO₂Ph (R2) (R3), wherein R2 and R3 are as defined in claim 1,

coupling with organometallic compounds of the formula R4M, wherein R4 is as defined in claim 1 and M is B (OH)₂、B(OAlk)₂、Sn(Alk)₃、Al(Alk)₂ZnHal, MgHal or ZrCp₂Hal；

Or

b) Reacting a compound of formula 1 as defined above with an organometallic compound such as an alkylboron compound or an alkyltin compound;

c) reacting the resulting compound of formula 3:

wherein M' is B (OAlk)₂Or Sn (alk)₃，R29、PG₁And R30 is as defined above, cross-coupled with a suitable electrophile of formula R4L ', wherein R4 is as defined above and L' is a group which may act as a leaving group, such as a halogen atom, a tosylate group, a mesylate group or a triflate group;

optionally, the step of (a) is carried out,

d) removing the group R29 in the resulting compound 2 obtained in step a or c:

wherein R29 is PG₂Wherein PG is₂、PG₁And R30 is as defined above;

e) by reaction with the appropriate formula L- (CH)₂)_mR1, wherein L is OH, a reactive group or-B (OH)₂Alkylating the resulting compound of formula 4A:

wherein R4 is as defined in claim 1, PG₁And R30 is as defined above, and if necessary separating the resulting regioisomer to obtain a compound wherein R29 is- (CH)₂)_mA compound of formula 2 of R1;

f) from the obtained compound wherein R29 is- (CH)₂)_mRemoval of PG from a compound of formula 2 of R1₁Wherein m and R1 are as defined above, R30 is SO₂Ph (R2) (R3), wherein R2 and R3 are as defined in claim 1;

g) from the obtained compound wherein R29 is- (CH)₂)_mRemoval of PG from a compound of formula 2 of R1₁A group wherein m and R1 are as defined above, R30 is hydrogen;

h) reacting the resulting compound of formula 5A:

wherein R4, m and R1 are as defined above, with the formula Cl-SO₂Sulfonyl chlorides of Ph (R2) (R3) to give compounds of formula (I), which are optionally converted into pharmaceutically acceptable salts.

15. A pharmaceutical composition comprising one or more compounds of formula (I) as defined in claims 1 to 11.

16. The pharmaceutical composition of claim 15, further comprising one or more chemotherapeutic agents.

17. A product or kit comprising a compound of formula (I) as defined in claims 1 to 13 or a pharmaceutical composition as defined in claims 15 to 16, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

18. A compound of formula (I) as defined in any one of claims 1 to 13 for use as a medicament.

19. A compound of formula (I) as defined in claims 1 to 13 for use in the treatment of a disease selected from cancer, cell proliferative disorders, viral infections, autoimmune and neurodegenerative disorders.

20. Use of a compound according to claim 19, wherein the cancer is selected from the group consisting of cancers such as bladder, breast, colon, kidney, liver, lung including small cell lung cancer, oesophageal, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin including squamous cell carcinoma; hematological lymphoid tumors including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, S-cell lymphoma, T-cell lymphoma, Hodgkin ' S lymphoma, non-Hodgkin ' S lymphoma, hairy cell lymphoma and BurKett ' S lymphoma; hematological tumors of the myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndromes, and promyelocytic leukemia; mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytomas, neuroblastomas, gliomas, and schwannomas; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, and kaposi's sarcoma.

21. Use of a compound according to claim 20, wherein the cell proliferative disorder is selected from benign prostate hyperplasia, familial adenomatous polyposis, multiple neurofibromatosis, psoriasis, vascular smooth muscle cell hyperplasia associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-operative stenosis and restenosis.