WO2009111260A1 - Phenylsulfonamide-substituted, pyrazolo[1, 5-a]pyrimidines, methods for preparation and uses thereof - Google Patents

Abstract

Phenylsulfonamide substituted, pyrazolo[1,5-a]pyrimidines are described. The compounds of the invention selectively inhibit Raf kinase activity and are useful for treating disorders associated with Raf kinases. Formula (I)

Description

PHENYLSULFONAMIDE-SUBSTITUTED, PYRAZOLO[I, 5-A]PYRIMIDINES₁ METHODS

FOR PREPARATION AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority benefit of U.S. Provisional Application Serial No. 61/067,670 filed

February 29, 2008, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to new pyrazolo[1 ,5-a]pyrimidine compositions that are useful for inhibiting abnormal growth of certain cell types. The invention is directed to certain phenylsulfonamide substituted, pyrazolo[1,5-a]pyrimidines, their corresponding pharmaceutically acceptable salts and methods for their preparation and use. The phenylsulfonamide substituted, pyrazolo[1 ,5-a]pyrimidines inhibit growth of tumor cells, which contain oncogenic forms of Receptor Tyrosine Kinases, K-Ras and Raf kinases.

BACKGROUND OF THE INVENTION

Raf is a multigene family expressing oncoprotein kinases: Raf-1 , A-Raf and B-Raf, as described in publications by McCubrey et al., in Leukemia, 12(12), 1903-1929 (1998); by

Ikawa et al., in MoI. and Cell. Biol. 8(6), 2651-2654 (1988); by Sithanandarn et al., in Oncogene

5, 1775-1780 (1990); by Konishi et al., in Biochem. and Biophys. Res. Comm. 216(2), 526-534

(1995). All three Raf kinases are functionally present in certain human hematopoietic cells, and their aberrant expression can result in abrogation of cytokine dependency. Their regulatory mechanisms differ in that C-Raf and A-Raf appear to require additional serine and tyrosine phosphorylation within the N region of the kinase domain for full activity, as described by Mason et al., in EMBO J. 18, 2137-2148 (1999). In addition B-Raf kinase appears to have a much higher basal kinase activity than either A-Raf kinase or C-Raf kinase. The three Raf kinases play critical roles in the transmission of mitogenic and anti-apoptotic signals. B-Raf kinase is frequently mutated in various human cancers, as described by Wan et al., in Cell 116, 855-867 (2004), indicating that specific Raf kinases are associated with cancer. The cytoplasmic serine/threonine kinase B-Raf kinases and receptor tyrosine kinases of the platelet-derived growth factor receptor (PDGFR) family are frequently activated in cancer by mutations of an equivalent amino acid. Structural studies have provided important insights into why these very different kinases share similar oncogenic hot spots and why the PDGFR juxtamembrane region is also a frequent oncogenic target, as described by Dibb in Nature Reviews, Cancer 4(9), 718- 27 (2004).

B-Raf kinase is one of three known Raf oncoprotein kinases involved in transmission of mitogenic and anti-apoptotic signals. B-Raf encodes a Ras-regulated kinase that mediates cell growth and malignant transformation pathway activation that controls cell growth and survival. Activation of a Ras/Raf/MEK pathway results in a cascade of events from the cell surface to the cell nucleus, ultimately affecting cell proliferation, apoptosis, differentiation and transformation. Activating B-Raf mutations have been found in 66% of malignant melanomas and in a smaller fraction of other cancers including those of the colorectum, as reported by Davies H., et al. (2002) Nature 417:906 and by Rajagopalan H., etal. (2002) Nature

418, 934. Recently, B-Raf has been shown to be frequently mutated in various human cancers, as described by Wan et al. (2004) Cell 116, 855-867. B-Raf mutations also account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLC). Certain B-Raf mutations reported to date in NSCLC are non-V600 (89%; P < IO^~7), strongly suggesting that B-Raf mutations in NSCLC are qualitatively different from those in melanomas. Thus, there may be therapeutic differences between lung cancers and melanomas in response to Raf kinase inhibitors, as described by Karasarides et al., in Oncogene 23(37), 6292-6298 (2004) and by Bollag et al., in Current Opinion in Invest. Drugs, 4(12), 1436-1441 (2003). Although uncommon, B-Raf mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy, as described by Brose et al., in Cancer Research 62(23):6997-7000 (2002) and in U.S. Patent Application Publication No. 2005/267060.

Raf kinases are also key components of signal transduction pathways by which specific extracellular stimuli elicit precise cellular responses in mammalian cells. Activated cell surface receptors activate Ras/Rap proteins at the inner aspect of the plasma membrane, which in turn recruit and activate Raf proteins. Activated Raf proteins phosphorylate and activate the intracellular protein kinases MEK1 and MEK2. In turn, activated MEKs catalyze phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK). A variety of cytoplasmic and nuclear substrates of activated MAPK are directly or indirectly associated with the cellular response to cellular environmental change. In fact, B-Raf mutations have been shown to predict sensitivity to pharmacological MEK inhibition by small molecule inhibitors by limiting tumor growth in B-Raf mutant xenografts, as described by Solit et a., in Nature, Letters to Editor, Nov. 6, 2005. Three distinct genes have been identified in mammals that encode Raf proteins; A-Raf, B-Raf and C-Raf (also known as Raf-1) and isoformic variants that result from differential splicing of mRNA are known. Therefore, it is desirable to identify and characterize compounds that inhibit growth of tumor cells, which contain oncogenic forms of Receptor Tyrosine Kinases, K-Ras, A-Raf kinase, B-Raf mutant kinase, B-Raf kinase and C-Raf kinase. International Patent Publication No. WO 2003091256 describes certain pyrazolo[1 ,5-a]pyrimidines as inhibitors of NADPH oxidase and the treating of diseases associated with NADPH oxidase. International Patent Publication No. WO 2006084015 describes certain substituted phenyl and substituted cyclic pyrazolo[1 ,5-a]pyrimidines as B-Raf kinase inhibitors and the treating of diseases associated with B-Raf kinase. Neither publication discloses phenylsulfonamide substituted, pyrazolo[1 ,5-a]pyrimidine compounds. Little is known regarding how phenylsulfonamide groups or certain functional groups, comprising phenylsulfonamide groups, substituted at various positions of the pyrazolo[1 ,5-a]pyrimidine ring framework influence structure-activity relationships (SAR) of phenylsulfonamide substituted, pyrazolo[1 ,5-a]pyrimidine compounds. There is a need for new compounds that selectively inhibit Raf kinase activity and that are useful for treating disorders associated with by any Raf kinase. Phenylsulfonamide substituted, pyrazolo[1 ,5-a]pyrimidine compounds of the present invention fulfill this unmet need and are useful in the treatment of specific diseases associated with certain Raf kinases in mammals. Another unmet need addressed by the present invention is that certain Raf kinases inhibitors are useful in treating cancer and comprise one component of a particular cancer therapy.

SUMMARY OF THE INVENTION

Accordingly, the invention provides a compound of formula A:

and pharmaceutically acceptable salts thereof;

wherein

R¹ is a 5-7 membered heterocyclyl ring or heteroaryl ring, said ring comprising 1-3 heteroatoms selected from N, O and S, and said ring optionally substituted with one to two substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, -S(O)_mNR^sR⁵, - NR⁵R⁵, -NR⁵S(O)_mR⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵JR⁷OR⁵, -N(R⁵JR⁷NR⁵R⁵, -NR⁵C(O)R⁵, - C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -OC(O)NR⁵R⁵, -NR⁵C(O)R⁵, - NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -

R⁶N(R⁵)R⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶S(O)_mNR⁵R⁵, -R⁶C(O)R⁵, -R⁶C(O)OR⁵, - R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶NR⁵S(O)_mR⁵, -R⁶OC(O)NR⁵R⁵, -R⁶NR⁵C(O)R⁵, - R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵;

,

R is a monocyclic aryl ring, a 6-14 membered monocyclic or bicycllc heteroaryl ring comprising

1-3 heteroatoms selected from N, O and S, or monocyclic heterocyclyl ring comprising 1-4 heteroatoms selected from N, O and S, said ring optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, -NR⁵R⁵, -NR⁵S(O)_mR⁵, -S(O)_mNR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵, -NR⁵C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -OC(O)NR⁵R⁵, NR⁵C(O)R⁵, - NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, - R⁶N(R⁵)R⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶NR⁵S(O)_mR⁵, -R⁶S(O)_mNR⁵R⁵, -R⁶C(O)R⁵, - R⁶C(O)OR⁵, -R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶OC(O)NR⁵R⁵, -R⁶NR⁵C(O)R⁵, - R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵;

R³ and R⁴ are each independently selected from H, alkyl of 1-8 carbon atoms, cycloalkyl of 3 to 8 atoms and a 5-7 membered monocyclic heteroaryl, said alkyl, cyloalkyl and heteroaryl optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵ and heteroaryl;

R⁵ is independently selected from H, alkyl of 1-8 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, frans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms and cycloalkyl of 3-7 carbons; or the two R⁵ substituents in NR⁵R⁵, together with the nitrogen to which they are attached, join to form a substituted ring comprising 2-7 carbon atoms, or a 5 to 8 atom ring, optionally comprising one to two additional heteroatoms selected from O, N and S(0)_m;

R⁶ is a divalent group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms;

R⁷ is a divalent alkyl group of 2-6 carbon atoms;

J is fluoro, chloro, bromo, or iodo; and

m is an integer of 0-2.

Accordingly, the invention provides a compound of formula B:

and pharmaceutically acceptable salts thereof;

wherein

R is selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -NR⁵R⁵, OR⁷OR⁵, - OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵JR⁷NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵)R⁷NR⁵R⁵ and -R⁶NR⁵R⁵; and R¹-R⁷ are as defined above.

The present invention also provides a pharmaceutical composition comprising a compound of formula A or formula B and a pharmaceutically acceptable carrier. The present invention also provides pharmaceutical compositions comprising compounds of formula A or formula B in combination with other kinase-inhibiting pharmaceutical compositions or chemotherapeutic agents, and a pharmaceutically acceptable carrier.

The present invention provides a method for making a compound of formula B:

and pharmaceutically acceptable salts thereof; comprising the steps of: (a) reacting a substituted ketone of formula 1

with an acetal of N,N-(Ci-C₆dialkyl)formamide or an acetal of

to provide an enaminone compound of formula 2

2 ; and

(b) reacting the compound of formula 2 with a substituted 3-aminopyrazole of formula 3

providing the compound of formula A or B, wherein R is selected from H, -J, -NO₂, -CN, -N₃, - CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -NR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵JR⁷NR⁵R⁵, - R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵JR⁷OR⁵, -R⁶N(R⁵JR⁷NR⁵R⁵ and -R⁶NR⁵R⁵; and R¹- R⁴ are defined above.

The present invention also provides a method for making a compound of formula B:

and pharmaceutically acceptable salts thereof; comprising the steps of: (a) reacting an e ennaammiinnoonnee c coommopoouunndd o off f foorrmmuullaa 22

with an aminopyrazole compound of formula 3a

to provide compounds of formula 4a and 4b

(b) halogenating one or both of the compounds of formula 4a and 4b to provide one or both of compounds of formula 5a and 5b

5a

(c) subjecting one or both of the compounds of formula 5a and 5b to a palladium catalyzed, Suzuki coupling with R²-aryl or R²-heteroaryl boronic acids or corresponding R²-boronate esters thereof to provide one or both of compounds of formula B in accordance with the invention, wherein R is selected from H, -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -NR⁵R⁵, - OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, - R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵JR⁷NR⁵R⁵ and -R⁶NR⁵R⁵; and R¹-R⁴ are defined as above.

The present invention provides additional independent steps of separating compounds of formula 4a and 4b prior to the halogenation step, separating compounds of formula 5a and 5b prior to the palladium catalyzed, Suzuki coupling step and separating compounds of formula A and B after the palladium catalyzed, Suzuki coupling step, respectively.

The invention also provides methods for inhibiting Raf kinase activity in a cell comprising contacting a cell with a compound of formula A or formula B, whereby the compound inhibits activity of a Raf kinase selected from A-Raf kinase, B-Raf kinase, mutant B-Raf kinase, and C-Raf kinase.

The present invention also provides a method of treating an A-Raf kinase, B-Raf kinase, mutant B-Raf kinase, or C-Raf kinase dependent condition, said condition comprising cancer or inflammation, by administering to a patient a pharmaceutically effective amount of a compound of formula A or formula B.

The present invention provides methods of treating mammalian diseases associated with a Raf kinase selected from A-Raf kinase, B-Raf kinase, mutant B-Raf kinase, and C-Raf kinase by administering to a patient a compound of formula A or formula B.

The present invention provides a method of treating cancer by administering to a patient a compound of formula A or formula B, wherein the cancer is selected from the group consisting of: breast, kidney, bladder, thyroid, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, skin, liver, prostate and brain cancer.

DETAILED DESCRIPTION OF THE INVENTION

Definitions The following definitions are used in connection with pyrazolo[1 ,5-a]pyrimidines of the invention. The term "alkyl" refers to the radical of saturated aliphatic groups of 1 to 8 carbon atoms, including straight-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In one embodiment, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone. The term "alkyl" can be used alone or as part of a chemical name, such as "alkylamine". The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple carbon-carbon bond, respectively. The term "cycloalkyl" refers to the radical of saturated cycloaliphatic rings of 3 to 10 carbon atoms, including unbranched cycloalkyl rings and branched cycloalkyl rings.

Unless otherwise defined, the term "aryl", as used herein, refers to an aromatic carbocyclic moiety, e.g. having from 6-20 carbon atoms, which may be a single ring

(monocyclic) or multiple rings fused together or linked covalently, wherein at least one of the rings is aromatic. Any suitable ring position of the aryl moiety may be covalently linked to the defined chemical structure. Examples of aryl include phenyl and napthyl. The aryl group may be optionally substituted. In addition to other optional substituents, the aryl group may be substituted by an oxo substituent meaning one of the ring carbon atoms is part of a carbonyl group. Unless otherwise defined, the term "heteroaryl" as used herein means an aromatic heterocyclic ring system, e.g. having from 5-20 ring atoms, which may be a single ring or multiple rings fused together or linked covalently, wherein at least one of the rings is aromatic.

The rings may contain one or more heteroatoms, e.g. 1 to 3 heteroatoms, selected from nitrogen, oxygen, or sulfur, wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. The heteroaryl group may be optionally substituted. In addition to other optional substituents, the heteroaryl group may be substituted by an oxo substituent meaning one of the ring carbon atoms is part of a carbonyl grρup.

The term "heterocyclic", "heterocycle" or "heterocyclyl" as used herein can be used interchangeably to refer to a stable, saturated or partially unsaturated monocyclic or multicyclic heterocyclic ring system having from 6 to 20 ring members, e.g. having from 5 to 7 ring members. The heterocyclic ring members are carbon atoms and one or more heteroatoms, e.g. 1 to 3 heteroatoms, selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally quaternized. The heterocyclic, heterocycle or heterocyclyl group may be optionally substituted. In addition to other optional substituents, the heterocyclic, heterocycle or heterocyclyl group may be substituted by an oxo substituent meaning one of the ring carbon atoms is part of a carbonyl group. The heterocyclic, heterocycle or heterocyclyl group may contain one of more fused rings.

As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. Typically, suitable substituents of organic compounds include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds as well as inorganic substituents such as halogen or amino. The substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents, halogen substituents and/or any suitable substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the suitable substituents of organic compounds.

As used herein, the term "pharmaceutically acceptable carrier" includes pharmaceutically acceptable diluents and excipients.

As used herein, the term "individual", "subject" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

According to an exemplary embodient, the invention provides a compound of formula A or formula B:

and pharmaceutically acceptable salts thereof;

wherein R, R -R , J and m are defined as above.

Suitable examples of R¹ include, but are not limited to for example, thienyl, furyl, pyridinyl, piperidinyl and morpholinyl. The heterocyclic ring or heteroaryl ring may be substituted to the pyrazolofi , 5-a]pyιϊmidine ring framework in any acceptable position. According to one embodiment, R¹ is 4-pyridinyl or 4-morpholinyl, optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, - NR⁵R⁵, -NR⁵S(O)_mR⁵, -S(O)_mNR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵, - NR⁵C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -OC(O)NR⁵R⁵, NR⁵C(O)R⁵, -NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, - R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵)R⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶NR⁵S(O)_mR⁵, -R⁶S(O)_mNR⁵R⁵, - R⁶C(O)R⁵, -R⁶C(O)OR⁵, -R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶OC(O)NR⁵R⁵, - R⁶NR⁵C(O)R⁵, -R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵.

Suitable examples of R² include, but are not limited to, halogen substituted phenyl,

Ci-C₆ alkylsulfonamido substituted phenyl, benzonitrile, hydroxyl substituted benzonitrile, C₁-C₆ alkoxy substituted benzonitrile, hydroxyphenyl (phenol), C₁-C₆ alkyl substituted hydroxyphenyl (phenol), halogen substituted hydroxyphenyl (phenol), Ci-C₆ alkoxyphenyl, halogen substituted C₁-C₆ alkoxyphenyl, hydroxypyridinyl, C₁-C₆ alkoxypyridinyl, amino phenyl (aniline), halogen substituted amino phenyl (aniline), hydroxyl substituted amino phenyl (aniline), C₁-C₆ alkoxy substituted phenylformamide, Ci-C₆ alkoxy substituted amino phenyl (aniline), urea substituted phenyl, benzamido, CrC₆ alkyl substituted benzamido, halogen substituted benzamido, indazolyl, C₁-C₆ alkyl substituted indazolyl, halogen substituted indazolyl, halo C₁-C₆ alkyl substituted indazolyl, perfluoro C₁-C₆ alkyl substituted indazolyl, benzamidazolyl, halogen substituted benzamidazolyl, oxo-dihydro-benzamidazolyl, dihydro-pyrrolodinyl, substituted dihydro-pyrrolodinyl, dihydro-indolyl, substituted dihydro-indolyl, and oxadiazolyl substituted phenyl. According to one embodiment, the monocyclic aryl ring and the bicyclic heteroaryl ring may be substituted to the pyrazolo[1 ,5-a]pyrimidine ring framework in any acceptable position.

According to one embodiment, R² is an aryl ring or a bicyclic ring of formula

where 3 ^■iinn

refers to a 5-7 membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, said ring optionally substituted with one to four substituents selected from -J, - NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, -NR⁵R⁵, -NR⁵S(O)_mR^s, -S(O)_mNR⁵R⁵, - OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵JR⁷OR⁵, -N(R⁵JR⁷NR⁵R⁵, -NR⁰C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, - C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -OC(O)NR⁵R⁵, NR⁵C(O)R⁵, -NR⁵C(O)OR⁵, - NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵JR⁷OR⁵, -R⁶N(R⁵JR⁷NR⁵R⁵, - R^bNR^sR⁵, -R⁶S(O)_mR⁵, -R⁶NR⁵S(O)₀₁R⁵, -R⁶S(O)_mNR⁵R⁵, -R⁶C(O)R⁵, -R⁶C(O)OR⁵, -

R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶OC(O)NR⁵R⁵, -R⁶NR⁵C(O)R⁵, -R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵.

According to a separate embodiment, R² is a phenyl ring or an indazolyl ring, optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃,

-OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, -NR⁵R⁵, -NR⁵S(O)_mR⁵, -S(O)_mNR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -

N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵, -NR⁵C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -

OC(O)OR⁵, -OC(O)NR⁵R⁵, NR⁵C(O)R⁵, -NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -

R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵)R⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶NR⁵S(O)_mR⁵, - R⁶S(O)_mNR⁵R⁵, -R⁶C(O)R⁵, -R⁶C(O)OR⁵, -R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -

R⁶OC(O)NR⁵R⁵, -R⁶NR⁵C(O)R⁵, -R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵.

According to a separate embodiment, R² is selected from halogen substituted phenyl, CrC₆ alkylsulfonamido substituted phenyl, carbamate substituted phenyl, CrC₆ alkoxy substituted phenylcarbamate, benzonitrile, hydroxyl substituted benzonitrile, C₁-C₆ alkoxy substituted benzonitrile, hydroxyphenyl, Ci-C₆ alkyl substituted hydroxyphenyl, halogen substituted hydroxyphenyl, C₁-C₆ alkoxyphenyl, halogen substituted CrC₆ alkoxyphenyl, hydroxypyridinyl, C₁-C₆ alkoxypyridinyl, amino phenyl, halogen substituted amino phenyl, hydroxyl substituted amino phenyl, formamide substituted phenyl, hydroxyl substituted phenylformamide, C₁-C₆ alkoxy substituted phenylformamide, C₁-C₆ alkoxy substituted amino phenyl, urea substituted phenyl, benzamido, CrC₆ alkyl substituted benzamido, halogen substituted benzamido, indazolyl, C₁-C₆ alkyl substituted indazolyl, halogen substituted indazolyl, halo CrC₆ alkyl substituted indazolyl, perfluoro d-C₆ alkyl substituted indazolyl, benzamidazolyl, halogen substituted benzamidazolyl, dihydro-pyrrolodinyl, substituted dihydro- pyrrolodinyl, dihydro-indolyl, substituted dihydro-indolyl and oxadiazolyl substituted phenyl.

According to one embodiment, R³ is H. According to a separate embodiment, R³ is independently selected from alkyl of 1-6 carbon atoms, cycloalkyl of 3 to 8 atoms and monocyclic heteroaryl, said alkyl, branched alkyl, cyloalkyl and heteroaryl optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, NR⁵R⁵, -N(R⁵JR⁷OR⁵, -N(R⁵)R⁷NR^SR⁵ and heteroaryl.

According to one embodiment, R⁴ is H. According to a separate embodiment, R⁴ is independently selected from alkyl of 1-6 carbon atoms, cycloalkyl of 3 to 8 atoms and monocyclic heteroaryl, said alkyl, branched alkyl, cyloalkyl and heteroaryl optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵,

NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵JR⁷NR⁵R⁵ and heteroaryl. The compounds of this invention may be prepared from: (a) commercially available starting materials (b) known starting materials which may be prepared as described in literature procedures or (c) new intermediates described in the schemes and experimental procedures herein.

Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformation proposed. This may necessitate judgement as to the order of synthetic steps.

Compounds of the present invention may be prepared as illustrated in the examples and in following reaction Schemes 1 to 3:

Referring to Scheme 1 , the reaction of ketones of formula 1 , which are commercially available or can be synthesized by the methods described in U.S. Patent No. 5,459,131 , are reacted with acetals of N,N-dialkylformamides or acetals of N,N-dialkylacetamides, carried out in an inert solvent or without a solvent to yield enaminone compounds, namely 3-dialkylamino-2- propen-1 -ones of formula 2, wherein R³ and R⁴ are defined above. The reaction of the substituted 3-aminopyrazole of formula 3, where R¹ and R² are hydrogen or are defined above, with an appropriately substituted 3-dϊalkylaminα-2-propen-1-one in weak acid such as glacial acetic acid or in an inert solvent such as toluene, acetonitrile or dimethoxyethane, at reflux temperature for several hours, or without solvent at 50-150° C, provides the desired compounds of formula A. Compounds of formula B are prepared in an analogous manner from ketones of formula 1

1 wherein R is selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -NR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵JR⁷NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵JR⁷NR⁵R⁵ and -R⁶NR⁵R⁵; and R¹-R⁷ are as described above.

Compounds of the invention may also be synthesized according to the route shown in Scheme 2. Thus, an enaminone of formula 2, where R³ and R⁴ are defined above, can react with an aminopyrazole of formula 3a, where R¹ is defined above, in weak acid such as glacial acetic acid or in an inert solvent such as toluene, acetonitrile or dimethoxyethane, at reflux temperature for several hours, or without solvent at 50-150° C, to provide compounds of formula 4a and 4b. Compounds 4a and 4b can be separated, chromatographically or via recrystallization, and halogenated to afford the corresponding halo-pyrazole derivative using N- halosuccinimides at room temperature to 50° C in chlorinated hydrocarbon solvents to give either a compound of formula 5a or a compound of formula 5b. Alternatively, the mixture of compounds 4a and 4b can be halogenated under these conditions with subsequent separation of compounds 5a and 5b. The halopyrazole compounds 5a and 5b are subjected to palladium catalyzed coupling reactions with organometallic reagents R₂-M(L)_n where M is tin, zinc or other suitable metal. Additionally, Suzuki couplings with aryl or heteroaryl boronic acids or boronate esters can be carried out to provide the compounds of the invention.

Scheme 2

Substituted 3-dimethylamino-1-(3-heteroaryl)-2-propen-1-ones are disclosed in U.S. Patent Nos. 4,281,000 and 4,521 ,422 and 3-dialkylamino-1-phenyl-2-propen-1-ones are disclosed in U.S. Patent Nos. 4,178,449 and 4,236,005. Various 3-amino-4-pyrazoles are disclosed in U.S. Patent Nos. 4,236,005; 4,281,000; 4,521 ,422; 4,626,538; 4,654347; and 4,900,836.

Pyrazolo[1 ,5-a]pyrimidines are prepared by condensation of 3-aminopyrazoles and substituted 3-aminopyrazoles with 1 ,3-dicarbonyl compounds as described in J. Med. Chem., 18, 645 (1974); J. Med. Chem. 18, 460 (1975); J. Med. Chem., 20, 386 (1977); Synthesis, 673 (1982) and references contained therein.

Scheme 3

Additional aminopyrazole intermediates of formula 3 are available according to the route shown in Scheme 3. Referring to Scheme 3, the condensation reaction of substituted acetonitriles of formula 7, wherein R² is as defined above or hydrogen, with substituted esters of formula 6 can be carried out in the presence of a base such as, but not limited to sodium ethoxide, in a suitable solvent such as ethanol to provide intermediate compounds of formula 8. Intermediate compounds 8 can subsequently be reacted with hydrazine hydrate in a suitable solvent such as ethanol to provide aminopyrazole compounds of formula 3, where R¹ and R² are defined above. For certain substituted intermediate compounds of formula 8, it is necessary to first react with phosphorus oxychloride at elevated temperatures, typically at reflux, to provide intermediate compounds of formula 9. Intermediate compounds 9 can be converted to substituted aminopyrazole compounds 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol. Substituted ester compounds of formula 6 and substituted acetonitrile compounds of formula 7 can be obtained from commercial sources or readily prepared by numerous literature procedures by those skilled in the art.

The R¹- R⁴ substituents can be further modified by known methods by those skilled in the art to provide new substituents.

Exemplary compounds of formula A prepared by methods of the present invention include the following compounds:

The compounds of formula A or formula B may be obtained as inorganic or organic salts using methods known to those skilled in the art, for example Richard C. Larock,

Comprehensive Organic Transformations, VCH publishers, 411-415, 1989. It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydroscopicity and solubility.

Pharmaceutically acceptable salts of the compounds of formula A or formula B with an acidic moiety may be formed from organic and inorganic bases. For example with alkali metals or alkaline earth metals such as sodium, potassium, lithium, calcium, or magnesium or organic bases and N- tetraalkylammonium salts such as N-tetrabutylammonium salts. Similarly, when a compound of this invention contains a basic moiety, salts may be formed from organic and inorganic acids. For example salts may be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Suitable examples of pharmaceutically acceptable salts include, but are not limited, to sulfate; citrate, acetate; oxalate; chloride; bromide; iodide; nitrate; bisulfate; phosphate; acid phosphate; isonicotinate; lactate; salicylate; acid citrate; tartrate; oleate; tannate; pantothenate; bitartrate; ascorbate; succinate; maleate; gentisinate; fumarate; gluconate; glucaronate; saccharate; formate; benzoate; glutamate; methanesulfonate; ethanesulfonate; benzenesulfonate; p- toluenesulfonate; pamoate (i.e., 1 ,1'-methylene-bis-(2-hydroxy-3-naphthoate)); and salts of fatty acids such as caproate, laurate, myristate, palmitate, stearate, oleate, linoleate, and linolenate salts.The compounds can also be used in the form of esters, carbamates and other conventional prodrug forms, which when administered in such form, convert to the active moiety in-vivo.

The present invention accordingly provides a pharmaceutical composition, which comprises an effective amount of a compound of formula A or formula B in combination or association with a pharmaceutically acceptable carrier. The compounds are usefully employed in an amount to detectably inhibit Raf kinase activity and in treating diseases associated with Raf kinases. Pharmaceutical compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable. As used herein, the term "effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).

The compounds of this invention may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration. Suitable carriers include but are not limited to, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight. In some embodiments, the formulations are administered transdermal^ which includes all methods of administration across the surface of the body and the inner linings of body passages including epithelial and mucosal tissues. Such administration may be in the form of a lotion, cream, colloid, foam, patch, suspension, or solution.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is sometimes desirable.

In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.

The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt may be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer treated by compounds of the present invention include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non- small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatia cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer. For the treatment of cancer, the compounds of this invention may be administered in combination with other antitumor substances or with radiation therapy. These other substances or radiation treatments may be given at the same or at different times as the compounds of this invention. These combined therapies may effect synergy and result in improved efficacy. For example, the compounds of this invention may be used in combination with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cisplatin or cyclophosamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, and antiestrogens such as tamoxifen.

As used in accordance with this invention, the term an "effective amount" of a compound means either directly administering such compound, or administering a prodrug, derivative, or analog which will form an effective amount of the compound within the body.

Methods of administration of a pharmaceutical composition of the invention are not specifically restricted, and can be administered in various preparations depending on the age, sex, and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules may be orally administered. Injection preparations may be administered individually or mixed with injection transfusions such as glucose solutions and amino acid solutions intravenously. If necessary, the injection preparations are administered singly intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories may be administered into the rectum.

The amount of the compound of formula A or formula B contained in a pharmaceutical composition according to the present invention is not specifically restricted, however, the dose should be sufficient to treat, ameliorate, or reduce the targeted symptoms.

The dosage of a pharmaceutical composition according to the present invention will depend on the method of use, the age, sex, and condition of the patient.

The present invention also provides methods of inhibition and treatment further comprising administering an additional inhibitor of an oncoprotein kinase of the Ras/Raf/MEK pathway.

The pharmaceutical compositions of the present invention may comprise the compound of the present invention alone or in combination with other oncoprotein kinase- inhibiting compounds or chemotherapeutic agents. Chemotherapeutic agents include, but are not limited to exemestane, formestane, anastrozole, letrozole, fadrozole, taxane and derivatives such as paclitaxel or docetaxel, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g., doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, tamoxifen, raloxifen, Sugen SU-5416,

Sugen SU-6668, and Herceptin.

Having described the invention, the invention is further illustrated by the following non-limiting examples.

EXAMPLES

Reference Example 1: 4-[3-methoxy-phenyl]-5-pyridin-4-yl-1H-pyrazol-3-amine

Reference example 1

Step 1 : To a 5 mL solution of dry EtOH was added 0.73 g (31.84 mmol) of Na metal (after removal of mineral oil with hexane). The mixture was stirred, with heating at 45°C for 1 hour until the solution turned clear. A mixture of 3 g (20.38 mmol) of the 3- (methoxyphenyl)acetonitrile and 3.9 g (28.66 mmol) of methyl isonicotinate in 26 mL of dry EtOH was added and the resulting brown solution was heated under reflux for 3 hours. After cooling, the residue was evaporated and purified by silica gel chromatography 9:1 to 4:1 methylene chloride/methanol to provide 1.75 g (34%) of 2-(3-methoxyphenyl)-3-oxo-3-pyridin-4- yl-propionitrile (I).

Step 2: A mixture of 1.7 g (6.74 mmol) of 2-(3-methoxyphenyl)-3-oxo-3-pyridin-4-yl- propionitrile and 17 mL POCI₃ was heated at 80° C for 18 hours. After cooling, the POCI₃ was evaporated off. To the residue was added toluene, which was evaporated off to dryness. This step was repeated to fully remove POCI₃. Ice and saturated sodium bicarbonate was added to the residue, and a solid precipitated out, provided 1 g of 3-chloro-2-(3-methoxyphenyl)-3-pyridin- 4-yl-acrylonitrile (II) as a white solid (57%). MS 271.1 [M+H].

Step 3: A mixture of 1 g (3.69 mmol) of 3~chloro-2-(3-methoxyphenyl)-3-pyridin-4-yl- acrylonitrile and 0.9 mL (18.6 mmol) hydrazine hydrate in 30 mL of ethanol was heated to reflux for 6.5 hours. The mixture was allowed to cool to room temperature and solvent was removed by evaporation. Aqueous sodium bicarbonate was stirred into the residue, and the resulting solid was collected by filtration. The solid was washed with water, then dried under vacuum to provide 0.92 g (94%) of 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazo(-3-amine. MS 267.2 [M+H].

Reference Example 2: 4-(4-fIuoro~3-methoxyphenyl)-3-pyridin-4~yl-1H-pyrazαl-5- amine The compound 4-(4-fluoro-3-methoxyphenyl)-3-pyridin-4-yl-1 H-pyrazol-5-amine was prepared by the procedure of 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine (Reference Example 1 ). MS: [M+H] 285.2

Reference Example 3: 3-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)phenol

A mixture of 4-(3-methoxyphenyl)-5-pyridin-4-yl-1 H-pyrazol-3-amine (3.0 g, 11.27 mmol) and pyridine hydrochloride (6.0 g, 51.92 mmol) was heated at 202° C for 1 hour. After cooling to room temperature, the mixture was stirred with ammonium hydroxide for 0.5 hr, and then filtered. The solid was set aside and the filtrate was evaporated to dryness to yield a solid residue. The combined solids were washed with 15 % methanol in methylene chloride. Evaporation of the filtrate provided a crude residue that was purified by silica gel (12% methanol in methylene chloride) to yield 2.21 g (78%) of 3-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)phenol as a beige solid, mp, 162°-164° C. MS: [M+H] 253.2.

Reference Example 4: 4-(4-Chloro-3-methoxyphenyl)-5-pyridin-4-yl-1 H-pyrazol-3- amine

The compound 4-(4-Chloro-3-methoxyphenyl)-5-pyridin-4-yl-1 H-pyrazol-3-amine was prepared by the procedure of 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine (Reference example 1 ). MS: [M+H] 301.2.

Reference Example 5: 5-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)-2-chlorophenol

The compound 5-(3-Amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)-2-chlorophenol was prepared following the procedure of 3-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)phenol, by reacting 4-(4- chloro-3-methoxyphenyl)-5-pyridin-4-yl-1 H-pyrazol-3-amine with pyridine hydrochloride. Purification by silica gel chromatography provided 5-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)-2- chlorophenol as a beige solid in 77% yield, mp, 273°-274° C. MS: [M+H] 287.1

Example 1 : 3-[3-(3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N- dimethylbenzenesulfonamide

Step 1 : 3-acetyl-N,N-dimethylbenzenesulfonamide. The compound 3- acetylbenzene-1-sulfonyl chloride (2 g, 9.1 mmol) in acetonitrile (29 ml) was cooled to O⁰C. Dimethylamine hydrochloride (933 mg, 11.4 mmol, 1.25 eq) and N,N-diisopropylethyIamine (2.4 mL, 13.7 mmol, 1.5 eq) were added and the reaction was stirred at room temperature 48 hours. The solvent was evaporated and the residue purified by column chromatography (eluted with 40% ethyl acetate/hexane) to provide 526 mg (25%) of 3-acetyl-N,N- dimethylbenzenesulfonamide as a white solid. MS [M + H] 228.1.

Step 2: 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide

A mixture of 3-acetyl-N,N-dimethylbenzenesulfonamide (526 mg, 2.3 mmol) and N₁N- dimethylformamide dimethyl acetal (7.8 ml_) was heated to 100° C and maintained overnight. The mixture was cooled and then concentrated to provide 644 mg (99%) of 3-(3- (dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide as an orange solid. MS: [M+H] 283.1.

Step 3: 3-[3-(3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N- dimethylbenzenesulfonamide

A mixture of 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide (0.05 g, 0.18 mmol) and 3-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)phenol (0.048 g, 0.19 mmol) in glacial acetic acid 94.0 ml_) was heated at 80° C for 16 hours. The reaction was cooled to room temperature and allowed to stand for 24 hours. A yellow solid precipitated out that was filtered, then washed with 1 mL of acetic acid and dried in-vacuo to provide 47 mg (55% yield) of 3-[3-(3- hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N- dimethylbenzenesulfonamide as a yellow solid. MS: [M+H] 472.3.

Example 2: 3-(3-(3-hydroxyphenyl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N- methylbenzenesulfonamide

Step 1. 3-Acetyl-N-methylbenzenesulfonamide

To a slurry of 3-acetylbenzene-1-sulfonyl chloride (0.7 g, 3.202 mmol) in acetonitrile (1OmL) and diisopropyl ethyl amine (4.8 mmol, 0.671 mL) was added methylamine (2M THF, 1.6 mL) at 0° C. The reaction was stirred at 25° C over 19 hours. Solvent was removed in-vacuo and the resulted oil was purified by Biotage™ chromatography (cartridge 40s), eluent 1 :2 ethyl acetate (EtOAc)/hexane to afford 3-acetyl-N-methylbenzenesulfonamide as a white solid (0.630 g, 92 %). MS (+ESI): 214 [M+H].

Step 2. 3-(3-Dimethylamino-acryloyl)-N-methyl-benzenesulfonamide

The compound 3-Acetyl-N-methylbenzenesulfonamide (0.630 g, 2.95 mmol) was dissolved in DMF-DMA (10 ml_) and heated to 100⁰C. After 7 hours solvent was removed under reduced pressure to give a brown, viscous oil. The crude product was further purified by Biotage™ chromatography (cartridge 40s), eluent 1 :2 EtOAc/hexane, then 100% EtOAc to obtain 3-(3- dimethylamino-acryloyl)-N-methyl-benzenesulfonamlde as a light yellow oil (0.357 g, 51 %). MS (+ESI): 269 [M+H].

Step 3. 3-(3-(3-Hydroxyphenyl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N- methylbenzenesulfonamide

A solution of 3-(3-dimethylamino-acryloyl)-N-methyl-benzenesulfonamide (0.357 g, 1.33 mmol) in acetic acid (10 ml_) and 3-(5-amino-3-pyridin-4-yl-1 H-pyrazol-4-yl)-phenol (0.403 g, 1.59 mmol) was heated at 100⁰C over 19h. Solvent was removed in-vacuo. The crude oil (0.60 g) was diluted in ethyl acetate (10 ml_) and washed with saturated aqueous NaHCO₃ (2x, 5 mL), and brine (5 mL). The organic layer was dried over magnesium sulfate (MgSO₄), filtered, and then concentrated in-vacuo to yield a crude oil. This material was further purified by Biotage™ Flash chromatography (cartridge 40s), eluent 1 :2 EtOAc/hexane then 2:1 EtOAc/hexane and finally with 100 % ethyl acetate to provide 3-(3-(3-hydroxyphenyl)-2-(pyridin-4-yl)pyrazolo[1 ,5- a]pyrimidin-7-yl)-N-methylbenzenesulfonamide as a semi-solid (0.025g, 3.7 %). MS (+ESI): 458 [M+H].

Example 3: 3-[3-(4-fluoro-3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin- 7-yl]- N,N-dimethylbenzenesulfonamide

A mixture of 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesu!fonamide (0.19 g, 0.7 mmol) and 4-(4-fluoro-3-methoxyphenyl)-3-pyridin-4-yl-1 H-pyrazol-5-amine (0.4 g, 1.4 mmol) in glacial acetic acid 94.0 mL) was heated to 80° C for 1 hour. After allowing the mixture to cool, excess solvent was evaporated and the residue was stirred with saturated sodium bicarbonate solution. The solid was collected by filtration, washed with water and then dried. The crude product was purified by silica gel (3% methanol in methylene chloride) to yield 0.29 g (84%) of 3-[3-(4-fluoro- 3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide was obtained as a yellow solid. MS: [M+H] 504.3.

Example 4: 3-[3-(4-fluoro-3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7- yl]-N,N-dimethylbenzenesulfonamide

3-[3-(4-Fluoro-3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N- dimethylbenzenesulfonamide (0.194 g, 0.385 mmol) was suspended in 10 mL dichloromethane at room temperature. The mixture was cooled to 0° C and to it was added 4.5 mL of boron tribromide (BBr₃) (1M in dichloromethane). After stirring at 0° C for 1.5 hours, then the solvent was evaporated. The resultant crude residue was made basic with ice-cold saturated NaHCO₃. The solid was filtered, re-dissolved in dichloromethane, and purified by flash chromatography, eluting with a gradient of methanol/methylene chloride to provide 0.065 g of 3-[3-(4-fluoro-3- hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide as a yellow solid (35% yield). MS: [M+H] 495.4.

Example 5: 3-(3-(1H-indazol-4-yl)-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide

Step 1 : N,N-dimethyl-3-(2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7- yl)benzenesulfonamide

A mixture of 3-(3-(dimethylamino)aGryloyl)-N,N-dimethylbenzenesulfonamide (200 mg, 0.7 mmol) and 5-pyridin-4-yl-2H-pyrazol-3-ylamine (113 mg, 0.7 mmol) in glacial acetic acid (7 mL) was heated at 80° C for 3.5 hours. After allowing the mixture to cool, excess solvent was evaporated and the residue was stirred with saturated sodium bicarbonate solution. The solid was collected by filtration, washed with water and dried to yield 241 mg (91%) of N,N-dimethyl- 3-(2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)benzenesulfonarnide as a yellow/tan solid. MS: [M+H] 380.2.

Step 2: 3-(3-iodo-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide

To a solution of N,N-dimethyl-3-(2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7- yl)benzenesulfonamide (238 mg, 0.63 mmol) in chloroform (23 mL) was added N- iodosuccinimide (282 mg, 1.25 mmol, 2 eq). The reaction mixture was stirred at room temperature 1.5 hours then treated with additional N-iodosuccinimide (563 mg, 4 eq). The reaction mixture was stirred at room temperature 3 additional hours, diluted with chloroform, washed (2 x, saturated sodium thiosulfate solution), dried over magnesium sulfate, filtered and then concentrated. The resulting product was purified by silica gel chromatography (eluted with ethyl acetate) to provide 145 mg (46%) of 3-(3-iodo-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7- yl)-N,N-dimethylbenzenesulfonamide as a yellow solid. MS [M + H] 505.9.

Step 3: 3-(3-(1 H-indazol-4-yl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide

To a slurry of 3-(3-iodo-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide (145 mg, 0.29 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-indazole (207 mg, 0.85 mmol) and PdCI₂ (dppf) (47 mg, 0.058 mmol) in DME (3 mL) and water (1 mL) was added K₂CO₃ (79 g, 0.58 mmol). The reaction flask was evacuated and filled with nitrogen three times, then heated at 80° C overnight. The reaction mixture was cooled, diluted with methylene chloride, washed (2 x, with saturated sodium bicarbonate solution), then dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified by silica gel chromatography (2 columns, the first was eluted with ethyl acetate, then the second column was eluted with 2-5% methanol in methylene chloride) to provide 47 mg (33%) of 3-(3- (1 H-indazol-4-yl)-2-(pyridin-4-yl)pyrazoIo[1 ,5-a]pyrimidin-7-yl)-N,N-dimethylbenzenesulfonamide as a yellow solid. MS [M + H] 496.3..

Example 6: N-[2-(Dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Step 1 :3-acetyl-N-[2-(dimethylamino)ethyl]-N-methyIbenzenesulfonamide

The compound 3-acetylbenzene-1 -sulfonyl chloride (2.18 g, 10 mmol) was dissolved in 60ml of THF. To this was added N,N,N'-trimethylethylenediamine (1.02g, 10 mmol). The mixture was stirred for 18 hours. Then it was poured into a separator funnel with 40ml sodium bicarbonate (50% saturated, aqueous). The mixture was then extracted with 2 x 15OmL ethyl acetate. The combined organic layers were dried over magnesium sulfate. After filtering off the drying agent it yielded 2.84g (100%) of 3-acetyl-N-[2-(dimethylamino)ethyl]-N-methylbenzenesulfonamide. MS [M + H] 285.2.

Step 2: N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N- methylbenzenesulfonamide

Using the procedure of Example 1 , step 2, 1.69 g (5 mmol) of N-[2-(dimethylamino)ethyI]-3- [(2E)-3-(dimethylamino)prop-2-enoyl]-N-methylbenzenesulfonamide was prepared from the reaction of 1.42 g (5 mmol) of 3-acetyl-N-[2-(dimethylamino)ethyl]-N-methylbenzenesulfonamide with N,N-dimethylformamide dimethyl acetal. MS [M + H] 340.3.

Step 3: N-[2-(dimethyiamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Using the procedure of Example 1 , step 3, N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide (52% yield) was prepared by the reaction of N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2-enoyl]- N-methylbenzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H] 543.4.

Example 7: 3-(3-(1 H-indol-4-yl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyritnidin-7-yl)-N,N- dimethylbenzenesulfonamide

To a slurry of 3-(3-iodo-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide (150 mg, 0.297 mmol), 1 H-indol-4-ylboronic acid (96 mg, 0.594 mmol) and PdCI₂ (dppf) (17 mg, 0.02 mmol) in DME (3 mL) and water (1 ml) was added K₂CO₃ (82 mg, 0.59 mmol). The reaction flask was evacuated and filled with nitrogen three times, then heated at 80° C for 3 hours. The reaction mixture was cooled, diluted with methylene chloride, then washed (2 x, saturated sodium bicarbonate solution), dried over sodium sulfate, filtered and then concentrated. The crude reaction mixture was purified by column chromatography (eluted with 10% acetone in methylene chloride) to provide 43 mg (29%) of 3-(3-(1 H-indol-4-yl)- 2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N-dimethylbenzene-sulfonamide as a yellow solid. MS [M + H] 495.3.

Example 8: N,N-dimethyl-3-(3-(2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-4-yl)-2- (pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)benzene-sulfonamide

Step 1 : 3-Bromo-benzene-1 ,2-diamine

To a solution of 4-bromo-benzo[1 ,2,5]thiadiazole (1.15g, 5.35 mmol) in methanol (10 ml_) was added sodium borohydride (203 mg, 5.35 mmol) and cobalt chloride hexahydrate (120 mg, 0.533 mmol). The mixture was refluxed for 3 hours, cooled to room temperature and then filtered to remove the black solid. The solvent was evaporated, water (100 ml_) was added and the product was extracted with Et₂O (3 x, 30 mL). The combined organic extracts were dried over Na₂Sθ₄ and the solvent removed, resulting in the air-unstable 3-bromo-benzene-1 ,2- diamine (810 mg, 81% yield). MS: 187.0 [M+H].

Step 2: 4-Bromo-1 ,3-dihydro-benzoimidazol-2-one

To a solution of 3-bromo-benzene-1,2-diamine (810 mg, 4.33 mmol) in THF (10 mL) was added triphosgene (2.57 g, 8.66 mmol) and triethylamine (1.15 mL, 13 mmol). The mixture was heat at 50° C over night. The solvent was evaporated, water (60 mL) was added and the product was extracted with EtOAc (3 x, 30 mL). The combined organic extracts were dried over Na₂SO₄ and the solvent removed, followed by silica gel chromatography to provide 4-bromo-1 ,3-dihydro- benzoimidazol-2-one (701 mg) in 76% yield. MS: 211.0 [M-H].

Step 3: 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 ,3-dihydro-benzoimidazol- 2-one

To a solution of 4-bromo-1 ,3-dihydro-benzoimidazol-2-one (701 mg, 3.29 mmol) in dimethyl sulfoxide (2 ml_) was added potassium acetate (803 g, 10.9 mmol), 1,1'-bis(diphenyl phosphino) ferrocene palladium chloride (PdCI₂ (dppf)) (134 mg, 0.16 mmol) and bis(pinacolato) diboron (1.67 g, 6.58 mmol). The mixture was degassed and heated in a microwave oven for 30 minutes at 150 ⁰C. The solvent was filtered through a pad of celite, water (60 ml_) was added and the product was extracted with EtOAc (3 x, 30 ml_). The combined organic extracts were dried over Na₂SO₄ (sodium sulfate), and the solvent removed to provide crude 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-1 ,3-dihydro-benzoimidazol-2-one which was used without further purification.

Step 4: N,N-dimethyl-3-(3-(2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-4-yl)-2-(pyridin-4- yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)benzenesulfonarnide

To a microwave reaction vial was added 3-(3-iodo-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)- N,N-dimethylbenzenesulfonamide (72 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-benzo[d]imidazol-2(3H)-one (74 mg, 0.28 mmol) and PdCI₂ (dppf) (11.6 mg, 0.014 mmol) in DME (2.4 ml_) and K₂CO₃ (0.142 ml of 2M solution, 0.28 mmol). The reaction was irradiated in the microwave at 100⁰C for 30 minutes. Additional catalyst was added (PdCI₂ (dppf) 11.6 mg, 0.014 mmol) and reacted again at 100° C for 30 minutes. The reaction mixture was cooled, diluted with methylene chloride, washed (2 x, saturated sodium bicarbonate solution), dried over sodium sulfate, filtered and concentrated. The crude reaction mixture was purified by column chromatography (eluted with 10% acetone in methylene chloride then 5% methanol in methylene chloride). It was repurifled by column chromatography (eluted with ethyl acetate then 10% acetone in methylene chloride then 4% methanol in methylene chloride) to provide 35 mg (49%) of N,N-dimethyl-3-(3-(2-oxo-2,3-dihydro-1 H-benzo[d]imidazol- 4-yl)-2-(pyridin-4-yl)pyrazoIo[1 ,5-a]pyrimidin-7-yl)benzenesulfonamide as a yellow solid. MS [M + H] 512.2.

Example 9: 3-(3-(1 H-indol-6-yl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide

To a slurry of 3-(3-iodo-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide (145 mg, 0.287 mmol), 1 H-indol-6-ylboronic acid (92 mg, 0.57 mmol) and PdCI₂ (dppf) (23 mg, 0.02 mmol) in DME (3 mL) was added K₂CO₃ (0.287 ml of a 2M solution, 0.57 mmol). The reaction flask was evacuated and filled with nitrogen three times then heated at 80° C for 4 hrs and left at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed (2 x saturated sodium bicarbonate solution), dried over sodium sulfate, filtered and then concentrated. The crude reaction mixture was purified by column chromatography (eluted with 10% acetone in methylene chloride) to provide 66 mg (46%) of 3-(3-(1 H-indol-6-yl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide as a yellow solid. MS [M + H] 495.3.

Example 10: 3-[3-(7-methoxy-1 H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide

Step 1: 1-bromo-4-methoxy-2-methyl-3-nitrobenzene

A mixture of 3-methyl-2-nitroanisole (1.13g, 6.76 mmol) and bromine (0.38 ml_, 7.35 mmol) in acetic acid (6mL) was stirred at room temperature overnight. The mixture was poured on to ice and solid was collected by filtration, washed with water and dried to yield 1.64 g (98%) of 1- bromo-4-rnethoxy-2-methyl-3-nitrobenzene as a white solid. MS: [M+H] 247.1.

Step 2: 3-brorno-6-methoxy-2-methylaniline

To a hot mixture of iron powder (2.16 g, 38.7 mmol), ammonium chloride (3.1 g, 58.02 mmol) and water (18 mL) in ethanol (50 ml_) was added 1-bromo-4-methoxy-2-methyl-3-nitrobenzene in portions over a period of 10 minutes. The resulting mixture was heated under reflux for 1 hour, then filtered hot through a pad of Celite™, washed with ethanol and ethyl acetate. The filtrate was evaporated to remove organic solvents, and the remaining residue was extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate provided 1.93 g (92%) of 3-bromo-6-methoxy-2- methylaniline as a white solid. MS: [M+H] 216.

Step 3: 4-bromo-7-methoxy-1 H-indazole

To a cold (0-5° C) solution of 3-bromo-6-methoxy-2-methylaniline (1.89 g, 8.75 mmol) in chloroform (20 mL) acetic anhydride was added dropwise (1.9 ml_, 20.14 mmol), followed by stirring for 5 minutes. The resulting mixture was allowed to warm to room temperature and then stirred for 1 hour. Potassium acetate (0.26g, 2.65 mmol) and isoamyl nitrite (2.53 mL, 18.83 mmol) were subsequently added, then the mixture was heated under reflux for 20 hours. After cooling to room temperature, solvent was evaporated to yield a brown solid. This solid was diluted with water, which was removed by evaporation to provide a solid residue. To the residue was added concentrated hydrochloric acid, and the resulting mixture was then heated at 50° C for 2 hours. The mixture was then cooled in an ice bath, and basified to pH 14 with a 50% potassium hydroxide solution. The solid was collected by filtration, washed with water, then dried in-vacuo and purified by silica gel chromatography to yield 1.75 g (88%) of 4-bromo-7- methoxy-1 H-indazole as a white solid. MS: [M+H]⁺ 227.0.

Step 4: 7-Methoxy-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-indazole

To a solution of 4-bromo-7-methoxy-1 H-indazole (0.7 g, 3.08 mmol) in DMSO (7ml_) was added potassium acetate (1.21 g, 12.3 mmol), 1 ,1 '-bis(diphenyl phosphino) ferrocene palladium chloride (0.076g, 0.093 mmol) and bis(pinacolato) diboron (0.95g, 3.74 mmol). The mixture was degassed and heated in microwave oven at 120° C for 3 hours. The solvent was filtered through a pad of celite, water (60 mL) was added and the mixture was then extracted with ethyl acetate. The ethyl acetate extracts were dried over anhydrous sodium sulfate, then filtered and the solvent was evaporated to dryness to yield a crude residue. Following purification by silica gel chromatography 7-Methoxy-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-indazole was obtained as a yellow foam in 38% yield. MS: [M+H] 275.1.

Step 5: 3-[3-(7-Methoxy-1 H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide

To a mixture of 7-methoxy-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-indazole (0.15 g, 0.297 mmol) in DME (2.5 mL) was added 3-(3-iodo-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl)- N,N-dimethylbenzenesulfonamide (0.13 g, 0.47 mmol), 1 ,1 '-bis(diphenyl phosphino) ferrocene palladium chloride (0.073g, 0.09 mmol) and solution of 2M sodium carbonate (0.6 mL). The mixture was degassed and heated in microwave oven at 100° C for 1.5 hours. The solvent was filtered through a pad of celite, water (60 mL) was added and the product was extracted with methylene chloride. The methylene chloride extract was dried over anhydrous Na₂SO₄ and the solvent was then evaporated to dryness to yield a crude residue. Following purification by reverse phase high performance liquid chromatography, RP-HPLC, 3-[3-(7-methoxy-1 H-indazol- 4-yl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide was obtained as an orange solid in 24% yield. MS: [M+H] 526.1

Example 11 : N-[2-(dimethylamino)ethyI]-3-[3-(3-methoxyphenyI)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonam!de

Step 1 : 3-acetyl-N-[2-(dimethylamino)ethyl]benzenesulfonamide

Using the procedure of Example 6, step 1 , 3-acetyl-N-[2- (dimethylamino)ethyl]benzenesulfonamide was prepared from the reaction of 3-acetylbenzene- 1-sulfonyl chloride with N,N-dimethyethylenediamine in 50% yield. MS: [M+H] 271.1.

Step 2: N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2- enoyljbenzenesulfonamide

To a solution of 3-acetyl-N-[2-(dimethylamino)ethyl]benzenesulfonamide (1.35g, 5 mmol) in 50 ml DMF was added 1 ,1-di-tert-butoxy-N,N-dimethylmethanamine (2.5g, 12 mmol). The mixture was heated to reflux for 6 hours. The solvent was removed by distillation to provide 1.6 g (5 mmol) of N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2- enoyljbenzenesulfonamide. MS: [M+H] 326.2. Step 3: N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide

Using the procedure of Example 1 , step 3, N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (65% yield) was prepared by the reaction of N-[2-(dimethylamino)ethyl]-3-[(2E)-3-(dimethylamino)prop-2- enoyljbenzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H] 529.2.

Example 12: N-[2-(dimethylamino)ethyl]-3-[3-(3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide

Using the procedure of Example 4, N-[2-(dimethylamino)ethyl]-3-[3-(3-hydroxyphenyl)-2-pyridin- 4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (58% yield) was prepared from the reaction of N-[2-(dimethyIamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4-yIpyrazolo[1 ,5- a]pyrimidin-7-yl]benzenesulfonamide with boron tribromide. MS [M + H] 515.3.

Example 13: N-[3-(dimethyIamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide

Step 1 : 3-acetyl-N-[3-(dimethylamino)propyl]benzenesulfonamide

Using the procedure of Example 6, step 1 , 3-acetyl-N-[3- (dimethylamino)propyl]benzenesulfonamide was prepared from the reaction of 3-acetylbenzene- 1-sulfonyl chloride with N,N-dimethyl-1 ,3-propanediamine in quantitative yield. MS: [M+H] 285.2.

Step 2: 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3(dimethylamino)propyl]- benzenesulfonamide

Using the procedure of Example 11, step 2, 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N- [3(dimethylamino)propyl]-benzenesulfonamide was prepared from the reaction of 3-acetyl-N-[3- (dimethylamino)propyl]benzenesulfonamide with 1 ,1-di-tert-butoxy-N,N-dimethylmethanamine in quantitative yield. MS [M + H] 340.2.

Step 3: N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide

Using the procedure of Example 1 , step 3, N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyI)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (75% yield) was prepared by the reaction of 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3(dimethylamino)propyl]- benzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H] 543.3.

Example 14: N-[3-(dimethylamino)propyl]-3-[3-(3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide

Using the procedure of Example 4, N-[3-(dimethylamino)propyl]-3-[3-(3-hydroxyphenyl)-2- pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (72% yield) was prepared from the reaction of N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]benzenesulfonamide with boron tribromide. MS [M + H] 529.3.

Example 15: N-[2-(dimethylamino)ethyl]-3-[3-(3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Using the procedure of Example 4, N-[2-(dimethylamino)ethyl]-3-[3-(3-hydroxyphenyl)-2-pyridin- 4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide (85% yield) was prepared from the reaction of N-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]-N-methylbenzenesulfonamide with boron tribromide. MS [M + H] 529.4.

Example 16: N-(3-hydroxypropyI)-3-[3-(3-rnethoxyphenyl)-2-pyridirt-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide Step 1 : 3-acetyI-N-(3-hydroxypropyI)benzenesulfonamide

Using the procedure of Example 6, step 1 , 3-acetyI-N-(3-hydroxypropyl)benzenesuIfonamide was prepared from the reaction of 3-acetylbenzene-1-sulfonyI chloride with 3-aminopropan-1-ol in 90% yield. MS: [M-H] 256.1.

Step 2: 3-[(2E)-3-(dimethylamino)prop-2-enoyI]-N-(3-hydroxypropyI)- benzenesulfonamide

Using the procedure of Example 11 , step 2, 3-[(2E)-3-(dimethy!amino)prop-2-enoy!]-N-(3- hydroxypropy!)-benzenesu!fonamide was prepared from the reaction of 3-acetyI-N-(3- hydroxypropy!)benzenesu!fonamide with 1 ,1-di-tert-butoxy-N,N-dimethyImethanamine in 86% yield. MS [M + H] 313.2.

Step 3: N-(3-hydroxypropyI)-3-[3-(3-methoxyphenyI)-2-pyridin-4-yIpyrazoIo[1 ,5- a]pyrimidin-7-yI]benzenesulfonamide

Using the procedure of Example 1 , step 3, N-(3-hydroxypropyl)-3-[3-(3-methoxyphenyl)-2- pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (4% yield) was prepared by the reaction of 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-(3-hydroxypropyl)-benzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1H-pyrazol-3-amine. MS [M + H] 516.3.

Example 17: 3-[3-(3-Methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide

Using the procedure of Example 1 , step 3, 3-[3-(3-Methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]-N,N-dimethylbenzenesulfonamide (63% yield) was prepared by the reaction of 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide with 4-[3-methoxyphenyl]-5- pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H 486.1.

Example 18: N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Step 1 : 3-Acetyl-N-(3-dimethylaminopropyl)-N-methyl-benzenesulfonamide

Using the procedure of Example 6, step 1 , 3-acetyl-N-(3-dimethylaminopropyl)-N-metriyl- benzenesulfonamide was prepared from the reaction of 3-acetylbenzene-1-sulfonyl chloride with N,N,N'-trimethylpropane-1 ,3-diarnine in quantitative yield. MS: [M+H] 298.9.

Step 2: 3-f(2E)-3-(dimethylamino)prop-2-enoyl]-N-f3-(dimethylamino)propyl]-N- methylbenzenesulfonamide

Using the procedure of Example 1 , step 2, 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3- (dimethylamino)propyl]-N-methylbenzenesulfonamide was prepared from the reaction of 3- acetyl-N-(3-dimethylaminopropyl)-N-methyl-benzenesulfonamide with N,N-dimethylformamide dimethyl acetal in quantitative yield. MS [M + H] 354.3.

Step 3: N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolof1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Using the procedure of Example 1 , step 3, N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)- 2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzene-sulfonamide (95% yield) was prepared by the reaction of 3-f(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3-(dimethylamino)propyl]- N-methylbenzene-sulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H 557.2.

Example 19: 3-[3-(4-Chloro-3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]-N,N-dimethylbenzenesulfonarnide

Using the procedure of Example 1 , step 3, 3-[3-(4-chloro-3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N-dimethylbenzenesulfonamide (31% yield) was prepared by the reaction of 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide with 4-(4-chloro- 3-methoxyphenyl)-5-pyridin-4-yl-1H-pyrazol-3-amine. MS [M + H] 520.0.

Example 20: 3-[3-(4-Chloro-3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]-N,N-dimethylbenzenesulfonamide

Using the procedure of Example 1 , step 3, 3-[3-(4-chloro-3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N,N-dimethylbenzenesulfonamide (60% yield) was prepared by the reaction of 3-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzenesulfonamide with 5-(3-amino- 5-pyridin-4-yl-1 H-pyrazol-4-yl)-2-chlorophenol. MS [M + H] 506.2.

Example 21 : N-(3-hydroxypropyl)-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

A mixture of N-(3-hydroxypropyl)-3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin- 7-yl]benzenesulfonamide (100 mg, 0.19 mmol) , 1 ml of dlmethylformamide dimethyl acetal, and 20 ml of DMF was heated to reflux and maintained for 6 hours. The solvent was removed by vacuum distillation under water aspirator pressure, and the resulting residue was partitioned between 2 x 10OmL ethyl acetate and 10OmL water. The combined organic layers were dried over magnesium sulfate. Filtration and then concentration gave 100 mg (97% yield) of N-(3- hydroxypropyl)-3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N- methylbenzenesulfonamide. MS [M + H] 530.2.

Example 22: N-[3-(1 H-imidazol-1-yl)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Step 1 : 3-acetyl-N-[3-(1 H-imidazol-1-yl)propyl]benzenesulfonamide

Using the procedure of Example 6, step 1 , 3-acetyl-N-[3-(1H-imidazol-1- yl)propyl]benzenesulfonamide was prepared from the reaction of 3-acetylbenzene-1-sulfonyl chloride with 3-imidazol-1-yl-propylamine in quantitative yield. MS: [M+H] 308.1.

Step 2: 3-[(2E)-3-(Dimethylamino)prop-2-enoyl]-N-[3-(1 H-imidazol-1-yl)propyl]-N- methylbenzenesulfonamide Using the procedure of Example 1 , step 2, 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3-(1H- imidazol-1-yl)propyl]-N-methylbenzenesulfonarnide was prepared from the reaction of 3-acetyl- N-[3-(1 H-imidazol-1-yl)propyl]benzenesulfonamide with N,N-dimethylformamide dimethyl acetal in 97% yield. MS [M + H] 377.2.

Step 3: N-[3-(1 H-imidazol-1-yl)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Using the procedure of Example 1 , step 3, N-[3-(1 H-imidazol-1-yl)propyl]-3-[3-(3- methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzene-sulfonamide (98% yield) was prepared by the reaction of 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-N-[3-(1H- imidazol-1-yl)propyl]-N-methylbenzene-sulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H- pyrazol-3-amine. MS [M + H] 580.3.

Example 23: N-[3-(dimethylamino)propyl]-3-[3-(3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzenesulfonamide

Using the procedure of Example 4, N-[3-(dimethylamino)propyl]-3-[3-(3-hydroxyphenyl)-2- pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-N-methylbenzene-sulfonamide (28% yield) was prepared from the reaction of N-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]-pyrimidin-7-yl]-N-methylbenzenesulfonamide with boron tribromide. MS [M + H] 543.4. Example 24: N-[2-(diethyIamino)ethyl]-N-ethyl-3-[3-(3-methoxyphenyl)-2-pyridin- 4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide

Step 1 : 3-acetyl-N-(2-(diethylamino)ethyl)-N-ethylbenzenesulfonamide

Using the procedure of Example 6, step 1 , 3-acetyl-N-(2-(diethylamino)ethyl)-N- ethylbenzenesulfonamide was prepared from the reaction of 3-acetylbenzene-1-sulfonyl chloride with N,N,N'-triethylethylenediamine in 89% yield. MS: [M+H] 327.2.

Step 2: N-(2-(diethylamino)ethyl)-3-(3-(dimethylamino)acryloyl)-N- ethylbenzenesulfonamide

Using the procedure of Example 1 , step 2, N-(2-(diethylamino)ethyl)-3-(3- (dimethylamino)acryloyl)-N-ethylbenzenesulfonamide was prepared from the reaction of 3- acetyl-N-(2-(diethylamino)ethyl)-N-ethylbenzenesulfonamide with N,N-dimethylformamide 5 dimethyl acetal in 90% yield, MS [M + H] 382.1.

Step 3: N-[2-(diethylamino)ethyl]-N-ethyl-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonarnide

Using the procedure of Example 1 , step 3, N-[2-(diethylamino)ethyl]-N-ethyl-3-[3-(3- methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (73% yield)0 was prepared by the reaction of N-(2-(diethylamino)ethyl)-3-(3-(dimethylamino)acryloyl)-N- ethylbenzenesulfonamide with 4-[3-methoxyphenyl]-5-pyridin-4-yl-1 H-pyrazol-3-amine. MS [M + H] 585.5.

Example 25: N-[2-(diethylamino)ethyl]-N-ethyl-3-[3-(3-hydroxyphenyl)-2-pyridin- 4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide

Using the procedure of Example 4, N-[2-(diethylamino)ethyl]-N-ethyl-3-[3-(3-hydroxyphenyl)-2-0 pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide (76% yield) was prepared from the reaction of N-[2-(diethylamino)ethyl]-N-ethyl-3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]benzenesulfonamide with boron tribromide. MS [M + H] 571.4.

STANDARD BIOLOGICAL AND PHARMALOGICAL TEST PROCEDURES

Evaluation of representative compounds of this invention in standard pharmacological test procedures indicated that the compounds of this invention possess significant anticancer activity and are inhibitors of Raf kinase. Based on the activity shown in the standard pharmacological test procedures, the compounds of this invention are therefore useful as antineoplastic agents. In particular, these compounds are useful in treating, inhibiting the growth of, or eradicating neoplasms such as those of the breast, kidney, bladder, thyroid, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, liver, prostate and skin. Compounds of the invention are useful as anti-inflammation agents and possess activity against inflammation associated with Raf kinases.

TESTING FOR RAF KINASE INHIBITORS

Compounds of formula A or formula were tested as Raf Kinase inhibitors for B-Raf kinase, mutant B-Raf kinase and C-Raf kinase, which are associated with inhibiting growth of tumor cells containing oncogenic forms of Receptor Yrosine Kinases, K-Ras and Raf kinases.

B-RAF KINASE:

B-RAF KINASE: Reagents: Flag/GST-tagged recombinant human B-Raf produced in Sf9 insect cells, human non-active Mek-1-GST (recombinant protein produced in E. coli); and a phospho-MEK1 specific poly-clonal Ab from Cell Signaling Technology (Cat. #9121).

TESTING FOR B-RAF KINASE INHIBITORS

B-Rafl Kinase Assay Procedure: B-Raf-1 is used to phosphorylate GST-MEK1. MEK1 phosphorylation is measured by a phospho-specific antibody (from Cell Signaling Technology, Cat. #9121) that detects phosphorylation of two serine residues at positions 217 and 221 on MEKL

The following Kinase Assay Protocol was employed in accordance with the invention:

B-Raf Assay Stock Solutions:

1. Assay Dilution Buffer (ADB): 20 mM MOPS, pH 7.2, 25 mM β-glycerol phosphate, 5mM EGTA, 1 mM sodium orthovanadate, 1mM dithiothreitol, 0.01% Triton X-100.

2. Magnesium/ATP Cocktail: ADB solution (minus Triton X-100) plus 200 μM cold ATP and 40 mM magnesium chloride.

4. Active Kinase: Active B-Raf: Used at 0.2 nM per assay point. 5. Non-active GST-MEK1 : Used at 2.8 nM final concentration).

6. TBST - Tris (50 mM, pH 7.5), NaCI (150 mM), Tween-20 (0.05 %)

7. Anti-GST Ab (GE)

8. Anti pMEK Ab (Upstate)

9. Anti-rabbit Ab / Europium conjugate (Wallac).

B-RAF ASSAY PROCEDURE:

1. Added 25 μL of ADB containing B-Raf and Mek per assay (i.e. per well of a 96 well plate)

2. Added 25 μL of 0.2 mM ATP and 40 mM magnesium chloride in Magnesuium/ATP Cocktail.

3. Incubated for 45 minutes at RT with occasional shaking.

4.Transfered this mixture to an anti-GST Ab coated 96 well plate (Nunc lmmunosorb plates coated o/n with a-GST. Plate freshly washed 3 x with TBS-T before use.

5. Incubated o/n at 30⁰C in cold room.

6. Washed 3 x with TBST, ed Anti-Phospho MEK1 (1:1000, dilution depended upon lot)

7. Incubated for 60 minutes at RT in a shaking incubator

8. Washed 3 x with TBST, add Anti-rabbit Ab / Europium conjugate (Wallac) (1 :500, dilution depended upon lot)

9. Incubated for 60 minutes at RT on a platform shaker.

10. Washed plate 3 x with TBS-T

11. Added 100 μL of Wallac Delfia Enhancement Solution and agitated for 10 minutes. 12. Read plates in Wallac Victor model Plate Reader.

13. Collected data and analyzed for single point and IC_5O determinations as described by Mallon R., et al. (2001) Anal. Biochem. 294:48.

TESTING FOR C-RAF KINASE INHIBITORS

Assayed in a Raf-MEK-MAP kinase cascade assay as described previously (Mallon

R, et al (2001) Anal. Biochem. 294:48.), except that C-Raf kinase was purchased from Upstate, Lake Placid, NY and used at a concentration of 0.215 nM per assay point.

TESTING FOR MUTANTS OF B-RAF KINASE INHIBITORS

Assayed in a Raf-MEK-MAP kinase cascade assay as described previously (Mallon R, et al (2001 ) Anal. Biochem. 294:48.), except that B-Raf kinase mutants (V600 E) were used.

ANALYSIS OF RESULTS:

B-Raf IC₅₀ determinations were performed on compounds of formula A from single point assays with > 80 % inhibition. Single point assay: % inhibition at 10 mg/mL (% inhibition = 1 - sample treated with compound of Formula A/ untreated control sample). The % inhibition was determined for each compound concentration. IC₅₀ determinations - Typically the B-Raf assay was run at compound concentrations from 1μM to 3 nM or 0.1 μM to 300 pM in half log dilutions.

Compounds of formula A exhibited IC₅₀ values rangng from 1μM to 0.1 nM, indicating that the compounds are effective inhibitors of B-Raf kinase, mutant B-Raf kinase and C-Raf kinase.

B-Raf IC₅₀ Data for compounds of Formula A

0

AM1 011 1

.00

AM103 T1

0.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula:

and pharmaceutically acceptable salts thereof;

wherein

R is selected from H, -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -NR⁵R⁵, -OR⁷OR⁵, - OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵JR⁷OR⁵, -R⁶N(R⁵)R⁷NR⁵R⁵ and -R⁶NR⁵R⁵;

-) R¹ is a 5-7 membered heterocyclyl ring or heteroaryl ring, said ring comprising 1-3 heteroatoms

O selected from N, O and S, and said ring optionally substituted with one to two substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, -S(O)_mNR⁵R⁵, -

NR⁵R⁵, -NR⁵S(O)_mR⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵, -NR⁵C(O)R⁵, -

C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -OC(O)NR⁵R⁵, -NR⁵C(O)R⁵, -

NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -

5 R⁶N(R⁵)R⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶S(O)_mNR⁵R⁵, -R⁶C(O)R⁵, -R⁶C(O)OR⁵, -

R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶NR⁵S(O)₀₁R⁵, -R⁶OC(O)NR⁵R⁵, -R⁶NR⁵C(O)R⁵, -

R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵;

R² is a monocyclic aryl ring, a 6-14 membered monocyclic or bicyclic heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, monocyclic heterocyclyl ring comprising 1-4 0 heteroatoms selected from N, O and S, said ring optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, -NR⁵R⁵, -NR⁵S(O)_mR⁵, -S(O)_mNR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵JR⁷NR⁵R⁵, -NR⁵C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -OC(O)NR⁵R⁵, NR⁵C(O)R⁵, - NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -5 R⁶N(R⁵)R⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R^βS(O)_mR⁵, -R⁶NR⁵S(O)_mR⁵, -R⁶S(O)₁₁₁NR⁵R⁵, -R⁶C(O)R⁵, - R⁶C(O)OR⁵, -R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶OC(O)NR⁵R⁵, -R⁶NR⁵C(O)R⁵, -

R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵;

R³ and R⁴ are each independently selected from H, alkyl of 1-8 carbon atoms, cycloalkyl of 3 to 8 atoms and a 5-7 membered monocyclic heteroaryl, said alkyl, cyloalkyl and heteroaryl, optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵ and heteroaryl;

R⁵ is independently selected from H, alkyl of 1-6 carbon atoms, branched alkyl of 3-8 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, frans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms and cycloalkyl of 3-7 carbons; wherein the two R⁵ substituents in NR⁵R⁵ optionally join to

O form a substituted ring comprising 2-7 carbon atoms, or a substituted 5 to 8 atom ring comprising one to two additional heteroatoms selected from O, N and S(O)_n,;

R⁶ is a divalent group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms;

R⁷ is a divalent alkyl group of 2-6 carbon atoms;

5 J is fluoro, chloro, bromo, or iodo; and

m is an integer of 0-2.

2. The compound of claim 1 , wherein R¹ is 4-pyridinyl or 4-morpholinyl, optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -

S(O)_mR⁵, -NR⁵R⁵, -NR⁵S(O)_mR⁵, -S(O)_mNR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -

N(R⁵JR⁷NR⁵R⁵, -NR⁵C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -

OC(O)NR⁵R⁵, NR⁵C(O)R⁵, -NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵JR⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶NR⁵S(O)_mR⁵, -R⁶S(O)_mNR⁵R⁵, - R⁶C(O)R⁵, -R⁶C(O)OR⁵, -R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶OC(O)NR⁵R⁵, - R⁶NR⁵C(O)R⁵, -R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵.

3. The compound of claim 2, wherein R² is an aryl ring or a bicyclic ring of formula

where ^■in Θ ^- ^ refers to a 5-7 membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, said ring optionally substituted with one to four substituents selected from -J, - NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁵, -OR⁵, -S(O)_mR⁵, -NR⁵R⁵, -NR⁵S(O)_mR⁵, -S(O)_mNR⁵R⁵, - OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, -N(R⁵)R⁷NR⁵R⁵, -NR⁵C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, - C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, -OC(O)NR⁵R⁵, NR⁵C(O)R⁵, -NR⁵C(O)OR⁵, - NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵JR⁷NR⁵R⁵, - R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶NR⁵S(O)_mR⁵, -R⁶S(O)_mNR⁵R⁵, -R⁶C(O)R⁵, -R⁶C(O)OR⁵, - R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶OC(O)NR⁵R⁵, -R⁶NR⁵C(O)R⁵, -R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵.

4. The compound of claim 2, wherein R² is a phenyl ring or an indazolyl ring, optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, - R⁵, -OR⁵, -S(O)_mR⁵, -NR⁵R⁵, -NR⁵S(O)_mR⁵, -S(O)₀₁NR⁵R⁵, -OR⁷OR⁵, -OR⁷NR⁵R⁵, -N(R⁵)R⁷OR⁵, - N(R⁵)R⁷NR⁵R⁵, -NR⁵C(O)R⁵, -C(O)R⁵, -C(O)OR⁵, -C(O)NR⁵R⁵, -OC(O)R⁵, -OC(O)OR⁵, - OC(O)NR⁵R⁵, NR⁵C(O)R⁵, -NR⁵C(O)OR⁵, -NR⁵C(O)NR⁵R⁵, -R⁶OR⁵, -R⁶OR⁷OR⁵, -R⁶OR⁷NR⁵R⁵, -R⁶N(R⁵)R⁷OR⁵, -R⁶N(R⁵)R⁷NR⁵R⁵, -R⁶NR⁵R⁵, -R⁶S(O)_mR⁵, -R⁶NR⁵S(O)₀₁R⁵, -R⁶S(O)_mNR⁵R⁵, - R⁶C(O)R⁵, -R⁶C(O)OR⁵, -R⁶C(O)NR⁵R⁵, -R⁶OC(O)R⁵, -R⁶OC(O)OR⁵, -R⁶OC(O)NR⁵R⁵, - R⁶NR⁵C(O)R⁵, -R⁶NR⁵C(O)OR⁵ and -R⁶NR⁵C(O)NR⁵R⁵.

5. A compound selected from 3-[3-(3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7- yl]-N,N-dimethylbenzenesulfonamide, 3-(3-(3-hydroxyphenyl)-2-(pyridin-4-yl)pyrazolo[1 ,5- a]pyrimidin-7-yl)-N-methylbenzenesulfonamide, 3-[3-(4-fluoro-3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide, 3-[3-(4-fluoro-3- hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]- N,N-dimethylbenzenesulfonamide,

3-(3-(1H-indazol-4-yl)-2-(pyridin-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)-N,N- dimethylbenzenesulfonamide, A/-[2-(dimethylamino)ethyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-A/-methylbenzene-sulfonamide, 3-[3-(1H-indol-4-yl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-Λ/,/V-dimethylbenzenesulfonamide, Λ/,Λ/-dimethyl-3-[3-(2-oxo-2,3- dihydro-1/-/-benzimidazol-4-yl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzene-sulfonamide,

3-[3-(1H-indol-6-yl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-Λ/,/V- dimethylbenzenesulfonamide, 3-[3-(7-methoxy-1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]-W,Λ/-dimethylbenzenesulfonamide, /V-[2-(dimethylamino)ethyl]-3-[3-(3- methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide, N-[Z-

(dimethylamino)ethyl]-3-[3-(3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7- yljbenzenesulfonamide, A/-[3-(dimethylamino)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide, Λ/-t3-(dimethylamino)propyl]-3-[3-(3- hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide, Λ/-[2-

(dimethylamino)ethyl]-3-[3-(3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-A/- methylbenzenesulfonamide, A/-(3-hydroxypropyl)-3-[3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolot1 ,5-a]pyrimidin-7-yl]benzenesulfonamide, 3-t3-(3-methoxyphenyl)-2-pyridin-4- ylpyrazolot1 ,5-a]pyrimidin-7-yl]-Λ/,A/-dimethylbenzenesulfonamide, Λ/-[3-(dimethylamino)propyl]- 3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolot1 ,5-a]pyrimidin-7-yl]-Λ/- methylbenzenesulfonamide, 3-[3-(4-chloro-3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5- a]pyrimidin-7-yl]-Λ/,A/-dimethylbenzenesulfonamide, 3-[3-(4-chloro-3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-Λ/,A/-dimethylbenzenesulfonamide, Λ/-(3-hydroxypropyl)-3-[3-(3- methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-Λ/-methylbenzenesulfonamide, A/-[3- (1/-/-imidazol-1-yl)propyl]-3-[3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-Λ/- methylbenzenesulfonamide, A/-[3-(dimethylamino)propyl]-3-t3-(3-hydroxyphenyl)-2-pyridin-4- ylpyrazolo[1 ,5-a]pyrimidin-7-yl]-W-methylbenzenesulfonamide, Λ/-[2-(diethylamino)ethyl]-Λ/-ethyl- 3-t3-(3-methoxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7-yl]benzenesulfonamide, A/-[2- (diethylamino)ethyl]-Λ/-ethyl-3-[3-(3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1 ,5-a]pyrimidin-7- yljbenzenesulfonamide and pharmaceutically acceptable salts thereof.

6. A method for making a compound of claim 1 , comprising the steps of:

(a) reacting a substituted ketone of formula 1

1 with an acetal of N,N-dialkylformamide or an acetal of N,N-dialkylacetamide to provide a enaminone compound of formula 2

² ; and

(b) reacting the enaminone compound of formula 2 with a substituted 3-aminopyrazole of formula 3

7. A method for making a compound of claim 1 , comprising the steps of:

(a) reacting an enaminone compound of formula 2

2 with an aminopyrazole compound of formula 3a

to provide compounds of formula 4a and 4b

(b) halogenating one or both of the compounds of formula 4a and 4b to provide one or both of compounds of formula 5a and 5b

5a

+

(c) subjecting one or both of the compounds of formula 5a and 5b to a palladium catalyzed, Suzuki coupling with R²-aryl or heteroaryl boronic acids or corresponding R²-boronate esters,

8. The method according to claim 7, wherein the compounds of formula 4a and 4b are separated prior to step (b).

9. The method according to claim 7, wherein the compounds of formula 5a and 5b are separated prior to step (c).

10. The method according to claim 7, wherein the compounds are separated after step (c).

11. A pharmaceutical composition comprising a compound according to any of claims 1-5 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound according to any of claims 1-5 in combination with other kinase-inhibiting pharmaceutical compositions or chemotherapeutic agents, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claims 11 or 12, capable of inhibiting Raf kinase

14. A method of treating a disease associated with inhibiting Raf kinase activity in a mammal comprising administering to the mammal a kinase-inhibiting amount of a compound according to any one of claims 1-5.

15. The method of claim 14, wherein the disease is associated with a B-Raf kinase-dependent condition, a mutant B-Raf kinase-dependent condition or a C-Raf kinase dependent condition.

16. The method of claim 15 wherein the disease comprises inflammation or cancer.

17. The method of claim 16, wherein the cancer is selected from the group consisting of: breast, kidney, bladder, thyroid, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, skin, liver, prostate and brain cancer.

18. A method of treating a B-Raf kinase-dependent cancer, by administering to a patient a compound any one of claims 1-5.

19. The method of claim 18, wherein the cancer is cancer is selected from the group consisting of: breast, kidney, bladder, thyroid, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, skin, liver, prostate and brain cancer.