WO2009108827A1

WO2009108827A1 - Fused tricyclic pyrazolo[1, 5-a]pyrimidines, methods for preparation and uses thereof

Info

Publication number: WO2009108827A1
Application number: PCT/US2009/035393
Authority: WO
Inventors: Jeremy Ian Levin; George Diamantidis; Jonathan David Bloom; Christoph Wolfgang Zapf
Original assignee: Wyeth
Priority date: 2008-02-29
Filing date: 2009-02-27
Publication date: 2009-09-03

Abstract

Fused, tricyclic pyrazolo{1,5-a]pyrimidine compounds of formula A or of formula B: and pharmaceutically acceptable salts thereof are described, which selectively inhibit Raf kinase activity and are useful for treating disorders mediated by certain Raf kinases.

Description

FUSED TRICYCLIC PYRAZOLO[I , 5-A]PYRIMIDINES, METHODS FOR PREPARATION

AND USES THEREOF

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 fused, tricyclic pyrazolo[1 ,5-a]pyrimidines, their corresponding pharmaceutically acceptable salts and methods for their preparation and use. The fused, tricyclic pyrazolo[1 ,5- a]pyrimidines inhibit growth of tumor cells, which are associated with oncogenic forms of Receptor Tyrosine Kinases, K-Ras and Raf kinases.

BACKGROUND OF THE INVENTION

Raf is a multigene family expressing oncoprotein kinases: A-Raf, B-Raf and C-Raf (also known as Raf-1 ), 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 1 16, 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 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., et al. (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 1 16, 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 < I0^"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 SoNt 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 RaM ) 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 include 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 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. The publication, however, does not disclose fused, tricyclic pyrazolo[1 ,5-a]pyrimidines. U.S. Patent No. 7,034,153 B2 describes certain corticotrophin releasing factor antagonists, including examples of certain dihydro-5H- cyclopenta[d]pyrazolo[1 ,5-a]pyrimidines compounds. However, no structure-activity relationships (SAR) have been described for other fused, tricyclic pyrazolo[5,1-a]pyrimidines and little is known regarding how other ring systems, including spirocyclic moieties, fused to the heterocycle ring framework influence the SAR of fused, tricyclic pyrazolo[5,1-a]pyrimidines. There is a need for new compounds that selectively inhibit Raf kinase activity and that are useful for treating disorders mediated by Raf kinases. Fused, tricyclic pyrazolo[5,1-a]pyrimidine compositions of the present invention fulfill this unmet need and are useful in the treatment of diseases associated with Raf kinases, including cancer and inflammation, in mammals.

SUMMARY OF THE INVENTION

Accordingly, the invention provides a compound of formula A or of formula B:

and pharmaceutically acceptable salts thereof;

wherein

R¹ is a 5-7 membered heterocyclic or heteroaryl ring, said ring comprising 1-3 heteroatoms selected from N, O and S, and said ring optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁷, -OR⁷, -S(O)_mR⁷, -NR⁷R⁷, - NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, - C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, -OC(O)OR⁷, -OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, - NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, - R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, R⁸NR⁷C(O)NR⁷R⁷, -ZR⁸R¹⁰, -ZR⁸NR⁷R⁷ and -ZR¹⁰;

R² is an aryl ring, a 10-14 membered bicyclic aryl ring, or a 10-14 membered bicyclic 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, -R⁷, -OR⁷, - S(O)_mR⁷, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, - NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, -OC(O)OR⁷, -OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, - R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, - R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷, -OPO(OR⁷)₂, -ZR⁸R¹⁰, -ZR⁸NR⁷R⁷ and -ZR¹⁰;

R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵, are independently selected from H, J, -C(O)OR⁷, - C(O)NR⁷R⁷, -NR⁷C(O)R⁷, -OR⁷, -CN, alkyl of 1-6 carbon atoms, branched alkyl of 1-8 carbon atoms, cycloalkyl ring of 3-10 carbons, aryl, 5-7 membered heterocyclic ring, 5-10 membered heteroaryl ring, said heterocyclic or heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein said alkyl, branched alkyl, cycloalkyl, heterocyclic, heteroaryl and aryl rings are optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, - CF₃, -OCF₃, -R⁷, -OR⁷, -S(O )_mR⁷, -S(O )_mR¹⁰, -NR⁷R⁷, -NR⁷S(O )_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, - N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, - OC(O)OR⁷, -OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, - R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, - R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷ and ZR¹⁰, wherein any of R⁴ and R¹², R⁴ and R¹⁴, R⁶ and R¹⁴, R⁴ and R⁵, R⁶ and R¹¹, R¹² and R¹³, or R¹⁴ and R¹⁵, are capable of joining together with the atoms to which they are attached, forming a 5-7 membered ring and wherein at least one of R⁴ and R¹², R⁴ and R¹⁴, R⁶ and R¹⁴, R⁴ and R⁵, R⁶ and R¹¹, R¹² and R¹³, or R¹⁴ and R¹⁵ is joined, forming a 5-7 membered ring;

R⁷ is independently H, or is independently selected from alkyl of 1-6 carbon atoms, branched alkyl of 1-8 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, a frans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, an aryl ring, and a 5-10 membered heteroaryl ring, optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, - R, -OR, -S(O)_mR, -NRR, -NRS(O)_mR, -OR⁹OR, -OR⁹NRR, -N(R)R⁹OR, -N(R)R⁹NRR, - NRC(O)R, -C(O)R, -C(O)OR, -C(O)NRR, -OC(O)R, -OC(O)OR, -OC(O)NRR, NRC(O)R, - NRC(O)OR, -NRC(O)NRR, -R⁸OR, -R⁸NRR, -R⁸S(0)_mR, -R⁸C(O)R, -R⁸C(O)OR, -R⁸C(O)NRR, - R⁸OC(O)R, -R⁸OC(O)OR, -R⁸OC(O)NRR, -R⁸NRC(O)R, -R⁸NRC(O)OR, -R⁸NRC(O)NRR and ZR¹⁰, wherein R is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, cycloalkyl of 3-10 carbon atoms, aryl of 6-10 carbon atoms or heteroaryl of 6-10 atoms, the heteroaryl comprising 1-3 heteroatoms selected from N, O and S;

R⁸ is a divalent group independently selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl;

R⁹ is independently a divalent alkyl group of 2-6 carbon atoms; R¹⁰ is independently selected from a cycloalkyl ring of 3-10 carbons, a bicycloalkyl ring of 3-10 carbons, an aryl ring, a 5-7 membered heterocyclic ring, a 5-7 membered heteroaryl ring, each heterocyclic ring or heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, and a heteroaryl ring fused to one to three aryl or heteroaryl rings; wherein any of the aryl, cycloalkyl, heterocyclic or heteroaryl rings is optionally substituted with one to four substituents selected from -H, -aryl, -CH₂-aryl, -NH-aryl, -O-aryl, -S(O)_m-aryl, -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁷, -OR⁷, -S(O)_mR⁷, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, - N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷-, -OC(O)OR⁷, - OC(O)NR⁷R⁷, -NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, - R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, - R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, and -R⁸NR⁷C(O)NR⁷R⁷;

J is fluoro, chloro, bromo, or iodo;

X is N, or C-R¹¹;

Y is N, or C-R¹³;

m is an integer of 0-2; and

Z is a divalent group independently selected from a bond, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, O, and -NR⁷.

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 compounds or chemotherapeutic agents, and a pharmaceutically acceptable carrier.

The present invention provides a method for making a compound of formula A or 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-(C₁-C₆dialkyl)formamide or an acetal of N,N-(C₁-C₆dialkyl)acetamide to provide an enaminone compound of formula 2:

2; and

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

providing the invented compounds of formula A or formula B, wherein R¹- R¹⁵, X, Y and Z are as defined above.

According to one embodiment, there is provided a method for making a compound of formula A or formula B, comprising the step of reacting a compound of formula A or formula B with a diol in the presence of an acid, wherein R⁴ and R⁵ together form a carbonyl in a compound of formula A or formula B. In a separate embodiment, compounds wherein R² is a methoxyphenyl moiety, or other masked phenol, are converted to a corresponding phenol (compound of formula A, R² = PhOH) by reacting the methoxyphenyl compounds with pyridine hydrochloride at elevated temperature, or boron tribromide.

The present invention also provides a method for making a compound of formula A or of formula B and pharmaceutically acceptable salts thereof; comprising the steps of: (a) reacting an enaminone of formula 2 with an aminopyrazole of formula 3a:

3a to provide compounds of formula 4 and 5:

5;

(b) halogenating one or both of the compounds of formula 4 and 5 to provide one or both of corresponding halo-pyrazole compounds of formula 6 or 7:

7; and

(c) subjecting one or both of the compounds of formula 6 and 7 to a palladium catalyzed, Suzuki coupling reaction with aryl or heteroaryl boronic acids or corresponding boronate esters to provide one or both of compounds of formula A or of formula B in accordance with the invention, wherein R¹- R¹⁵' X, Y and Z are as defined above.

The present invention provides additional independent steps of separating compounds of formula 4 and 5 prior to the halogenation step, separating compounds of formula 6 and 7 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 present invention also provides intermediate compounds of formula 10 or formula 11 :

10 11

that are used for preparing aminopyrazoles of formula 3. The resulting aminopyrazoles prepared from the intermediates provide an alternative method for preparing an alternative method for making compounds of formula A and of formula B.

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, B-Raf kinase mutants, 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 methods of treating cancer 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 1-8 carbon atoms, including straight-chain alkyl groups, and branched-chain alkyl groups. In one embodiment, a straight chain or branched chain alkyl comprises 1-6 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 3-8 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. Examples of heteroaryl include 3- pyridinyl, 4-pyridinyl, 1-H-indazol-4-yl, or indol-1-yl. 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 group.

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, including a spirocyclic and bridged heterocyclic ring system, e.g. having from 5 to 10 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.

The term "fused, tricyclic pyrazolo[1 ,5-a]pyrimidines" refers to a fused three ring system, wherein the ring fused to the pyrazolo[1 ,5-a]pyrimidine ring comprises a cycloalkyl, or heterocyclyl ring. The term "fused, spirotricyclic pyrazolo[1 ,5-a]pyrimidines" refers to a fused three ring system wherein the ring fused to the tricyclic pyrazolo[1 ,5-a]pyrimidine ring comprises a spirocyclic ring. Suitable examples of such ring systems are provided in the Examples section of the specification.

The term "bicyclic aryl ring or heteroaryl ring" refers to a ring framework of formula

or

The symbol I ^⁷ —) ^/ refers to a 5-7 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O or S. The term "Het" refers to a 6-membered heteroaryl ring containing 1-2 nitrogen atoms. Either bridged bicyclic heteroaryl ring is substituted with one to four substituents, each substituent independently selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁷, -OR⁷, -S(O)_mR⁷, -NR⁷R⁷, and -NR⁷S(O)_mR⁷.

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 of formula B:

and pharmaceutically acceptable salts thereof;

wherein R¹- R¹⁵, X, Y and Z are as defined above.

Suitable examples of R¹ include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, thiophenyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrrolidyl, oxolanyl, thiolanyl, piperidinyl, piperazinyl, thiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, and morpholinyl. The heterocyclic ring or heteroaryl ring may be substituted to the pyrazolo[1 , 5-a]pyrimidine 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, -R⁷, -OR⁷, -S(O )_mR⁷, - NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, - C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, -OC(O)OR⁷, -OC(O)NR⁷R⁷, NR⁷C(O)R⁷, - NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, - R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, - R⁸NR⁷C(O)NR⁷R⁷, -OPO(OR⁷)₂, -YR⁸R¹⁰, -YR⁸NR⁷R⁷ and -YR¹⁰.

Suitable examples of R² include, but are not limited to, halogen substituted phenyl, C₁-C₆ alkylsulfonamido substituted phenyl, carbamate substituted phenyl, C₁-C₆ alkoxy substituted phenylcarbamate, benzonitrile, hydroxyl substituted benzonitrile, C₁-C₆ alkoxy substituted benzonitrile, hydroxyphenyl (phenol), C₁-C₆ alkyl substituted hydroxyphenyl (phenol), halogen substituted hydroxyphenyl (phenol), C₁-C₆ alkoxyphenyl, halogen substituted C₁-C₆ alkoxyphenyl, hydroxypyridinyl, C₁-C₆ alkoxypyridinyl, amino phenyl (aniline), halogen substituted amino phenyl (aniline), hydroxyl substituted amino phenyl (aniline), formamide substituted phenyl, hydroxyl substituted phenylformamide, C₁-C₆ alkoxy substituted phenylformamide, C₁-C₆ alkoxy substituted amino phenyl (aniline), urea substituted phenyl, benzamido, C₁-C₆ 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. Other suitable examples of R² include, but are not limited to, indolyl, benzotriazolyl, oxindolyl, benzothiazolonyl and benzooxazolonyl. 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

wherein ^~y 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, -R⁷, -OR⁷, -S(0)_mR⁷, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, - OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, - OC(O)R⁷, -OC(O)OR⁷, -OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, - R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, - R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷, -YR⁸R¹⁰, -YR⁸NR⁷R⁷ and - YR¹⁰. 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, -R⁷, -OR⁷, -S(O)_mR⁷, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, - N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, -OC(O)OR⁷, - OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, - R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, - R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷, -YR⁸R¹⁰, -YR⁸NR⁷R⁷ and -YR¹⁰.

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, CrC₆ alkoxy substituted benzonitrile, hydroxyphenyl, C-i-Cβ alkyl substituted hydroxyphenyl, halogen substituted hydroxyphenyl, d-C₆ alkoxyphenyl, halogen substituted CrC₆ alkoxyphenyl, hydroxypyridinyl, C-i-Cβ alkoxypyridinyl, amino phenyl, halogen substituted amino phenyl, hydroxyl substituted amino phenyl, formamide substituted phenyl, hydroxyl substituted phenylformamide, C-i-Cβ alkoxy substituted phenylformamide, C-i-Cβ alkoxy substituted amino phenyl, urea substituted phenyl, benzamido, CrC₆ alkyl substituted benzamido, halogen substituted benzamido, indazolyl, Ci-Cβ alkyl substituted indazolyl, halogen substituted indazolyl, halo CrC₆ alkyl substituted indazolyl, perfluoro CrC₆ 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, X is N and R⁴ and R¹² join together with the atoms to which they are attached forming a ring. According to a separate embodiment, Y is N and R⁶ and R¹⁴ join together with the atoms to which they are attached, forming a ring.

According to one embodiment, X is C-R¹¹ and R⁶ and R¹¹ join together with the atoms to which they are attached, forming a ring. According to a separate embodiment, X is C- R¹¹ and R⁴ and R⁵ join together with the atoms to which they are attached, forming a ring.

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 4:

SCHEME 1

Referring to Scheme 1 , cyclic ketones of formula 1 are reacted with acetals of N,N- dialkylformamides or acetals of Λ/,Λ/-dialkylacetamide, carried out in an inert solvent or without a solvent to provide enaminones of formula 2. The reaction of the substituted 3-aminopyrazole of formula 3, where R¹ is as defined above, and R² is as defined above, or hydrogen, with an appropriately substituted enaminone of formula 2 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 compounds of formula A and formula B. In some cases chemical modification of compounds of formula A and B, according to methods known by those skilled in the art of organic synthesis, may be desired to provide additional compounds of the invention. For example, where R⁴ and R⁵ together form a carbonyl in compounds of formula A or B, compounds of the invention are available through reacting compounds of formula A or formula B with diols in the presence of acids such as mineral acids, organic acids including toluenesulfonic acid, or Lewis acids. In the case of compounds of formula A, wherein R² is a methoxyphenyl moiety, or other masked phenol, the corresponding phenol (A, R² = PhOH) is provided by reaction with pyridine hydrochloride at elevated temperature, or boron tribromide. Compounds of the invention may also be synthesized according to the route shown in Scheme 2.

SCHEME 2

Thus, reacting an enaminone of formula 2 with an aminopyrazole of formula 3a 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 compounds of formula 4 and 5. One or both of compounds of formula 4 and 5 are halogenated to afford one or both of corresponding halo-pyrazole compounds of formula 6 and 7, using Λ/-halosuccininmides at room temperature to 50° C in chlorinated hydrocarbon solvents. Compounds 4 and 5 can be separated prior to a halogenating step, using chromatography or using recrystallization. Alternatively, the mixture of compounds of formula 4 and 5 can be halogenated under these conditions with subsequent separation of compounds of formula 6 and 7. One or both of the halopyrazoles compounds of formula 6 and 7 are subjected to palladium catalyzed, Suzuki coupling reactions using aryl or heteroaryl boronic acids or corresponding boronate esters to provide one or both of compounds of the invention. 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.

Additional aminopyrazole intermediate compounds of formula 3, useful for preparing compounds of formula A or formula B, are available according to the route shown in Scheme 3.

SCHEME 3

Referring to Scheme 3, the condensation reaction of substituted acetonitriles of formula 9, wherein R² is as defined above or hydrogen, with substituted esters of formula 8 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 10. Intermediate compounds of formula 10 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 10, reaction with phosphorus oxychloride at elevated temperatures, typically at reflux, provides intermediate compounds of formula 11. Intermediate compounds of formula 1 1 can be converted to substituted aminopyrazole compounds of formula 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol. Substituted esters of formula 8 and substituted acetonitrile compounds of formula 9 can be obtained from commercial sources or readily prepared by numerous literature procedures by those skilled in the art. Aminopyrazole compounds of formula 3 can also be prepared from an alternative route starting from aldehyde compounds of formula 12, as shown in Scheme 3. In the first step of this alternative route, aldehyde compounds of formula 12, which are commercially available or can be prepared by known methods, are reacted typically at room temperature with phosphonate compounds of formula 13 (which can be prepared using the procedure described in Tet. Lett., 1988, 39, 1717- 1720) in a suitable solvent such as tetrahydrofuran, using a base such as, but not limited to for example, cesium carbonate to provide intermediate compounds of formula 14. Intermediate compounds of formula 14 are subsequently heated, typically at 8O⁰C, in a mixture of chloroform, phosphorus oxychloride or the like, and dimethylformamide to give the corresponding substituted 3-chloropropenals. The crude 3-chloropropenals are treated with hydroxylamine in a suitable solvent such as dimethylformamide, typically at room temperature, to provide the corresponding 3-chloropropenal oximes, which are then treated with a suitable dehydrating agent such as, but not limited to for example, phosphorus oxychloride, typically at room temperature, to give the corresponding 3-chloroacrylonitriles. The intermediate 3- chloroacrylonitriles can then be converted into the desired substituted aminopyrazole compounds of formula 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol.

The present invention also provides another method for making a compound of formula A or of formula B comprising the steps of using intermediates of formula 10 or an alternative aminopyrazole intermediate of formula 11. As shown in Scheme 4, a condensation reaction of substituted acetonitriles of formula 9, wherein R² is as defined above or hydrogen, with substituted esters of formula 8 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 10. Intermediate compounds of formula 10 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 herein before defined. For certain substituted intermediate compounds of formula 10, it is necessary to first react with phosphorus oxychloride at elevated temperatures, typically at reflux, to provide intermediate compounds of formula 11. Intermediate compounds of formula can be converted to substituted aminopyrazole compounds of formula 3 by subsequent reaction with hydrazine hydrate in a suitable solvent such as ethanol.

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

with an acetal of N,N-dialkylformamides or an acetal of N,N-dialkylacetamide, carried out in an inert solvent or without a solvent to give an enaminone of formula 2:

2; and

(b) reacting the enaminone of formula 2 and a substituted 3-aminopyrazole of formula 3, where R¹ and R² are as defined above or hydrogen, 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, providing the compounds of formula A and B.

According to one embodiment, one method of preparing compounds of formula A or formula B, where R⁴ and R⁵ together form a carbonyl, comprises the step of reacting the compounds of formula A or formula B with diols in the presence of acids such as mineral acids, organic acids including toluenesulfonic acid, or Lewis acids.

and pharmaceutically acceptable salts thereof; comprising the steps of: (a) reacting an enaminone of formula 2 with an aminopyrazole of formula 3a:

3a

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, providing compounds of formula 4 and 5:

4 and 5;

(b) halogenating one or both of the compounds of formula 4 and 5, using Λ/-halosuccininmides at room temperature to 50° C in chlorinated hydrocarbon solvents, to provide one or both of corresponding halo-pyrazole compounds of formula 6 and 7:

6 and 7; and

(c) subjecting one or both of the halopyrazole compounds of formula 6 and 7 to palladium catalyzed, Suzuki coupling reactions using aryl or heteroaryl boronic acids or boronate esters to provide one or both of compounds of formula A or of formula B in accordance with the invention. Compounds 4 and 5 can be separated prior to a halogenating step, using chromatography or using recrystallization. Alternatively, the mixture of compounds of formula 4 and 5 can be separated prior to or after the halogenating step. The mixture of compounds of formula 6 and 7 can also beseparated prior to or after the palladium catalyzed Suzuki coupling step.

SCHEME 4

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

I acceptable salts thereof.

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, 41 1-415, 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. 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 of 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

Example 1 : Ethyl 3-(3-hydroxyphenyl)-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H-6,9- epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-12-carboxylate

Step 1 : To a solution of 2.Og (0.010 mmol) of N-carbethoxy-4-tropinone was added 9 ml. of Λ/,Λ/-dimethylformamide dimethyl acetal and the resulting mixture was heated to reflux for 12 hours, then cooled to room temperature and concentrated in vacuo and used without further purification. Step 2: To 1.825 g (7.24 mmol) of the enaminone from Step 1 in 25 mL of acetic acid was added 1.20 g (7.50 mmol) of 5-pyridin-4-yl-2H-pyrazol-3-ylamine and the resulting mixture was heated at 85-95° C for 4 hours, then let cool to room temperature and concentrated in vacuo. The residue was diluted with chloroform and the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform/methanol (98:2) to provide

1.23 g of pure ethyl 2-pyridin-4-yl-7,8,9,10-tetrahydro-6H-6,9-epiminocyclohepta[e]pyrazolo[1 ,5- a]pyrimidine-12-carboxylate and 0.2 g of a mixture of ethyl 2-pyridin-4-yl-7, 8,9,10-tetrahydro-6H-

6, θ-epiminocycloheptatelpyrazoloπ ^-alpyrimidine-i 2-carboxylate and ethyl 2-pyridin-4-yl- 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrazolo[1 ,5-a]pyrimidine-12-carboxylate.

Step 3: To a mixture of 0.246g (0.705 mmol) of ethyl 2-pyridin-4-yl-7,8,9,10- tetrahydro-ΘH-θ^-epiminocyclohepta^pyrazoloti ^-alpyrimidine-^-carboxylate from Step 2 in 30 mL of chloroform was added 1.03 g (4.58 mmol) of N-iodosuccinimide and the resulting mixture was stirred at room temperature for 4 hours and then diluted with chloroform/methanol (10:1 ). The organics were washed with sodium bisulfite solution and then water, dried over sodium sulfate, filtered and the concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1 :1 ) to provide 0.213 g of ethyl 3-iodo-2-pyridin-4- yl-7, 8, 9, 10-tetrahydro-6H-6,9-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-12-carboxylate.

Step 4: To a solution of 0.193g (0.406 mmol) of ethyl 3-iodo-2-pyridin-4-yl-7,8,9,10- tetrahydro-ΘH-θ.θ-epiminocycloheptateJpyrazoloti .δ-aJpyrimidine-i 2-carboxylate (Example 1 ,

Step 3) in 5.4 mL of dimethoxyethane and 1.5 mL of water was added 0.1 12g (0.813 mmol) of potassium carbonate and 0.1 12g (0.813 mmol) of 3-hydroxyphenyl boronic acid. The resulting mixture was degassed with a stream of nitrogen for 10 minutes and then 0.034g (0.041 mmol) of [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane, was added and the resulting mixture was heated to 100° C in a sealed tube for 4 hours and then let cool to room temperature. The reaction mixture was filtered, and the filtrate was extracted with chloroform/methanol (10:1 ). The organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform/methanol (98:2) to give 0.123g of ethyl 3-(3-hydroxyphenyl)-2-pyridin-4- yl-7,8,9, 10-tetrahydro-6H-6,9-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-12-carboxylate as a white solid. MS: [M+H] 442.3.

Example 2: 2-Chloro-5-[12-methyl-8-(phenylsulfonyl)-2-pyridin-4-yl-7,8,9, 10- tetrahydro-6H-7, 10-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidin-3-yl]phenol

Step 1 : β-Benzenesulfonyl-δ-methyl-δ-aza-bicycloβ^.iJoctan^-one (0.085g, 0.304 mmol), prepared according to the procedure of Takahashi, et al., Chem. Lett., (1989), 593-596, was dissolved in 1 ml. of Λ/,Λ/-dimethylformamide dimethyl acetal and heated to 100° C. After 5 hours, the solvent was removed under reduced pressure to give a brown, viscous oil. The crude, residual oil was purified by Biotage™ chromatography (cartridge 40s), eluting with a gradient of ethyl acetate/hexanes (1 :2), 100% ethyl acetate and 10% methanol in ethyl acetate to provide the enaminone θ-benzenesulfonyl-S-dimethylaminomethylene-δ-methyl-δ-aza-bicycIo [3.2.1] octan-2-one as a light yellow oil (0.065 g, 64.3%). MS: [M+H] 335.

Step 2: To 77 ml. of dry ethanol was added 1.93 g (83.8 mmol) of sodium metal (after removal of mineral oil with hexane) and the mixture was stirred at room temperature for 30 minutes until the metal had completely dissolved. A mixture of 9.67 g (53.74 mmol) of 4-chloro- 3-methoxy-benzeneacetonitrile and 10.38 g (75.57 mmol) of methyl isonicotinate in 10 ml. of dry ethanol was then added and the resulting brown solution was heated at reflux for 2.5 hours. After cooling, the solvent was evaporated and ice was added to the resulting mixture followed by extraction with ether. The aqueous layer was neutralized with acetic acid, cooled and diluted with water. Collection of the resulting precipitate and drying in vacuo gave 13 g (84% yield) of 2- (4-chloro-3-methoxyphenyl)-3-oxo-3-pyridin-4-ylpropanenitrile.

A mixture of 13.5 g (47.09 mmol) of 2-(4-chloro-3-methoxyphenyl)-3-oxo-3-pyridin-4- ylpropanenitrile and 125 ml. phosphorus oxychloride was heated at 80° C for 18 hours. After cooling, the phosphorus oxychloride was evaporated off. To the resulting residue was added toluene, and the mixture was then evaporated to dryness. This step was repeated to fully remove phosphorus oxychloride. Ice and saturated sodium bicarbonate were added to the residue, and a solid precipitated out, providing 12.4 g (86% yield) of 3-chloro-2-(4-chloro-3- methoxyphenyl)-3-pyridin-4-ylacrylonitrile as a white solid. MS: [M+H] 305.1 A mixture of 12.4 g (40.6 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-3-pyridin- 4-ylacrylonitrile and 9.3 mL (191.7 mmol) hydrazine hydrate in 400 ml. of ethanol was heated at reflux for 5 hours. The mixture was allowed to cool to room temperature and the 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, ether, and then dried under vacuum to provide 10.8 g (89% yield) of 4-(4-chloro-3-methoxyphenyl)-5-pyridin-4-yl-1 H- pyrazol-3-amine. MS: [M+H] 301.2

To a 150° C melt of 5.76g (49.9 mmol) of pyridine hydrochloride was added 0.5g (1.66 mmol) of 4-(4-chloro-3-methoxyphenyl)-5-pyridin-4-yl-1 H-pyrazol-3-amine and the resulting mixture was heated at 180° C for 1 hour and 220° C for an additional 1 hour. The resulting mixture was cooled to 100° C and 30 mL of ammonium hydroxide solution was added and the solvent was then removed in vacuo. The residue was washed with 15% methanol/dichloromethane and the filtrate was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica gel eluting with a gradient of 5-12% methanol/dichloromethane to provide 0.366g (77%) of 5-(3-amino-5-pyridin-4- yl-1 H-pyrazol-4-yl)-2-chlorophenol as an off-white solid. MS: [M+H]⁺ 287.1

Step 3: A solution of β-benzenesulfonyl-S-dimethylaminomethylene-δ-methyl-δ-aza- bicyclo [3.2.1] octan-2-one (0.065g, 0.29 mmol) and 5-(3-amino-5-pyridin-4-yl-1 H-pyrazol-4-yl)- 2-chlorophenol (0.083g, 0.3 mmol) in acetic acid was heated at 100° C for 19 hours. The reaction mixture was then cooled and the solvent was removed in vacuo. The residue was diluted in ethyl acetate (10 mL) and the organics were washed with saturated aqueous sodium bicarbonate (2x5 mL) and brine (5 mL). The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by HPLC (Gilson), eluting by gradient to provide 2-chloro-5-[12-methyl-8-(phenylsulfonyl)-2-pyridin-4-yl-7, 8,9,10-tetrahydro- 61-1-7,10-epiminocyclo-hepta[e]pyrazolo[1 ,5-a]pyrimidin-3-yl]phenol as an amorphous solid (0.02g, 7.2%). MS: [M+H] 558.3.

Example 3: Methyl 3-(4-chloro-3-hydroxyphenyl)-12-methyl-2-pyridin-4-yl-7,8,9,10- tetrahydro-6H-7, 10-epiminocyclohepta-[e]pyrazolo[1 ,5-a]pyrimidine-8-carboxylate

Step 1 : 8-Methyl-2-oxo-8-aza-bicyclo[3.2.1]octane-6-carboxylic acid methyl ester (1.7 g, 8.62 mmol), prepared according to the procedure of Sawa, et al., Bioorg. Med. Chem. Lett., 8, (1998) 647-652, was dissolved in Λ/,Λ/-dimethylformamide dimethyl acetal (25 ml.) and heated to 100° C for 5 hours. The solvent was then removed under reduced pressure to give a brown viscous oil. The crude oil was purified by Biotage chromatography (cartridge 40s), eluting with a gradient of ethyl acetate/hexanes (1 :2), 100% ethyl acetate and 10% methanol in ethyl acetate to afford methyl (3Z)-3-[(dimethylamino)methylene]-8-methyl-2-oxo-8- azabicyclo[3.2.1]octane-6-carboxylate as a dark, reddish oil (1.6 g, 73.7%). MS: [M+H] 253.

Step 2: A solution of methyl (3Z)-3-[(dimethylamino)methylene]-8-methyl-2-oxo-8- azabicyclo[3.2.1]octane-6-carboxylate (0.167g, 0.66 mmol) and 5-(3-amino-5-pyridin-4-yl-1 H- pyrazol-4-yl)-2-chlorophenol (0.190 g, 0.66 mmol) in acetic acid (5ml_) was heated at 100⁰ C for 19 hours. The reaction mixture was then cooled and the solvent was removed in vacuo. The crude oil was diluted with ethyl acetate (10 ml_) and the organics were washed with saturated aqueous sodium bicarbonate (2x5 ml.) and brine (5 ml_), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by HPLC (Gilson) to provide methyl 3-(4- chloro-3-hydroxyphenyl)-12-methyl-2-pyridin-4-yl-7, 8,9,10-tetrahydro-6H-7, 10- epiminocyclohepta-tejpyrazoloπ ^-ajpyrimidine-δ-carboxylate as a yellow amorphous solid (0.04 g, 12.7 %). MS: [M+H] 476.2.

Example 4: 2-Chloro-5-[8-(hydroxymethyl)-12-methyl-2-pyridin-4-yl-7,8,9,10- tetrahydro-6H-7, 10-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidin-3-yl]phenol

To a solution of the product of Example 3, methyl 3-(4-chloro-3-hydroxyphenyl)-12- methyl-2-pyridin-4-yl-7,8,9, 10-tetrahydro-6H-7, 10-epiminocyclohepta[e]pyrazolo[1 ,5- a]pyrimidine-8-carboxylate (0.220 g, 0.462 mmol), in THF (10 ml.) was added lithium aluminum hydride (2M in THF, 0.554 mmol, 0.6 ml.) at 0° C. The reaction was allowed to warm to room temperature over 19 hours and was then quenched with water (3ml_) and 1 N sodium hydroxide (1 mL). The resulting mixture was stirred for 1.5 hours and filtered to give a clear, yellowish solution that was concentrated in vacuo to give a crude solid. The crude solid was purified by Biotage™ Flash 40s chromatography; eluting with 10% methanol in ethyl acetate to provide 2- chloro-5-[8-(hydroxymethyl)-12-methyl-2-pyridin-4-yl-7, 8,9,10-tetrahydro-6H-7, 10-epiminocyclo- hepta[e]pyrazolo[1 ,5-a]pyrimidin-3-yl]phenol as a yellow solid (0.034 g, 17%). MS: [M+H] 448.3.

Example 5: 12-Benzyl-3-(4-chloro-3-methoxyphenyl)-8-(phenylsulfonyl)-2- pyridin-4-yl-7,8,9, 10-tetrahydro-6H-7, 10-epiminocyclo-hepta[e]pyrazolo[1 ,5-a]pyrimidine

Step 1 : According to the procedure of Takahashi, et ai, Chem. Lett., (1989), 593-

596, 1-benzylpyridinium-3-olate (1.0 g, 4.52 mmol) was suspended in tetrahydrofuran (60 mL) and phenyl vinyl sulfone (1.52 g, 9.03 mmol) was added. The reaction was then heated to reflux (95° C) for 20 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was suspended in ethyl acetate (10 mL). The solid was collected by filtration and washed with cold ethyl acetate (10 ml.) to give 8-benzyl-6-(phenylsulfonyl)-8- azabicyclo[3.2.1]oct-3-en-2-one as a light, fluffy solid (1.1g, 68.7 %) MS: [M+H]⁺ 354.

Step 2: A solution of 8-benzyl-6-(phenylsulfonyl)-8-azabicyclo[3.2.1]oct-3-en-2-one

(1.1 g, 3.1 1 mmol) in methanokacetone (20 ml.) was added to 10% palladium on carbon (100 mg) and was subjected to catalytic hydrogenation at room temperature and atmospheric pressure for 20 hours. The resulting slurry was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give a crude solid that was purified by Biotage™

Flash 40s chromatography; eluting with ethyl acetate: hexanes (2:1 ) to provide 8-benzyl-6-

(phenylsulfonyl)-8-azabicyclo[3.2.1]octan-2-one as a yellow solid (0.725 g, 66.3 %). MS: [M+H] 356.

Step 3: δ-Benzyl-β-tøhenylsulfonyO-δ-azabicycloβe.iJoctane-one (0.420 g, 1.18 mmol) was dissolved in Λ/,Λ/-dimethylformamide dimethyl acetal (25 ml.) and heated to 100° C for 7 hours. The solvent was then removed under reduced pressure to give a brown, viscous oil. The crude oil was purified by Biotage™ chromatography (cartridge 40s), eluting with a gradient of ethyl acetate-heaxanes (1 :1 ), 100% ethyl acetate, and 10% methanol in ethyl acetate to afford 8-benzyl-3-[(dimethylamino)methylene]-6-(phenylsulfonyl)-8-azabicyclo [3.2.1] octane- one as a dark, reddish oil (0.3 g, 61.8 %). MS: [M+H] 411.

Step 4: A solution of 8-benzyl-3-[(dimethylamino)methylene]-6-(phenylsulfonyl)-8- azabicyclo[3.2.1]octan-2-one (0.229 g, 0.56 mmol) and 4-(4-chloro-3-methoxyphenyl)-5-pyridin- 4-yl-1 H-pyrazol-3-amine (0.184 g, 0.62 mmol), prepared according to the procedure of Example 2, Step 2, in acetic acid (5ml_) was heated at 100° C for 19 hours. The solvent was then removed in vacuo and the resulting crude oil was diluted in dichloromethane (10 ml.) and the organics were washed with saturated aqueous sodium bicarbonate (2 x 5 ml.) and brine (5 ml_). The organics was next dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by Biotage™ chromatography (cartridge 40s), eluting with a gradient of ethyl acetate/hexanes (3:1 ) and 100% ethyl acetate to afford 12-benzyl-3-(4-chloro-3- methoxyphenyl)-8-(phenylsulfonyl)-2-pyridin-4-yl-7, 8,9,10-tetrahydro-6H-7, 10- epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine as a yellow crystalline solid (0.21 g, 58.2 %). MS: [M+H] 648.4.

Example 6: (8S)-3-(4-Chloro-3-hydroxyphenyl)-12-methyl-2-pyridin-4-yl-7,8,9,10- tetrahydro-6H-7, 10-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-8-carboxylic acid

A solution of the product of Example 4, 2-chloro-5-[8-(hydroxymethyl)-12-methyl-2- pyridin-4-yl-7,8,9, 10-tetrahydro-6H-7, 10-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidin-3- yl]phenol (0.27 g, 0.551 mmol), in 4N HCI (4m L) was heated at 100° C for 3 hours under a nitrogen atmosphere. The solution was then allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The reaction was quenched with ammonium hydroxide (0.5 mL) and concentrated in vacuo. The resulting solid was suspended in ethyl acetate:methanol:acetonitrile (1 :0.1 :0.1 ) for 10 minutes with stirring and then filtered. The filtrate was concentrated in vacuo to give a crude solid that was purified by Biotage™ Flash 40s chromatography, eluting with 10% methanol in ethyl acetate to provide (8S)-3-(4-chloro-3- hydroxyphenyl)-12-methyl-2-pyridin-4-yl-7, 8,9,10-tetrahydro-6H-7, 10- epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-8-carboxylic acid as a yellow solid (0.034 g, 17%). MS: [M+H] 461.3.

Example 7: 3-(2'-Pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'- pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenol

Step 1 : To a solution of 2.Og (12.8 mmol) of 1 ,4-cyclohexanedione mono-ethylene ketal was added 9 mL of Λ/,Λ/-dimethylformamide dimethyl acetal and the resulting mixture was heated to reflux for 12 hours and then cooled to room temperature, then concentrated in vacuo and used without further purification. Step 2: To 0.528 g (2.50 mmol) of the enaminone from Step 1 in 10 mL of acetic acid was added 0.4Og (2.50 mmol) of 5-pyridin-4-yl-2h-pyrazol-3-ylamine and the resulting mixture was heated at 85-95° C for 4 hours and then let cool to room temperature and concentrated in vacuo. The residue was diluted with chloroform and organics were washed with saturated sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes

(5:1 ) to provide 0.161 g of pure 2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'- pyrazolo[1 ,5- a]quinazoline] and 0.18 g of a mixture of 2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3- dioxolane-2,7'-pyrazolo[1 ,5-a]quinazoline] and 2'-(pyridin-4-yl)-6',8'-dihydro-5'H- spiro[[1 ,3]dioxolane-2,7'-pyrazolo[5,1-b]quinazoline].

Step 3: To a mixture of 0.152g (0.494 mmol) of 2'-pyridin-4-yl-8',9'-dihydro-6'H- spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5-a]quinazoline] from Step 2 in 20 mL of chloroform was added 0.722g (3.208 mmol) of N-iodosuccinimide and the resulting mixture was stirred at room temperature for 4 hours and then filtered. The collected solid was washed with dichloromethane to provide 0.181 g of pure 3'-iodo-2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'- pyrazolo[1 ,5-a]quinazoline] as a yellow solid.

Step 4: To a solution of 0.165g (0.378 mmol) of 3'-iodo-2'-pyridin-4-yl-8',9'-dihydro- 6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5-a]quinazoline] from Step 3 in 5 mL of dimethoxyethane and 1.4 mL of water was added 0.104g (0.754 mmol) of potassium carbonate and 0.104g (0.756 mmol) of 3-hydroxyphenyl boronic acid. The resulting mixture was degassed with a stream of nitrogen for 10 minutes and then 0.032g (0.039 mmol) of [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane, was added and the resulting mixture was heated to 100° C in a sealed tube for 4 hours and then let cool to room temperature. The reaction mixture was filtered, and the filtrate was extracted with chloroform/methanol (10:1 ). The organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform/methanol (98:2) to give 0.067g of 3-(2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3- dioxolane-2,7'-pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenol as a tan solid. MS: [M+H] 401.3.

Example 8: 3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3- dioxolane-2,7'-pyrazolo[1 ,5-a]quinazoline]

According to the procedure of Example 7, a mixture of 3'-iodo-2'-pyridin-4-yl-8',9'- dihydro-6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5- a]quinazoline] (650 mg, 1.5 mmol), 3- methoxyboronic acid (340 mg, 2.25 mmol), [1 ,1 ^*- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane, dimethoxyethane (5 ml.) and 2M sodium carbonate (1.5 ml_), provided 0.55g of 3'-(4- methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5- a]quinazoline] as a brown foam. MS: [M+H] 415.3.

Example 9: 3-(2'-Pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'- pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenyl pivalate

According to the procedure of Example 7, a mixture of 2,2-dimethyl-propionic acid 3- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl ester (680 mg, 2.25 mg), 3'-iodo-2'-pyridin- 4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5- a]quinazoline] (650 mg, 1.5 mmol), [1 ,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane, dimethoxyethane (7 ml.) and 2M sodium carbonate (1.5 ml.) provided 0.14g of 3-(2'-pyridin-4-yl- 8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenyl pivalate as a brown solid. MS: [M+H] 485.4.

Example 10: 3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-7'H-spiro[1 ,3- dioxolane-2,6'-pyrazolo[1 ,5-a]quinazoline]

Step 1 : 1 ,3-Cyclohexanedione (5.2 g, 46 mmol) and Λ/,Λ/-dimethylformamide dimethyl acetal (5.5 g, 46 mmol) were heated at 100° C for 2 hours. Upon cooling, an orange solid precipitated, which was stirred with ether (50 ml.) and collected by filtration to give 6.7 g of 2-dimethylaminomethylene-cyclohexane-1 ,3-dione as an orange powder.

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

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

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 at reflux for 6.5 hours. The mixture was allowed to cool to room temperature and the 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, and then dried under vacuum to provide 0.92 g (94% yield) of 4-(3-methoxy-phenyl)-5-pyridin-4-yl-2H-pyrazol-3- amine. MS 267.2 [M+H]. Step 3: 4-(3-Methoxy-phenyl)-5-pyridin-4-yl-2H-pyrazol-3-ylamine (490 mg, 1.84 mmol) and 2-dimethylaminomethylene-cyclohexane-1 ,3-dione (310 mg, 1.84) were heated in acetic acid (4 mL) for 1 hour at 100° C. Upon cooling, a beige precipitate formed. The crude reaction mixture was then diluted with ether and the solid was collected by filtration to give 600 mg of 3-(3-methoxyphenyl)-2-pyridin-4-yl-8,9-dihydropyrazolo[1 ,5-a]quinazolin-6(7H)-one as a beige solid.

Step 4: 3-(3-Methoxyphenyl)-2-pyridin-4-yl-8,9-dihydropyrazolo[1 ,5-a]quinazolin- 6(7H)-one (400 mg, 1.1 mmol) was dissolved in dichloromethane (20 mL) and to this solution was added ethylene glycol (1 mL), triethyl orthoformate (1 mL), and p-toluenesulfonic acid (278 mg, 1.6 mmol). A small portion of 4A sieves was then added to the reaction mixture and the reaction was stirred for 1 hour. The mixture was next filtered, and the filtrate was dried over sodium sulfate, passed through Magnesol and evaporated to give 450 mg of 3'-(3- methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-7'H-spiro[1 ,3-dioxolane-2,6'-pyrazolo[1 ,5- a]quinazoline] as an off-white solid. MS: [M+H] 415.3.

Example 1 1 : 3-(2'-Pyridin-4-yl-8',9'-dihydro-7'H-spiro[1 ,3-dioxolane-2,6'- pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenol

Step 1 : A solution of the product of Example 10, 3'-(3-methoxyphenyl)-2'-pyridin-4- yl-8',9'-dihydro-7'H-spiro[1 ,3-dioxolane-2,6'-pyrazolo[1 ,5-a]quinazoline] (150 mg, 0.35 mmol), in dichloromethane (10 mL) was cooled to 0⁰ C and to this was added a 1 M solution of boron tribromide (1.7 mL, 1.7 mmol). The ice bath was removed and the orange suspension allowed to warm to room temperature and stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow solid. Trituration and filtration with ethanol afforded 40 mg of 3-(3-hydroxyphenyl)-2-pyridin-4-yl-8,9- dihydropyrazolo[1 ,5-a]quinazolin-6(7H)- one as a yellow powder. Step 2: 3-(3-Hydroxyphenyl)-2-pyridin-4-yl-8,9-dihydropyrazolo[1 ,5-a]quinazolin- 6(7H)- one (87 mg, 0.24 mmol) was dissolved in dichloromethane (5 ml.) and to this solution was added ethylene glycol (0.25 ml_), triethyl orthoformate (0.25 ml.) and p-toluenesulfonic acid (50 mg, 1.6 mmol). To the resulting mixture was added a small portion of 4A molecular sieves and the reaction was stirred for 1 hour. The mixture was then filtered, then the filtrate was dried over sodium sulfate, passed through Magnesol and concentrated in vacuo to give 450 mg of 3- (2'-pyridin-4-yl-8',9'-dihydro-7'H-spiro[1 ,3-dioxolane-2,6'-pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenol as an off-white solid. MS: [M+H] 401.3

Example 12: tert-Butyl 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-1 H,6'H- spiro[piperidine-4,7'-pyrazolo[1 ,5-a]quinazoline]-1 -carboxylate

Step 1 : A solution of 4-piperidinemethanol (5.76 g, 50.0 mmol) and triethylamine (7.30 ml_, 52.5 mmol, 1.05 equiv.) in dichloromethane (150 ml.) was cooled to 0⁰C. A solution of di-terf-butyl dicarbonate (11.46 g, 52.5 mmol, 1.05 equiv.) in dichloromethane (2O mL) was added via an addition funnel, leading to a gentle boiling of the solvent. The reaction was allowed to proceed for 16 hours during which the reaction had reached room temperature. The organic phase was then extracted twice with 1 N HCI (75 ml_), then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford terf-butyl 4-(hydroxymethyl)piperidine-1 -carboxylate as a white solid (10.70 g, 99%).

Step 2: terf-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (9.0 g, 41.9 mmol) was dissolved in dichloromethane (84 ml.) and cooled to 0° C. Dess-Martin periodinane (19.5 g, 46.0 mol) was dissolved in dichloromethane (153 ml_, 0.3 M) and added dropwise to the alcohol via addition funnel. After 3 hours, consumption of the starting material was confirmed by TLC analysis (ethyl acetate:hexanes, 3:7). The reaction was quenched by the addition of a 1 :1 mixture of sodium bicarbonate and sodium thiosulfate (200 mL). The organic layer was collected and the aqueous phase extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1 :1 ) to provide terf-butyl 4-formylpiperidine-i-carboxylate in quantitative yield as a colorless oil.

Step 3: te/t-Butyl 4-formylpiperidine-i-carboxylate (4.07 g, 19.1 mmol) was dissolved in ethanol (120 ml.) to which 3-buten-2-one (1.72 ml_, 21.0 mmol, 1.1 equiv.) was added. A solution of potassium hydroxide (0.54 g, 9.55 mmol, 0.5 equiv.) in ethanol (15 ml.) was added dropwise to the reaction. The reaction was allowed to stir at 70° C over night after which the solvent was removed under reduced pressure. The residue was dissolved in an aqueous solution of sodium bicarbonate (100 ml.) and extracted three times with ethyl acetate (75 ml_).

The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1 :4) to provide terf-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate as a slightly yellow oil (1.69 g, 33%).

Step 4: terf-Butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (1.69 g, 6.37 mmol) was dissolved in ethyl acetate (86 ml.) to which palladium on charcoal (169 mg) was added. The reaction was allowed to stir under an atmosphere of hydrogen for 3 hours, after which the solids were removed by filtration through a plug of Magnesol. The filtrate was concentrated under reduced pressure to give terf-butyl 9-oxo-3-azaspiro[5.5]undecane-3- carboxylate, as a slightly yellow oil (1.57g, 92%).

Step 5: terf-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (629 mg, 2.35 mmol) was heated to 1 10° C in the presence of Λ/,Λ/-dimethylformamide dimethyl acetal (0.94 ml_, 7.06 mmol, 3 equiv.). The progress of the reaction was monitored by ¹H-NMR spectroscopy by removing 3 μl_ of the reaction and diluting it into CDCI₃. After 9 h the starting material was consumed and the crude enaminone, terf-butyl 8-((dimethylamino)methylene)-9-oxo-3- azaspiro[5.5]undecane-3-carboxylate, was obtained by removal of the volatiles under reduced pressure (722 mg) and used directly in the subsequent reaction.

Step 6: The crude terf-butyl 8-((dimethylamino)methylene)-9-oxo-3- azaspiro[5.5]undecane-3-carboxylate from Step 5 (710 mg) was dissolved in ethanol (4.5 ml.) and treated with acetic acid (1.26 ml_, 22.04 mmol) and 4-(3-methoxyphenyl)-5-pyridin-4-yl-1 H- pyrazol-3-amine (556 mg, 2.20 mmol). The mixture was stirred at 80° C for 4.5 hours, after which volatile compounds were removed under reduced pressure. The residue was purified by column chromatography by eluting with a gradient of dichloromethane, 0.5% methanol in dichloromethane, followed by 0.8% methanol in dichloromethane to give the desired terf-butyl 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-1 H,6'H-spiro[piperidine-4,7'-pyrazolo[1 ,5- a]quinazoline]-1-carboxylate as a yellow solid (200 mg, 16%, 2 steps). The regioisomeric product of this reaction, terf-butyl 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-5',6'-dihydro-8'H- spiro[piperidine-4,7'-pyrazolo[5,1-b]quinazoline]-1-carboxylate, was also obtained as yellow solid (75 mg, 6%, 2 steps) by further eluting with 3% methanol in methylene chloride. MS: [M+H] 526.5.

Examples 13a and 13b: 3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H- spiro[piperidine-4,7'-pyrazolo[1 ,5-a]quinazoline] and 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-5',6'- dihydro-8'H-spiro[piperidine-4,7'-pyrazolo[5, 1 -b]quinazoline]

te/f-Butyl 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-1 H,6'H- spiro[piperidine-

4,7'-pyrazolo[1 ,5-a]quinazoline]-1-carboxylate (150 mg, 0.29 mmol) was dissolved in dichloromethane (5 ml.) and treated with trifluoroacetic acid (0.5 ml_). After stirring for 1.5 hours at room temperature, the reaction was complete by mass spectrometric analysis. The reaction was extracted with 10% sodium carbonate (20 ml.) and the aqueous layer was washed twice with dichloromethane (10 ml_). The combined organic layers were dried over magnesium sulfate, then filtered and concentrated in vacuo to give 121 mg of 3'-(3-methoxyphenyl)-2'- pyridin-4-yl-8',9'-dihydro-6'H-spiro[piperidine-4,7'-pyrazolo[1 ,5-a]quinazoline] (13a) as a yellow solid. MS: [M+H] 426.3.

Using the same procedure, terf-butyl 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-5',6'- dihydro-8'H-spiro[piperidine-4,7'-pyrazolo[5,1-b]quinazoline]-1-carboxylate was converted into 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-5',6'-dihydro-8'H-spiro[piperidine-4,7'-pyrazolo[5,1- b]quinazoline] (13b). MS: [M+H] 426.3.

Example 14: 3-(2'-Pyridin-4-yl-8',9'-dihydro-6'H-spiro[piperidine-4,7'-pyrazolo[1 ,5- a]quinazolin]-3'-yl)phenol

3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[piperidine-4,7'-pyrazolo- [1 ,5-a]quinazoline] (57 mg, 0.134 mmol) was dissolved in dichloromethane (1.2 ml.) and treated with a 1 M solution of boron tribromide in dichloromethane (0.67 ml_, 0.67 mmol, 5 equiv.). The progress of the reaction was monitored by LCMS and after 2 hours the reaction was quenched by addition of saturated aqueous sodium bicarbonate (5 ml_). The aqueous layer was extracted seven times with 10% methanol in dichloromethane and the combined organic layers were dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting orange solid was dissolved in 1 N HCI (4 ml.) and tetrahydrofuran (1 ml_). This solution was stirred at 65° C for 2 hours, after which it was neutralized by addition of saturated aqueous sodium bicarbonate (10 ml_). This mixture was extracted 15 times with 10% methanol in dichloromethane and the combined organics were dried over magnesium sulfate, then filtered and concentrated in vacuo to provide 3-(2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[piperidine-4,7'-pyrazolo[1 ,5-a]quinazolin]-3'- yl)phenol as a yellow solid (25 mg, 45%). MS: [M+H]⁺ 412.3.

Example 15: 4-Bromo-3'-(4-bromo-3-methoxyphenyl)-2'-pyridin-4-yl-4,5,8',9'- tetrahydro-3H,7'H-spiro[furan-2,6'-pyrazolo[1 ,5-a]quinazoline]

Step 1 : To a solution of the product of Example 10, Step 2, 3-(3-methoxyphenyl)-2- pyridin-4-yl-8,9-dihydropyrazolo[1 ,5-a]quinazolin-6(7H)-one (496 mg, 1.34 mmol), in 5 ml. of anhydrous tetrahydrofuran was added allylmagnesium bromide (1.47 mmol, 1.47 ml. of a 1.0 M ether solution). The mixture was stirred at room temperature for 1 hour, then saturated ammonium chloride was added, and the mixture was extracted into ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 460 mg of 6- allyl-3-(3-methoxyphenyl)-2-pyridin-4-yl-6,7,8,9-tetrahydropyrazolo[1 ,5-a]quinazolin-6-ol as a yellow foam.

Step 2: 6-Allyl-3-(3-methoxyphenyl)-2-pyridin-4-yl-6,7,8,9-tetrahydropyrazolo[1 ,5- a]quinazolin-6-ol (365 mg, 0.88 mmol) was dissolved in dichloromethane (10 ml.) and cooled to 0° C. Bromine was added dropwise until the persistence of yellow color. The ice bath was removed and the mixture was stirred for 30 minutes at room temperature. The mixture was then partitioned between ethyl acetate and water. The ethyl acetate solution was dried over magnesium sulfate, then filtered and concentrated in vacuo to give a brown oil. The brown oil was purified by column chromatography eluting with 3% methanol/dichloromethane to give 410 mg of 3-(4-bromo-3-methoxyphenyl)-6-(2,3-dibromopropyl)-2-pyridin-4-yl-6,7,8,9- tetrahydropyrazolo[1 ,5-a]quinazolin-6-ol as a yellow foam.

Step 3: The 3-(4-bromo-3-methoxyphenyl)-6-(2,3-dibromopropyl)-2-pyridin-4-yl- 6,7,8,9-tetrahydropyrazolo[1 ,5-a]quinazolin-6-ol (300 mg, 0.46 mmol) is dissolved in anhydrous tetrahydrofuran (5 ml.) and sodium hydride (200 mg) was added. Stirring was continued until gas evolution ceased. The mixture was then partitioned between ethyl acetate and water. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. The oil was purified by column chromatography eluting with 3% methanol/dichloromethane to give 52 mg of 4-bromo-3'-(4-bromo-3-methoxyphenyl)-2'-pyridin-4- yl-4,5,8',9'-tetrahydro-3H,7'H-spiro[furan-2,6'-pyrazolo[1 ,5-a]quinazoline] as a yellow solid. MS: [M+H] 569.2.

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-Raf 1 Kinase Assay Procedure: B-RaM 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, 1 mM 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:

I . 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

I I . 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 IC50 determinations as described by Mallon R., et al. (2001 ) Anal. Biochem. 294:48. TESTING FOR C-RAF KINASE INHIBITORS

Assayed in a Raf-M EK-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 or formula B 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 1 μM to 3 nM or 0.1 μM to 300 pm in half log dilutions.

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

B-Raf IC50 Data for compounds of Formula A or Formula B

= Not tested

Claims

WHAT IS CLAIMED IS:

1. A compound of formula A or B:

and pharmaceutically acceptable salts thereof;

wherein

R² is an aryl ring, a 10-14 membered bicyclic aryl ring, or a 10-14 membered bicyclic 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, -R⁷, -OR⁷, -

S(O)_mR⁷, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -

NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, -OC(O)OR⁷, -OC(O)NR⁷R⁷,

NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, - R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -

R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷, -OPO(OR⁷)₂, -ZR⁸R¹⁰, -ZR⁸NR⁷R⁷ and -ZR¹⁰;

R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵, are independently selected from H, J, -C(O)OR⁷, -

C(O)NR⁷R⁷, -NR⁷C(O)R⁷, -OR⁷, -CN, alkyl of 1-6 carbon atoms, branched alkyl of 1-8 carbon atoms, cycloalkyl ring of 3-10 carbons, aryl, 5-7 membered heterocyclic ring, 5-10 membered heteroaryl ring, said heterocyclic or heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein said alkyl, branched alkyl, cycloalkyl, heterocyclic, heteroaryl and aryl rings are optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, - CF₃, -OCF₃, -R⁷, -OR⁷, -S(O)_mR⁷, -S(O)_mR¹⁰, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, - N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, - OC(O)OR⁷, -OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, - R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, - R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷ and ZR¹⁰, wherein any of R⁴ and R¹², R⁴ and R¹⁴, R⁶ and R¹⁴, R⁴ and R⁵, R⁶ and R¹¹, R¹² and R¹³, or R¹⁴ and R¹⁵, are capable of joining together with the atoms to which they are attached, forming a 5-7 membered ring and wherein at least one of R⁴ and R¹², R⁴ and R¹⁴, R⁶ and R¹⁴, R⁴ and R⁵, R⁶ and R¹¹, R¹² and R¹³, or R¹⁴ and R¹⁵ is joined, forming a 5-7 membered ring;

R⁷ is independently H, or is independently selected from alkyl of 1-6 carbon atoms, branched alkyl of 1-8 carbon atoms, c/s-alkenyl of 2-6 carbon atoms, a frans-alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, an aryl ring, and a 5-10 membered heteroaryl ring, optionally substituted with one to four substituents selected from -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, - R, -OR, -S(0)_mR, -NRR, -NRS(0)_mR, -OR⁹OR, -OR⁹NRR, -N(R)R⁹OR, -N(R)R⁹NRR, - NRC(O)R, -C(O)R, -C(O)OR, -C(O)NRR, -OC(O)R, -OC(O)OR, -OC(O)NRR, NRC(O)R, - NRC(O)OR, -NRC(O)NRR, -R⁸OR, -R⁸NRR, -R⁸S(0)_mR, -R⁸C(O)R, -R⁸C(O)OR, -R⁸C(O)NRR, - R⁸OC(O)R, -R⁸OC(O)OR, -R⁸OC(O)NRR, -R⁸NRC(O)R, -R⁸NRC(O)OR, -R⁸NRC(O)NRR and ZR¹⁰, wherein R is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, cycloalkyl of 3-10 carbon atoms, aryl of 6-10 carbon atoms or heteroaryl of 6-10 atoms, the heteroaryl comprising 1-3 heteroatoms selected from N, O and S;

R⁹ is independently a divalent alkyl group of 2-6 carbon atoms;

R¹⁰ is independently selected from a cycloalkyl ring of 3-10 carbons, a bicycloalkyl ring of 3-10 carbons, an aryl ring, a heterocyclic ring, a heteroaryl ring, each heterocyclic ring or heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, and a heteroaryl ring fused to one to three aryl or heteroaryl rings; wherein any of the aryl, cycloalkyl, heterocyclic or heteroaryl rings is optionally substituted with one to four substituents selected from -H, -aryl, -CH₂-aryl, -NH- aryl, -O-aryl, -S(O)_m-aryl, -J, -NO₂, -CN, -N₃, -CHO, -CF₃, -OCF₃, -R⁷, -OR⁷, -S(0)_mR⁷, -NR⁷R⁷, - NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, - C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷-, -OC(O)OR⁷, -OC(O)NR⁷R⁷, -NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -

NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, - R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, - R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, and -R⁸NR⁷C(O)NR⁷R⁷;

J is fluoro, chloro, bromo, or iodo;

X is N, or C-R¹¹;

Y is N, or C-R¹³;

m is an integer of 0-2; and

Z is a divalent group independently selected from a bond, alkyl of 1 -6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, O, and -NR⁷.

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, -R⁷, -OR⁷, -

NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -

R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, - R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷, -OPO(OR⁷)₂, -YR⁸R¹⁰, -YR⁸NR⁷R⁷ and -YR¹⁰.

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

_| A wherein '^_y 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, -R⁷, -OR⁷, -S(O)_mR⁷, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -

OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, -N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -

OC(O)R⁷, -OC(O)OR⁷, -OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -

R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, -R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -

R⁸OC(O)NR⁷R⁷, -R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷, -YR⁸R¹⁰, -YR⁸NR⁷R⁷ and - YR¹⁰.

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, - R⁷, -OR⁷, -S(O)_mR⁷, -NR⁷R⁷, -NR⁷S(O)_mR⁷, -OR⁹OR⁷, -OR⁹NR⁷R⁷, -N(R⁷)R⁹OR⁷, - N(R⁷)R⁹NR⁷R⁷, -NR⁷C(O)R⁷, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁷R⁷, -OC(O)R⁷, -OC(O)OR⁷, - OC(O)NR⁷R⁷, NR⁷C(O)R⁷, -NR⁷C(O)OR⁷, -NR⁷C(O)NR⁷R⁷, -R⁸OR⁷, -R⁸NR⁷R⁷, -R⁸S(O)_mR⁷, - R⁸C(O)R⁷, -R⁸C(O)OR⁷, -R⁸C(O)NR⁷R⁷, -R⁸OC(O)R⁷, -R⁸OC(O)OR⁷, -R⁸OC(O)NR⁷R⁷, - R⁸NR⁷C(O)R⁷, -R⁸NR⁷C(O)OR⁷, -R⁸NR⁷C(O)NR⁷R⁷, -YR⁸R¹⁰, -YR⁸NR⁷R⁷ and -YR¹⁰.

5. The compound of any one of claims 1-4, wherein X is N and R⁴ and R¹² are joined, together with the atoms to which they are attached, forming a ring.

6. The compound of any one of claims 1-4, wherein Y is N and R⁶ and R¹⁴ are joined, together with the atoms to which they are attached, forming a ring.

7. The compound of any one of claims 1-4, wherein X is C-R¹¹ and R⁶ and R¹¹ are joined, together with the atoms to which they are attached, forming a ring.

8. The compound of any one of claims 1-4, wherein X is C-R¹¹ and R⁴ and R⁵ are joined, together with the atoms to which they are attached, forming a ring.

9. A compound selected from: Ethyl 3-(3-hydroxyphenyl)-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H- 6,9-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-12-carboxylate, 2-Chloro-5-[12-methyl-8- (phenylsulfonyl)-2-pyridin-4-yl-7,8,9, 10-tetrahydro-6H- 7, 10-epiminocyclohepta[e]pyrazolo[1 ,5- a]pyrimidin-3-yl]phenol, Methyl 3-(4-chloro-3-hydroxyphenyl)-12-methyl-2-pyridin-4-yl-7,8,9,10- tetrahydro-6H-7, 10-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-8-carboxylate, 2-Chloro-5-[8- (hydroxymethyl)-12-methyl-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H-7,10- epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidin-3-yl]phenol, 12-Benzyl-3-(4-chloro-3- methoxyphenyl)-8-(phenylsulfonyl)-2-pyridin-4-yl-7,8,9, 10-tetrahydro-6H-7, 1 O-epiminocyclo- hepta[e]pyrazolo[1 ,5-a]pyrimidine, (8S)-3-(4-Chloro-3-hydroxyphenyl)-12-methyl-2-pyridin-4-yl- 7,8,9, 10-tetrahydro-6H-7, 10-epiminocyclohepta[e]pyrazolo[1 ,5-a]pyrimidine-8-carboxylic acid, 3- (2'-Pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenol, 3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5- a]quinazoline], 3-(2'-Pyridin-4-yl-8',9'-dihydro-6'H-spiro[1 ,3-dioxolane-2,7'-pyrazolo[1 ,5- a]quinazolin]-3'-yl)phenyl pivalate, 3'-(3-Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-7'H- spiro[1 ,3-dioxolane-2,6'-pyrazolo[1 ,5-a]quinazoline], 3-(2'-Pyridin-4-yl-8',9'-dihydro-7'H-spiro[1 ,3- dioxolane-2,6'-pyrazolo[1 ,5-a]quinazolin]-3'-yl)phenol, terf-Butyl 3'-(3-methoxyphenyl)-2'-pyridin- 4-yl-8',9'-dihydro-1 H,6'H- spiro[piperidine-4,7'-pyrazolo[1 ,5-a]quinazoline]-1-carboxylate, 3'-(3- Methoxyphenyl)-2'-pyridin-4-yl-8',9'-dihydro-6'H-spiro[piperidine-4,7'-pyrazolo[1 ,5-a]quinazoline], 3'-(3-methoxyphenyl)-2'-pyridin-4-yl-5',6'-dihydro-8'H-spiro[piperidine-4,7'-pyrazolo[5,1- b]quinazoline], 3-(2'-Pyridin-4-yl-8',9'-dihydro-6'H-spiro[piperidine-4,7'-pyrazolo[1 ,5- a]quinazolin]-3'-yl)phenol, 4-Bromo-3'-(4-bromo-3-methoxyphenyl)-2'-pyridin-4-yl-4,5,8',9'- tetrahydro-3H,7'H-spiro[furan-2,6'-pyrazolo[1 ,5-a]quinazoline], and pharmaceutically acceptable salts thereof.

10. A method for making a compound of claim 1 comprising the steps of: (a) reacting a substituted ketone of formula 1 :

with an acetal of N,N-dialkylformamide or an acetal of N,N-dialkylacetamide, providing an enaminone compound of formula 2:

2; and

11. A method for making a compound of claim 1 comprising the steps of: (a) reacting an enaminone compound of formula 2:

with an aminopyrazole of formula 3a:

3a providing compounds of formula 4 and 5

(b) halogenating one or both of the compounds of formula 4 and 5, providing one or both of corresponding halo-pyrazole compounds of formula 6 and 7:

7; and

(c) subjecting one or both of the compounds of formula 6 and 7 to a palladium catalyzed, Suzuki coupling reaction using aryl or heteroaryl boronic acids or corresponding boronate esters.

12. The method according to claim 1 1 , wherein the compounds of formula 4 and 5 are separated prior to step (b).

13. The method according to claim 1 1 , wherein the compounds of formula 6 and 7 are separated prior to step (c).

14. The method according to claim 1 1 , wherein the compounds of formula A and B are separated after step (c).

15. A pharmaceutical composition comprising a compound according to any of claims 1 -9 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, capable of inhibiting Raf kinase activity.

17. 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 1-9.

18. A method of treating a B-Raf kinase-dependent cancer, by administering to a patient a compound any one of claims 1-9.

19. The method of claim 18, 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.