Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors

Field of Invention

The invention generally relates to new chemical compounds and processes. More particularly, the invention provides enantiomerically pure aminoheteroaryl compounds, particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity, and methods for synthesizing and using such compounds. Preferred compounds are c-Met inhibitors useful for the treatment of abnormal cell growth such as cancers.

Background

In many human cancers, the hepatocyte growth factor receptor (c-MET or HGFR) or receptor tyrosine kinase (RTK) has been shown to be involved in oncogenesis, tumor progression with enhanced cell motility and invasion, as well as metastasis ( see eg Ma, PC, Maulik, G., Christensen, J. & Salgia, R. (2003b) Cancer Metastasis Rev, 22, 309-25 Maulik, G., Shrikhande, A., Kijima, T ., Ma, PC, Morrison, PT & Salgia, R. (2002b). Cytokine Growth Factor Rev, 13, 41-59). c-MET (HGFR) can be activated through overexpression or mutations in various human cancers including small cell lung cancer (SCLC) (Ma, PC, Kijima, T., Maulik, G., Fox,

EA, Sattler, M., Griffin, JD, Johnson, BE & Salgia, R. (2003a). Cancer Res, 63, 6272-6281).

c-MET is a receptor tyrosine kinase that is encoded by the Met proto-oncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also called dispersal factor (SF). Jiang et al., Crit. Rev. oncol. Hematol. 39: 209-248 (1999). c-MET and HGF are expressed in numerous tissues, although their expression is normally limited primarily to cells of epithelial and mesenchymal origin, respectively. c-MET and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of three-dimensional tubular structures (eg, renal tubular cells, gland formation). , etc.). In addition to its effects on epithelial cells, HGF/SF has been reported to be an angiogenic factor, and c-MET signaling in endothelial cells can induce many of the cellular responses required for angiogenesis (proliferation, motility, invasion). .

The c-MET receptor has been shown to be expressed in numerous human cancers. c-Met and its ligand, HGF, have been shown to be co-expressed at high levels in various human cancers (particularly sarcomas). However, as the receptor and ligand are normally expressed by different cell types, c-MET signaling is more commonly regulated by tumor-stroma (tumor-host) interactions. In addition, c-MET gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germline mutations that activate c-MET kinase are prone to multiple renal tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-MET and/or HGF/SF with the disease progression status of different types of cancers (including cancers of the lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin and bones). In addition, overexpression of c-MET or HGF has been shown to correlate with poor prognosis and disease onset in numerous major human cancers including lung, liver, gastric, and breast. c-MET has also been directly implicated in cancers without a satisfactory treatment regimen such as pancreatic cancer, glioma, and hepatocellular carcinoma.

Examples of c-MET (HGFR) inhibitors, their synthesis and use can be found in US Patent Application No.⁹ 10/786,610, entitled Aminoheteroaryl Compounds as Protein Kinase Inhibitors, filed February 26, 2004, and the corresponding international application PCT/US2004/005495 ​​with the same title, filed February 26, 2004. 2004, the disclosures of which are incorporated herein by reference in their entirety.

It would be desirable to have new inhibitors of c-MET (HGFR) and methods of using such inhibitors for the treatment of abnormal cell growth, such as cancer.

Summary

In one embodiment, the invention provides an enantiomerically pure compound of formula 1

<img file="ECSP077276A_D0001.tif" />

in which

YesNoCR¹²;

R.¹ is selected from hydrogen, halogen, C6.12 aryl, 5-12 membered heteroaryl, C3.12 cycloalkyl, 3-12 membered heteroalicyclyl, -O(CR⁶R.⁷)nR⁴, -C(O)R⁴, -C(O)OR⁴, -CN, -NO2, -S(O)mR⁴, SO2NR⁴R.⁵, -C(O)NR⁴R.⁵. -NR⁴C(O)R⁵, -C(=NR⁶)NR⁴R.⁵, alkyl C_V8, alkenyl C₂.₈ and alkynyl C₂.₈; and each hydrogen in R¹ is optionally substituted by one or more R groups³;

R.² is hydrogen, halogen, CV12 alkyl, C2_12 alkenyl, C212 alkynyl, C3.12 cycloalkyl, Cs 12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, -S(O)2OR⁴, -NO2, NR⁴R.⁵, -(CR⁶R.⁷)rOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -O(CR⁶R.⁷)nR⁴, -NR⁴C(O)R⁵, -(CR⁶R.⁷)rC(O)OR⁴, (CR⁶R.⁷)nNCR⁴R.⁵, -C(=NR⁶)NR⁴R.⁵, -NR⁴C(O)NR⁵R.⁶, -NR⁴SW)_pR.^and or -C(O)NR⁴R.⁵ and each hydrogen in R²is optionally replaced by R⁸;

each R³ is independently halogen, Ci_i2 alkyl, C2_i2 alkenyl, C2.i2 alkynyl, C3.12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, S(O)2OR⁴, -NO2, -NR⁴R.⁵, -(CR⁶R.⁷)nOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -O(CR⁶R.⁷)nR⁴, -NR⁴C(O)R^AND, (CR⁶R.⁷)nC(O)OR⁴, -(CR⁶R.⁷)nOR⁴, -(CR⁶R.⁷)nC(O)NR⁴R.⁵, -(CR⁶R.⁷)nNCR⁴R.^AND, -C(=NR⁶)NR⁴R.⁵,NR⁴C(O)NR⁵R.⁶, -NR⁴S(O)pR⁵ or -C(O)NR⁴R.⁵, each hydrogen in R³ is optionally substituted by R groups⁸, and the R groups³ on adjacent atoms can combine to form a C6 aryl.i₂, 5-12 membered heteroaryl, C cycloalkyl₃_Yo₂ or a 3-12 membered heteroalicyclic group;

each R⁴,R⁵,R⁶ and R⁷ is independently hydrogen, halogen, C1-i2 alkyl, C2.i2 alkenyl, C2.12 alkynyl, C3.12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl; or any two of R⁴,R⁵,R^yes and R⁷ attached to the same nitrogen atom, together with the nitrogen to which they are attached, may combine to form a 3- to 12-membered heteroalicyclic or 5-12-membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and Yes; or any two of R⁴,R⁶,R^yes and R⁷ attached to the same carbon atom can combine to form a C3 cycloalkyl.i₂, aryl C₅-Yo₂, 3-12 membered heteroalicyclic group or 5-12 membered heteroaryl; and each hydrogen in R⁴,R⁵,R⁶ and R⁷ is optionally replaced by R⁸;

each R⁸ is independently halogen, alkyl Ci.i₂, alkenyl C₂.Yo₂, alkynyl C₂.₁₂, C-cycloalkyl₃-12, Ce-12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -NH₂, -CN, -OH, -0Ci-i alkyl₂, -O-(CH₂)_no-cycloalkyl C₃.-|₂, -O-(CH₂)_no-ar¡lo C₆-Yo₂, -0-(CH₂)_no(3-12 membered heteroalicyclyl) or -0-(CH₂)_r(heteroaryl of 5-12 members); and each hydrogen in R⁸ is optionally replaced by R¹¹;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C112 alkyl, C312 cycloalkyl, C6 12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, -S(O)2OR⁴, N02, -NR⁴R.⁵, -(CR⁶R.⁷)nOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -NR⁴C(O)R⁵, -(CR⁶R.⁷)rC(O)OR⁴, -(CR⁶R.⁷)nNCR⁴R.⁵, -NR⁴C(O)NR⁵R.⁶, -NR⁴S(O)pR⁵ or -C(O)NR⁴R.⁵; R.⁹ or R¹⁰ can combine with a ring atom of A or a substituent of A to form a C cycloalkyl₃_₁₂, 3-12 membered heteroalicyclyl, aryl C₆_₁₂ or a 5-12 membered heteroaryl ring fused with A; and each hydrogen in R⁹ and R¹⁰ is optionally replaced by R³;

each R¹¹ is independently halogen, 0^alkyl, C^^alkoxy, C3.12cycloalkyl, Cs.12aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -O-Ci_i2 alkyl, -0-(CH2)rc C3 cloalkyl. 12, -O-(CH2)naryl C6.12, -0-(CH2)n(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or - CN and each hydrogen in R¹¹ is optionally substituted by halogen, -OH, -CN, -Ci_i2 alkyl which may be partially or fully halogenated, -O-C^ alkyl which may be partially or fully halogenated, -CO, -SO or -S0₂;

R.¹² is hydrogen, halogen, C^u alkyl, C2_i2 alkenyl, C2.12 alkynyl, C3.12 cycloalkyl, Cs.12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, -S(O)2OR⁴, -NO2, NR⁴R.⁵, -(CR^B.R.⁷)rOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -O(CR⁶R.⁷)nR⁴, -NR⁴C(O)R⁵, -(CR⁶R.⁷)rC(O)OR⁴, (CR⁶R.⁷)nNCR⁴R.⁵, -C(=NR⁶)NR⁴R.⁵, -NR⁴C(O)NR⁵R.⁶, -NR⁴SW)_pR.⁵ or -C(O)NR⁴R.⁵ and each hydrogen in R¹²is optionally replaced by R³;

each R¹³ is independently halogen, CV12 alkyl, C212 alkenyl, C2.12 alkynyl, C3.12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, S(O)2OR⁴, -NO2j -NR⁴R.⁵, -(CR⁶R.⁷)nOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -O(CR⁶R.⁷)nR⁴, -NR⁴C(O)R⁵, (CR⁶R.⁷)nC(O)OR⁴, -(CR⁶R.⁷)nOR⁴, -(CR⁶R.⁷)nC(O)NR⁴R.⁵, -(CR⁶R.⁷)nNCR⁴R.⁵, -C(=NR⁶)NR⁴R.⁵,NR⁴C(O)NR⁵R.⁶, -NR⁴S(O)pR⁵, -C(O)NR⁴R.⁵, -(CR⁶R.⁷)n(3-12 membered heteroalicyclyl), (CR⁶R.⁷)n(C3.12cycloalkyl), -(CR⁶R.⁷)n(aryl C₆.₁₂), -(CR⁶R.⁷)n(5-12 membered heteroaryl), (CR⁶R.⁷)nC(O)NR⁴R.⁵, or -(CR⁶R.⁷)nC(O)R⁴, the R groups¹³ on adjacent atoms can combine to form a C6 aryl group.₁₂, 5-12 membered heteroaryl, C cycloalkyl₃.₁₂ or 3-12 membered heteroalicyclic and each hydrogen in R¹³ is optionally replaced by R³;

each m is independently 0,1 or 2;

each n is independently 0,1,2,304;

each p is independently 1 or 2;

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In a particular aspect of this embodiment, R² it's hydrogen.

In another particular aspect of this embodiment, Y is N.

In another particular aspect of this embodiment, Y is N and R² it's hydrogen.

In another particular aspect of this embodiment, Y is CR¹².

In another particular aspect of this embodiment, Y is CR¹² and R¹² it's H.

In another particular aspect of this embodiment and in combination with any other non-contradictory particular aspect, R¹ is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine group , dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane, or phenyl and each hydrogen in R¹ is optionally substituted by one or more R groups³.

In another particular aspect of this embodiment and in combination with any other non-contradictory particular aspect, R¹ is a fused ring heteroaryl group and each hydrogen in R¹ is optionally substituted by one or more R groups³.

In another particular aspect of this embodiment and in combination with any other non-contradictory particular aspect, R¹ it's hydrogen.

In another particular aspect of this embodiment and in combination with any other non-contradictory particular aspect, R¹ it is a halogen.

In another embodiment, the invention provides an enantiomerically pure compound of formula 1a

<img file="ECSP077276A_D0002.tif" />

in which:

YesNoCH;

R.¹ is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine group , dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane, azitidine or phenyl; and each hydrogen in R¹ is optionally replaced by

R.³;

each R³ is independently halogen, C^u alkyl, C2.12 alkenyl, C2.12 alkynyl, C3_i2 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, S(O)2OR⁴, -NO2, -NR⁴R.⁵, -(CR^B.R.⁷)nOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -O(CR⁶R.⁷)nR⁴, -NR⁴C(O)R^£, (CR³R.⁷)nC(O)OR⁴, -(CR⁶R.⁷)nOR⁴, -(CR⁶R.⁷)nC(O)NR⁴R.⁵, -(CR⁶R.⁷)nNCR⁴R.⁵, -C(=NR⁶)NR⁴R.⁵,NR⁴C(O)NR⁵R.⁶, -NR⁴S(O)pR⁵ or -C(O)NR⁴R.⁵, each hydrogen in R³ is optionally replaced by R⁸ and the R groups³ on adjacent atoms can combine to form a C6_ aryl group₁₂, 512-membered heteroaryl, C-cycloalkyl₃.₁₂ or 3-12 membered heteroalicyclic;

each R⁴,R⁵,R⁶ and R⁷ is independently hydrogen, halogen, alkyl (\₁₂, alkenyl C₂.₁₂, alkynyl C₂.₁₂, C-cycloalkyl₃.₁₂, aryl C₆_Yo₂, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl; or any two of R⁴,R⁵,R³ and R⁷ attached to the same nitrogen atom, together with the nitrogen to which they are attached, may combine to form a 3- to 12-membered heteroalicyclic or 5-12-membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R⁴,R⁵,R³ and R⁷ attached to the same carbon atom can combine to form a C cycloalkyl group₃.₁₂, aryl C₆-Yo₂, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl; and each hydrogen in R⁴,R⁵,R⁶ and R⁷ is optionally replaced by R⁸;

each R⁸ is independently halogen, C alkyl_V12, alkenyl C₂_₁₂, alkynyl C₂.₁₂, C-cycloalkyl₃_12, aryl C₆.₁₂, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -NH₂, -CN, -OH, -0C alkyl_V12, -O-(CH₂)_noC cycloalkyl₃.₁₂, -O-(CH₂)_noaryl C₆_₁₂, -O-(CH₂)_no(3-12 membered heteroalicyl) or -O-(CH₂)_no(5-12 membered heteroaryl); and each hydrogen in R⁸ is optionally replaced by R¹¹;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C^ alkyl, C3.12 cycloalkyl, C6 aryl. 12, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, -S(O)2OR⁴, N02, -NR⁴R.⁵, -(CR⁶R.⁷)nOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -NR⁴C(O)R⁵, -(CR⁶R.⁷)rC(O)OR⁴, -(CR⁶R.⁷)nNCR⁴R.⁵, -NR⁴C(O)NR⁵R.⁶, -NR⁴S(O)pR⁵ or -C(O)NR⁴R.⁵; R.⁹ or R¹⁰ can combine with a ring atom of A or a substituent of A to form a C cycloalkyl ring₃.Yo₂, 3-12 membered heteroalicyclic, aryl C₆-12 or 5-12 membered heteroaryl fused with A; and each hydrogen in R⁹ and R¹⁰ is optionally replaced by R³;

each R¹¹ is independently halogen, 0^2 alkyl, ΰνΐ2 alkoxy, C3.12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -O-Cm2 alkyl, -0-(CH2)nC3 cycloalkyl . 12, -0-(CH2)rarylC6.12, -0-(CH2)n(3-12 membered heteroalicyclyl), -0-(CH2)r(5-12 membered heteroaryl) or -CN and each hydrogen in R¹¹ is optionally substituted by halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -O-C112 alkyl which may be partially or fully halogenated, -CO, -SO or -S0₂;

each R¹³ is independently halogen, C1.12alkyl, C2.12alkenyl, C2.12alkynyl, C3.12cycloalkyl, Ce-12aryl, 3-12 membered heteroalicyclyl, 5-12 membered heteroaryl, -S(O)mR⁴, -SO2NR⁴R.⁵, S(O)2OR⁴, -N02i -NR⁴R.⁶, -(CR⁶R.⁷)nOR⁴, -CN, -C(O)R⁴, -OC(O)R⁴, -O(CR⁶R.⁷)nR⁴, -NR⁴C(O)R^£, (CR⁸R.⁷)nC(O)OR⁴, -(CR⁶R.⁷)nOR⁴, -(CR³R.⁷)nC(O)NR⁴R.⁵, -(CR³R.⁷)nNCR⁴R.⁵, -C(=NR³)NR⁴R.⁵,NR⁴C(O)NR⁶R.⁶, -NR⁴S(O)pR^yes, -C(O)NR⁴R.⁶, -(CR⁶R.⁷)n(heteroallic¡cle of 3-12 members), (CR^andR.⁷)n(C3-i2cycloalkyl), -(CR⁶R.⁷)n(aryl C₆-Yo₂), -(CR⁶R.⁷)n(5-12 membered heteroaryl), (CR⁶R.⁷)nC(O)NR⁴R.⁵, or -(CR³R.⁷)nC(O)R⁴, the R groups¹³ on adjacent atoms can combine to form a C6 aryl group.₁₂, 5-12 membered heteroaryl, C cycloalkyl₃.₁₂ or 3-12 membered heteroalicyclic and each hydrogen in R¹³ is optionally replaced by R³;

each m is independently 0,1 or 2;

each n is independently 0,1,2,304;

each p is independently 1 or 2;

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another embodiment, the invention provides an enantiomerically pure compound selected from the group consisting of 5-Bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2 -ylamine; 5-iodine-

3-[(R)1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-lamin; 5-bromo-3-[1(ñ)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyridin-2-ylamine; 4-{5-Amino-6-[(/?)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid; (4-{5Amino-6-[(R)-1 -(2,6-dichloro-3-f luoro-f en yl)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazin-1 -yl-methanone; 4-(4-{5-Amino-6-[(/3)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoyl) tert-butyl ester -piperazine-1 carboxylic acid; 3-[(1 /3)-1 -(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-(p¡peraz¡n-1 -ylcarbonyl)fen¡l]p¡r¡din -2-amine; 4-{6amino-5-[(1 /3)-1 -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-A/-[2-(dimethylam¡no)ethyl]- /\/-methylbenzamide; (4-{6amino-5-[( 1 /3)-1 -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}phenyl)methanol; 4-{6-amino-5-[(1/3)-1 -(2,6-dichloro-3fluorophenyl)ethoxy]pyridin-3-yl}-/\/-[3-(dimethylam¡no)propyl] -/\/-methylbenzamide; 4-(4-{6-amino-5-[(1/3)-1-(2,6-dichloro-3-fluorophenyl)ethoxy¡]pyridin-3-yl}benzoyl)piperazine-1-carboxylate tere-butyl; 3-[(fi)-1 -(2,6-Dichloro-3f fluoro-phenyl)-ethox¡]-5-[1 -(1 -methyl-piperidin-4-yl) -1 Hp¡razol- 4-il]-p¡r¡d¡n-2-¡lam ¡na; 1 -[4-(4-{6-Am in o-5-[(/?)-1 (2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3- Il}-pyrazol-1-yl)-piperidin-1-ylj-2-hydroxy-ethanone; 3-[(ñ)-1-(2,6Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)- pi rid in-2-¡lam ¡na; 3-[(R)-1 -(2,6-Dichloro-3fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazo I-4-¡I)-pyridin- 2-lamina; 3-[(R)-1 -(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-(1-piperidin-4-¡I-1 Hp¡ razol-4-yl)-p razin-2-ylamine; 3-[(fi)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1Hpyrazol-4-yl)-pyrazin-2-ylamine; 1-[4-(4-{5-Amino-6-[(ñ)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-p¡razin-2- ¡l}pyrazol-1-yl)-piperidin-1-yl]-2-hydroxy-ethanone; 3-[(phy)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1 -(1-methylpiperidin-4-yl)-1H-pyrazo I-4-¡ I]-p¡razin-2-ilam i na; 1 -[4-(4-{5-Amino-6-[(phy)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]p¡razin-2-¡I}-p ¡razol-1-yl)-piperidin-1-yl]-2-dimethylamino-ethanone; 3-((/3)-1 -(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5(1-piperidin-4-yl-1Hp¡razol-4-yl)-p¡ r¡d¡n-2-¡lam¡na; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In another embodiment, the invention provides a pharmaceutical composition comprising any of the compounds of the invention and a pharmaceutically acceptable carrier. Examples of such compositions are described below.

Preferred compounds of the invention include those having c-MET inhibitory activity as defined by any one or more of CI₅₀, K¡, or percentage inhibition (%l). Whether a compound has such activity can be readily determined by one skilled in the art by performing the appropriate assay, and descriptions of such assays are set forth in the Examples section of this document. In one embodiment, particularly preferred compounds have a c-MET K¡ of less than 5 μΜ or less than 2 μΜ or less than 1 μΜ or less than 500 nM or less than 200 nM or less of 100 nM. In another embodiment, particularly preferred compounds have an inhibition of c-MET at 1 μΜ of at least 10%, or of at least 20%, or of at least 30%, or of at least 40%, or of at least 40%. less than 50% or at least 60% or at least 70% or at least 80% or at least 90%. Methods for measuring c-MET/HGFR activity are described in the Examples herein.

In another embodiment, the invention provides a method of treating abnormal cell growth in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention.

In a specific embodiment of any of the methods of the invention described herein, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer. , cutaneous or infraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid gland cancer, parathyroid gland cancer, cancer of the the adrenal gland, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureteral cancer, Renal cell carcinoma, carcinoma of the renal pelvis, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of the previous cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy, or restenosis.

In another embodiment, the invention provides a method of treating an HGFR-mediated disorder in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention.

In more specific embodiments of any of the methods of the invention described herein, the method further comprises administering to the mammal an amount of one or more substances selected from among antitumor agents, anti-angiogenesis agents, signal transduction inhibitors, and agents antiproliferatives, which amounts are jointly effective in treating said abnormal cell growth. Such substances include those described in PCT Publications No.^and WO 00/38715, WO 00/38716, WO 00/38717, WO 00/38718, WO 00/38719, WO 00/38730, WO 00/38665, WO 00/37107 and WO 00/38786, the disclosures of which are incorporated in this document by reference in its entirety.

Examples of antitumor agents include mitotic inhibitors, for example vinca alkaloid derivatives such as vinblastine, vinorelbine, vindescine and vincristine; colquines, allocoquine, halichondrin, colchicinic acid /V-benzoyltrimethyl-methyl ether, dolastatin 10, maistansin, rhizoxin, taxanes such as taxol (paclitaxel), docetaxel (Taxotere), 2'-A/-[3-(dimet ¡lam¡no)propyl]glutaramate (taxol derivative), thiocolchicine, trityl cysteine, teniposide, methotrexate, azathioprine, fluorouricil, cytokine arabinoside, 2',2'-difluorodeoxycytidine (gemcitabine), adriamycin, and mitamycin. Alkylation agents, for example cis-platinum, carboplatinum, oxyplatinum, iproplatinum, /V-acetyl-DL-sarcosyl-L-leucine ethyl ester (Asaley or Asalex), 1,4-cyclohexadien-1,4-dicarbamic acid , 2,5-b/s-(1 -azirdinyl)-3,6-dioxo-, diethyl ester (diaziquone), 1,4-b/s-(methanesulfonyloxy)butane (bisulfan or leucosulfan), chlorozotocin, clomesone, cyanomorpholinodoxorubicin, cyclodisone, dianhydroglactitol, fluorodopan, hepsulfam, mitomycin C, hycanteonemitomycin C, mitozolamide, 1-(2-chloroethyl)-4-(3-chloropropyl)-p¡peraz¡na dihydrochloride, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, tea hydrochloride >/s(3-mesyloxypropyl)amine, mitomycin, nitrosourea agents such as cyclohexyl-chloroethylnitrosourea, methylcyclohexyl-chloroethylnitrosourea, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitroso-urea , t>/s(2-chloroethyl)nitrosourea, procarbazine, dacarbazine, nitrogen mustard related compounds such as mechloroethamine, cyclophosphamide, ifosamide, melphalan, chlorambucil, estramustine sodium phosphate, streptozoin, and temozolamide. DNA antimetabolites, e.g. 5-fluorouracil, cytosine arabinoside, hydroxyurea, 2-[(3-hydroxy¡-2pyrinodinyl)methylene]-hydrazinecarbothioamide, deoxyfluorouridine, 5-hydroxy-2-formylpyridine-thiosemicarbazone, alpha-2'- deoxy-6-thioguanosine, aphidicolin glycinate, 5-azadeoxycytidine, beta-thioguanine-deoxyriboside, cyclocytidine, guanazole, inosine glycodialdehyde, macbezine II, pyrazolimidazole, cladribine, pentostatin, thioguanine, mercaptopurine, bleomycin, 2-chlorodeoxyadenosine, thymidylate synthase inhibitors such as raltitrexed and pemetrexed disodium, clofarabine, floxuridine and fludarabine. DNA/RNA antimetabolites, for example, L-alanosine, 5-azacitidine, acivicin, aminopterin and derivatives thereof such as A/-[2-chloro-5-[[(2,4-diam¡no acid -5-methyl-6-quinazol¡n¡l)methyl]am¡no]benzo¡l]-L-aspart¡co acid A/-[4[[(2,4-d¡am ¡no-5-et¡l-6-quinazol¡n¡l)methyl]amino]benzo¡l]-L-aspart¡c acid, /V-[2-chloro-4-[[( 2,4Diam¡nopteridinyl)methyl]am¡no]benzoyl]-l_-aspartic acid, Baker's antifol soluble, dichloroallyl lawsone, brequinar, ftoraf, dihydro-5-azacitidine, methotrexate, tetrasodium salt of A/-(phosphonoacetyl)-L-aspartic acid, pyrazofuran, trimetrexate, plicamycin, actinomycin D, cryptophycin and analogs such as cryptophycin-52 or, for example, one of the preferred antimetabolites described in the Application of European Patent No.^yes 239362 such as M-(5-[/y-(3,4-d¡h¡dro-2-methyl-4-oxoquinazol¡n-6-¡lmethyl)-/y-met acid ¡lam¡no]-2-teno¡l)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalation antibiotics, for example adriamycin and bleomycin; proteins, eg interferon; and anti-hormones, for example anti-estrogens such as Nolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™ (4'-cyano-3-(4fluorophenylsulfonyl)-2-hydroxy-2-methyl-3' -(trifluoromethyl)propionanilide). Such conjoint treatment can be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

Anti-angiogenesis agents include MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloprotease inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No.^yes 97304971.1 (filed July 8, 1997), European Patent Application No.^yes99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published January 13, 1998). WO 98/33768 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), Patent Publication European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published October 17, 1999). June 1999), PCT International Application No.⁹ PCT/IB98/01113 (filed July 21, 1998), European Patent Application No.⁹ 99302232.1 (Filed March 25, 1999), Great Britain Patent Application No. 9912961.1 (Filed June 3, 1999), United States Provisional Application No.⁹ 60/148,464 (filed August 12, 1999), US Patent 5,863,949 (issued January 26, 1999), US Patent 5,861,510 (issued January 19, 1999), and Publication of European Patent 780,386 (issued June 25, 1997), all of which are incorporated herein by reference in their entireties. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. Those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).

Examples of MMP inhibitors include AG-3340, RO 32-3555, RS 13-0830, and the following compounds: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxy¡carbamoyl- cyclopentyl)-amino]propionic; 3-Exo-3-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-8-oxabicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; (2ñ,3fí) 1-[4-(2-chloro-4-fluoro-benzyloxy¡)benzenesulfonyl]-3-hydroxy-3-methyl-piperidin-2-carboxylic acid hydroxyamide; 4-[4-(4-Fluoro-phenox¡)benzenesulfonylaminoj-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenox¡)benzenesulfonylaminoj-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[4-(4-Chloro-phenoxy)benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide; (2fi,3ñ) 1-[4-(4-Fluoro-2-methylbenzyloxy¡)-benzenesulfonyl]-3-hydroxy¡-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenox¡)benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-am¡no]-propionic acid; 3-[[4-(4-fluoro-phenoxy¡)benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic acid; 3-exo-acid hydroxyamide

3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic; acid hydroxyamide

3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic; 3-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts, solvates and hydrates thereof.

Examples of signal transduction inhibitors include agents that can inhibit EGFR (Epidermal Growth Factor Receptor) responses, such as anti-EGFR antibodies, anti-EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example HERCEPTIN™ (Genentech, Inc. of South San Francisco, California, United States).

EGFR inhibitors are described, for example, in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published April 22, 1998). January 1998) and US Patent 5,747,498 (issued May 5, 1998). Agents that inhibit EGFR include, but are not limited to, C225 and anti-EGFR monoclonal antibodies 22Mab (ImClone Systems Incorporated of New York, New York, USA), compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim ), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck &amp; Co. of Whitehouse Station, New Jersey, USA), VRCTC310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusetts).

VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, California, USA), may also be combined or co-administered with the composition. VEGF inhibitors are described, for example, in WO 99/24440 (published May 20, 1999), International Application PCT/IB99/00797 (filed May 3, 1999), WO 95/ 21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), US Patent No. 5,834,504 (issued November 10, 1998), WO 98/50356 (published on November 12, 1998), US Patent 5,883,113 (issued March 16, 1999), US Patent 5,886,020 (issued March 23, 1999), US Patent No.^yes 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999), WO 97/32856 (published Sept. 12, 1997), WO 97/22596 (published Sept. 26, 1999). WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO98 /02437 (published January 22, 1998), all of which are incorporated herein by reference in their entireties. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal antibody bevacizumab (Genentech, Inc. of South San Francisco, California); and angiozyme, a synthetic phybozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome pie), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), can be given in combination with the composition. Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999); WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO

95/19970 (issued July 27, 1995), US Patent 5,587,458 (issued December 24, 1996), and US Patent 5,877,305 (issued March 2, 1999), each of which are incorporated herein by reference in their entirety. ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No.⁹ 60/117,341, filed January 27, 1999, and in US Provisional Application No.⁹60/117,346 filed January 27, 1999, both of which are incorporated herein by reference in their entireties.

Other antiproliferative agents that can be used include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the PDGFr receptor tyrosine kinase, including the compounds described and claimed in the following US Patent Applications: 09/221946 (filed December 28, 1998 ); 09/454058 (filed December 2, 1999), 09/501163 (filed February 9, 2000); 09/539930 (filed March 31, 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds described and claimed in the following US Provisional Patent Applications 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed November 30, 1999) and 60/200834 (filed May 1, 2000). Each of the foregoing patent applications and provisional patent applications is incorporated herein by reference in its entirety.

The compositions of the invention may also be used with other agents useful in the treatment of abnormal cell growth or cancer, including, but not limited to, agents capable of potentiating anti-tumor immune responses, such as antibodies against CTLA4 (cytotoxic lymphocyte antigen 4) , and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors. Antibodies specific to CTLA4 that can be used in the present invention include those described in US Provisional Application 60/113,647 (filed December 23, 1998), which is incorporated herein by reference in its entirety.

Definitions

Unless otherwise indicated, the following terms used in the specification and claims have the meanings indicated below. Variables defined in this section, such as R, X, n, and the like, are for reference only in this section, and are not meant to have the same meaning that may be used outside of this definitions section. In addition, many of the groups defined in this document can be optionally substituted. The list in this section of definitions of typical substituents is illustrative and is not intended to limit in any way the substituents defined in this specification and in the claims.

"Alkyl" refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms. carbon atoms, or from 1 to 4 carbon atoms. Lower alkyl refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, /so-butyl, ert-butyl, pentyl, and the like. Alkyl can be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, W-carbamyl, O-thiocarbamyl, A/-thiocarbamyl , C-amido, A/-amido, Ccarboxy, O-carbox¡, nitro, silyl, amino and -NR^xR.^and, where R^x and R^and are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl, and, in combination, a five or six membered heteroalicyclic ring.

"Cycloalkyl" refers to a monocyclic ring group of 3 to 8 members all of which are carbon, a fused bicyclic 5-membered/6-membered or 6-membered/6-membered all of carbon ring group, or a multicyclic fused ring group (a fused ring system means that each ring in the system shares an adjacent pair of carbon atoms with each of the other rings in the system) where one or more of the rings may contain one or more double bonds but neither ring has a fully conjugated p, electron system. Examples, without limitation, are cycloalkyl groups; cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like. A cycloalkyl group can be substituted or unsubstituted. Typical substituent groups include alkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, /V-carbamyl, C-amido, /V-amido, nitro, amino and -NR^xR.^and, with R^x and R^and as defined above. Illustrative examples of cycloalkyl are derived, but are not limited to, from the following:

Alkenyl refers to an alkyl group, as defined herein, composed of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

Alkynyl refers to an alkyl group, as defined herein, composed of at least 2 carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

Aryl refers to monocyclic or polycyclic fused ring groups with all ring members of carbon atoms, from 6 to 12 carbon atoms having a fully conjugated pi electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl, and anthracenyl. The aryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carbox¡, O-carboxy, O-carbamyl, /V-carbamyl, O- thiocarbamyl, /V-thiocarbamyl, C-amido, /V-amido, sulfinyl, sulfonyl, amino and -NR^xR.^and with R* and R^and as defined above.

"Heteroaryl" refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three, or four hetero ring atoms selected from N, O, and S, with the remaining ring atoms being C, and furthermore, having a fully conjugated pi electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole. The heteroaryl group may be substituted or unsubstituted. Typical substituents include alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carbox¡, O-carboxy, sulfinyl, sulfonyl, O-carbamyl , /V-carbamyl, Othiocarbamyl, /V-thiocarbamyl, C-amido, /V-amido, amino and -NR^xR.^and with R^x and R^and as defined above.

A pharmaceutically acceptable heteroaryl is one that is sufficiently stable to be bound to a compound of the invention, formulated into a pharmaceutical composition, and subsequently administered to a patient in need thereof.

Examples of typical monocyclic heteroaryl groups include, but are not limited to:

<td colspan="3">ό Ó ü</td><td>TO EITHER</td><td>h u</td>

<td>pyrrole</td><td>fu rano</td><td>thiophene</td><td>pyrazole</td><td>imidazole</td>

<td>(pyrrolyl)</td><td>(furanyl)</td><td>(thiophenyl)</td><td>(pyrazolyl)</td><td>(imidazolyl)</td>

<td> 0</td><td>0 No.</td><td>either</td><td>X No.</td><td>to or No.</td>

<td>isoxazole</td><td>oxazole</td><td>sothiazole</td><td>thiazole</td><td>1,2,3,-triazole</td>

<td>(isoxazolyl)</td><td>(oxazolyl)</td><td>(isothiazolyl)</td><td>(thiazolyl)</td><td>(1,2,3-triazolyl)</td>

<td>h Λ NN</td><td> 0</td><td></td><td>íJ N—</td><td>no.^xno</td>

<td>1,3,4-trlazole</td><td colspan="3">1 -oxa-2,3-d iazole 1 -oxa-2,4-d iazo I</td><td>1-oxa-2,5-diazole</td>

<td>(1,3,4-triazolyl)</td><td colspan="4">(1-oxa-2,3-diazolyl) (1-oxa-2,4-diazolyl) (1-oxa-2,5-diazolyl)</td>

<td>TO NN</td><td> 0</td><td></td><td></td><td>zAw</td>

<td>1-oxa-3,4-diazole</td><td colspan="3">1 -thia-2,3-d iazo I 1 -thia-2,4-d iazo I</td><td>1-thia-2,5-diazole</td>

<td colspan="4">(1-oxa-3,4-diazolyl) (1-thia-2,3-diazolyl) (1-thia-2,4-diazolyl)</td><td>(1-thia-2,5-diazolyl)</td>

<td>TO NN</td><td>To (\ 1/ NN</td><td> 0</td><td>/Nx. AN u</td><td>either.</td>

<td>1-thia-3,4-diazole</td><td>tetrazole</td><td>pyridine</td><td>pyridazine</td><td>pyrimidine</td>

<td colspan="2">(1-thia-3,4-diazolyl) (tetrazolyl)</td><td>(pyridinyl)</td><td>(pyridazinyl)</td><td>(pyrimidinyl)</td>

<img file="ECSP077276A_D0003.tif" />

pyrazine (pyrazinyl)

Examples of suitable fused ring heteroaryl groups include, but are not limited to:

<img file="ECSP077276A_D0004.tif" />

benzofuran banzothiophene indole (benzofuranyl) (benzothiophenyl) (indolyl)

<img file="ECSP077276A_D0005.tif" />

<img file="ECSP077276A_D0006.tif" />

indazole benzimidazole (benzimidazolyl)

<img file="ECSP077276A_D0007.tif" />

(indazolyl)

<img file="ECSP077276A_D0008.tif" />

benzotriazole (benzotriazolyl) pyrrolo[2,3-b]pyridine (pyrrolo[2,3-bjpyridinyl) pyrrolo[2,3-c]pyridine (pyrrolo[2,3-c]pyridinyl) pyrrclo[3, 2-c]pyridine (pyrrolo[3,2-c]pyridine)

<img file="ECSP077276A_D0009.tif" />

<img file="ECSP077276A_D0010.tif" />

pyrrolo[3,2-b]pyridine (pyrrolo[3,2-b]pyridinyl) imidazo[4,5-b]pyridine (midazo[4,5-b ]pyridin¡lo) imidazo[4,5-c]pyridira (imldazo[4,5-c]pyridin¡lo) pyrazolo[4,3-d]pyridine (p¡razolo[4,3-d]p lol)

<img file="ECSP077276A_D0011.tif" />

plrazolo[4,3-c]plridine pyrazolo[3,4-c]pyridine plrazolo[3,4-b]pyridine isoindole pyrazolo[4,3-c]pyridine lo) (pyrazolo[3,4-c]pyr¡d¡n¡lo) (pyrazolo[3,4-b]pyridin¡lo) (isolndoílo)

<img file="ECSP077276A_D0012.tif" />

<img file="ECSP077276A_D0013.tif" />

Indazol (indazolyl) purine (purinil) indolizlna imidazofl ,2-ajp.iridine imidazo[1,5-aJpir dira (indolininil) (imidazo[1.2-a]pyridinyl) (imldazo[1,5-aJpyridinyl )

<img file="ECSP077276A_D0014.tif" />

<img file="ECSP077276A_D0015.tif" />

pyrrolo[1,5-a]pyridine pyrrolo[1,2-b]pyridazi na imidazo[1,2-cJpi r¡midi na (P¡razolo[1,5-alpyridinyl) (pyrrolo[1 -2, b]pyridazin¡lo) (imidazo[1,2-oJpyriniidinlo)

<img file="ECSP077276A_D0016.tif" />

<img file="ECSP077276A_D0017.tif" />

<img file="ECSP077276A_D0018.tif" />

quinoline (quinolinyl) isoquinoline (Isoquinolinyl) cinnoline quinazoline (cinnolinyl) (azaquinazoline)

<img file="ECSP077276A_D0019.tif" />

<img file="ECSP077276A_D0020.tif" />

<img file="ECSP077276A_D0021.tif" />

quinoxaline (quinoxalinyl) phthalazine 1,6-naphthyridine (phthalazinyl) (1,6-naphthyridinyl)

1,7-naphthyridine (1,7-naphthyridinyl)

<img file="ECSP077276A_D0022.tif" />

<img file="ECSP077276A_D0023.tif" />

<img file="ECSP077276A_D0024.tif" />

<img file="ECSP077276A_D0025.tif" />

1,8-naphthyridine (1,8-naphthyridinyl)

1,5-naphthyridine (1,5-naphthyridinyl)

2,6-naphthyridine (2,6-naffiridinyl)

2,7-naftyridyre (2,7-naphthyridinyl)

<img file="ECSP077276A_D0026.tif" />

<img file="ECSP077276A_D0027.tif" />

<img file="ECSP077276A_D0028.tif" />

p¡rido[3,2-d]pyrimid¡na (pyrido[3,2-d]pyr¡m¡din¡lo) pindo[4,3-d]pyrimid¡na (pyr¡do[4_F3-d]pyrimidin¡lo) p¡rdo[3,4~d]p¡r¡m¡dina (prndo[3,4-d]pyrimidin¡lo)

<img file="ECSP077276A_D0029.tif" />

<img file="ECSP077276A_D0030.tif" />

<img file="ECSP077276A_D0031.tif" />

p¡rdo[2,3-d]pyrim¡na (pyrido[2,3-d]pyrimidin¡lo) pyrido[2,3-b] pyrazine (pirldo[2,3-blpyraz¡ nilo) pyrido[3,4-b]pyrazine (pyrido[3,4-b]pyrazinyl)

<img file="ECSP077276A_D0032.tif" />

<img file="ECSP077276A_D0033.tif" />

pyrimido[5,4-d]pyrindine (pyrimido[5,4-d]pyrimidinyl) pyrazino[2,3-b]pyrazine (pyrazino[2,3-b] pyraz¡n¡lo) primido[4,5-d]p¡rim¡dina (p¡rim¡do[4,5-d]p¡r¡m¡d¡nilo)

"Heteroalicyclyl" or "heterocycle" refers to a monocyclic or fused ring group having 3 to 12 ring atoms in the ring or rings, and where one or two ring atoms are heteroatoms selected from N, O, and S(O)._no (where n is 0, 1, or 2), the remainder of ring atoms being C. Rings may also have one or more double bonds. However, the rings do not have a fully conjugated p, electron system. Examples of suitable saturated heteroalicyclic groups include, but are not limited to:

/Δ oxirane (oxiranil)

Δ tiaran (tiaramle)

ΔE? EJ aziridine oxetane thiathane (aziridinyl) (oxetanyl) (thiatanil)

<img file="ECSP077276A_D0034.tif" />

azetldine tetrahydrofuran (azetidinyl) (tetrahydrofuranyl)

<img file="ECSP077276A_D0035.tif" />

tetrahydrothiophene (tetrahydrothiophenyl) pyrrolidine (pyrrolidinyl) tetrahydropyran tetrahydrothiopyran (tetrathihydropyranyl) (tetrahydrothiopyranyl)

<img file="ECSP077276A_D0036.tif" />

<img file="ECSP077276A_D0037.tif" />

piperidine (piperidinyl)

1,4-dioxane (1,4-dioxanil)

1,4-oxathiane (1,4-oxathianyl) morpholine (morpholinyl)

1,4-dlthiano (1,4-dithianyl)

<img file="ECSP077276A_D0038.tif" />

H piperazine (piperazinyl)

<img file="ECSP077276A_D0039.tif" />

1,4-azathian (1,4-azathianyl)

O oxepane (oxepanil)

O tiepane (thiepanil)

<img file="ECSP077276A_D0040.tif" />

azepanO (azepanil)

<img file="ECSP077276A_D0041.tif" />

<img file="ECSP077276A_D0042.tif" />

1,4-d¡oxepane (1,4-dioxepanil)

1,4-oxathiepane (1,4-oxathiepanyl)

1,4-oxaazepanO (1,4-oxaazepanyl)

1,4-dltiepane (1,4-dithiepanyl)

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1,4-teazepane (1,4-thieazepanil)

1,4-diazepane (1,4-diazepanil)

Examples of suitable partially unsaturated heteroalicyclic groups include, but are not limited to:

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3,4-dihydro-2H-pyran (3,4-dihydro -2H-pyranyl)

5,6-dihydro-2H-pyran 2H-pyran (5,6-dihydro-2H-pyran ilo) (2H-pyran ilo)

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1,2,3,4-tetrahydropyridine (1,2,3,4-tetrahydropyridinyl)

1,2,5,6-tetrahydropyridine (1,2,5,6-tetrahydropyridinyl)

The heterocyclo group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, carboxy substituted lower alkyl, hydroxy ester, or mono or dialkylamino.

Hydroxy refers to a -OH group.

Alkoxy refers to an -O-(alkyl) group or an -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

Haloalkoxy refers to a group -O-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.

"Aryloxy" refers to an -O-aryl group or an O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.

Mercapto refers to a -SH group.

"Alkylthio" refers to an -S-(alkyl) group or an -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

"Arylthio" refers to an -S-aryl group or an -S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like and derivatives thereof.

Acyl or carbonyl refers to a group -C(O)R, where R is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl optionally substituted with one or more, preferably one, two or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo, and -NR groups^xR.^and, heteroaryl (attached through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo, and -NR groups^xR.^and and heteroalicyclyl (attached through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo, and -NR groups.^xR.^and. Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like.

Aldehyde refers to an acyl group in which R is hydrogen.

"Thioacyl" or "thiocarbonyl" refers to a group -C(S)R, with R as defined above. A thiocarbonyl group refers to a -C(S)R group, with R as defined above. A C-carboxy group refers to a -C(O)OR group, with R as defined above. An O-carboxy group refers to a group -OC(O)R with R as defined above. "Ester" refers to a group -C(O)OR with R as defined herein with the exception that R cannot be hydrogen.

Acetyl group refers to a group -C(O)CH₃.

Halo group refers to fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

"Trihalomethyl group" refers to a methyl group having three halo substituents, such as a trifluoromethyl group.

Cyano refers to a -C=N group.

A sulfinyl group refers to a group -S(O)R where in addition to being as defined above, R can also be a hydroxy group.

A sulfonyl group refers to a group -S(O)₂where R in addition to being as defined above, R can also be a hydroxy group.

S-sulfonamido refers to a group -S(O)₂NR^xR.^and, with R^x and R^and as defined above.

W-sulfonamido refers to a -NR group^xSW)₂R.^and, with R^x and R^and as defined above.

O-carbamyl refers to a group -OC(O)NR^xR.^and, with R^x and R^and as defined above.

/V-carbamyl refers to an R group^andOC(O)NR^x, with R^x and R^and as defined above.

O-thiocarbamyl refers to a group -OC(S)NR^xR.^and, with R^x and R^and as defined above.

W-thiocarbamyl refers to an R group^andOC(S)NR^x, with R^x and R^and as defined above.

Amino refers to a -NR group^xR.^and in the gue R^x and R^and they are both hydrogen.

C-amido refers to a group -C(O)NR^xR.^and, with R^x and R^andas defined above.

/V-amido refers to an R group^xC(O)NR^and-, with R^x and R^andas defined above.

Nitro refers to a group -NO₂.

Haloalkyl means an alkyl, preferably lower alkyl, which is substituted with one or more of the same or different halo atoms, for example, -CH₂CI, -CF₃, -CH₂CF₃, -CH₂ICC₃ and the like.

"Hydroxyalkyl" means an alkyl, preferably lower alkyl, which is substituted with one, two or three hydroxy groups; for example, hydroxymethyl, 1 or 2-hydroxyethyl, 1,2-, 1,3- or 2,3-dihydroxypropyl and the like.

Aralkyl means alkyl, preferably lower alkyl, which is substituted with an aryl group as defined above; for example, -CH₂-phenyl, -(CH₂)₂phenyl, -(CH₂)₃phenyl, CH₃CH(CH)₃)CH₂phenyl and the like and derivatives thereof.

Heteroaralkyl group means alkyl, preferably lower alkyl, which is substituted by a heteroaryl group; for example, -CH₂pyridinyl, -(CH₂)₂pyrimidine, -(CH₂)₃imidazolyl, and the like, and derivatives thereof.

Monoalkylamino means a radical -NHR in which R is an unsubstituted alkyl or cycloalkyl group; for example methylamino, (1-methylethyl)amino, cyclohexylamino and the like.

Dialkylamno means a radical -NRR in which each R is independently an unsubstituted alkyl or cycloalkyl group; dimethylamino, diethylamino, (1-methylethylj-ethylamino, cyclohexylmethylamino, cyclopentylmethylamino and the like.

Optionally or optionally means that the event or circumstance described below may but need not occur, and that the description includes instances in which the event or circumstance does occur and instances in which it does not. For example, "heterocycle group optionally substituted with an alkyl group" means that alkyl may, but need not, be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is unsubstituted. with the rent group.

A pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. . The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

As used herein, a physiologically/pharmaceutically acceptable vehicle refers to a vehicle or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

A pharmaceutically acceptable carrier refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts that retain the efficacy and biological properties of the parent compound. Such salts include:

(1) Acid addition salts, which can be obtained by reacting the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid and the like, or with organics such as acetic acid, oxalic acid, melic acid (D) or (L), maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, eg, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

PK refers to receptor protein tyrosine kinase (RTK), non-receptor or cellular tyrosine kinase (CTK) and serine-threonine kinases (STK).

Modulation or modulating refers to the alteration of the catalytic activity of RTK, CTK and STK. In particular, modulating refers to the activation of the catalytic activity of RTK, CTK and STK, preferably to the activation or inhibition of the catalytic activity of RTK, CTK and STK, depending on the concentration of the compound or the salt at which the RTK, CTK or STK is exposed, or more preferably, the inhibition of the catalytic activity of RTK, CTK and STK.

Catalytic activity refers to the rate of tyrosine phosphorylation under the direct or indirect influence of RTK and/or CTK or serine and threonine phosphorylation under the direct or indirect influence of STK.

Contacting refers to bringing a compound of this invention and a target PK together in such a way that the compound can affect the catalytic activity of the PK, directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such contacting can be done in vitro", ie in a test tube, a petri dish or the like. In a test tube, contacting can involve just a compound and a PK of interest, or it can involve whole cells. Cells can also be maintained or grown in cell culture plates and contacted with a compound in such medium. In this context, the ability of a particular compound to affect a PK-related disorder, i.e. IC₅₀ of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple procedures exist, and are well known to those skilled in the art, for bringing PKs into contact with compounds including, but not limited to, direct cell microinjection and numerous transmembrane transport techniques.

In vitro refers to procedures performed in an artificial environment such as, for example, without limitation, in a test tube or culture medium.

In vivo" refers to procedures performed on a living organism, such as, without limitation, a mouse, rat, or rabbit.

PK-related disorder, PK-directed disorder and abnormal PK activity refer to a condition characterized by inappropriate PK catalytic activity, i.e. under-activity or more commonly over-activity, where the particular PK may be an RTK, a CTK or a STK. Inappropriate catalytic activity can be achieved as a result of: (1) PK expression in cells that do not normally express PK, (2) increased PK expression leading to unwanted cell growth, differentiation and/or proliferation, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. PK overactivity refers to amplification of the gene encoding a particular PK or the production of a level of PK activity that can be correlated with a disorder of cell proliferation, differentiation, and/or growth (i.e., when the level of PK increases, the severity of one or more of the symptoms of the cell disorder increases). Under-activity is, of course, the opposite, where the severity of one or more symptoms of a cellular disorder increases when the level of PK activity decreases.

"Treating" and "treatment" refer to a method of alleviating or abrogating a PK-mediated cellular disorder and/or its associated symptoms. With particular regard to cancer, these terms simply mean that the life expectancy of an individual suffering from cancer will be increased or that one or more of the symptoms of the disease will be reduced.

Organism refers to any living entity comprising at least one cell. A living organism can be as simple as, for example, a single eukaryotic cell, or as complex as a mammal, including a human.

"Therapeutically effective amount" refers to that amount of the compound to be administered that will alleviate to some extent one or more of the symptoms of the disorder to be treated. With respect to cancer treatment, a therapeutically effective amount refers to the amount that has at least one of the following effects:

(1) reduce the size of the tumor;

(2) inhibit (ie, slow to some extent, preferably interrupt) tumor metastasis;

(3) to some extent inhibit (ie, to some extent slow, preferably interrupt) tumor growth, and (4) to some extent alleviate (or, preferably, eliminate) one or more symptoms associated with cancer. Controlling means observing or detecting the effect of bringing a compound into contact with a cell expressing a particular PK. The observed or detected effect may be a change in the cellular phenotype, in the catalytic activity of a PK, or a change in the interaction of a PK with a natural binding partner. Techniques for observing or detecting such effects are well known in the art. The effect is selected from among a change or no change in a cell phenotype, a change or no change in the catalytic activity of said protein kinase, or a change or no change in the interaction of said protein kinase with a binding partner. natural in a final aspect of this invention.

Cellular phenotype refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics can be measured by techniques well known in the art.

"Natural binding partner" refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners may play a role in signal propagation in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with the PK may manifest itself as an increase or decrease in the concentration of the natural binding partner/PK complex and, as a result, in an observable change in the capacity of the PK. to mediate signal transduction.

As used herein, the terms "optically pure", "enantiomerically pure", "enantiomerically pure" and "optically pure enantiomer" mean a composition comprising one enantiomer of a compound and substantially free of the opposite enantiomer of the compound. A typical optically pure compound comprises more than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of the opposite enantiomer of the compound, more preferably, more than about 90% by weight of one enantiomer of the compound. and less than about 10% by weight of the opposite enantiomer of the compound, even more preferably more than about 95% by weight of one enantiomer of the compound and less than about 5% by weight of the opposite enantiomer of the compound, and even more preferably more than about 97% by weight of one enantiomer of the compound and less about 3% by weight of the opposite enantiomer of the compound.

Detailed description

General schemes for synthesizing the compounds of the invention can be found in the Examples section of this document.

Some of the general procedures are shown with reference to the synthesis of compounds in which the 1-(2,6-dichloro-3-fluorophenyl)-ethoxy moiety is the pure (ñ) isomer, and some are shown with reference to compounds in which said moiety is a racemic mixture. It is to be understood that the procedures herein can be used to produce enantiomerically pure (phi) racemic or isomeric compounds by choosing the corresponding enantiomerically pure racemic or isomeric starting material.

The procedures shown herein can be used to produce a wide variety of enantiomerically pure compounds by selection of the appropriate enantiomerically pure starting material. In addition to the compounds shown herein, the invention also provides enantiomerically pure compounds corresponding to the compounds 3-[1-(2,6-dichloro-

3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine and 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine shown in Application for United States patent with the N^g Serial 10/786,610 (PCT/US2004/005495); in the United States Application with the N^g Serial to be assigned, Docket Number PC 32546, filed August 26, 2004 and entitled Pyrazolo-Substituted Aminoheteroaryl Compounds as Protein Kinase Inhibitors; (Pyrazolo-Substituted Aminoheteroaryl Compounds as Protein Inhibitors

kinase); and in the United States Application with N^yes Serial to be Assigned, Docket Number PC 32548, filed August 26, 2004 and entitled Aminoheteroaryl Compounds as Protein Kinase Inhibitors. The descriptions of these documents are incorporated herein by reference in their entirety.

Unless otherwise indicated, all references herein to compounds of the invention include references to salts, solvates, hydrates, and complexes thereof and to solvates, hydrates, and salt complexes thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.

Pharmaceutically acceptable salts include basic and acid addition salts (including disalts). Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide salts. /bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

Suitable basic salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

For a discussion of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth, (Wiley-VCH, Weinheim, Germany, 2002), the disclosure of which is incorporated herein by reference in its entirety.

A pharmaceutically acceptable salt of the compounds of the invention can be readily prepared by mixing together solutions of the compound and the desired base or acid, as appropriate. The salt can precipitate out of solution and can be collected by filtration or recovered by evaporation of the solvent. The degree of ionization in salt can vary from fully ionized to nearly non-ionized.

The compounds of the invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when said solvent is water. Pharmaceutically acceptable solvates according to the invention include hydrates and solvates in which the solvent of crystallization may be isotopically substituted, for example D₂oh d₆-acetone, d₈-DMSO.

Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which, unlike the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and/or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized, or non-ionized. For a discussion of such complexes see J Pharm Sci, 64(8), 1269-1288 to Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety.

Also within the scope of the invention are polymorphs, prodrugs and isomers (including optical, geometric and tautomeric isomers) of the compounds of the invention.

Derivatives of compounds of the invention which may have little or no pharmacological activity by themselves can be converted, when administered to a patient, into compounds of the invention, for example, by hydrolytic cleavage. Such derivatives are called "pro-drugs." Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.

Prodrugs according to the invention can, for example, be produced by replacing the appropriate functionalities present in the compounds of the invention with certain moieties known to those skilled in the art as pro-moieties as described, for example, in "Design of Prodrugs by H. Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

Some examples of prodrugs according to the invention include:

(i) when the compound contains a carboxylic acid (-COOH) functionality, an ester thereof, eg, replacement of the hydrogen with alkyl (CrCs);

(ii) when the compound contains an alcohol (-OH) functionality, an ether thereof, for example, replacement of the hydrogen by alkanoyloxymethyl (CrC₆); and (iii) when the compound contains primary or secondary amino functionality (-NH₂ or -NHR where R^H), an amide thereof, eg, replacement of one or both hydrogens by (C1-C10)alkanoyl.

Other examples of replacement groups according to the above examples and examples of other types of prodrugs can be found in the references mentioned above.

Finally, certain compounds of the invention may themselves act as prodrugs of other compounds of the invention.

Compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. When a compound of the invention contains an alkenyl or alkenylene group, cis/trans (or Z/E) geometric isomers are possible. When the compound contains, for example, a keto or oxime group, or an aromatic moiety, tautomeric isomerism (tautomerism) may occur. A single compound may show more than one type of isomerism.

Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds showing more than one type of isomerism and mixtures of one or more thereof. Also included are acid or basic addition salts in which the counterion is optically active, eg D-lactate or L-lysine, or racemic, eg DL-tartrate or DL-arginine.

The cis/trans Isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate from a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). .

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol or, in the case the compound contains an acidic or basic moiety, an acid or base such as tartaric acid. or 1 -phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% isopropanol, typically 2-20% and 0-5% of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate provides the enriched mixture.

Stereoisomeric clusters can be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by EL Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

The present invention also includes isotopically labeled compounds of the invention, in which one or more atoms are replaced by an atom having the same atomic number but a different atomic mass or mass number from the atomic mass or mass number normally found in nature. Examples of suitable isotopes for inclusion in compounds of the invention include isotopes of hydrogen, such as²h and³H, carbon, such as¹¹c,¹³c and¹⁴C, chlorine such as^3BCI, fluoride, such as¹⁸F, iodine, such as¹²³ly¹²⁶l, nitrogen, such as¹³No and¹⁶N, oxygen, such as¹⁵EITHER,¹⁷or and¹⁸Or, phosphorus, such as³²P and sulfur, such as³⁵S. Certain isotopically labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in studies of drug and/or substrate distribution in tissues. The radioactive isotopes tritium,³H, and carbon 14,¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and easy means of detection. Substitution with heavier isotopes such as deuterium,²H may provide certain therapeutic advantages resulting from increased metabolic stability, eg, increased half-life in vivo or reduced dosing requirements, and therefore may be preferred in some circumstances. Substitution with isotopes that emit positrons, such as¹¹c,¹⁸F,¹⁵or and¹³N may be useful in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy.

The isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by analogous procedures to those described herein, using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed.

Pharmaceutically acceptable solvates according to the invention include those in which the solvent of crystallization may be isotopically substituted, for example D₂oh d₆-acetone, d₆DMSO.

Compounds of the invention intended for pharmaceutical use may be administered in the form of crystalline or amorphous products, or mixtures thereof. They can be obtained, for example, in the form of solid pellets, powders or films by methods such as precipitation, crystallization, freeze-drying, spray-drying or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

The compounds may be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered in the form of a formulation together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the administration of compounds of the invention and processes for their preparation will be readily apparent to those skilled in the art. Such compositions and procedures for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19^to Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

Oral Administration

The compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound directly enters the bloodstream from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids or powders, dragees (including liquid-filled ones), chewing gums, multi- and nano-particulates, gels, solid solution, liposomes, films. (including muco-adhesive), suppositories, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in hard or soft capsules and typically include a vehicle, for example water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, eg from a stamp.

The compounds of the invention may also be used in rapidly dissolving and rapidly disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated in this document by reference in its entirety.

For tablet dosage forms, depending on the dosage, the drug may constitute from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Tablets can also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. When present, surfactants are typically in amounts from 0.2% by weight to 5% by weight of the tablet and glidants are typically from 0.2% by weight to 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are generally present in amounts of 0.25% by weight to 10% by weight, preferably 0.5% by weight to 3% by weight of the tablet.

Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.

Illustrative tablets contain up to about 80% by weight drug, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight diluent, from about 2% by weight to about 10% by weight of disintegrant and from about 0.25% by weight to about 10% by weight of lubricant.

Tablet blends can be compressed directly or with a roller to form tablets. Tablet blends or portions of blends may alternatively be wet, dry or melt granulated, melt frozen, or extruded prior to tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

The tablet formulation is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), whose description is incorporated herein by reference in its entirety.

Solid formulations for oral administration can be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

Suitable modified release formulations are described in US Pat. No.⁹ 6,106,864. Details of other suitable delivery technologies such as high energy dispersions and osmotic and coated particles are found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The descriptions of these references are incorporated herein by reference in their entirety.

Parenteral Administration

The compounds of the invention may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrastemal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needle injectors (including microneedles), needleless injectors, and infusion techniques.

Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably at a pH of 3 to 9), but, for some applications, may more suitably be formulated as a sterile non-aqueous solution or as a dry form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water.

Preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be readily carried out using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the preparation of parenteral solutions can be increased through the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration can be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Thus, the compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-eluting stents and PGLA microspheres.

Topical Administration

The compounds of the invention can also be administered topically to the skin or mucosa, ie by the dermal or transdermal route. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petroleum jelly, white petroleum jelly, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated; see, for example, J Pharm Sci, 88 (10) 955-958 to Finnin and Morgan (October 1999). Other means of topical administration include administration by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless (eg, Powderject™, Bioject™, etc.) injection. The descriptions of these references are incorporated herein by reference in their entirety.

Formulations for topical administration can be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

Inhaled / Intranasal Administration

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, in the form of an admixture, for example, in a dry mixture with lactose, or in the form of a mixed component particle, by example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3 ,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or amplifying the release of the active agent, a propellant(s) as a solvent and an optional surfactant, such as sorbitan toleate, oleic acid or an oligolactic acid.

Before being used in a dry powder or suspension formulation, the drug product is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any suitable comminuting process such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (made, for example, of gelatin or HPMC), blister packs and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 gg to 20 mg of the compound of the invention per actuation and the actuation volume may range from 1 μΙ to 100 μΙ. A typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavorings such as menthol and levomenthol, or sweeteners such as saccharin or saccharin sodium, may be added to formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. Units according to the invention are typically arranged to administer a metered dose or "puff" containing a desired amount of the compound of the invention. The total daily dose can be administered in a single dose or, more usually, in divided doses throughout the day.

Rectal/Intravaqinal Administration

The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, weigh or enema. Cocoa butter is a traditional suppository base but various alternatives can be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

Ocular Administration

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in pH-adjusted sterile isotonic saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (eg sponges with absorbable gels, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses, and particulate or vesicle systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, for example, gellan gum, may be incorporated together with a preservative such as benzalkonium chloride. Such formulations can also be administered by iontophoresis.

Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted or programmed release.

Other Technologies

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the modes of administration mentioned above.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, ie, as a carrier, diluent or solubilizer. Most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in PCT Publications No.⁵ WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties.

Dosage

The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this amount would be from about 0.07 to about 7,000 mg/day, preferably from about 0.7 to about 2,500 mg/day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, although in other cases even higher doses can be used without causing any detrimental side effects, with such higher dosages typically divided into several doses. smaller for administration throughout the day.

Parts Kit

While it is desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the invention that two or more pharmaceutical compositions may be conveniently combined, at least one of which contains a compound of according to the invention, in the form of a kit suitable for the co-administration of the compositions. In this way, the kit of the invention includes two or more different pharmaceutical compositions, at least one of which contains a compound of the invention and means to separately store said compositions, such as a container, divided vial or divided foil package. . An example of such a kit is the known blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, eg oral and parenteral, for administering the different compositions at different dosage intervals, or for titrating the different compositions against each other. To encourage acceptance, the kit typically includes instructions for administration and may be provided with a reminder system.

examples

In the following examples, Et means ethyl, Ac means acetyl, Me means methyl, Ms means methanesulfonyl (CH₃SW₂), ¡Pr means isopropyl, HATU means 2-(7aza-1H-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, Ph means phenyl, Boc means tert-butoxycarbonyl, EtOAc means acetate ethyl, HOAc means acetic acid, NEt₃ or et₃N means triethylamine; THF means tetrahydrofuran, DIO means diisopropylcarbodiimide, HOBt means hydroxy benzotriazole, MeOH means methanol, ¡-PrOAc means isopropyl acetate; KOAc means Potassium Acetate, DMSO means Dimethyl Sulfoxide, AcCI means Acetyl Chloride, CDCI₃ means deuterated chloroform, MTBE means methyl f-butyl ether, DMF means dimethylformamide, Ac₂O stands for acetic anhydride, Me₃SOI stands for trimethylsulfoxonium iodide, DMAP stands for 4-dimethylaminopyridine, dppf stands for ferrocene diphenylphosphino, DME stands for ethylene glycol dimethyl ether, HOBT stands for 1-hydroxybenzotriazole, EDC stands for 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.

The following examples are given to illustrate the present invention. It is to be understood, however, that the invention is not limited to the specific details or conditions described in these examples.

Reagents can be synthesized as shown herein, or are available from commercial sources (eg, Aldrich, Milwaukee, WI; Acros, Morris Plains, NJ; Biosynth International, Naperville, IL; Frontier Scientific, Logan, UT; TCI America, Portland, OR; Combi-Blocks, San Diego, CA; Matrix Scientific, Columbia, SC; Acros, Morris Plains, NJ; Alfa Aesar, Ward Hill, MA; Apollo Scientific, UK; etc) or can be synthesized by known procedures in technique.

The synthesis of several specific reagents is shown in US Patent Application No.^g 10/786,610 entitled Aminoheteroaryl Compounds as Protein Kinase Inhibitors, filed February 26, 2004, and the corresponding international application PCT/US2004/005495 ​​of the same title, filed February 26, 2004. 2004. Other reagents can be synthesized by adapting the procedures contained in such documents, and one skilled in the art can readily adapt those procedures to produce the desired compounds. In addition, these references contain general procedures and specific examples for the preparation of a large number of heteroarylamino compounds, and such procedures and examples can be readily adapted by one skilled in the art for the preparation of compounds of the present invention. The descriptions of these references are incorporated herein by reference in their entirety.

When referring to a general or illustrative synthetic procedure, one skilled in the art can readily determine the appropriate reagents, if not indicated, by extrapolation from the general or illustrative procedures. Some of the general procedures are given as examples for preparing specific compounds. One skilled in the art can easily adapt such procedures to the synthesis of other compounds. It is to be understood that the R groups shown in the general procedures are intended to be generic and non-limiting, and do not correspond to the definitions of the R groups elsewhere in this document. Each such R group represents one or more chemical moieties that may be the same as or different from other chemical moieties also represented by the same R symbol. One skilled in the art can readily appreciate the proper range of R groups in the illustrative syntheses. Furthermore, the representation of an unsubstituted position in the structures shown or indicated in the general procedures is for convenience and does not preclude substitution as described elsewhere in this document. For specific groups that may be present, as R groups in the general procedures or as optional substituents not shown, refer to the descriptions in the remainder of this document, including the claims, summary, and detailed description.

Some of the general procedures are shown with reference to the synthesis of compounds in which the 1 -(2,6-dichloro-3-fluorophenyl)-ethoxy moiety is the pure (R)-isomer, and some are shown with reference to compounds wherein said moiety is a racemic mixture. It is to be understood that the procedures herein can be used to produce enantiomerically pure racemic or (R)-isomeric compounds by choosing the corresponding enantiomerically pure racemic or (R)-isomeric starting material.

The procedures shown herein can be used to produce a wide variety of enantiomerically pure compounds by selection of the appropriate enantiomerically pure starting material. In addition to the compounds shown herein, the invention also provides enantiomerically pure compounds corresponding to the compounds 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine and 3 -[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyrazin-2-ylamine shown in the United States patent application with the N⁹ Serial 10/786,610 (PCT/US2004/005495); in the United States application with the N⁹ serial to be assigned, docket number PC 32546, filed August 26, 2004, entitled Pyrazolo-Substituted Aminoheteroaryl Compouds as Protein Kinase Inhibitors; and in the application of the United States with the N⁹ Serial to assign, N⁹ Docket PC 32548, filed August 26, 2004, entitled Aminoheteroaryl Compounds as Protein Kinase Inhibitors. The descriptions of these documents are incorporated herein by reference in their entirety.

Selection of Starting Materials

5-bromo-3-f1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-D¡r¡d¡n-2-¡lam¡na (racemate):

<img file="ECSP077276A_D0047.tif" />

1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred in THF (150 mL, 0.5 M) at 0⁹C using an ice bath for 10 min. Lithium aluminum hydride (2.75 g, 0.072 mol) was added slowly. The reaction was stirred at room temperature for 3h. The reaction was cooled in an ice bath and water (3 mL) was added dropwise followed by the slow addition of 15% NaOH (3 mL). The mixture was stirred at room temperature for 30 min. 15% NaOH (9 mL) and MgSO4 were added and the mixture filtered to remove solids. The solids were washed with THF (50 mL) and the filtrate was concentrated to give 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (14.8 g, 95% yield) as a yellow oil.¹H NMR (400 MHz, DMSO-d6) δ 1.45 (d, 3H), 5.42 (m, 2H), 7.32 (m, 1H), 7.42 (m, 1H).

2. To a stirred solution of triphenylphosphine (8.2 g, 0.03 mol) and DEAD (13.65 mL of a 40% soln in toluene) in THF (200 mL) at 0⁹C was added a solution of 1 -(2,6-dichloro-3-fluoro-phenyl)-ethanol (4.55 g, 0.021 mol) and 3-hydroxy-nitropyridine (3.35 g, 0.023 mol) in THF (200 mi). The resulting bright orange solution was stirred under a nitrogen atmosphere at room temperature for 4 hours, by which time all starting materials had been consumed. The solvent was removed and the crude material was loaded dry on silica gel and eluted with ethyl acetate-hexanes (20:80), yielding 3-(2,6-dichloro-3-fluoro-benzyloxy)-2- nitro-pyridine (6.21 g, 0.021 mol, 98%) as a pink solid.¹H NMR (CDCI₃, 300 MHz) δ 1.8-1.85 (d, 3H), 6.0-6.15 (c, 1H), 7.0-7.1 (t, 1Η), 7.2-7 .21 (d, 1H), 7.25-7.5 (m, 2H), 8.0-8.05 (d, 1H).

3. In a stirred mixture of AcOH (650 ml) and EtOH (500 ml) were suspended 3-(2,6-dichloro-3fluoro-benzyloxy¡)-2-n¡tro-pyr¡d¡na (9.43 g, 0.028 mol) and iron chips (15.7 g, 0.28 mol). The reaction was slowly heated to reflux and allowed to stir for 1h. The reaction was cooled to room temperature and then diethyl ether (500 ml) and water (500 ml) were added. The solution was carefully neutralized by the addition of sodium carbonate. The combined organic extracts were washed with NaHCO₃ sat. (2 x 100 mi), H₂O (2 x 100 mL) and brine (1 x 100 mL), then dried (Na₂SW₄), were filtered and concentrated to dryness in vacuo, yielding 3-(2,6-dichloro-3-fluoro-benz¡lox¡)-pyrid¡n-2ylamine (9.04 g, 0.027 mol, 99% ) as a light pink solid.¹H NMR (CDCI₃, 300 MHz) δ 1.8-1.85 (d, 3H), 4.9-5.2 (bs, 2H), 6.7-6.84 (c, 1H), 7.0-7, 1 (m, 1H), 7.2-7.3 (m, 1H), 7.6-7.7 (m, 1H).

4. A stirring solution of 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrile was cooled to 0^yesC using an ice bath. To this solution was added portionwise N-bromosuccinimide (NBS) (5.33 g, 0.03 mol). The reaction was stirred at 0⁹C for 15 min. The reaction was concentrated to dryness in vacuo. The resulting dark oil was dissolved in EtOAc (500 mL) and purified by silica gel chromatography. Solvents were then removed in vacuo, yielding 5-bromo-3(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (5.8 g, 0.015 mol, 51%) as a crystalline white solid.¹H NMR (CDCI₃, 300 MHz) δ 1.85-1.95 (d, 3H), 4.7-5.0 (bs, 2H), 5.9-6.01 (c, 1H), 6.8-6, 95 (d, 1H), 7.01-7.2 (t, 1H), 7.4-7.45 (m, 1H), 7.8-7.85 (d, 1H).

5-vodo-3-[1-(2.6-d¡chloro-3-fluoro-phenyl-ethox¡1-D¡rid¡n-2-lam¡na (racemate):

<img file="ECSP077276A_D0048.tif" />

To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (10.0 g, 33.2 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added M-iodosuccinimide (11.2 g, 49.8 mmol). The mixture was stirred at room temperature for 4 h and the reaction was quenched with Na solution.₂S₂EITHER₅. After evaporation, the residue was partitioned between ethyl acetate and water. The organic phase was washed with 2N NaOH solution and brine and dried over Na₂SW₄. The crude product was purified on a silica gel column to give 5-iodo-3-[1-(2,6-d¡chloro-3-fluoro-phenyl)-ethoxy¡]-pyr¡d¡n -2-ylamine (7.1 g, 50% yield). MS m/z427 [M+1],¹H NMR (400 MHz, DMSO-D₆) δ ppm 1.74 (d, J =

6.57 Hz, 3H) 5.91 - 5.99 (m, 3H) 6.82 (d, J = 1.26 Hz, 1H) 7.46 (t, J = 8.72 Hz, 1H) 7 .56 (dd, J = 8.97, 4.93 Hz, 1H) 7.62 (d, J = 1.52 Hz, 1H).

5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-D¡raz¡n-2-lam¡na (racemate):

<img file="ECSP077276A_D0049.tif" />

1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred in THF (150 mL, 0.5 M) at 0⁹C using an ice bath for 10 min. Lithium aluminum hydride (de Aldrich, 2.75 g, 0.072 mol) was added slowly. The reaction was stirred at room temperature for 3h. The reaction was cooled in an ice bath and water (3 mL) was added dropwise followed by the slow addition of 15% NaOH (3 mL). The mixture was stirred at room temperature for 30 min. 15% NaOH (9 mL), MgSO4 were added and the mixture filtered to remove solids. The solids were washed with THF (50 mL) and the filtrate was concentrated to give 1(2,6-dichloro-3-fluoro-phenyl)-ethanol (14.8 g, 95% yield as a yellow oil.¹H NMR (400 MHz, DMSO-ds) δ 1.45 (d, 3H), 5.42 (m, 2H), 7.32 (m, 1H), 7.42 (m, 1H).

2. 5-Bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine was prepared following procedure 2 below, starting from 1-(2,6 -dichloro-3-fluoro-phenyl)-ethanol and 3,5-dibromopyrazin-2-ylamine.¹H NMR (400 MHz, DMSO-d₆) δ 1.74 (d, 3H), 6.40 (m, 1H), 6.52 (sa, 2H), 7.30 (m, 1H), 7.48 (m, 1H), 7.56 (s, 1H); MS m/z 382 (M+1).

Enantiomerically pure starting materials

PLE is an enzyme produced by Roche and marketed by Biocatalytics Inc. in the form of a crude hog liver esterase preparation, commonly known as PLE-AS (purchased from Biocatalytics as ICR-123, marketed as a suspension in ammonium sulfate). The enzyme is classified in the CAS registry as a “carboxylic ester hydrolase, CAS N⁹9016-18-6”. The corresponding enzyme classification number is EC 3.1.1.1. The enzyme is known to have a broad substrate specificity with respect to the hydrolysis of a wide variety of esters. Lipase activity is determined using a procedure based on the hydrolysis of ethyl butyrate in a pH titrator. 1 LU (lipase unit) is the amount of enzyme that releases 1 μιηοΙ of titratable butyric acid per minute at 22⁹C, pH 8.2. The preparation presented herein (PLEAS, in the form of a suspension) is normally shipped as an opaque brown-green liquid with a claimed activity of >45 LU/mg (protein content approximately 40 mg/ml).

(1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol

(1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol, shown as compound (S-1) in the schemes below, was prepared by a combination of enzymatic hydrolysis of 1(2,6-acetate -dichloro-3-fluorophenyl)ethyl racemic, esterification and chemical hydrolysis with inversion according to the

Scheme B. Racemic 1-(2,6-dichloro-3-fluorophenyl)ethyl acetate (Compound A2) was prepared according to Scheme A.

Scheme A

<img file="ECSP077276A_D0050.tif" />

^F To the^F A2

1-(2,6-dichloro-3-fluorophenyl)ethanol (A1): Sodium borohydride (90 mg, 2.4 mmol) was added to a solution of 2',6'-dichloro-3'-fluoro-acetophenone ( Aldrich, catalog No.⁹ 52.294-5) (207 mg, 1 mmol) in 2 mL CH₃anhydrous OH. The reaction mixture was stirred at room temperature for 1h, then evaporated to give a colorless oily residue. The residue was purified by flash chromatography (eluting with 0 —> 10% EtOAc in hexanes) to give compound A1 as a colorless oil (180 mg, 0.88 mmol, 86.5% yield); MS (APCI) (MH)' 208;¹H NMR (400 MHz, chloroform-D) δ ppm 1.64 (d, J =

6.82 Hz, 3H) 3.02 (d, J=9.85 Hz, 1H) 6.97-7.07 (m, 1H) 7.19-7.33 (m, 1H).

1-(2,6-dichloro-3-fluorophenyl)ethyl acetate (A2): Acetic anhydride (1.42 mL, 15 mmol) and pyridine (1.7 mL, 21 mmol) were added sequentially to a solution of compound A1 (2.2 g, 10.5 mmol) in 20 mL of CH₂IC₂. The reaction mixture was stirred at room temperature for 12 h, then evaporated to give a yellowish oily residue. The residue was purified by flash chromatography (eluting with 7->9% EtOAc in hexanes) to give compound A2 as a colorless oil (2.26 g, 9.0 mmol, 85.6% yield);¹H NMR (400 MHz, chloroform-D) δ ppm 1.88 (d, J = 6.82 Hz, 3H) 2.31 (s, 3H) 6.62 (c, J = 6.82 Hz, 1H) 7.25 (t, J = 8.46 Hz, 1H) 7.49 (dd, J = 8.84, 5.05 Hz, 1H).

Scheme B

<img file="ECSP077276A_D0051.tif" />

<img file="ECSP077276A_D0052.tif" />

<img file="ECSP077276A_D0053.tif" />

To a 50 mL jacketed flask equipped with a pH electrode, overhead stirrer, and base (1 M NaOH) addition line, was added 1.2 mL of potassium phosphate buffer.

100 mM at pH 7.0 and 0.13 ml of PLE AS suspension. Compound A2 (0.13 g, 0.5 mmol, 1.00 equiv.) was then added dropwise and the resulting mixture was stirred at room temperature for 20 h, keeping the pH of the reaction constant at 7, 0 using 1 M NaOH. Both the conversion and the ee values ​​of the reaction were monitored by HPLC-IF and stopped after 50% of the starting material was consumed (approximately 17 hours under these conditions). The mixture was then extracted three times with 10 ml of ethyl acetate, recovering the ester and alcohol as a mixture of R-1 and S-2,

Methanesulfonyl chloride (0.06 mL, 0.6 mmol) was added to a solution of a mixture of R-1 and S-2 (0.48 mmol) in 4 mL of pyridine under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3h and then evaporated to obtain an oil. To the mixture was added water (20 ml) and then EtOAc (20 ml x 2) was added to extract the aqueous solution. The organic phases were combined, dried, filtered and evaporated to give a mixture of R-3 and S-2. This mixture was used in the next reaction step without further purification.¹H NMR (400 MHz, chloroform-D) δ ppm 1.66 (d, J = 7.1 Hz, 3H) 1.84 (d, J = 7.1 Hz, 3H) 2.09 (s, 3H) 2.92 (s, 3H) 6.39 (c, J = 7.0 Hz, 1H) 6.46 (c, J = 6.8 Hz, 1H) 6.98-7.07 (m, 1H) 7.07-7.17 (m, 1H) 7.23-7.30 (m, 1H) 7.34 (dd, J = 8.8, 4.80 Hz, 1H).

Potassium acetate (0.027 g, 0.26 mmol) was added to a mixture of R-3 and S-2 (0.48 mmol) in 4 mL DMF under a nitrogen atmosphere. The reaction mixture was heated to 100^B.C for 12h. To the reaction mixture was added water (20 ml) and EtOAc (20 ml x 2) was added to extract the aqueous solution. The combined organic phase was dried, filtered and evaporated to give an oil of S-2 (72 mg, 61% yield in two steps). Chirality ee: 97.6%.¹H NMR (400 MHz, chloroform-D) δ ppm 1.66 (d, J = 7.1 Hz, 3H) 2.09 (s, 3H) 6.39 (c, J = 6.8 Hz, 1H) 7.02 (t, J=8.5 Hz, 1H) 7.22-7.30 (m, 1H).

Sodium methoxide (19 mmol; 0.5 M in methanol) was slowly added to compound S-2 (4.64 g,

18.8 mmol) in a nitrogen atmosphere at 0⁹C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and H was added.₂Or (100 mi). The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 ml x 2) was added to extract the aqueous solution. The combined organic phases were dried over Na₂SW₄, filtered and evaporated to obtain a white solid (4.36 g, 94.9% yield); CFS-MS: 97% of us.¹H NMR (400 MHz, chloroform-D) δ ppm 1.65 (d, J = 6.8 Hz, 3H) 5.58 (c, J = 6.9 Hz, 1H) 6.96-7.10 ( m, 1H) 7.22-7.36 (m, 1H).

3-[(1ñ)-1-(2,6-d¡chloro-3-fluorofen¡l)ethoxy¡l-2-nitroD¡r¡d¡na

<img file="ECSP077276A_D0054.tif" />

To a stirred solution of (1S)-1-(2,6-dichloro-3- fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was kept at room temperature for 1 h, then diisopropyl azo-dicarboxylate (0.34 mL, 1.65 mmol) was added at 0⁹C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated in vacuo to give an oil. The residue was purified by flash chromatography (eluting with 20^25% ​​EtOAc in hexanes) to give the title compound as a white solid (321.5 mg, 0.97 mmol, 88.3% yield); MS (APCI) (M+F)⁺331; CFS-MS: 99.5% of us.¹H NMR (400 MHz, chloroform-D) δ ppm 1.85 (d, J = 6.6 Hz, 3H) 6.10 (c, J = 6.6 Hz, 1H) 7.04-7.13 ( m, 1H) 7.21 (dd, J = 8.5, 1.14 Hz, 1H) 7.30 (dd, J = 9.0, 4.9 Hz, 1H) 7.37 (dd, J = 8.6, 4.6Hz, 1H) 8.04 (dd, J = 4.6, 1.3Hz, 1H).

3-í(1 ñ)-1 -(2,6-d¡chloro-3-fluorophenyl)ethoxy¡lD¡r¡d¡n-2-am¡na

F

<img file="ECSP077276A_D0055.tif" />

Iron (365 mg) was added to a stirred solution of 3-[(1phy)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine (321 mg, 0.97 mmol) in a mixed of EtOH (2 mL) and 2 M HCI (0.2 mL) at 0⁹C. The resulting solution was heated to 85⁹C for 2h. To the cooled reaction mixture, Celite (0.5 g) was added. This mixture was filtered over a pad of celite and evaporated to give the title compound as a dark oil. MS (APCI) (M+F)⁺ 301.

5-bromo-3-[1(fi)-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-DÍridin-2-ylamine:

<img file="ECSP077276A_D0056.tif" />

The enantiomerically pure R-isomer was prepared as described above for the racemate, but using the enantiomerically pure starting materials described above.¹H NMR (400 MHz, DMSO-d_yes) δ 1.74 (d, 3H), 6.40 (m, 1H), 6.52 (sa, 2H), 7.30 (m, 1H), 7.48 (m, 1H), 7.56 (yes,

<img file="ECSP077276A_D0057.tif" />

Periodic acid (60 mg, 0.24 mmol), iodine (130 mg, 0.5 mmol), and sulfuric acid (0.03 mL) were added sequentially to a stirred solution of 3-[(1 R)-1-( 2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (0.97 mmol) in a mixture of acetic acid (3 mL) and H₂Or (0.5 mi). The resulting solution was heated to 80⁹C for 5h. The cooled reaction mixture was quenched with Na₂SW₃ (80 mg) and basified with Na₂CO₃ (2 x 100 mL) at pH 7. CH was added₂IC₂ (2 x 50 ml) to extract the aqueous solution. The combined organic phases were dried over Na₂SW₄, then filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 35 -> 40% EtOAc in hexanes) to give the title compound as a yellow oil (254 mg, 0.6 mmol, 61.6% yield); MS (APCI) (M+F)⁺ 426,¹H NMR (400 MHz, chloroform-D) δ ppm 1.81 (d, J = 6.8 Hz, 3H) 4.86 (s, 2H) 5.98 (c, J = 6.57 Hz, 1H) 6.96 (d, J = 1.5 Hz, 1H) 7.08 (dd, J = 9.0, 8.0 Hz, 1H) 7.31 (dd, J = 8.8, 4.8 Hz , 1H) 7.78 (d, J = 1.8 Hz, 1H).

5-bromo-3-[(ñ)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-D¡raz¡n-2-¡lam¡na:

<img file="ECSP077276A_D0058.tif" />

The title compound was prepared according to procedure 2, starting from (1 S)-1-(2,6-dichloro-3-fluorophenyl)ethanol.¹H NMR (400 MHz, DMSO-dg) δ 7.53 (s, 1H), 7.48 (m, 1H), 7.39 (t, 1H), 6.48 (s, 2H), 6.41 (c, 1H), 1.74 (d, 3H); LCMS: 381 [M+1 ]; k¡ of c-Met: 0.796 μΜ.

General scheme I for the synthesis of 5-aryl-3-(benc¡lox¡-substituted)-p¡r¡d¡n-2-¡lam¡na (6):

<img file="ECSP077276A_D0059.tif" />

.Br

NBSCHgCN

—.—---►

<img file="ECSP077276A_D0060.tif" />

General procedure 1 for the synthesis of 5-Bromo-3-(benzyloxy-substituted)-pyridin-2-ylamine (5):

1. Preparation of 3-(benzyloxy-substituted)-2-nitro-pyridine (3): To a stirred solution of Cs₂CO₃ (1.0 molar equivalent) in DMF (0.2 M) under N atmosphere₂ containing 3-hydroxy-4-nitropyridine (Aldrich, 1.0 molar equivalent) is added substituted benzyl bromide (1.0 molar equivalent). The mixture is stirred for 6 h at room temperature. The reaction is then diluted with EtOAc and partitioned with H₂O. The aqueous phase is extracted twice with EtOAc. Afterwards, the organic phases are combined, washed with H₂O and brine, dry over Na₂SW₄, filtered and concentrated to dryness in vacuo, yielding 3-(substituted-benzyloxy)-2-nitro-pyridine (3) as a solid.

2. Preparation of 3-(substituted-benzyloxy)-pyridin-2-lamin (4): In a stirred mixture of AcOH and EtOH (1.3:1) are suspended 3-(substituted-benzyloxy-2-nitro- pyridine (1.0 molar equiv, 1 M) and iron chips (1.0 molar equiv) The reaction is slowly refluxed and allowed to stir for 1 h The reaction is cooled to room temperature and then filtered through a pad of celite The resulting filtrate is neutralized with NH₄OH conc. and then extracted three times with EtOAc. The combined organic extracts are washed with NaHCO₃ saturated, H₂O and brine, dry over Na₂SW₄, filter and concentrate to dryness in vacuo to yield 3-(substituted-benzyloxy)-pyridin-2-ylamine (4) as a solid.

3. Preparation of 5-bromo-3-(substituted-benzyloxy)-pyridin-2-ylamine (5): A stirred solution of 3-(substituted-benzyloxy)-pyridin-2-ylamine (4) (1.0 molar equivalent) in acetonitrile is cooled to 0²C using an ice bath. To this solution is added /V-bromosuccinimide (Aldrich, 1.0 molar equivalent) portionwise. The reaction is stirred at 0⁹C for 15 min. The reaction is concentrated to dryness in vacuo. The resulting dark oil is dissolved in EtOAc and partitioned with H₂O. The organic phase is then washed twice with NaHCO₃ saturated and once with brine. Activated charcoal is added to the organic phase and heated to reflux. The solution is then cooled to room temperature and filtered through a pad of celite. The organic phase is then concentrated to dryness in vacuo to one third of the original volume. The solids are then removed by filtration, yielding 5-bromo-3-(substituted-benzyloxy)-pyridin-2-ylamine (5) as a solid.

General scheme II for the synthesis of 5-Aril-3-(benzyloxy-substituted)-pyrazin-2-ylamine

<img file="ECSP077276A_D0061.tif" />

ArB{OH)_?

PcKPPhskClz

DME/Na₂CO3/H₃EITHER

80°C

<img file="ECSP077276A_D0062.tif" />

General procedure 2 for the synthesis of 5-Bromo-3-(benzyloxy-substituted)-pyrazin-2-ylamine.

<img file="ECSP077276A_D0063.tif" />

NH_z

To an ice-cold solution of substituted benzyl alcohol (1.0 molar equivalent) and anhydrous tetrahydrofuran (0.14 M) was slowly added sodium hydride (1.0 molar equivalent) under a nitrogen atmosphere. After stirring for 30 minutes, 3,5-dibromopyrazin-2-ylamine (1.0 molar equivalent) in tetrahydrofuran (0.56 M) was added dropwise at a rapid rate via addition funnel. . Once the addition was complete, the ice bath was removed and the reaction was heated to reflux under nitrogen and monitored by reverse phase HPLC. After 18 h, HPLC showed that most of the starting 3,5-dibromopyrazin-2-ylamine had been consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified using silica gel eluting with 1:1 ethyl acetate/dichloromethane to afford 5-bromo-3-(substituted-benzyloxy)-pyrazin-2-ylamine as a white solid with a 60-90% yield.

General procedure 3 for the synthesis of 5-Aril-3-(benzyloxy-substituted)-pyridin-2-ylamine and 5-Aril-3(benzyloxy-substituted)-pyrazin-2-ylamine.

<img file="ECSP077276A_D0064.tif" />

aryl boric acid

PS(pph)₃)í>ci2 DME/Na₂CO3/H₂or 80°C

<img file="ECSP077276A_D0065.tif" />

A mixture of 5-bromo-3-(substituted-benzyloxy)-pyridin-2-ylamine or 5-bromo-3-(substituted-benzyloxy)pyrazin-2-ylamine (1 molar equivalent), arylboric acid or ester ( 1.2 molar equivalents), b/s(triphenylphosphine)palladium II chloride (0.03 molar equivalents) and sodium carbonate (3.0 molar equivalents) in ethylene glycol dimethyl ether and water (10: 0.5, 0.03 M) is degassed and charged three times with nitrogen and then refluxed under nitrogen overnight. The reaction is cooled to room temperature and diluted with ethyl acetate. The mixture is washed with water and brine, dried over Na₂SW₄ and purified on a silica gel column to give 5-aryl-3-(substituted-benzyloxy)-pyridin-2-ylamine, or 5-aryl-3-(substituted-benzyloxy)-pyrazin-2 -ylamine.

<img file="ECSP077276A_D0066.tif" />

To a solution of 6-amino-5-(benzyloxy-substituted)-pyridin-3-yl]-benzoic acid (1 molar equivalent), 1-hydroxybenzotriazole hydrate (HOBT, 1.2 molar equivalent) and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 1.2 molar equivalents) in DMF (0.2 M) is added amine (1.2 molar equivalents). The reaction solution is stirred at room temperature overnight, then diluted with EtOAc and partitioned with H₂O. The organic phase is separated and the aqueous is extracted with EtOAc. The organic phases are combined, washed with NaHCO₃ saturated and concentrated to dryness in vacuo. The material is purified using column chromatography (silica gel, 99:1 to 95:5 CH₂IC₂/MeOH). The product-containing fractions are concentrated in vacuo to yield the amide product.

General procedure 5 for the preparation of 3-(benzyloxy-substituted)-5-(3-dialkylam¡nomethyl-1H-indol-5yl)-pyridin-2-ylam¡na:

<img file="ECSP077276A_D0067.tif" />

To a solution of benzotriazole (1.0 molar equivalent) in dichloromethane (0.2 M) is added amine (1.0 molar equivalent). The reaction is stirred for 5 minutes at room temperature, after which formaldehyde (37% by weight, 1.0 molar equivalent) is added and the reaction is capped and stirred at room temperature for 3 h. After TLC (10% ethyl acetate:dichloromethane) shows consumption of the starting benzotriazole, the reaction is dried over anhydrous magnesium sulfate (10 g), filtered, and concentrated in vacuo. The crude product is purified on a silica gel column eluting with 1:1 ethyl acetate·dichloromethane to afford the desired product as a white solid.

To a solution of the intermediate aminomethylbenzotriazole (1.0 molar equivalent) in dichloromethane (0.43 M) is added aluminum chloride (2.0 molar equivalent) followed by 3-(2,6-dichloro-benzyloxy¡)-5 (1H-indol-5-yl)-pyridin-2-ylamine (1.1 molar equivalents). The reaction is covered and heated with stirring to 40⁹C for 3-4 h. The reaction is then removed from the heat and allowed to cool to room temperature. The reaction mixture is diluted with sodium hydroxide (0.2M) and chloroform, capped again, and shaken vigorously at room temperature to dissolve the residue in the vial. The chloroform is removed from the aqueous phase, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product is purified on a silica gel column, first eluting with 1:1 ethyl acetate:dichloromethane to elute less polar impurities, then eluting the product with 90:9:1 chloroform:methanol:ammonium hydroxide. . (Yields 10-67%)

General procedure 6 for the synthesis of 3-(substituted-benzyloxy)-5-phenyl-pyridin-2-ylamine using 3-(3methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine :

<img file="ECSP077276A_D0068.tif" />

<img file="ECSP077276A_D0069.tif" />

To a solution of 3-benzyloxy¡-5-phenyl-pyr¡d¡n-2-¡lam¡na (Example I-87, 3.27 g, 11.8 mmol) in methanol (30 mL) was added pd(OH)₂ (2.5g, 2.37mmol). The mixture was degassed and charged three times with hydrogen and then stirred under an atmosphere provided by a balloon of hydrogen for 5 h. The reaction was filtered through a pad of celite, washed with methanol, and condensed. After drying in a high vacuum, 2-amino-5-phenyl-p¡ñd¡n-3-ol (2.04 g, 93% yield) was obtained. MS m/z 187 [M+1],

To a solution of 2-amino-5-phenyl-pyridin-3-ol (2.04 g, 10.95 mmol) in THF (anhydrous, 30 mL) was slowly added NaH (1.31 g, 32.85 mmol). The mixture was stirred under a nitrogen atmosphere for 20 minutes, then triphyll chloride (3.66 g, 13.14 mmol) was added. The reaction was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water and dried over Na₂SW₄. After filtration and condensation, the crude product was purified on a silica gel column eluting with EtOAc-Hexane (1:10) to give 5-phenyl-2-(trit¡l-amino)-pyrid¡ n-3-ol (1.09 g, 23% yield). MS m/z427 [M+1 ].

To a solution of 5-phenyl-2-(trit¡l-am¡no)-pyr¡d¡n-3-ol (100 mg, 0.24 mmol) in THF (3 mL) was added Cs₂CO₃ (79mg, 0.24mmol). The mixture was stirred at room temperature for 20 minutes, then 3-methoxybenzyl bromide (0.037 mL, 0.26 mmol) was added. The reaction was stirred at room temperature overnight, diluted with dichloromethane (5ml) and filtered to remove salts. The solvents were evaporated and the residue was dissolved in 10% trifluoroacetic acid in dichloromethane (2ml). The reaction was stirred for 2h and evaporated. The residue was dissolved in dichloromethane, washed with NaHCO₃ sat. and dried on Na₂SW₄. After filtration and concentration, the crude product was purified on a silica gel column eluting with methanol-dichloromethane (3% to 15% gradient) to give

3-(3-methoxy-benzyloxy)-5-phenylpyridin-2-ylamine as a white solid (43.5 mg, 60% yield).

General procedure 7 for the synthesis of 3-(benz¡loxy-substituted)-5-aryl-pyridin-2-ylamine using 5-[4-(2morpholin-4-yl-ethoxy)-phenyl]-3-( 3-nitro-benz¡lox¡)-pyrid¡n-2-ylamine:

A / íj u

JU HC/'y NHi, no₂

To a solution of 2-amino-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-ol (prepared according to the procedures for 2-amino-5 -phenyl-pyridin-3-ol in Example I-88 of the United States Patent Application with the N⁹ serial 10/786,610 (PCT/US2004/005495) (45.5 mg, 0.14 mmol) in DMF (3 mL) at 0^QC was added NaH (60% in oil) (5.6 mg, 0.14 mmol) and the mixture was stirred at 0^gC for 20 min. Then, 1-bromomethyl-3-nitro-benzene was added and the mixture was stirred at 0⁹C for 1 h and at room temperature for 2 h. Cold 1N aqueous HCl (0.1 mL) was added and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (CH₂IC₂:MeOH:NH₄OH = 100:3:0.3), giving 5[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine as a yellow solid (44 mg, 68%).

General procedure 8 for the synthesis of {4-[6-Amino-5-(benzyloxy-substituted)-pyridin-3-yl]-phenyl}-[(2fi)-2pyrrolidin-1-ylmethyl-pyrrolidin- 1 -yl]-methanone using {4-[6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-

3-¡l]-phenylj-[(2fí)-2-pyrrolidin-1 -ylmethyl-pyrrolidin-1 -yl]-methanone:

Q

o nh₂

CKxOH

N HOBt/EDC ,V\ DMF

<img file="ECSP077276A_D0070.tif" />

1. 6-Amino-5-benzyloxy¡-nicotinic acid was prepared according to procedure 3 from 3-benzyloxy-5-bromo-pyridin-2-ylamine and 4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid. MS m/z 321 (M+1).

2. [4-(6-amino-5-benz¡lox¡-pyridin-3-yl)-phenyl]-[(2fí)-2-pyrrolid¡n-1 -iImethyl-pyrrolidin-1 -yl] was prepared methanone following procedure 4 using 6-amino-5-benzylox¡-n¡cotin¡co acid and (2/?)-pyrrolidin-1-ylmethyl-pyrrolidine (prepared in Example I-39 of US Patent Application with N⁹ Serial No. 10/786,610 (PCT/US2004/005495)). MS m/z 457 (M+1).

3. To a solution of [4-(6-am¡no-5-benzyloxy-pyridin-3-yl)-phenyl]-[(2A?)-pyrrolidin-1 -ylmethyl-pyrrolidin1 -yl]-methanone (2.28 g, 5.00 mmol) in methanol (25 mL) was added 10% Pd/C (100 mg). The mixture was degassed and charged three times with hydrogen and then stirred under an atmosphere provided by a balloon of hydrogen overnight. The reaction was filtered through a pad of celite, washed with methanol, and condensed. After drying under high vacuum, [4-(6-amino-5-hydroxy-pyridin-3-yl)phenyl]-[(2R)-2-pyrrol¡d¡n-1 -ylmethyl-pyrrolidin-1 was obtained. -yl)-methanone (1.74 g, 95% yield).¹H NMR (400 MHz, DMSO-ds) δ 7.79 (s, 1H), 7.54 (m, 3H), 7.46 (m, 2H), 7.14 (s, 1H), 5.68 (s, 2H), 4.22 (m, 1H), 3.45 (m, 2H), 2.66 (m, 1H), 2.52 (m,4H), 1.96 (m,2H) , 1.84 (m, 3H), 1.64 (m, 4H); MS m/z 367 (M+1).

4. To a stirred solution of [4-(6-am¡no-5-h¡drox¡-pyr¡d¡n-3-¡l)-fen¡l]-[(2R)-2-p¡rrol¡ d¡n-1 -ylmethylpyrrolidin-1 -ylj-methanone (100 mg, 0.27 mmol) in anhydrous DMF (15 mL) under N₂ to 0⁹C was added sodium hydride (60% dispersion in mineral oil, 11 mg, 0.49 mmol). The mixture was allowed to stir at 0⁹C for 30 min. 1 -(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.046 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was diluted with EtOAc and partitioned with H₂O. The aqueous phase was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with H₂O (1 x 15 ml) and brine (1 x 15 ml), dried over MgSO₄, filtered, concentrated, and purified on a silica gel column to yield {4-[6-am¡no-5-(4-fluoro-2-tfluoromethylbenzyloxy)-pyrid¡n-3-yl] -phenyl}-[(2/?)-2-pyrrolidin-1 -ylmethyl-pyrrolidin-1 -ylj-methanone in the form of off-white crystals.

General Procedure 9 for the synthesis of 2-dialkylamino-ethanesulfonic acid [6-amino-5-(benzyloxy-substituted)-pyridin-3-yl]-phenyl-amide using {4-[6- 2-Diethylamino-ethanesulfonic acid amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}amide.

<img file="ECSP077276A_D0071.tif" />

1. To a solution of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5 g, 22.8 mmol) in dichloromethane (120 ml ) was added /V-methylmorpholine (7.5 mL, 68.4 mmol). This mixture was cooled to 0⁹C in a nitrogen atmosphere. Then 2-chloroethanesulfonyl chloride (2.5 mL, 23.9 mmol) in dichloromethane (60 mL) was added dropwise with stirring. Once the addition was complete, the flask was shaken at 0⁹C for 1 hr then at room temperature while monitoring by TLC (1:1 ethyl acetate:hexanes) and staining with ninhydrin. After 4 h of stirring, some of the starting boronic ester still remained and an additional 0.2 equivalents (0.5 ml) of 2-chloroethanesulfonyl chloride in dichloromethane (25 ml) was added dropwise at room temperature. After 1 h, the boric ester had been consumed as demonstrated by TLC and the total reaction volume was halved by rotary evaporator. The contents were diluted with ethyl acetate (200 mL), washed with 50% brine (2 x 100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified using silica gel (120 g) and eluting with 10% ethyl acetate and dichloromethane to yield [4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2- Ethenesulfonic acid yl)-phenyl]-amide as a white solid (6.2 g, 20.2 mmol, 89% yield).¹H NMR (CDCI₃, 300 MHz) δ 7.76 (d, J = 8.4, 2H), 7.12 (d, J = 8.45, 2H) 6.65 (s, 1H), 6.55 (dd, J = 9.77, 6.7.1H), 6.31 (d, J = 16.54.1H), 5.96 (d, J = 9.8.1H), 1.33 (s, 12H) .

2. To a solution of ethenesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (0.500 g, 1.6 mmol) in methanol (5 mL) was added diethylamine (0.707 g, 4.0 mmol) in methanol (5 mL) and the reaction stirred at room temperature and monitored by TLC (1:1 ethyl acetate: hexanes). After 2h the reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate (50ml) and water (50ml). The ethyl acetate was then washed with 50% brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using a 10 g pre-packed silica gel column, eluting with 1:1 ethyl acetate:dichloromethane to give [4-(4,4,5,5-tetramethyl-[1,3, 2-Diethylamino-ethanesulfonic acid 2]dioxaborolan-2-yl)-phenyl]-amide as a white solid (0.346 g, 0.90 mmol, 56%).¹H NMR (CDCI₃, 300 MHz) δ 7.78 (d, J = 6.65, 2H) 7.15 (d, J = 6.66, 2H), 3.20 (m, 2H), 3.0 (m, 2H ), 2.55 (c, J = 7.15, 7.16, 4H), 1.34 (s, 12H), 1.05 (t, J = 7.19, 6H).

3. 2-Diethylamino-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide was prepared following the general coupling procedure from Suzuki 3 from 5-bromo-3-(2-chloro-3,6-d¡fluoro-benzyloxy)-pyr¡d¡n-2-¡lam¡na and [4-(4,4,5,5 2-Diethylaminoethanesulfonic acid -tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-amide prepared in part 2 as a white solid in 60% yield.

General Procedure 10:

1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (3 g, 0.013 mol) was dissolved in dichloromethane (350 ml) to which pyridine was added (1.02 g, 0.013 mol) and 4-nitrophenyl chloroformate. The reaction was stirred for 13 h, at which time TLC analysis showed consumption of all starting materials. The solution was washed with NaHCO₃ saturated (3 x 50 ml), water (3 x 50 ml) and brine (3 x 50 ml). The organic phase was dried over Na₂SW₄ and the solvent was removed, yielding a white crystalline solid, [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid phenyl ester, 4 0.45g, 91%.¹H NMR (CDCI₃ 300 MHz) δ 1.4 (s, 12H), 7.1 (sa, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8 .3 (d, 2H).

<img file="ECSP077276A_D0072.tif" />

EITHER'^D.'EITHER

J—ko

(Aci Φ Pyridine

CH₂IC₂/Reflux

NO₂

<img file="ECSP077276A_D0073.tif" />

<img file="ECSP077276A_D0074.tif" />

+

br

<img file="ECSP077276A_D0075.tif" />

F

Pd(PPti₃)₄

na₂CO₃dme/h₂either

ElgN/CHjCh

EITHER

UmA.iR

HN N

<img file="ECSP077276A_D0076.tif" />

2: [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]carbamic acid phenyl ester (500 mg, 1.3 mmol) was dissolved in dichloromethane anhydrous (0.5 mL) and triethylamine (0.187 mL, 1.3 mmol). To this stirred solution was added 1-methylpiperazine (or any other amine) (0.144 mL, 1.3 mmol). The solution immediately turned yellow and TLC analysis showed consumption of all starting material. The reaction was washed with water (3 x 500ml) and saturated sodium bicarbonate (2 x 200ml) and dried before removal of the solvents in vacuo. Boron esters were used without purification.

3: To a mixture of 2.1 mL DME and 2.8 mL Na₂CO₃ 2 N were added 100 mg of the bromide structure, 1 equivalent of boric acid and 5 mol% Pd(PPh₃)₄. The reaction was stirred and heated to 80⁵C overnight in a two drachma vial (3.544 g). The crude mixture was filtered through celite and extracted with EtOAc (2 x 100 mL). The combined extracts were washed with NaHCO₃ (1 x 100 mL), followed by water (1 x 100 mL) and then saturated brine (1 x 100 mL). The resulting mixture was concentrated in vacuo. The residue was dissolved in hexane and purified by column chromatography.

General procedure 11:

<img file="ECSP077276A_D0077.tif" />

<img file="ECSP077276A_D0078.tif" />

1: Still solution of 3-[1 -(2,6-Dichloro-3-f I uo ro -fen i I)-ethoxy]-pyrid in-2-i I am i na (10.0 g, 33.2 mmol) in acetonitrile (600 ml) and acetic acid (120 ml) was added N-iodosuccinimide (11.2 g, 49.8 mmol). The mixture was stirred at room temperature for 4 h and the reaction was quenched with Na solution.₂S₂EITHER₅. After evaporation, the residue was partitioned between ethyl acetate and water. The organic phase was washed with 2N NaOH solution and brine and dried over Na₂SW₄. The crude product was purified on a silica gel column to give 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethox¡]-5-iodo-p¡ñd¡n -2-ylamine (7.1 g, 50% yield). MS m/z 427 [M+1]

2: To a solution of 3-[1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 16.6 mmol ) and prop-2-ynyl-carbamic acid tert-butyl ester (3.1 g, 20.0 mmol) in THF (60 mL) and Et₃N (60 mL) was added with Cul (63 mg, 0.3 mmol) and Pd(PPh₃)₄ (384mg, 0.3mmol). The mixture was stirred under a nitrogen atmosphere and monitored by TLC until the reaction was complete. The mixture was extracted with EtOAc and washed with water. The crude product was purified on a silica gel column eluting with 20-40% EtOAc in hexanes to give (3-{6-amino-5-[1-(2,6-dichloro- 3-fluorophenyl)-ethoxy]-pyridin-3-¡l}-prop-2-yn¡l)-carbamic (2.2 g, 29% yield).

3: (3-{6-Amino-5-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy¡]pyridin-3-yl}-prop- acid tert-butyl ester solution 2-ynyl)-carbamic acid in 25% TFA in dichloromethane was stirred for 2 h, then washed with 2N NaOH, twice with water, brine, and dried over Na₂SW₄. After filtration and evaporation, 5-(3-amino-prop-1 -ynyl)-3-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin- was obtained. 2-ylamine with a yield of 93%.

4: To a solution of 5-(3-amino-prop-1-ynyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (0.282 mmol, 1 equiv.) and 4-nitrophenyl chloroformate (1 equiv.) in anhydrous dichloromethane (10 mL), pyridine (1 equiv.) was added. The reaction was stirred for 4 h under a nitrogen atmosphere and then the selected amine (1 equiv) and triethylamine (1 equiv) were added. The mixture was refluxed for 5 minutes and cooled to room temperature. The reaction mixture was washed with water. The organic phase was evaporated and purified on a silica gel column eluting with 0-20% methanol in dichloromethane on previously packed silica columns. The final yields varied between

<img file="ECSP077276A_D0079.tif" />

¡lamine (prepared in procedure 11) (400 mg, 1.1 mmol) in dichloromethane (17 mL) was added chloroacetyl chloride (153 mg, 1.4 mmol). The reaction was stirred at room temperature with TLC monitoring for completion of the reaction. After completion, the solvent was evaporated, yielding the crude product.

2: To a solution of A/-(3-{6-Am¡no-5-[1-(2,6-d¡chloro-3-fluoro-fen¡l)-ethox¡]-pyr¡d¡ n-3-yl}-prop-2ynyl)-2-chloro-acetamide (1 equiv.) in acetonitrile (5 equiv.) was added the individual amine (5 equiv.).

The mixture was refluxed under a nitrogen atmosphere overnight. After evaporation of the solvent, the residue was purified on a silica gel column eluting with 1-10% methanol in dichloromethane to give the product in 47-97% yields.

General procedure 13:

<img file="ECSP077276A_D0080.tif" />

<img file="ECSP077276A_D0081.tif" />

1. To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH₃CN (600 mi) at 0⁵C /V-bromosuccinimide (37.1 g, 0.21 mol) was added over 30 minutes. The mixture was stirred for 0.5h, after which the reaction was diluted with EtOAc (900ml) and partitioned with H2O (900ml). The organic phase was washed with brine and dried (Na2SO4), filtered, and concentrated to dryness in vacuo to yield 3-benzyloxy¡-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mole, 53%).¹H NMR (CDCI3, 300 MHz) δ 4.63-4.78 (bs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33 -7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).

2. To a stirred mixture of 3-benz¡lox¡-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol) in a mixture of DME (600 mL) and H₂OR (600 mL) was added 4-carboxymethylboric acid (29.9 g, 0.11 mol), Pd(PPh₃)₄ (6.4 g, 5.55 mmol) and Na₂CO₃ (82.0g, 0.78mol). The reaction was slowly heated to reflux and allowed to stir for 3h. The reaction was cooled to room temperature, then diluted with CH₂IC₂ (1.5 I) and partitioned with H₂OR (700 mi). The organic phase was washed with NaHCO₃ saturated (700 ml), dried (Na₂SW₄), was filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica gel, 1:1 to 4:1 EtOAc:hexanes) and the fractions containing the product were combined and concentrated in vacuo to yield 4-( 6-am¡no-5-benz¡lox¡-pyrid¡n-3-¡l)-benzo¡co (29.4 g, 0.086 mol, 79%).¹H NMR (CDCIg, 300 MHz) δ 3.92 (s, 3H), 4.82-4.94 (bs, 2H), 5.15 (s, 2H), 7.22 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.54 (d, 2H, J, 8.6), 7.98 (d, 1H, J, 1.8 Hz), 8.06(d, 2H, J, 8.6Hz).

3. To a stirring solution of 4-(6-amino-5-benzyloxy-pyridin-3-yl)benzoic acid methyl ester (10.0 g, 0.03 mol) in EtOH:H₂Or (95:5, 600 mL) was added Pd/C (15.9 g, 0.015 mol) (reaction was degassed in vacuo). The solution was allowed to stir under an atmosphere of H₂ for 22h. The solution was filtered through wet celite and the celite was washed with EtOH. The filtrate was concentrated in vacuo to yield 4-(6-amino-5-hydroxy-pyridin-3-yl)-benzoic acid methyl ester (2.3 g, 9.3 mmol, 31%).¹H NMR (MeOD, 300 MHz) δ 3.90 (s, 3H), 7.21 (d, 1H, J, 1.9 Hz), 7.62 (d, 2H, J, 8.5 Hz), 7.76 (d, 1H, J, 1.9Hz), 8.04 (d, 2H, J, 8.5Hz).

4. To a stirring solution of 4-(6-amino-5-hydroxy-pyridin-3-yl)benzoic acid methyl ester (2.3 g, 9.3 mmol) in CH₂IC₂ (180 mL) were added A/,A/-di¡sopropyl¡lam¡ne (3.2 mL, 0.019 mol), 4-methyl-benzenesulfonyl chloride (2.66 g, 0.014 mol) and PS -DMAP (catalytic amount). The reaction was stirred at room temperature for 6h, then filtered to remove the resin. The resin was washed with CH₂IC₂ (3 x 20 ml) and the combined fractions were washed with 10% citric acid (100 ml) and saturated NaCI (100 ml), dried (Na₂SW₄), were filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (silica gel, from CH₂IC₂ 100% at 95:5 CH₂IC₂:MeOH) and fractions containing the desired product were combined and concentrated in vacuo to yield 4-[6-amino-5-(toluene-4-sulfonyloxy)-pyridin-3-yl]-benzoic acid methyl ester ( 3.3g, 8.2mmol, 88%).¹h

NMR (CDCI3, 300 MHz) δ 2.47 (s, 3H), 3.93 (s, 3H), 4.81-4.88 (bs, 2H), 7.36-7.44 (m, 5H ), 7.81 (d, 2H, J, 8.3 Hz), 8.05 (d, 2H, J, 8.4 Hz), 8.19-8.27 (sa, 1H).

5. To a stirred solution of 1 -(3-fluoro-2-trifluoromethyl-phenyl)-ethanol (2.0 g, 9.6 mmol) in anhydrous DMF (500 mL) at 0^yesC in an atmosphere of N₂ NaH (0.38 g, 9.6 mmol) was added. The reaction was allowed to stir for 0.5h. A solution of 4-[6-amino-5-(toluene-4sulfonyloxy¡)-pyrid¡n-3-yl]-benzo¡co acid methyl ester (3.8 g, 9.6 mmol) was added. in anhydrous DMF (30 ml) to the reaction mixture which was slowly allowed to warm to room temperature and stirred for 21 h at this temperature. The reaction was diluted with EtOAc (500 mL) and H₂Or (100 mi). The organic phase was separated off and the aqueous phase was further extracted with EtOAc (1 x 200 mL). The organic phases were combined and washed with brine (1 x 100 mL), dried over Na₂SW₄ and concentrated to dryness in vacuo. The crude mixture was purified by column chromatography (silica gel, 40:60 to 70:30 EtOAc:hexanes) and fractions containing product were combined and concentrated in vacuo to yield 4-{ acid methyl ester. 6am¡no-5-[1-(3-fluoro-2-tr¡fluoromethyl-fen¡l)-ethox¡]-p¡ñd¡n-3-¡l}-benzo¡co (1,4 g, 3.2 mmol, 34%).¹H NMR (CDCI3, 300 MHz) δ 1.73 (d, 3H, J, 6.2 Hz), 3.91 (s, 3H), 4.87-4.64 (bs, 2H), 5.81 (c, 1H, J, 6.1, 6.3Hz), 6.92 (d, 1H, J, 1.8Hz), 7.38 (d, 2H, J, 8.5Hz), 7 .46-7.66 (m, 3H), 7.93 (d, 1H, J, 1.8 Hz), 8.02 (d, 2H, J, 8.5 Hz).

6. To a stirred solution of 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethylphenyl)-ethoxy]-pyridin-3-yl}-benzoic acid methyl ester (1 0.4 g, 3.2 mmol) in hot IPA (72 mL) was added with H₂OR (38 mL) containing LiOH (0.68 g, 16.2 mmol). The reaction was heated at reflux for 3.5h. The reaction was quenched, diluted with EtOAc (200 mL) and extracted after cooling. The organic phase was washed with brine (50 mL), dried over Na₂SW₄ and concentrated in vacuo to yield 4-{6-amino-5[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-l}-benzoic acid (1.2 g, 2.8 mmol, 88%).¹H NMR (MeOD, 300 MHz) δ 1.75 (d, 3H, J, 6.2 Hz), 4.88-4.93 (m, 1H), 7.01 (d, 1H, J, 1, 8 Hz), 7.39 (d, 2H, J, 8.3 Hz), 7.52-7.67 (m, 3H), 7.80 (d, 1H, J, 1.8 Hz), 7 .97 (d, 2H, J, 8.3Hz).

7. Preparation of amide compounds: A stirring solution of the acid 4-{6-amino-5-[1 -(3fluoro-2-trifluoromethyl-phenyl)-ethox¡]-p¡r¡d¡n-3 -¡l}-benzo¡co (50 mg, 0.12 mmol), EDC (27.0 mg, 0.13 mmol) and HOBt (18.0 mg, 0.13 mmol) in DMF (2 mL) were added to a two drachma vial (3.54 g) containing NHR!R₂ (0.12mmol). The reaction was stirred at room temperature for 18h. The reaction was then diluted with CH₂IC₂ (3 mi) and divided with H₂O. The organic phase was separated and washed with saturated NaCI (1 x 2 mL) and NaHCO₃ saturated (1x2 mi). The organic phase was concentrated to dryness in vacuo. The material was purified using column chromatography (silica gel, 99:1 to 95:5 CH₂IC₂/MeOH). Fractions containing the product were concentrated in vacuo to yield the amide compounds.

General procedure 14:

<img file="ECSP077276A_D0082.tif" />

<img file="ECSP077276A_D0083.tif" />

1: To a mixture of 1 -(2-chloroethyl)pyrrolidine hydrochloride (200 mg, 1.18 mmol) and 4-(4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2 -yl)-phenyl]-1H-pyrazole (229 mg, 1.19 mmol) in DMF (6 mL) added Cs₂CO₃. The mixture was stirred at room temperature overnight. Then, to the mixture was added water (10 ml). The product was extracted with EtOAc (3x10 ml). The combined extracts were then washed with brine (5x10 mL) to remove DMF, then dried over Na₂SW₄ and concentrated (142 mg, 41% yield).

2: To a mixture of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (200 mg,

0.468 mmol), pinacol-boric ester (1.2 equiv.) and Na₂CO₃ (149 mg, 1.41 mmol) in water (1.25 mL) and dimethyl ethyl glycol (3.75 mL, 0.1 M) was added Pd(PPh₃)₂IC₂ (16 mg, 0.020 mmol) in a microwave reaction vessel. The system was degassed and charged with nitrogen. The mixture was stirred at 160-C in a microwave apparatus for 15 minutes. The mixture was cooled to room temperature followed by the addition of water (10 ml). The product was extracted with EtOAc (3 x 20 mL), dried over Na₂SW₄ and concentrated. The crude product was purified by reverse phase HPLC with 0.1% TFA in water and acetonitrile.

General procedure 15:

<img file="ECSP077276A_D0084.tif" />

1: To a solution of 3H-oxazolo[4,5-b]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added A/-bromosuccinim ¡da (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 h and the reaction was quenched with Na solution.₂S₂EITHER₅. After evaporation, the residue was partitioned between ethyl acetate and water. The organic phase was washed with 2N NaOH solution and brine and dried over Na₂SW₄. The crude product was purified on a silica gel column to give 6-bromo-3W-oxazolo[4,5-b]pyridin-2-one (11.5 g, 55% yield).

2: 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (21.5 g, 100 mmol) was suspended in NaOH solution (2N, 250 mL, 500 mmol). The mixture was refluxed overnight and a clear solution was obtained. After cooling to room temperature, the reaction solution was neutralized to pH ~7. A large amount of CO was released₂ and a precipitate was also observed. The product was filtered, washed with water and dried under high vacuum to provide 2-amino-5-bromo-pyridin-3-ol as an off-white solid (17.8 g, 98% yield). ).

3: To a solution of 2-amino-5-bromo-pyridin-3-ol (358 mg, 1.89 mmol) in DMF (8 mL) was added Cs₂CO₃ (620mg, 1.89mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. Bromo compound (0.9 equiv) in DMF (5 mL) was slowly added to the reaction mixture. The reaction solution was stirred under a nitrogen atmosphere for five h, then partitioned between water and ethyl acetate. The organic phase was washed three times with brine and dried over MgSO.₄. The crude product was purified on a silica gel column eluting with hexane-ethyl acetate (4:1) to give the product in 70%-80% yield.

General Procedure 16 using Example I-488 of the United States Patent Application with N⁹ Serial 10/786.610 (PCT/US2004/005495):

<img file="ECSP077276A_D0085.tif" />

1. To a solution of 3-benzyloxy-5-bromo-pyridin-2-lamin (1 g, 3.58 mmol) in dimethyl sulfoxide (7 mL) was added sequentially /s(pinacolato)diborane (1, 0 g, 3.94 mmol), potassium acetate (1.05 g, 10.7 mmol) [1.1'-£>/s(diphenylphosphino)ferrozine]dichloropalladium(II), complex with dichloromethane (1:1) (146mg, 0.18mmol). The mixture was heated to 80⁹C for 16 h and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate was washed with water (2 x 50 ml) and dried over magnesium sulphate. Concentration in vacuo gave the crude borate as a brown solid (1.13 g, 97%).^{1 2}H NMR (CDCI₃) δ 1.32 (s, 12H), 5.08 (s, 2H), 5.44 (sa, 2H), 7.33-7.42 (m, 6H), 8.03 (s, 1H ).

2. An 18 mL reaction vessel was charged with crude 3-benzyloxy-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine ( 161 mg, 0.49 mmol), dimethoxyethane (3 mL) and 2-bromopyridine (117 mg, 0.74 mmol). To this solution was added [1,1't»/'s(d¡fen¡lfosf¡no)ferroc¡na]dichloropalladium(II), complexed with dichloromethane (1:1) (20 mg, 0. 05 mmol) and a 2M solution of cesium carbonate in water (0.75 mL, 1.5 mmol). The reactor was heated to 80⁹C for 66 h under a nitrogen atmosphere and then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (5ml) and water (5ml). The organic phase was washed with more water (5ml) and diluted with dimethylformamide (5ml). To the organic solution was added polymer-bound sultanic acid (0.5 g, 2.1 mmol) and the resulting mixture was gently stirred for 2 h. The resin was filtered and washed with dimethylformamide, methanol and methylene chloride (3 x 5 ml each solvent). The polymer was then reacted with 2M ammonia in methanol for 1h. The resin was filtered and washed with additional 2M ammonia in methanol (2 x 5 mL) and the combined filtrates concentrated in vacuo. Purification of the crude product by flash column chromatography gave 52.2 mg of the product as a tan solid (38% yield).

General procedure 17:

<img file="ECSP077276A_D0086.tif" />

1. To the solution of 3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2¡l)-pyridin-2 -ylamine (method 16) (10.0 g, 24.3 mmol) in i-butyl alcohol (50 mL) was added boc anhydride (5.83 g, 26.7 mmol) and the reaction stirred at room temperature. environment for one night. Additional boc anhydride (2.25 g, 10.3 mmol) was added and the reaction stirred again overnight. The material was concentrated to a viscous black oil and used as such.

2. The crude boric ester (24.3 mmol theoretical) in THF (150 mL) was added to a solution of sodium bicarbonate (16.3 g, 194 mmol) in water (150 mL) and acetone (23 mL). The mixture was cooled to 2^SC and oxone (13.5 g, 21.9 mmol) was added slowly, keeping the temperature below 8^SC. After the addition was complete, the reaction was stirred for 5 minutes and then quenched with sodium bisulfite (14.2 g) in water (28 mL). Ethyl acetate (200 ml) was added and the phases were separated. The aqueous phase was neutralized with 6N HCI and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with water (250 ml) and brine (250 ml), dried (Na2SO4) and concentrated to a crude black oil. Silica gel chromatography (ethyl acetate/hexane) gave the product as a light brown foam (4.78 g, 49.0%).¹H NMR (CDCI3) δ 1.48 (s, 9H), 1.74 (d, 3H), 5.75 (c, 1H), 6.61 (d, 1H), 6.89 (dt, 1H) , 6.94-7.04 (m, 2H), 7.26(d, 1H), 8.19 (bs, 1H). MS m/z401 (M+H)⁺.

3. To cesium carbonate in a 2 dram vial (3.54 g) was added [3-(2-chloro-3,6-difluoro-benzyloxy)-5-hydroxy-pyridin- 2-yl]-carbamic acid (100 mg, 0.25 mmol) in anhydrous DMF (1 mL) followed by benzyl bromide (89.2 μΙ, 0.75 mmol). The vial was stoppered and shaken at 90^yesC for one night. The reaction was filtered through a 5 mL Chem-Elut tube pre-moistened with water (3.5 mL) and eluted with 1:1 ethyl acetate:methylene chloride. After partial concentration, 4N HCI in dioxane (1-2 mL) was added and the solution was concentrated. Reverse phase chromatography (water:acetonitol, 0.05% TFA) followed by lyophilization gave the desired product as an off-white amorphous solid (25.3 mg, 20.0%) and the b/s product -addition as a brown amorphous solid (35.2 mg, 23.7%).

General procedure 18:

<img file="ECSP077276A_D0087.tif" />

<img file="ECSP077276A_D0088.tif" />

<img file="ECSP077276A_D0089.tif" />

Sodium borohydride (1.5 molar equivalents) is added to a solution of ketone (3.89 mmol) in 10 mL of ethanol under a nitrogen atmosphere. The resulting mixture is stirred at room temperature for 12h. The mixture is then placed in an ice bath and quenched with dilute aqueous HCI. The ethanol is evaporated and EtOAc is added to extract the aqueous solution. The EtOAc phase is dried over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give an oily residue, compound A5. The residue is used without further purification.

3-Hydroxy-2-nitropyridine (1.1 molar equivalents) and triphenylphosphine (1.5 molar equivalents) are added to a solution of compound A5 (1.1 mmol) in 10 mL THF. The reaction mixture is then placed in an ice bath and diisopropyl azodicarboxylate (1.5 molar equivalents) is added. The ice bath is removed and the mixture is stirred at room temperature for 12h. The solvent is evaporated, giving a yellow oily residue. The residue is purified by chromatography on silica gel (eluting with EtOAc in hexanes) to give compound A1.

2 M HCl (0.2 ml) is added to the solution of compound A1 (0.97 mmol) in 2 ml of ethanol. The mixture is then placed in an ice bath and Fe powder (365 mg) is slowly added. The reaction is heated to 85^gC for 1 h and cool to room temperature. Celite (0.5 g) is added to stir and the resulting mixture is filtered through a pad of celite and rinsed with ethanol. The filtrate is evaporated to give a brown oily residue, compound A2. The residue is used without further purification.

Periodic acid (0.25 molar equivalents), iodine (0.5 molar equivalents), H₂0 (0.5 ml) and concentrated sulfuric acid (0.03 ml) to a solution of compound A2 in 3 ml of acetic acid. The reaction mixture is heated to 85⁹C for 5h. The reaction mixture is then cooled in an ice bath and made basic with Na.₂CO₃ saturated ac. at a pH of 3-4. Ethyl acetate is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a brown oily residue. The residue is purified by silica gel chromatography (eluting with EtOAc and hexanes) to give the desired product, compound A3.

General procedure 19:

<img file="ECSP077276A_D0090.tif" />

<img file="ECSP077276A_D0091.tif" />

<img file="ECSP077276A_D0092.tif" />

Boric ester or boric acid (1.3 molar equivalents) is added to a solution of compound A3 (0.47 mmol) in 5 mL of DME. The mixture is purged several times with nitrogen and then dichloroth>/s(triphenylphosphino)palladium(II) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalents) in 1 mL of H is added to the reaction mixture.₂O and the resulting solution is heated to 85⁹C for 12h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound A4.

<img file="ECSP077276A_D0093.tif" />

Compound A6 was prepared using General Procedure 19. 0-(7azabenzotriazol-1-yl)-/V,/V,/V',/V-tetramethyluronium phosphorus pentafluoride (HATU) (1.1 molar equivalents), diisopropylethylamine, (5 molar equivalents) and amine (1.3 molar equivalents) to a solution of compound A6 (0.17 mmol) in 3 ml of DMF under a nitrogen atmosphere. The reaction is allowed to stir at room temperature for 12 h. NaHCO is added to the reaction mixture.₃ saturated to stop the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a brown oily residue. Purify the residue by silica gel chromatography (eluting with EtOAc and hexanes) to give the desired amide product, compound A7, as a yellow oil.

General procedure 21:

<img file="ECSP077276A_D0094.tif" />

Acid (16 molar equivalents or less) is added to compound A7 (0.13 mmol) at room temperature. The resulting solution is stirred at room temperature or heated to 60^yesC for 12h. The reaction mixture is evaporated and the residue is purified by chromatography on silica gel (eluting with CH₃OH, EtOAc and CH₂IC₂), giving the desired amide product, compound A8, as a yellowish to white solid.

<img file="ECSP077276A_D0095.tif" />

<img file="ECSP077276A_D0096.tif" />

Compound A9 is prepared using general procedure 19. Ditero-butyl dicarbonate (3 molar equivalents) and 4-(dimethylamino)pyridine (0.14 molar equivalents) are added to a solution of compound A9 (3 mmol) in 20 ml of DMF. The reaction mixture is stirred at room temperature for 12 h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a yellow brown oily residue. Purify the residue by silica gel chromatography (eluting with 25^30% EtOAc in hexanes) to give the desired product, compound A10, as a yellowish oil (87.8% yield). Ozone is bubbled through a solution of compound A10 in 50 mL of CH₂IC₂ to -78⁵C and dimethyl sulfide is added to quench the reaction. To the reaction mixture is added saturated sodium chloride and EtOAc is added to extract the aqueous solution. The combined EtOAc layer is dried over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a yellow oily residue. The residue is purified by silica gel chromatography (eluting with 35->40% EtOAc in hexanes) to give the desired product, compound A11, as a yellowish oil (58.4% yield). General Procedure 23: Reductive Amination

<img file="ECSP077276A_D0097.tif" />

^Α11 A12 A13

Amine hydrochloride salt (1.2 molar equivalents), sodium acetate (2 molar equivalents to the amine hydrochloride salt) are added to a solution of compound A11 (0.45 mmol) in 4 mL of CH₃OH in a nitrogen atmosphere. To the reaction mixture is added molecular sieve (0.5 g) and then sodium cyanoborohydride (2 molar equivalents) is added. The resulting mixture is stirred at room temperature for 12 h under a nitrogen atmosphere. The reaction mixture is filtered through a pad of celite and the filtrate is evaporated and purified by chromatography on silica gel (eluting with CH₃OH, EtOAc and CH₂IC₂), giving the desired product, compound A12 as an oil (52.6% yield). Acid (16 molar equivalents or less) is added to compound A12 (0.17 mmol) at room temperature. The resulting solution is stirred at room temperature or heated to 60^yesC for 12h. The reaction mixture is evaporated and the residue is purified by chromatography on silica gel (eluting with CH₃OH, EtOAc and CH₂IC₂), giving the desired product, compound A13.

General procedure 24:

<img file="ECSP077276A_D0098.tif" />

<img file="ECSP077276A_D0099.tif" />

O-Phenyldiamines (1.2 molar equivalents) and sodium bisulfite (2.1 molar equivalents) are added to a solution of compound A11 (0.41 mmol) in 5 ml of DMA. The resulting solution is heated to 110^yesC for 12h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a yellow brown oily residue. The residue is purified by silica gel chromatography (eluting with EtOAc in hexanes) to give the desired product, compound A14. Acid (16 molar equivalents or less) is added to compound A14 (0.16 mmol) at room temperature. The resulting solution is stirred at room temperature or heated at 60°C for 12h. The reaction mixture is evaporated and the residue is purified by chromatography on silica gel (eluting with CH₃OH, EtOAc and CH₂IC₂), giving the desired amide product, compound A15. General Procedure 25:

<img file="ECSP077276A_D0100.tif" />

Di-ert-butyl dicarbonate (3 molar equivalents) and 4-(dimethylamino)pyridine (0.14 molar equivalents) are added to a solution of compound A3b (2 mmol) in 10 ml of DMF. The reaction mixture is stirred at room temperature for 12 h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a yellow brown oily residue (compound a16). The residue is used without further purification.

£>/s(pinacolato)diboron (1.2 molar equivalents) and potassium acetate (3.4 molar equivalents) are added to a solution of compound a16 in 4 ml of DMSO. The mixture is purged several times with nitrogen and then dichlorob/s(triphenylphosphino)palladio(II) (0.05 molar equivalent) is added. The resulting solution is heated to 80^yesC for 12h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc layer over Na2SO4. The Na2SO4 is filtered off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by silica gel chromatography (eluting with 30% EtOAc in hexanes) to give the desired product, compound A17 (76% yield). HCI (5 molar equivalents) is added to a solution of compound A17 (0.43 mmol) in 4 mL of CH2CI2. The resulting mixture is heated to 50^QC for 12h. Saturated NaHCO3 is added to the reaction mixture to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give the desired product (compound A18) as a yellow solid (75% yield).

General Procedure 26:

<img file="ECSP077276A_D0101.tif" />

Compound A17 (1.3 molar equivalents) is added to a solution of aryl halide (0.36 mmol) in 3 ml of DME. The mixture is purged several times with nitrogen and then dichlorob/s(tr¡fen¡lfosf¡no)pallad¡o(II) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalents) in 0.8 mL of H is added to the reaction mixture.₂O and the resulting solution is heated to 85⁹C for 12h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by silica gel chromatography (eluting with EtOAc in hexanes) to give the desired product, compound A19 (74.4% yield). HCl (5 molar equivalents) is added to a solution of compound A19 (0.26 mmol) in 10 mL isopropyl alcohol. The resulting mixture is heated to 50⁹C for 12h. The solvent is evaporated, giving the desired product, compound A20.

General procedure 27:

<img file="ECSP077276A_D0102.tif" />

<img file="ECSP077276A_D0103.tif" />

Compound A18 (1.3 molar equivalents) is added to a solution of aryl halide (0.21 mmol) in 3 ml of DME. The mixture is purged several times with nitrogen and then dichloroZ?/s(triphenylphosphino)palladium(II) (0.05 molar equivalents) is added. Sodium carbonate (3 molar equivalents) in 0.6 mL of H is added to the reaction mixture.₂O and the resulting solution is heated to 85⁹C for 12h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound A21.

General procedure 28:

<img file="ECSP077276A_D0104.tif" />

Amine (1.5 molar equivalents) and K are added₂CO₃ (1.5 molar equivalents) to a solution of 4-halobenzyl halide (1.0 molar equivalent) in 2 ml of toluene. The resulting mixture is microwaved using a Smith synthesizer (150⁹C, 1h). To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give the desired product, compound A23. The residue is used in procedure 11 without further purification to synthesize compound A22.

General procedure 29:

<img file="ECSP077276A_D0105.tif" />

Amine (1.2 molar equivalents) and diisopropylamine (5 molar equivalents) are added to a solution of 4-bromobenzenesulfonyl chloride (0.77 mmol) in 5 mL of CHCI₃ in a nitrogen atmosphere. The resulting mixture is stirred at room temperature for 4 h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give the desired product, compound A25. The residue is used in procedure 11 without further purification to synthesize compound A24.

General procedure 30:

<img file="ECSP077276A_D0106.tif" />

Boric ester or boric acid (1.2 molar equivalents) is added to a solution of 1-chloro-4-iodobenzene (0.84 mmol) in 10 mL (DME) under a nitrogen atmosphere. The mixture is purged several times with nitrogen and then dichloro£>/s(triphenylphosphin)palladio(II) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalents) in 1.8 mL of H is added to the reaction mixture.₂O and the resulting solution is heated to 85²C for 12h. To the reaction mixture, water is added to quench the reaction. Then EtOAc is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound A27. Compound A27 is used in procedure 11 to synthesize compound A26.

General procedure 31 for the chiral separation of racemates:

The racemic sample is purified using CFSEM preparative supercritical fluid chromatography. Illustrative purification conditions: Chiralpak AD-H column, 250 x 21 mm, 5 microns, 100A column (Column N^yes:ADH0CJ-C1003); column temperature 35²C; 35% methanol (with 0.1% isopropylamine)-CO-modified mobile phase₂; prep flow rate 52 mL/min; isobaric pressure at 120 bar (12000 kPa).

General Procedure 32: using (4-{6-Amino-5-[1 -(3-trifluoromethyl-phenyl)-ethoxy¡]-pyrid¡n-3-¡l}-phenyl)-(3,5dimethyl-piperazine- 1-yl)-methanone

<img file="ECSP077276A_D0107.tif" />

<img file="ECSP077276A_D0108.tif" />

on site

To a mixture of 4-[4-(6-amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0 0.23 mmol) and 1 -(1-bromo-ethyl)-3-trifluoromethyl-benzene (64 mg, 0.25 mmol) in DMF (2 mL) was added NaH (12 mg, 0.47 mmol) at 0.^yesC. The mixture was stirred overnight. LCMS showed the reaction to be complete and the DMF and water were removed. To the residue was added TFA (2 mL) and stirred at room temperature for 3 h. TFA was removed followed by the addition of methanol. The residue was purified by prep. HPLC to provide (4-{6-Amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-

3-l}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (30 mg, 25.7% yield).

General Procedure 33: using (4-{6-amino-5-[1 -(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-l}-phenyl)-(3,5dimethyl-piperazin-1 -yl)-methanone

<img file="ECSP077276A_D0109.tif" />

in sllu

To a mixture of 4-[4-(6-amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (50 mg, 0 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 mL) added Cs₂CO₃ 2 M (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight and then heated to 70⁹C for 8 h, LCMS showed the reaction to be complete. The DMF and water were removed. To the residue was added TFA (2 mL) and stirred at room temperature for 3 h. The TFA was removed, followed by the addition of methanol. The residue was purified by prep. HPLC to provide (4-{6-amino-5-[1 -(2-tr¡fluoromethyl-phenyl)-ethoxy]-pyridin-3-¡l}-phenyl)-( 3,5-dimethyl-piperazin1-1)-methanone (20 mg, 34.2% yield).

General Procedure 34: using {4-[6-Amino-5-(2-methyl-benzyloxy¡)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin1-¡l)-methanone

<img file="ECSP077276A_D0110.tif" />

on site

To a mixture of (2fí,6S)-4-[4-(6-amino-5-h¡drox¡-p¡r¡d¡n-3-¡l)-benzo¡l acid tert-butyl ester ]-

2,6-dimethyl-piperazine-1-carboxylic acid (100 mg, 0.23 mmol) and l-bromomethyl-2-methyl-benzene (47 mg, 0.25 mmol) in DMF (2 mL) added Cs₂CO₃ 2 M (0.35 ml, 0.7 mmol) followed by water (0.5 ml). The mixture was stirred at room temperature overnight. LCMS showed the reaction to be complete, the DMF was removed, followed by the addition of 4N HCl in dioxane (2 mL) and the reaction stirred at room temperature for 3 h. Volatiles were removed followed by the addition of methanol. This solution was purified by prep. HPLC to give {4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-d ¡methyl-piperazin-1 yl)-methanone (47 mg, 46.6% yield).

General Procedure 35: using (6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3fluoro-phenyl )-ethoxy]-pyridin-3-¡l}-phenyl)-methanone

<img file="ECSP077276A_D0111.tif" />

1) Pd(dppf)2CI₂CsjCOg DME

2) HCI/Dioxane

<img file="ECSP077276A_D0112.tif" />

To a mixture of [3-(4-iodo-benzoyl)-3-aza-bicyclo[3.1.0]hex-6-yl]carbamic acid tert-butyl ester (100 mg, 0.234 mmol) and 3-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl[1_!3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (100 mg, 0.234 mmol) in DME (2 mL) was added with Pd(dppf)₂IC₂-CH₂IC₂ (10 mg, 0.012 mmol) and Cs₂CO₃ (351mg, 0.702mmol). The mixture was sparged with nitrogen for 10 min and then microwaved at 150⁹C for 30 min. The LCMS verified that the reaction was complete. The crude reaction mixture was diluted with ethyl acetate followed by washings with water and brine. The solution was dried over MgSO₄. Purification by HPLC prep. provided a solid. The solid was stirred with 4N HCI/dioxane (3ml) for 3h at room temperature. Removal of volatiles gave a residue which was purified by prep. HPLC to provide (6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5 -[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyridin-3-¡l}-phenyl)-methanone (30 mg, 26% yield).

General Procedure 36: using 5-[ 1 -(2,6-Dichloro-3-f I or oro-phenyl)-ethoxy]-6'-(2-morpholin-4-yl-ethoxy)[3,3' ]bipyridin¡l-6-ylam¡na

<img file="ECSP077276A_D0113.tif" />

F

6'-amino-5'-[1 -(2₅6-dichloro-3-fluoro-phenyl)-ethoxy]-[3₅3']bipyridinyl-6-ol (78 mg, 0.20

To a mixture of mmol), tlphenylphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL, 0.22 mmol). After stirring overnight, more PPh was added.₃ (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol). After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPh was added.₃ (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol). After stirring overnight, the mixture was partitioned between dichloromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na₂SW₄ and concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of dichloromethane, methanol to give 5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6' -(2-morphol¡n-4-¡l-ethoxy)-[3,3']b¡p¡r¡d¡n¡l-6-¡lam¡na (53 mg, 53%).

General Procedure 37: Using Example I-650 of the United States Patent Application with N⁹Serial 10/786.610 (PCT/US2004/005495)

<img file="ECSP077276A_D0114.tif" />

F

F

3-(2,6-Dichloro-3-fluoro-benz¡loxy)-5-thiazol-2-yl-pyridin-2-ylamine: To a microwave tube equipped with a stir bar, the material of iodo-pyridyl batch (300 mg, 0.702 mmol), teiraqu/s(triphenylphosphine)palladio(0) (40 mg, 5 mol%) and tetrahydrofuran (anhydrous, 6 mL). The vial was capped and purged with nitrogen for 5 minutes. Then 2-thiazolylzinc bromide (0.5 M in THF, 1.4 mmol, 2.8 mL) was added via syringe. The vial was heated to 120⁹C in the microwave for 10 minutes. TLC (1:1 ethyl acetate:methylene chloride) showed a large amount of starting material remaining. More 2-thiazolylzinc bromide (0.5 M in THF, 500 μΙ) was added and the vial was heated to 120^yesC in the microwave for 20 minutes. TLC (1:1 ethyl acetate:methylene chloride) showed a large amount of starting material still remaining. More 2-thiazolylzinc bromide (0.5 M in THF, 500 μΙ) was added and the vial was heated to 120⁹C in the microwave for 60 minutes. The TLC (1:1 ethyl acetate:methylene chloride) still showed a large amount of starting material which was still remaining but had also become very cloudy. The contents of the vial were poured into a sat. from NH₄CI (10 ml) and this solution was extracted with ethyl acetate (2 x 30 ml). The combined ethyl acetate layers were dried over Na₂SW₄, filtered and concentrated in vacuo. The crude product was loaded onto a pre-packed 10 g silica gel column and 1:1 ethyl acetate:methylene chloride was used to elute the desired product. (40mg, 15%).

General Procedure 38: Using Example I-652 of the United States Patent Application with N⁹number 10/786.610 (PCT/US2004/005495)

<img file="ECSP077276A_D0115.tif" />

3-[1-(2,6-Dichloro-3-f I or oro-pheni I)-ethoxy]-5-(1-methyl-1H-imidazo I-2-yl)-pyridin -2-ylamin: N-methylimidazole (92 mg, 1.1 mmol) was dissolved in tetrahydrofuran (anhydrous, 4 mL) in a 50 mL round bottom flask. The flask was cooled with a dry ice/acetone bath under a nitrogen atmosphere. N-Butyllithium (2.5 M, 562 μΙ, 1.4 mmol) was added via syringe in 100 μΙ portions over 5 minutes. The reaction was stirred at -70⁹C for 30 min. Solid zinc chloride (anhydrous, 383 mg, 2.8 mmol) was added and the reaction stirred for 15 minutes. The ice bath was then removed and the reaction was allowed to warm to room temperature. Once all of the zinc chloride was in solution and the reaction at room temperature, an iodine scaffold (400 mg, 0.936 mmol) in tetrahydrofuran (anhydrous, 4 mL) was added, followed by etraqu/s(tphenylphosphine) palladium(0) (108 mg, 10 mol%) and the reaction heated to reflux. The reaction was monitored by LC/MS until all of the starting iodine scaffold was consumed. The reaction was allowed to cool and then was diluted with sat. from NH₄CI (20 mi). This solution was extracted with ethyl acetate (2 x 50 ml). The combined ethyl acetate layers were dried over Na₂SW₄, filtered and concentrated in vacuo. The crude product was loaded onto a 10 g column of pre-packed silica gel and 10% methanol:ethyl acetate was used to elute the desired product (25 mg, 7%).

General Procedure 39: Using Example I-657 of the United States Patent Application with N⁹number 10/786.610 (PCT/US2004/005495)

<img file="ECSP077276A_D0116.tif" />

A 6-Amino-5-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitinol (400 mg, 1.23 mmol) in 70 mL dry methanol at 0⁹C was bubbled with HCI gas for 3 minutes. It was stirred overnight at 3⁹C. The volatiles were removed and the solids washed with diethyl ether, yielding the imidate quantitatively. To 200 mg of the imidate in 4 ml of methanol at 0⁹C was added 2N methylamine in THF (837 μΙ). Leave stirring at 0^yesC for about 1 h, then allow to warm to rt overnight. The volatiles were removed and the residue was chromatographed with 10-20% methanol/dichloromethane to yield 70 mg of product.

General procedure 40:

<img file="ECSP077276A_D0117.tif" />

<img file="ECSP077276A_D0118.tif" />

<img file="ECSP077276A_D0119.tif" />

1. 6-Nitro-5-hydroxynicotinic acid (B2): To a solution of 5-hydroxynicotinic acid (B1) (7.0 g, 50 mmol) in H₂SW₄ concentrate, 9 ml of HNO were added₃ smoking (90%) (9 mi). The reaction mixture was stirred at 55-60⁵C in a hermetically sealed test tube for four days. The mixture was then poured onto ice and the pH adjusted to 3 with 50% NaOH. MgSO4 was added to saturate the aqueous mixture, which was then extracted with isopropyl alcohol (4 x 45 mL). After removal of the isopropyl alcohol under reduced pressure, 5.93 g (64% yield) of B2 was obtained as a yellow solid. MS (APCI), (M+F)⁺185,¹H NMR (DMSO-ds) δ 8.01 (d, 1H, Ar-H), 8.41 (d, 1H, Ar-H).

2. 2,6-Dichlorobenzyl-6-nitro-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B3): 6-nitro5-hydroxynicotinic acid (B2) (3.4 g, 18.5 mmol), 2,6-dichlorobenzyl bromide (8.88 g, 37 mmol) and DIPEA (5.5 g, 42.5 mmol) in DMF (25 mL) in a 250 mL round bottom flask and the reaction shaken at room temperature for 4.5 h, then concentrated under reduced pressure. The resulting mixture was poured onto ice and filtered. The collected solid was dried under reduced pressure to give 4.25 g (46% yield) of B3. MS (APCI) (M+F)⁺ 503, ¹H NMR (DMSO-d₅) δ 5.47 (s, 2H, ArCH₂O), 5.71 (s, 2H, ArCH₂O), 7.24-7.43 (m, 6H, Ar-H), 8.26 (d, 1H, Ar-H), 8.66 (d, 1H, Ar-H).

3. 2,6-Dichlorobenzyl-6-amino-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B4): A mixture of 2,6-dichlorobenzyl-6-nitro-5-[(2,6-dichlorobenzyl) oxy]nicotinate (B3) (5.5 g, 10.96 mmol), iron powder (0.92 g, 16.43 mmol), glacial acetic acid (20 ml) and methanol (17 ml) were stirred at 85^SC for three hours. The reaction mixture was concentrated to near dryness and ammonium hydroxide (30%) was added to neutralize the mixture. A minimal amount of DMF was added to dissolve the reaction mixture, which was purified by flash column chromatography (eluent: EtOAc-EtOH, 9:1), giving 4.5 g (87%) of B4 as a solid. pale yellow. MS (APCI) (M+F)⁺ 473.

4. 6-Amino-5-[(2,6-dichlorobenzyl)oxy]nicotinic acid (B5): A mixture of 2,6-dichlorobenzyl-6amino-5-[(2,6-dichlorobenzyl)oxy]nicotinate ( B4) (3.5 g, 7.4 mmol), lithium hydroxide (0.41 g, 17 mmol), water (22 mL) and methanol (30 mL) was stirred and refluxed at 85⁵C for 5h. The mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in water, extracted with Et2O/hexane (1:1.4 x 25 mL) and neutralized with H11N to form a white precipitate, which was filtered and dried under reduced pressure to give 1.83 grams (79%) of B5 as a white solid. MS (APCI) (M+F)⁺ 313.¹H NMR (DMSO-d6) δ 5.26 (s, 2H, ArCH₂0), 6.37 (s, 2H, NH₂), 7.43-7.48 (t, 1H, Ar-H), 7.54 (s, 2H, Ar-H), 7.56 (s, 1H, Ar-H), 8.18 (s , 1H, Ar-H).

<img file="ECSP077276A_D0120.tif" />

R'RNH

HATU, DMF, °C, 2hr

<img file="ECSP077276A_D0121.tif" />

To a series of 400 μΙ of a 0.2 M solution of different amines in DMF in a 96-well plate was added 400 μΙ (0.2 M in DMF) of 4-[6-amino-5-(2) ,6-dichloro-3-fluoro-benzyloxy)pyridin-3-ylj-benzoic acid, 80 μΙ triethylamine (1 M in DMF) and 160 μΙ HATU (0.5 M in DMF) and the reactions were shaken at 70⁵C for 2h. The solvent was removed using the SpeedVac apparatus and the crude reaction mixtures were redissolved in DMSO and transferred using a liquid handler to a 1 mL 96-well plate, giving a theoretical final concentration of ~10 mM. Reactions were analyzed and positive product identification was performed using LC/MS. The stock solution was diluted to 50 nM and assayed for percent inhibition of c-MET at 50 nM.

General procedure 41:

<img file="ECSP077276A_D0122.tif" />

HATU, DMF, “C, 2hr

<img file="ECSP077276A_D0123.tif" />

To a series of 400 μΙ of a 0.2 M solution of different amines in DMF in a 96-well plate was added 400 μΙ (0.2 M in DMF) of 6-amino-5-[(2,6 -dichlorobenzyl)oxy]nicotin, 80 μΙ triethylamine (1 M in DMF) and 160 μΙ HATU (0.5 M in DMF) and the reactions were shaken at 70⁹C for 2h. The solvent was removed using the SpeedVac apparatus and the crude reaction mixtures were redissolved in DMSO and transferred using a liquid handler to a 1 mL 96-well plate, giving a theoretical final concentration of ~10 mM. Reactions were analyzed and positive product identification was performed using LC/MS. The stock solution was diluted to 1 μΜ and assayed.

General Procedure 42 using 2-(4-{6-amino-5-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1 µl)- /V-(3-d¡met¡lam¡no-prop¡l)-isobut¡ram¡da

<img file="ECSP077276A_D0124.tif" />

To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5 g, 25.77 mmol) and acid methyl ester 2 -bromo-2-methyl-propionic (12.6 g, 27.06 mmol) in DMF (85 mL), Cs was added₂CO₃ (12.6g, 38.65mmol). The reaction mixture was heated to 90⁹C in an oil bath overnight.

The reaction solution was cooled to room temperature and partitioned between water and ethyl acetate. The combined ethyl acetate solution was washed five times with water, dried over Na₂SW₄ and concentrated to give the product 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2yl)-pyrazol-1-ylj-propionic acid methyl ester (4.776 g, 63% yield).

To a solution of 3-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethox¡]-5-iodo-pyrid¡n-2-¡lamine (6.363 g, 14.901 mmol) and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-ylj-propionic acid methyl ester (4.6 g, 15, 64 mmol) in DME (27 ml) was added a solution of CsF (6.79 g, 44.7 mmol) in water (9.3 ml). The reaction mixture was degassed 3 times with N₂. Pd(dppf)CH was added₂IC₂ and the reaction mixture was degassed 3 times with N₂. The reaction was heated to 120⁹C in the microwave (subsequently Pd was added in 30 minute intervals until the reaction was complete). Water was added and the reaction was extracted with EtOAc, dried over Na₂SW₄ and concentrated to give 2-(4-{6-amino-5-[1-(2,6-dichloro-3-f I or oro-phenyl)-ethoxy]-pyridin-3- ÍI}-p¡ razol-1 -yl)-2-methyl-propionic acid. The crude product was purified by column chromatography on silica gel with a gradient of 25%-50% EtOAc/hexanes to give 2-(4-{6-amino-5-[1-(2, 6-dichloro-3-fluoro-phenyl)ethoxy]-pyridin-3-yl}-pyrazol-1 -yl)-2-methyl-propionic acid (1.46 g, 21% yield) with an R_F of 0.11 (50% EtOAc/hexanes).

To a solution of the methyl ester (2.92 g, 6.25 mmol) in MeOH (31 mL) was added a solution of LiOH (450 mg, 18.76 mmol) in water (6.25 mL). The reaction was heated to 60²C until LCMS showed hydrolysis to be complete (approximately 45 minutes). The MeOH was removed in vacuo and MeOH (2.5 mL) and water (1 mL) were added. The pH was adjusted to pH 5 with 1N HCl, at which point the product precipitated. The acidic product 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-

3-yl}-pyrazol-1-yl)-2-methyl-propionic acid after filtration (2.825 g, quant.).

To a solution of 2-(4-{6-amino-5-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy¡]-pyridin-3-yl}-pyrazol-1-yl acid )2-methyl-propionic acid (1.00 g, 2.20 mmol) in DMF (5.5 mL) was added HOBT (300 mg, 2.20 mmol), EDC (633 mg, 3.30 mmol) and /V,A/-dimethyl-propane-1,3-diamine (225 mg, 2.20 mmol). The reaction was stirred overnight at room temperature. The reaction was then purified by prep HPLC. Reverse phase C-18 eluting with acetonitrile/water with 0.1% acetic acid to give 2-(4-{6-amino-5-[1 -(2,6dichloro-3-fluoro-phenyl)- ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-A/-(3-dimethylamino-propyl)-isobutyramide (170 mg, 14% yield).

General Procedure 43 using 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-methyl-pyrazol-1-yl)-pyridin-2-ylamine

<img file="ECSP077276A_D0125.tif" />

F

To a stirred solution of 3-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (100 mg, 0.23 mmol) and 3- methyl-1 /-/-pyrazole (59 mg, 0.70 mmol) in DMSO (1 mL) was added K₃PO₄ (101 mg, 0.47 mmol), dodecane (0.015 mL, 0.05 mmol), cyclohexanediamine (0.009 mL, 0.07 mmol), and copper iodide (Cul) (14 mg, 0.07 mmol). The solution was bubbled with nitrogen for 5 minutes and then microwaved at 150⁹C for 2 hours. LCMS verified the reaction to be complete and the mixture was purified by prep. HPLC, leaving 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-methyl-pyrazole- 1-yl)pyridin-2-ylamine (30 mg), 34.2% yield

General procedure 44

<img file="ECSP077276A_D0126.tif" />

2,5-Dibromopyridine (1 molar equiv.) was dissolved in anhydrous toluene (0.085 M) and cooled to -78⁵C. n-BuL¡ (1.2 molar equiv.) was added slowly over 5 minutes and then the resulting mixture was allowed to stir at -78^gC. After 2 h, RiCOR2 (1.3 molar equiv) was added and the solution was kept at 78²C. After 1 h, saturated aqueous NH4Cl was added and the solution was warmed to room temperature. The product was extracted with EtOAc (3 x) and the organic extracts combined, dried (Na₂SW₄), concentrated and purified by column chromatography (10% EtOAc/100% Hexanes-EtOAc) to give crude product. It was used directly in General Procedure 27, giving 25.

General procedure 45

<img file="ECSP077276A_D0127.tif" />

<img file="ECSP077276A_D0128.tif" />

To a solution of 3-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (1.8 g, 6.04 mmol), 98% zinc cyanide % (2.07 g, 12.07 mmol) and 97% 1.1'-£?7s(diphenylphosphino)-ferrocene (0.4 g, 0.712 mmol) in DMF (48 mL) was added to the complex. of [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) with dichloromethane (1:1) (0.25 g, 0.30 mmol). The reaction mixture was heated to 150^yesC overnight under a nitrogen atmosphere. The reaction was diluted with EtOAc (50 mL), washed with 4:1:4 NH₄IC saturated/NH₄28% OH/H₂O (2 x 28 mL) and dried over Na₂SW₄. The crude mixture was purified on a silica gel column eluting with a 25%-50% linear gradient (EtOAc/hexanes) to give 2-[1-(2-aminopyridin-3-yloxy)-ethyl]- 3-chloro-4-dimethylamino-benzonitrile as a yellow solid (37% yield) and 2-[1 -(2-amino-pyridin-3-yloxy)-ethyl]-4- dimethylamino-isophthalonitrile as a dark brown solid (33% yield).

GENERAL PROCEDURE 46 or ^AA^Ot-Bu^brVNH ___ÍS°.^h'^kgC°³ , _br-tiNY^other’^BU you boo₄NBr θ

DCM

To a mixture of 4-bromo-imidazole (995 mg, 6.77 mmol), potassium hydroxide (380 mg, 6.77 mmol), potassium carbonate (936 mg, 6.77 mmol) and tetra-n-butylammonium bromide (109 mg, 0.339 mmol) in dichloromethane (7 mL) was added tert-butyl bromoacetate (0.50 mL, 3.4 mmol). After stirring overnight, the reaction was filtered. The filtrate was dried over sodium sulfate, filtered, and concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of dichloromethane, ethyl acetate to give (4-bromo-imidazol-1-yl)-acetic acid tert-butyl ester (696 mg, 79%).

General procedure 47

HO

<img file="ECSP077276A_D0129.tif" />

A 4M solution of hydrochloric acid in dioxane (0.22 mL, 0.89 mmol) was added to a solution of ert-butyl ester (4-{6-amino-5-[1-(2,6- dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-imidazol-1-yl)acetic acid (86 mg, 0.18 mmol) in dichloromethane (2 mL). After stirring for two days, the reaction was concentrated by rotary evaporator and the residue dissolved in a minimal amount of methanol. This solution was added dropwise to ether and the resulting mixture was allowed to stand overnight. The mixture was filtered and the precipitate was washed with ether and air dried to give the acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-pyrid ¡n-3-yl}-imidazol-1-yl)-acetic acid (83 mg, 93%).

General procedure 48

H“CI k'⁰ . BrDMF lk

A mixture of 4-bromo-imidazole (217 mg, 1.48 mmol) and cesium carbonate (875 mg, 2.69 mmol) in dimethylformamide (5 mL) was stirred for 30 minutes. 4-(2-Chloro-ethyl)-morpholine hydrochloride (250 mg, 1.34 mmol) was added and the mixture was heated to 50⁹C. After heating overnight the reaction was concentrated by rotary evaporator. The residue was suspended in a mixture of dichloromethane and methanol and filtered. The filtrate was concentrated by rotary evaporator. The residue was purified by silica gel chromatography using a dichloromethane, methanol gradient elution to provide 4-[2-(4-Bromo-imidazol-1-yl)-ethyl]-morpholine (148 mg, 42%). General procedure 49

N-O NIS

<img file="ECSP077276A_D0130.tif" />

<img file="ECSP077276A_D0131.tif" />

Yo

Isoxazole (0.64 mL, 10 mmol) was added to a solution of /V-iodosuccinimide (2.3 g, 10 mmol) in trifluoroacetic acid (20 mL). After stirring overnight, water (50 mL), hexanes (50 mL), and sodium bisulfite were added to the reaction. The phases were separated and the organic phase was dried over Na₂SW₄, filtered and concentrated by rotary evaporator to give 4-iodo-isoxazole (218 mg, 11%).

General procedure 50

<img file="ECSP077276A_D0132.tif" />

Trifluoroacetic acid (5 mL) was added to a solution of 6'-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethox¡]-[3,3']b¡p¡r ¡d¡n¡l-6-¡lb/s-(íert-butoxycarbon¡l)-amine (1.3 g, 2.0 mmol) in dichloromethane (15 mL).

After 3 hours, equal portions of water and saturated aqueous sodium bicarbonate were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na₂SW₄ and concentrated by rotary evaporator to give 6'-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-[3,3']bipyridinyl-6-ylamine (968 mg, 106%).

A test tube was charged with 6'-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3']bipyridinyl-6ylamine ( 92 mg, 0.20 mmol), 4-pyrrolidin-1-yl-piperidine (0.62 g, 4.0 mmol) and /V-methylpyrrolidinone (0.8 mL). The test tube was sealed and the mixture was heated to 80^gC for one night. The temperature was increased to 100^gC for 5.5 hours and then heating was discontinued. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO₄ and concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of dichloromethane, methanol and ammonium hydroxide to give 5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-4pyrrolid¡ n-1-1-3,4,5,6-tetrahydro-2H-[1,2';5',3]terpyridin-6-ylamine (53 mg, 50%).

General procedure 51

br

<img file="ECSP077276A_D0133.tif" />

br

HO

<img file="ECSP077276A_D0134.tif" />

NaHDMSO

<img file="ECSP077276A_D0135.tif" />

Sodium hydride (56 mg, 2.3 mmol) was added to a solution of piperidin-4-ol (214 mg, 2.11 mmol) in DMSO (8 mL). After stirring for 30 minutes, 2,5-dibromopyrindine was added. After stirring for 24 hours, sodium hydride (56 mg, 2.3 mmol) was added. After stirring for an additional 24 hours, the reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO₄ and concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of dichloromethane, methanol and ammonium hydroxide to give 5-bromo-2-(piperidin-4-yloxy)-pyridine (316 mg, 58%).

General procedure 52

<img file="ECSP077276A_D0136.tif" />

BrNMP Br

A test tube was charged with 2,5-dibromopyridine (0.24 g, 1.0 mmol), dibromopyridine tert-butyl ester.

4-amino-piperidin-1-carboxylic acid (0.22 g, 1.1 mmol), di-isopropylethylamine (0.19 mL, 1.1 mmol) and /Vmethylpyrrolidinone (1.0 mL). The test tube was sealed and the mixture was heated to 80^gC for one night. The temperature was increased to 120^yesC and warmed overnight. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO₄ and concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of ethyl acetate and hexanes to give 4-(5-Bromo-pyridin-2-lamino)-acid tert-butyl ester. p¡per¡n-1 -carboxylic acid (36 mg, 10%).

General Procedure 53

<img file="ECSP077276A_D0137.tif" />

4-(4-{6-Amino-5-[1-(2,6-dichloro-3-ethoxy-phenyl)-ethoxy]-pyridin-3-yl}-benzoyl)piperazin-1 tert-butyl ester -carboxylic: To 4 ml of DMSO was added 0.124 ml of ethanol followed by 32 mg of NaH. After stirring for 30 minutes, 250 mg of 4-(4-{6-amino-

5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoyl)-piperazine-1-carboxylic acid and the reaction was heated to

40^yesC. After three hours, the reaction was cooled and poured into water to precipitate. After neutralization to pH 6, 200 mg of a tan solid, 77%, was isolated.

General procedure 54 'o.

Ome

MeO alcohol

Benzyl 2,4,6-trimethoxl, NaH

<img file="ECSP077276A_D0138.tif" />

<img file="ECSP077276A_D0139.tif" />

F

<img file="ECSP077276A_D0140.tif" />

TFA/EtgSiH (4-{6-Amino-5-[1 -(2,6-dichloro-3-hidrox¡-fen¡l)-ethoxy]-p¡r¡d¡n-3-¡l }-phenyl)-p¡peraz¡n-1 -yl-methanone: To 140 mg of 4-[4-(6-amino-5-{1-[2,6-dichloro-3-dichloro- -(2,4,6-trimethoxy-benzyloxy)-phenyl]-ethoxy}pyridin-3-yl)-benzoyl]-piperazine-1-carboxylic acid (from general procedure 53) was added 1 mL of TFA and the solution immediately turned reddish in color followed by the addition of 100 μΙ triethylsilane 3 seconds later. The solution turned yellow. After stirring for four hours, 5 mL of toluene was added and the solvent was removed in vacuo. Chromatography with 10% MeOH/CH₂IC₂ to NH₄0.5 to 1% OH/9.5 to 9% MeOH/CH₂IC₂ at 90% led to 55 mg of a white solid, 62% yield.

General procedure 55

R.

<img file="ECSP077276A_D0141.tif" />

^νή₂

A18

2-(4-bromo-2-methoxyphenoxy¡)ethanol (8a): Potassium carbonate (1.4 g, 10 mmol) was added to a solution of ethylene carbonate (1.8 g, 20 mmol) and 4-bromo -2-methoxyphenol (1.05 g, 5 mmol) in 5 mL of toluene under an inert atmosphere. The reaction was heated to 115^SC for 12h. To the reaction mixture, water (50 ml) and ethyl acetate (2 x 100 ml) were added to stir. The organic phases were combined, dried, filtered and evaporated to give a yellow oily residue. The residue was purified by flash chromatography (eluting with 40-+45% ​​EtOAc in hexanes) to give compound 8a as a light brown yellow oil (1 g; 4.13 mmol; 82.6% yield); MS (APCI) (M+F)⁺ 246.¹H NMR (400 MHz, chloroform-D) δ ppm 2.83 (t, J = 6.3 Hz, 1H) 3.84 (s, 3H) 3.89-4.01 (m, 2H) 4.03 -4.13 (m, 2H) 6.78 (d, J = 8.3 Hz, 1H) 6.99 (d, 1H) 7.02 (d, 1H).

4-Bromo-1-(2-chloroethoxy)-2-methoxy¡benzene (8b): Thionyl chloride (0.3 ml) was added to a solution of compound 1 in 1 ml of pyridine in an ice bath. The reaction was stirred in the ice bath for 10 minutes and then heated to 100⁹C for 2h. The reaction was cooled to room temperature and quenched with dil. HCI (1M). CH was added₂IC₂ (2 x 100 ml) to extract the aqueous solution. The combined organic phases were dried over Na₂SW₄ and then concentrated in vacuo. The residue was purified by flash chromatography (eluting with 10-»15% EtOAc in hexanes) to give compound 8b as a colorless oil (485 mg, 1.84 mmol, 50.3% yield); MS (APCI) (M+F)⁺ 264.¹H NMR (400 MHz, chloroform-D) δ ppm 3.81 (t, J = 6.2 Hz, 2H) 3.85 (s, 3H) 4.23 (t, J = 6.2 Hz, 2H) 6.78 (d, J=8.6Hz, 1H).

Compound 9: Compounds of formula 9 can be formed following the illustrative procedure: Compound A18 (1.3 molar equivalents) is added to a solution of aryl halide (0.51 mmol) in 7 mL of DME. The mixture is purged several times with nitrogen and then dichlorob/s(t~phen¡lfosf¡no)palladium(II) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalents) in 1.5 mL of H is added to the reaction mixture.₂O and the resulting solution is heated to 85⁹C for 12h. To the reaction mixture is added water (20 ml) to quench the reaction. Then EtOAc (50 mL x 2) is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound 9.

Compound 10: Compounds of formula 10 can be formed following the illustrative procedure: Amine (7 molar equivalents) is added to a solution of compound 9 (0.17 mmol) in 3 mL of 2-methoxyethanol. The resulting solution is heated to 85⁹C for 12h. To the reaction mixture is added water (20 ml) to quench the reaction. Then EtOAc (50 mL x 2) is added to extract the aqueous solution. The EtOAc phase is dried over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a light brown oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound 10.

General procedure 56

<img file="ECSP077276A_D0142.tif" />

<img file="ECSP077276A_D0143.tif" />

Compound 14: Compounds of formula 14 can be formed following the illustrative procedure: Lithium hexamethyldisililazide (1.2 molar equivalents; 1 M in THF) is added to a solution of alcohol (1 mmol) in 2 mL THF. The mixture is stirred at room temperature under a nitrogen atmosphere for 30 min and then 5-bromo-2-chloropyrimidine (1 molar equivalent) is added. The resulting solution is heated to 75⁹C for 12h. To the reaction mixture is added water (20 ml) to quench the reaction. Then EtOAc (50 mL x 2) is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ It is filtered off and the filtrate is evaporated, giving an oily residue. The residue is purified by silica gel chromatography (eluting with EtOAc in hexanes) to give the desired product, compound 14.

Compound 11: Compound A18 (1.3 molar equivalents) is added to a solution of 5-bromo-2-chloropimidine or compound 14 (1 mmol) in 24 mL of DME. The mixture is purged several times with nitrogen and then dichlorob/s(triphenylphosphino)palladio(II) (0.05 molar equivalents) is added. Sodium carbonate (3 molar equivalents) in 3 mL of H is added to the reaction mixture.₂O and the resulting solution is heated to 85⁹C for 12h. To the reaction mixture is added water (50 ml) to quench the reaction. Then EtOAc (100 mL x 2) is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by flash chromatography (eluting with 40-»55% EtOAc in hexanes) to give compound 11.

Compound 12: Amine (2 molar equivalents) is added to a solution of compound 11 in 3 ml of n-butanol. The reaction mixture is irradiated in the microwave at 120²C for 30 min. The resulting mixture is poured into a mixture of H₂O and EtOAc (100 ml; v:v: 1:1). The organic phase is dried, filtered and evaporated, giving a light brown oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound 12.

Compound 13: Acid (16 molar equivalents or less) is added to compound 12 (0.14 mmol) at room temperature. The resulting solution is stirred at room temperature or heated to 60⁹C for 12h. The reaction mixture is evaporated and the residue is purified by chromatography on silica gel (eluting with CH₃OH, EtOAc and CH₂IC₂), giving the desired amide product, compound 13, as a yellowish to white solid.

General procedure 57

<img file="ECSP077276A_D0144.tif" />

A18 18¹⁷

Compound 15: Sodium hydride (1.3 molar equivalents) and RX (1.1 molar equivalents) were added to a solution of 2-amino-5-bromopyrindine (0.84 mmol) in 3 mL of DMF. The reaction mixture is irradiated in the microwave at 100⁹C for 20 min. The resulting mixture is poured into a mixture of H₂O and EtOAc (100 ml; v:v: 1:1). The organic phase is dried, filtered and evaporated, giving a light brown oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound 15.

Compound 16: Compound A18 (1.3 molar equivalents) is added to a solution of compound 15 (0.25 mmol) in 5 mL of DME. The mixture is purged several times with nitrogen and then dichlorob/s(tñfen¡lfosf¡no)pallad¡o(II) (0.05 molar equivalents) is added. Sodium carbonate (3 molar equivalents) in 0.8 mL of H is added to the reaction mixture.₂O and the resulting solution is heated to 85⁹C for 12h. To the reaction mixture is added water (50 ml) to quench the reaction. Then EtOAc (100 mL x 2) is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filter off and the filtrate is evaporated to give a dark brown oily residue. The residue is purified by flash chromatography (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound 16.

Compound 17: Acid (16 molar equivalents or less) is added to compound 16 (0.114 mmol) at room temperature. The resulting solution is stirred at room temperature or heated to 60⁹C for 12h. The reaction mixture is evaporated and the residue is purified by chromatography on silica gel (eluting with CH₃OH, EtOAc and CH₂IC₂), giving the desired amide product, compound 17, as a yellowish to white solid.

General procedure 58

<img file="ECSP077276A_D0145.tif" />

<img file="ECSP077276A_D0146.tif" />

ha

<img file="ECSP077276A_D0147.tif" />

<img file="ECSP077276A_D0148.tif" />

has MO 1-11

1-(í-Butoxycarbonyl)azetidine-3-carboxylic acid (1-1) (AXL016917, 1000 mg, 4.97 mmol) was dissolved in MeOH (5 mL)/Toluene (20 mL) and then cooled to 0⁹C. TMSCHNN (trimethylsilyldiazomethane) (7.45 mmol) was then added dropwise over 15 minutes with some bubbling observed. The color started out transparent and slowly turned yellow. The solution was stirred for 10 min at 0⁹C and then warmed to room temperature for 30 minutes. The solution was then concentrated and pumped off the toluene to provide 1.055 g of 1-i-butyl 3-methyl-azetidine-1,3-dicarboxylate (1-2) which was used directly in the next step without purification. (99% gross yield).

1-tert-Butyl 3-methyl-azetidine-1,3-dicarboxylate (1055 mg, 4.90 mmol) was dissolved in THF (17 mL) and then cooled to 0⁹C. MeOH (0.397 mL, 9.80 mmol) and LiBH were added sequentially₄ (14.7mmol). The reaction was warmed to room temperature for 3h. Then 10% aqueous sodium potassium tartrate tetrahydrate (Rochelle's Salt) (30 mL) and EtOAc (30 mL) were added and the solution was stirred at room temperature for 30 minutes. The organic phase was separated and then dried (Na₂SW₄) and concentrated to give 674 mg of t-butyl 3-(hydroxymethyl)azetidin-1-carboxylate (1-3) as a crude product (clear oil). The product was used directly in the next step without purification.

i-Butyl 3-(hydroxymethyl)azetidine-1-carboxylate (674 mg, 3.60 mmol) was dissolved in CH₂IC₂ (13 mL, 0.25 M) and then sequentially added Et₃N (1.0 mL, 7.20 mmol), DMAP (44 mg, 0.360 mmol), and methanesulfonyl chloride (0.31 mL, 3.96 mmol) to 0^yesC with the addition of MsCI proceeding slowly. The solution was warmed to rt for 1h. After 15 h, NaHCO was added.₃ aqueous saturated (50 mL) and then the product was extracted with CH₂IC₂ (2 x 50 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na₂SW₄), were concentrated and purified by flash chromatography (Biotage Horizon-10% EtOAc/100% hexanes-EtOAc) to give 962 mg of (1-4) as an oil (quantitative).

NaH (95%, 96 mg, 3.99 mmol) in DMF (10 mL) was combined under N atmosphere.₂ to aunt Then 4-bromopyrazole (533 mg, 3.63 mmol) was added and the mixture was stirred at rt. After 30 minutes, (1-4) was added and the solution was heated to 95⁹C. After 2 h, NH were added₄Saturated aqueous CI (50 mL) and then EtOAc (50 mL). The organic extract was dried (Na₂SW₄) and concentrated then carried through a short layer of silica gel with 50% EtOAc/Hexanes to give 846 mg of crude (1-5) which was used directly in the next step (74% crude yield ).

(1-5) (846 mg, 2.68 mmol), (1-6) (815 mg, 3.21 mmol), [1,1'-b/s(diphenylphosphin)ferrocenejdichloropalladium ( 108 mg, 0.133 mmol) and KOAc (893 mg, 9.10 mmol) in DMSO (10 mL, purged with N₂ for 10 minutes) and then the solution was heated to 80⁹C. After 16 h, the solution was filtered through Celite and then H were added.₂O (50ml) and EtOAc (50ml). The organic phase was extracted and dried (Na₂SW₄), concentrated and then passed through a plug of silica with EtOAc at

50%/Hexane. The solvent was concentrated to provide 1.22 g of crude (1-7) which was used directly in the next step.

Boric ester (1-7) (4144 mg, 11.4 mmol), (1-8) (2890 mg, 7.60 mmol), dichlorob/s(tphenylphosphine)palladium(II) (534 mg, 0.760 mmol) , DME (40 mL, degassed for 30 min with N₂) and Na₂CO₃1 N (40 mL, degassed for 30 min with N₂) were combined and heated to 80⁹C. After 16 h, the reaction was cooled to rt and EtOAc (80 mL) was added. The solution was filtered through celite and then water (80ml) was added. The organic phase was separated, dried (Na₂SW₄) and concentrated. The product was purified by flash chromatography to give 1486 mg of (1-9) as a tan solid (36%).

1 gram of DOWEX 50WX2-400 ion exchange resin was prepared by washing it with H₂OR (500 mL), H 1:1₂O/MeOH, MeOH (5 x 250 mL), CH₂IC₂ (500 ml) and hexanes (500 ml). The DOWEX was then dried in a vacuum oven at 40⁹C for 1 day. (1-9) was dissolved in MeOH and then DOWEX (588 mg, 1.096 mmol) was added. The solution was stirred at rt for 2h. The solution was then filtered and the resin washed with MeOH (3 x 200 mL) and the wash discarded. The resin was then washed with NH₃ 3.5M/MeOH and collected. The solution was then concentrated to provide 374 mg of (1-10) as a gummy solid (78%).

To form compounds of formula (1-11), the following illustrative procedure may be followed. Dissolve 1 molar equivalent of (1-10) in DMF or CH₂IC₂ and then a base (3 molar equivalents) and/or coupling reagent (1.5 molar equivalents) is added. To the solution is added XR (1.1 molar equivalents), where X is, for example, Cl, Br, I, OMs, COCl, CO, COOH, ethylene, or carbonate and R is a desired group such as those shown in the examples in this document or similar groups. The resulting solution is stirred at rt for 4 h. H are added₂O and EtOAc and the organic phase is extracted, dried (Na₂SW₄) and concentrates. The crude product can be purified by preparative HPLC or other procedures well known in the art to provide product (1-11).

General procedure 59

<img file="ECSP077276A_D0149.tif" />

WHO

<img file="ECSP077276A_D0150.tif" />

mouth

24(91%)

<img file="ECSP077276A_D0151.tif" />

Pd(II)(PPh₃)₂Cl₂/

na₂CO3/DME/85°C

110

<img file="ECSP077276A_D0152.tif" />

NaH/DMF/

R.

2-10(63%)

2-11(85%)

2-12

<img file="ECSP077276A_D0153.tif" />

2^(97%)

HCI4M in Dioxane

CHA

<img file="ECSP077276A_D0154.tif" />

3-Azetidinol (2-2): A reaction mixture of /V-benzhydrinlazetidin-3-ol HCl salt (2.76 g, 10.0 mmol) with palladium hydroxide, 20% Pd (basis dry) on C (400 mg) in 50 mL MeOH was hydrogenated at 379.211 kPa (55 psi) for 48 h. The reaction mixture was filtered through a pad of Celite and washed well with MeOH. The filtrate was concentrated in vacuo in a water bath at room temperature. The residue is treated with ether (3 x 30 ml) and the solvent is decanted. The solid was air dried to give 571 mg of the HCl salt product (2-2) as a white solid (52% yield).¹H NMR (400 MHz, DMSO-D₆) δ ppm 3.33 (s, 1H) 3.63-3.80 (m, 2H) 3.93-4.09 (m, 2H) 4.40-4.58 (m, 1H) 6.18 (d, J = 6.32Hz, 1H).

3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester (3-3): To a stirred and cooled (0-C bath) solution of compound (2-2) (570 mg, 5.20 mmol) in 10 mL of EtOH were added Et₃N (1.8 mL, 13.0 mmol) and di-tert-butyl dicarbonate (1.702 g, 7.38 mmol). The resulting clear solution mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (200ml) and 0.5N citric acid solution (30ml) and brine (30ml). The organic phase was dried (Na₂SW₄) and then concentrated in vacuo to give 899 mg (2-3) as a clear oil (52%).¹H NMR (400 MHz, chloroform-D) δ ppm 1.42 (s, 9 H) 3.78 (dd, J = 9.47, 4.42 Hz, 2H) 4.13 (dd, J = 9, 35, 6.57 Hz, 2H) 4.49-4.63 (m, 1H).

3-Methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (2-4): To a solution of compound (2-3) (466 mg, 2.69 mmol) with Et₃N (0.75 mL, 5.38 mmol) and 4-(dimethylamino)-pyridine (33 mg, 0.269 mmol) in 10 mL CH₂IC₂ to 0²C was added methanesulfonyl chloride (0.25 mL 3.23 mmol). The resulting brown solution mixture was stirred from 0^yesC at room temperature overnight. The reaction mixture was quenched with NaHCO.₃ and then it was divided between CH₂IC₂ (200 mL) and a saturated solution of NaHCO₃ (50 ml). The organic phase was dried (Na₂SW₄) and then filtered through a pad of silica gel, eluted with hexane:EtOAc/1:1; the filtrate was concentrated in vacuo to give 614 mg (2; 4) as a yellow oil (91% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 1.43 (s, 9H) 3.05 (s, 3H) 4.08 (dd, J = 10.36, 4.29 Hz, 2H) 4, 26 (dd, J=10.36, 6.82Hz, 2H) 5.11-5.26 (m, 1H).

1-(3-Azetidine-1-carboxylic acid tert-butyl ester)-4-bromopyrazole (2-6): A 5 mL microwave tube was charged with compound (2-4) (304 mg, 1, 21mmol); 4-bromopyrazole (2-5.178 mg, 1.21 mmol) and 60% NaH in mineral oil (73 mg, 1.82 mmol) with 2 mL of DMF. The resulting mixture was microwaved at 110®C for 30 minutes. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO solution.₃ (2 x 50ml); brine (50ml). The organic phase was dried (Na₂SW₄) and then concentrated in vacuo to give 360 ​​mg of (2-6) as a yellow oil (98%).¹H NMR (400 MHz, DMSO-D₆) δ ppm 1.36-1.43 (m, 9H) 4.08 (s, 2H) 4.18-4.31 (m, 2H) 5.12-5.22 (m, 1H)

7.67 (s, 1H), 8.14 (s, 1H).

tert-butyl 3-(4-(4,4,5,5-Tetramethyl-1,3-dioxoborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1carboxylate (2-8): A mixture of compound (2-6) (225 mg, 0.74 mmol) and t»ís(pinacolato)diboron (2-7, 227 mg, 0.89 mmol) with KOAc (247 mg, 2.52 mmol) in 3 mL of DMSO was purged with N₂ for 15 min and then PdCI was added₂(dppf)₂-CH₂IC₂ (30mg, 2.52mmol). The resulting mixture was stirred at 80²C in N atmosphere₂ for one night. After cooling to room temperature, the mixture was filtered through a pad of Celite and washed well with EtOAc. The filtrate was extracted with H₂OR (2 x 50 mL) and brine (50 mL). The organic phase was dried (Na₂SW₄) and then concentrated in vacuo. The residue was then filtered through a pad of silica gel and eluted with hexane:EtOAc/3:2. The filtrate was concentrated in vacuo to give 250 mg of (2-8) as a clear oil (97% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 1.18-1.27 (m, 9H) 1.28-1.34 (m, 6H) 1.41-1.49 (m, 6H ) 4.22-4.33 (m, 2H) 4.36 (t, J = 8.59 Hz, 2H) 4.98-5.13 (m, 1H) 7.83 (s, 2H).

3-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-1H-pyrazol-1-yl)azetidine-1-carboxylate ert-butyl (2-10): A mixture of compound (2-8) (459 mg; 1.31 mmol) and 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-iodopyridin-2 -amine (2-9) (374 mg, 0.88 mmol) in 13 mL of anhydrous ethylene glycol dimethyl ether (DME) was purged with N₂ for 15 min, then Pd(ll)(PPh) was added₃)₂IC₂ (46 mg, 0.07 mmol) and continued purging with N₂ for 15 more minutes. 1.0 N Na solution was added₂CO₃(3.9 mL, 3.9 mmol) after purging with N₂ during 15 minutes. The resulting mixture was stirred at 85^andC under N2 atmosphere overnight. The reaction mixture was filtered through a pad of Celite and washed well with MeOH. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2 x 50 mL); brine (50ml). The organic phase was dried (Na2SO4) and then concentrated in vacuo. The residue was purified with a Biotage system (25 M, 100% CH2CI2; 100% CH2CI2 to 90% CH2CI2 with 10% MeOH) to collect the desired fraction to give 421 mg of (2-10) as of a brown fat (92% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 1.17-1.26 (m, 9H) 1.80 -1.87 (m, 3H) 4.04-4.18 (m, 2H) 4 .20-4.33 (m, 2H) 4.34-4.41 (m, 1H) 4.79 (s, 2H) 5.02 (d, J = 7.58 Hz, 1H) 7.04 ( t, J = 8.46 Hz, 1H) 7.33-7.41 (m, 1H) 7.44-7.52 (m, 1H) 7.53-7.58 (m, 1H) 7.59 -7.65 (m, 1H) 7.72-7.78 (m, 1H); EMCL stall, for C24H₂₆IC₂FN₅EITHER₃ (M+H) 523, found 523.

5-(1-Azetidin-3-yl-1 H-pyrazol-4-yl)-3-[1 -(2,6-dichloro-3-fluorophenyI) ethoxy]pyridin-2-amina (2-11): A mixture of compound (2-10) (421 mg, 0.81 mmol) with 4.0 M HCI in dioxane (2.0 mL, 8.1 mmol) in 5 mL of CH₂IC₂ stirred at room temperature for 2.0 hours. The reaction mixture was concentrated in vacuo. The residue was treated with EtOAc. The precipitated solid was filtered off and washed well with EtOAc and hexane then dried in vacuo to give 275 mg of (2-11) as a sand colored solid from the HCl salt (81% yield).¹H NMR (400 MHz, DMSO-D_and) δ ppm 1.79-1.89 (m, 3H) 3.56 (s, 1H) 4.35 (s, 4H) 5.40 (s, 1H) 6.23 (d, J = 6.57 Hz, 2H) 7.09 (s, 1H) 7.40 -7.54 (m, 1H) 7.59 (dd, J = 8.84, 5.05 Hz, 1H) 7.73-7.83 (m, 1H) 7.86 (s, 1H) 8.12 (s, 1H) 9.20 (s, 1H). EMCL stall, for C₁₉h₁₈IC₂FN₅OR (M+H) 423, found 423.

Compounds of formula 2-12 can be prepared by the following illustrative procedure: To a reaction mixture of compound (2-11) (1.0 equiv.) with Et₃N (2.0 equiv.) in 2.0 mL DMF at room temperature is added alkyl bromide (1.1 equiv.). The resulting mixture is stirred under an atmosphere of N₂ at room temperature overnight. The reaction mixture is partitioned between EtOAc (200 mL) and saturated NaHCO solution.₃ (2 x 50 mi); brine (50 ml). The organic phase is dried (Na₂SW₄) and then concentrated in vacuo. The residue is purified by a Dionex system (5% to 95% MeCN:H₂Or with 0.1% HOAc buffer to collect the desired fraction, giving (2;12).

Alternatively, compounds of formula 2-12 can be prepared by the following illustrative procedure: To a reaction solution of alkylamine (1.0 equiv.) with iPr₂EtN(diisopropylethylamine) (3.0 equiv.) in 2.0 mL DMF is added HATU (1.5 equiv.). After stirring for 30 minutes, compound (2-11) (1.0 equiv.) is added. The resulting mixture is stirred at room temperature overnight. The reaction mixture is partitioned between EtOAc (200 mL) and saturated NaHCO solution.₃ (2 x 50 ml) and brine (50 ml). The organic phase is dried (Na₂SW₄) and concentrated in vacuo. The residue is purified by a Dionex system (5% to 95% MeCN:H₂Or with 0.1% HOAc to collect the desired product, giving (2-12).

General Procedure 60:

<img file="ECSP077276A_D0155.tif" />

<img file="ECSP077276A_D0156.tif" />

<img file="ECSP077276A_D0157.tif" />

<img file="ECSP077276A_D0158.tif" />

ert-butyl 1-Oxa-6-azaspiro[2.5]octane-6-carboxylate (3-2): A solution of dimethylsulfoxonium methylide was prepared under an atmosphere of N₂ from a 60% dispersion of NaH in mineral oil (440 mg, 11.0 mmol) and trimethylsulfoxonium iodide (2.421 g, 11.0 mmol) in 5 mL anhydrous DMSO. Another solution of 1-Boc-4-oxo-1-piperidine carboxylate (3-1.1.993 g, 10.0 mmol) in 5 mL DMSO was added dropwise. The resulting mixture was stirred at 55^SC for 6 hours. The cooled reaction mixture was poured into ice-H₂0 and extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with H₂O (50 ml) and brine (50 ml), then dried (Na₂SW₄) and then concentrated in vacuo to give 1.4791 g of (3-2) as a yellow oil (69% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 1.37-1.52 (m, 11H) 1.71-1.84 (m, 2H) 2.63-2.72 (m, 2H) 3 .35-3.49 (m, 2H) 3.62-3.78 (m, 2H).

4- Hidrox¡-4-{[4-(4,4,5,5-tetramethy I-1,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole-1 -i IJmethy I} piperidine -1-tert -butyl carboxylate (3-4): A mixture of compound (3-2) (214 mg; 1.0 mmol) and 4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan -2-yl)-1H-pyrazole (3-3, 194 mg, 1.0 mmol) with a dispersion of 60% NaH in mineral oil (60 mg, 1.5 mmol) in 3 mL of DMF was stirred to 90⁹C for 3 hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 soln (50 mL) and brine (50 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to give 361 mg of (3-4) as a yellow fat (89% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 1.21-1.34 (m, 12H) 1.39-1.50 (m, 9H) 1.56-1.78 (m, 4H) 3.14 (s, 2H) 3.72-3.91 (m, J = 32.34 Hz, 2H) 4.05 (s, 2H) 7.65 (s, 1H) 7.80 (s, 1H ) 8.00 (s, 1H). EMCL stall, for C20H₃₄BN₃EITHER₅ (M+H) 408, found 408, HPLC purity 85%.

4-[(4-{6-Amino-5-[1 -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-1 /-/-pyrazol-1-yl)methyl]- tert-Butyl 4-hydroxypiperidine-1-carboxylate (3-6): A mixture of compound (3-4) (361 mg, 0.89 mmol) and

3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-iodopyridin-2-amine (3-5) (378 mg, 0.89 mmol) in 9.0 mL of ethylene glycol dimethyl ether , anhydrous (DME) was purged with N₂ for 15 min and then Pd(ll)(PPh) was added₃)₂IC₂ (32 mg, 0.05 mmol) and continued purging with N₂ for 15 more minutes. Another 1.0 N Na solution was added₂CO₃ (3.9 mL, 3.9 mmol) after purging with N₂ during 15 minutes. The resulting mixture was stirred at 85⁹C under N2 atmosphere overnight. The reaction mixture was filtered through a pad of Celite and washed well with MeOH. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2 x 50 mL); and brine (50 mL). The organic phase was dried (Na2SO4) and then concentrated in vacuo. The residue was purified by Dionex system (25 to 95% MeCN:H2O with 0.1% HOAc buffer) to collect the desired fraction to give 147 mg of (3-6) as a white solid ( 28% yield).¹H NMR (400 MHz, DMSO-D3) δ ppm 1.34-1.39 (m, 9H) 1.70-1.77 (m, 2H) 1.79 (d, J = 6.57 Hz, 3H) 3.06 (d, J = 12.63 Hz, 2H) 3.62 (s, 2H) 4.03 (s, 2H) 4.79 (s, 1H) 5.66 (s, 2H) 6 .08 (d, J = 6.82 Hz, 1H) 6.86 (d, J = 1.52 Hz, 1H) 7.44 (t, J = 8.72 Hz, 1H) 7.51 -7, 58 (m, 2H) 7.58-7.65 (m, 2H) 7.73 (d, J = 1.52 Hz, 1H) 7.78 (s, 1H). EMCL stall, for C₂₇h₃₂IC₂FN₅EITHER₄ (M+H) 581, found 581, HPLC purity 87%.

4-[(4-{6-amino-5-[1 -(2,6-dichloro-3-f I uorophenyl)ethoxy]pyridin-3-yl}-1 /-/-pyrazol-1-yl ) methylpiperidin-4-ol (A 7): A mixture of compound (3-6) (145 mg, 0.25 mmol) with 4.0 M HCI in dioxane (2.0 mL, 8.1 mmol) in 5 ml CH₂IC₂ stirred at room temperature for 2.0 hours. The reaction mixture was concentrated in vacuo. The residue was purified by Dionex system (5 to 95% MeCN:H₂Or with 0.1% HOAc buffer to collect the desired fraction, giving 76 mg of (3-7) as a yellow fat (63% yield).¹H NMR (400 MHz, DMSO-D₆) δ ppm 1.41-1.55 (m, 2H) 1.59-1.71 (m, 2H) 1.81 (d, J = 6.57 Hz, 3H) 2.88-3.00 ( m, 2H) 3.02-3.14 (m, 2H) 4.08 (s, 2H) 5.17 (s, 2H) 6.14-6.27 (m, J = 6.57 Hz, 1H ) 7.05 (s, 1H) 7.40-7.49 (m, J = 8.72, 8.72 Hz, 1H) 7.51 -7.60 (m, J = 9.09, 4, 80 Hz, 1H) 7.63 (s, 1H) 7.76 (s, 1H) 7.91 (s, 1H) 8.51 (s, 1H) 8.81 (s, 1H). EMCL stall, for C₂₂h₂₄IC₂FN₅EITHER₂ (M+H) 481, found 481, HPLC purity 98%. Anal. (C)₂₂h₂₄IC₂FN₅EITHER₂x2.2HOAcx2.3H₂O) C, Η, N.

General procedure 61:

<img file="ECSP077276A_D0159.tif" />

(l)MeSO₂Cl

et₃N/DMAP

CH₂C1₂ rd(dppf)_?ch₂Cl;

KOAc/DMSO/80°C

<img file="ECSP077276A_D0160.tif" />

)

<img file="ECSP077276A_D0161.tif" />

Ethyl 2-[(4-Bromo-1 /-/-pyrazol-1-yl)methyl]cyclopropanecarboxylate (4-3): To a reaction solution of ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (4-1) ( 577 mg, 4.0 mmol) with Et₃N (1.1 mL, 8.0 mmol) and DMAP (49 mg, 0.4 mmol) in 12 mL CH₂IC₂ to 0^yesC was added methanesulfonyl chloride (0.4 mL, 4.8 mmol). The resulting brown suspension mixture was stirred at 0^yesC at room temperature in N atmosphere₂ for one night. The reaction mixture was quenched with NaHCO.₃ and then it was divided between CH₂IC₂ (200 ml) and a saturated solution of NaHCO₃ (50 mi); brine (50 ml). The organic phase was dried (Na₂SW₄) and then filtered through a pad of silica gel, eluted with hexane:EtOAc/1:1. The filtrate was concentrated in vacuo to give 880 mg of ethyl 2-{[(methylsulfon¡l)ox¡]methyl}cyclopropanecarboxylate as a yellow oil (99% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 0.91-1.02 (m, 1H) 1.26 (c, J = 6.99 Hz, 3H) 1.29-1.36 (m, 1H ) 1.63-1.74 (m, 1H) 1.79-1.92 (m, 1H) 3.02 (s, 3H) 3.994.24 (m, 4H).

A mixture of ethyl 2-{[(methylsulfonyl)oxy]methyl}cyclopropanecarboxylate (880 mg, 4.0 mmol), 4-bromopyrazole (4-2,588 mg, 4.0 mmol) and 60% NaH was formed. in mineral oil (240 mg, 6.0 mmol) with 3.0 mL of DMF. The resulting mixture was stirred at 90⁹C in N2 atmosphere for four hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2 x 50 mL); brine (50 ml). The organic phase was dried (Na2SO4) and then concentrated in vacuo to give 812 mg of (4-3) as a yellow oil (74%).¹H NMR (400 MHz, chloroform-D) δ ppm 0.85 (dd, J = 7.96, 3.16 Hz, 1H) 0.88-0.98 (m, 1H) 1.18-1.29 (m, 3H) 1.56-1.71 (m, 1H) 1.79-1.94 (m, 1H) 3.96-4.08 (m, 2H) 4.07-4.17 (m , 2H) 7.45 (d, J = 3.79 Hz, 2H). EMCL stall, for C10H₁₃BrN₂EITHER₂ (M+H) 274, found 274, HPLC purity 95%.

Ethyl 2-{[4-(4,4,5,5-Tetramethyl-1,3-dioxoborolan-2-yl)-1H-pyrazol-1-yl]methyl}cyclopropanecarboxylate (4-4 ): A mixture of compound (4-3) (812 mg, 2.97 mmol) and µ/s(pinacolato)diboron (906 mg, 3.57 mmol) with KOAc (991 mg, 10.10 mmol) in 10.0 ml of DMSO was purged with N₂ for 15 minutes and then PdCI was added₂(dppf)₂-CH₂IC₂ (122mg, 0.15mmol). The resulting mixture was stirred at 80⁹C in atmosphere of

No.₂ for one night. After cooling to room temperature, the mixture was filtered through a pad of Celite and washed well with EtOAc. The filtrate was extracted with H₂Or (2 x 50 ml) and brine (50 ml). The organic phase was dried (Na₂SW₄) and then concentrated in vacuo. The residue was then filtered through a pad of silica gel and eluted with hexane:EtOAc/3:1. The filtrate was concentrated in vacuo to give 945 mg of (4-4) as a yellow oil (98% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 0.85 (dd, J = 7.83, 3.03 Hz, 1H) 0.90-0.96 (m, 1H) 1.20-1.24 (m, 3H) 1.29-1.34 (m, 12H) 1.62-1.71 (m, 1H) 1.84-1.97 (m, 1H) 3.96 -4.07 ( m, 1H) 4.06-4.14 (m, 2H) 4.15-4.23 (m, J = 14.27, 6.44 Hz, 1H) 7.73 (s, 1H) 7.77 (s, 1H).

2-[(4-{6-amino-5-[1 -(2,6-dichloro-3-f I uorophenyl)ethoxy]pyridin-3-yl}-1 /-/-pyrazol-1-yl) ethyl methyl]cyclopropanecarboxylate (4-6): A mixture of compound (4-4) (643 mg; 2.01 mmol) and 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy] -5-iodopyridin-2-amine (4-5) (572 mg, 1.34 mmol) in 20.0 mL of anhydrous ethylene glycol dimethyl ether (DME) was purged with N₂ for 15 min, then Pd(ll)(PPh) was added₃)₂IC₂ (71 mg, 0.1 mmol) and continued purging with N₂ for 15 more minutes. Another 1.0 N Na solution was added₂CO₃ (6.0 mL, 6.0 mmol) after purging with N₂ during 15 minutes. The resulting mixture was stirred at 85⁹C under N2 atmosphere overnight. The reaction mixture was filtered through a pad of Celite and washed well with MeOH. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 soln (2 x 50 mL) and brine (50 mL). The organic phase was dried (Na2SO4) and then concentrated in vacuo. The residue was purified by Biotage system (100% 25 M CH2CI2; 100% CH2CI2 to 90% CH2CI2:10% MeOH) to collect the desired fraction to give 600 mg of (4-6) as a brown fat (91% yield).¹H NMR (400 MHz, DMSO-Ds) δ ppm 0.96-1.10 (m, 2H) 1.15 (t, J = 7.07 Hz, 2H) 1.74 (s, 3H) 1.79 (d, J = 6.57 Hz, 3H) 3.95-4.14 (m, 4H) 5.66 (s, 2H) 6.08 (d, J = 6.57 Hz, 1H) 6.88 (s, 1H) 7.43 (t, J = 8.72 Hz, 1H) 7,497.62 (m, 2H) 7.73 (s, 1H) 7.88 (s, 1H). EMCL stall, for C₂₃h₂₃IC₂FN₄EITHER₃ (M+H) 494, found 494, HPLC purity 95%.

2-[(4-{6-amino-5-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridi η-3-yl}-1H-pyrazol-1 yl)methyl acid ]cyclopropanecarboxylic (4-7): To a reaction solution of compound (4-6) (377 mg, 0.76 mmol) in 5.0 mL of MeOH at room temperature under N atmosphere₂ another 2.0 N NaOH solution (2) (1.5 mL, 3.04 mmol) was added. The resulting mixture was stirred at 80^yesC for 3 hours. The reaction mixture was concentrated in vacuo to remove most of the MeOH and acidified with 2M HCl to pH 4.0. The mixture was extracted with CH2CI2 (2 x 200 ml); the organic phases were washed with brine (50 ml), dried (Na2SO4) and concentrated in vacuo to give 324 mg of (4-7) as a yellow solid, (92% yield).¹H NMR (400 MHz, DMSO-D6) δ ppm 0.92-1.04 (m, 2H) 1.57-1.72 (m, 2H) 1.76 -1.90 (m, 3H) 3, 98-4.18 (m, 2H) 6.46 (s, 2H) 6.89-7.02 (m, 1H) 7.29-7.52 (m, 2H) 7.52-7.63 ( m, 2H) 7.73 (d, J = 1.52 Hz, 1H) 7.94 (s, 1H) 12.19 (s, 1H). EMCL stall, for C₂₁h₁₉IC₂FN₄EITHER₃ (MH) 463, found 463, HPLC purity 87%.

2-[(4-{6-amino-5-[1 -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-1H-pyrazol-1-yl)methyl]- A/methylcyclopropanecarboxamide (4-8) (R = Me, R' = H): To a reaction solution of (4-7) (1.0 equiv.) with ¡Pr₂EtN (2.0 equiv) in 1.0 ml DMF was added with HATU (1.5 equiv). After stirring for 30 minutes, alkylamine (1.1 equiv.) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO solution.₃ (2 x 50 ml) and brine (50 ml). The organic phase was dried (Na₂SW₄) and concentrated in vacuo. The sample was converted to the free base by partitioning between EtOAc (200 mL) and saturated NaHCO solution.₃ (50 ml) and brine (50 ml). The organic phase was dried (Na₂SW₄) and concentrated in vacuo. The residue was treated with 1.0 mL of H₂O and lyophilized to give (4-8).

General procedure 62:

br

<img file="ECSP077276A_D0162.tif" />

<img file="ECSP077276A_D0163.tif" />

To a solution of 5-bromo-3-[(R)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (12.83 g, 33.76 mmol) In anhydrous DMF (100 mL) were added di-ferc-butyl dicarbonate (21.25 g, 97.35 mmol) and 4-dimethylaminopyridine (0.793 g, 6.49 mmol). The reaction was stirred at room temperature for 18 hours under a nitrogen atmosphere. To the mixture was added a saturated solution of NaHCO₃ (300 ml) and extracted with EtOAc (3 x 250 ml). The combined extracts were washed with water (5 x 100 mL), NaHCO₃ sat. and brine and then dried over Na₂SW₄. After filtration, evaporation and drying under high vacuum, 5-bromo-3-[(R)-1-(2,6-d¡chloro-3-fluoro-phenyl)-ethoxy¡] was obtained. -p¡ñdin-2-díboc-protected sheet as an off-white foamy solid (19.59 g, 100% yield).¹H NMR (DMSO-d_yes, 400 MHz) 5 8.18 (d, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.48 (t, 1H), 6.25 (c, 1H), 1.75 (d, 3H), 1.39 (s, 9H), 1.19 (s, 9H).

To a solution of the di-boc protected 5-bromo-3-[(phy)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (19.58 g , 33.76 mmol) in DMSO (68 mL) were added potassium acetate (11.26 g, 114.78 mmol) and b/s(pinacolato)diboron (10.29 g, 40.51 mmol). The mixture was degassed, charged three times with nitrogen, then Pd(dppf)CI was added.₂-CH₂Cl2 (1.38g, 1.69mmol). The reaction mixture was degassed and charged three times with nitrogen and then stirred in an 80° oil bath.^QC under a nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered through a pad of celite which was washed with ethyl acetate. The combined ethyl acetate solution (700ml) was washed with water (5 x 100ml) and brine (100ml) and dried over Na2SO4. After filtration and concentration, the residue was purified on a silica gel column eluting with EtOAc/Hexane (0%-50%) to give 3-[(ñ)-1-(2,6-dichloro-3 -fluorophenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]d¡oxaborolan-2-¡l)-pyridin-2-ylamine protected with di-boc in form of a foamy solid (20.59 g, 97% yield).¹H NMR (DMSO-d6, 400 MHz) δ 8.20 (d, 1H), 7.70 (d, 1H), 7.63 (dd, 1H), 7.47 (t, 1H), 6.20 (c, 1H), 1.73 (d, 3H), 1.50-1.13 (m, 30H).

To a solution of 3-[(fi)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2] di-boc-protected dioxaborolan2-µl)-pyridin-2-ylamine (20.34 g, 32.42 mmol) in CH₂IC₂ (80 mL) was added a solution of dry HCI in dioxane (4N, 40.5 mL, 162 mmol). The reaction solution was stirred in an oil bath at 40²C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (400 mL) and then washed carefully but quickly with NaHCO₃ saturated until the water phase was basic (pH >8). The organic phase was washed with brine and dried over Na₂SW₄. After filtration, evaporation and drying under high vacuum, 3-[(R)-1-(2,6dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5 -tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-lamin as an off-white foamy solid (13.48 g, 97% yield).¹H NMR (DMSO-d₃, 400 MHz) δ 8.01 (d, 1H), 7.27 (dd, 1H), 7.17 (d, 1H), 7.03 (t, 1H), 6.12 (c, 1H), 5.08 (bs, 2H), 1.81 (d, 3H), 1.30 (s, 6H), 1.28 (S.6H).

To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl[ 1,3,2]d¡oxaborolan-2-¡l)-pyrid¡n-2-¡lam¡na (4.2711 g, 10.0 mmol) and 4-(4 -bromopyrazol-1-yl)-piperidine-1-carboxylic acid (see procedure 11) (3.9628 g, 12.0 mmol) in DME (40 mL) was added Na solution₂CO₃ (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged three times with nitrogen. To the solution was added Pd(PPh₃)₂IC₂ (351mg, 0.50mmol). The reaction solution was degassed and again charged three times with nitrogen. The reaction solution was stirred in an oil bath at 87⁹C for approximately 16 hours (or until pinacol borane ester was consumed), cooled to room temperature, and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na₂SW₄ and concentrated. The crude product was purified on a silica gel column eluting with an EtOAc/hexane system (0% EtOAc to 100% EtOAc) to give 4-(4-{6-amino-5- [(fi)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid (3.4167 g, yield 65%, -95% purity) with an R_F of 0.15 (50% EtOAc/Hexanes). MS m/e550 (M+1)⁺.

To a solution of 4-(4-{6-amino-5-[(phy)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-pyridin-3-yl acid tert-butyl ester }-pyrazol-1-yl)-pipendin-1-carboxylic acid (566.7 mg, 1.03 mmol) in methanol (5 mL) or dichloromethane (30 mL) was added 4N HCI/dioxane (15 mL). The solution was stirred for approximately 1 hour or until deprotection was complete. The solvents were evaporated and the residue was dissolved in methanol and purified on a reverse phase preparative HPLC C-18 column eluting with 5% to 30% acetonitrile/water with 0.1% acetic acid with a linear gradient. After lyophilization, 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1 Hpyrazole acetate was obtained -4-yl)-pyridin-2-ylamine as a white solid (410 mg, 78% yield, 100% HPLC purity, 96.4% ee).¹H NMR (DMSO-d₆, 400 MHz) δ 7.84 (s, 1H), 7.68 (d, 1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (c, 1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m , 2H), 1.88 (m, 2Η), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e450 (M+1)⁺.

General procedure 63:

<img file="ECSP077276A_D0164.tif" />

F

To a suspension of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin2-ylamine as the HCl salt (Method 6) (150 mg, 0.288 mmol) in CH₂IC₂ (2 ml) NEt was added₃ (0.121 mL, 0.863 mmol) and stirred for 30 minutes at room temperature. The reaction was cooled to 0⁹C, chlorocarbonylmethyl ester of acetic acid was added and stirred for 1 hour at room temperature. The reaction was monitored by LC-MS and after conversion to the desired product was complete, water (2 mL) was added. The reaction was extracted with EtOAc (4x10 mL), dried over Na₂SW₄ and concentrated to give a quantitative yield of 2-[4-(4-{6-amino-5-[1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-pyridin-3-yl} Acetic acid -pyrazol-1-yl)-piperidin-1-ylj-2-oxo-ethyl-ester (164 mg, quant.).

To a solution of 2-[4-(4-{6-amino-5-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-¡l}-pyrazole-1 Acetic acid -yl)piperidin-1-ylj-2-oxo-ethyl-ester (164 mg, 0.298 mmol) in MeOH (4 mL) was added with LiOH (7 mg, 0.298 mmol) dissolved in 1 mL of water. The reaction was stirred for 30 minutes at room temperature, at which time LC-MS showed complete conversion to 1 -[4-(4-{6-amino-5-[1 -(2,6dichloro-3- fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-hydroxy-ethanone. The product was purified on reverse phase preparative HPLC C-18 column eluting with acetonitrile/water containing 0.1% acetic acid from 10% to 40%.

General Procedure 64:

<img file="ECSP077276A_D0165.tif" />

<img file="ECSP077276A_D0166.tif" />

A 100 mL flask with a stir bar was dried in an oven and cooled under an atmosphere of dry nitrogen. The flask was fitted with a rubber syringe cap. The flask was immersed in an ice-water bath under a nitrogen atmosphere and 1.6 ml (1.6 mmol) of a 1.0 M solution of borane in THF was introduced. Then, 2-(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy¡]p¡razin-2-yl}-pyrazol-1- acid was introduced yl)-2-methyl-propionic acid (method 5) (0.1 g, 0.221 mmol) in anhydrous THF (1.0 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours and 6N HCI (1.1 mL) was slowly added and then HCl was introduced.₂O (1.1 ml) and MeOH (7.4 ml). The reaction mixture was continuously stirred overnight. Most of the solvents were evaporated in vacuo and then 1N NaOH solution was used to adjust the pH to 11. Water was added and the solution was extracted with EtOAc (3 x 30 mL) and dried over Na₂SW₄. After filtration and concentration, the crude product was purified with reverse phase preparative HPLC eluting with 10% to 60% acetonitrile/water containing 0.1% acetic acid. After lyophilization of the pure fractions, 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-f-en-yl)-ethoxy]-pyridin-3-acetate was obtained -yl}-pyrazol-1-yl)-2-methylpropan-1-ol as a white solid (21 mg, 22% yield).

General Procedure 65:

<img file="ECSP077276A_D0167.tif" />

1:1 tfa/ch₂ci₂

<img file="ECSP077276A_D0168.tif" />

To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (7.94 g,

39.45 mmol) in CH₂IC₂ (100 mi), cooled to 0⁹C, NEt was slowly added₃ (5.54 mL, 39.45 mmol) followed by methanesulfonyl chloride (3.06 mL, 39.45 mmol) and DMAP (48 mg, 0.39 mmol). The mixture was stirred at room temperature overnight. To the mixture was added water (30 ml). The extraction with

CH₂IC₂ (3 x 30 ml) followed by drying (Na₂SW₄) and removal of the solvent in vacuo gave 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester as a white solid (11.00 g, >99% yield).¹H NMR (CDCI₃, 400 MHz) δ 4.89 (m, 1H), 3.69 (m, 2H), 3.31 (m, 2H), 3.04 (s, 3H),

1.95 (m, 2H), 1.83 (m, 2H), 1.46 (s, 9H).

To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0^yesC, NaH (60% in mineral oil) (3.13 g, 78.133 mmol) was added slowly. The solution was stirred for 1 hour at 0⁹C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g, 71.03 mmol) was added slowly and the reaction was heated to 100^yesC overnight or until pyrazole was consumed according to NMR. The reaction was cooled to room temperature and water (20 mL) was added followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCl (4 x 20 mL), dried over Na2SO4, and concentrated to give 4-(4-bromopyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as of an orange oil. The oil was purified using silica gel chromatography eluting with 10% EtOAc/hexanes to 25% EtOAc/hexanes to give 4-(4-bromo-pyrazol-1-yl)-piperidin-1 tert-butyl ester -carboxylic acid as a white solid (10.55 g, 45% yield) with Rf = 0.4 (25% EtOAc/hexanes, using iodine as colorant).¹H NMR (CDCI3, 400 MHz) δ 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m , 2H), 1.88 (m, 2H), 1.47 (s, 9H).

To a solution of 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.515 mmol) in CH₂IC₂ (3 ml) TFA (3 ml) was added. The reaction was stirred at room temperature until LCMS indicated reaction completion. Solvents were removed in vacuo and the residue was dissolved in MeOH (15 mL). The pH of the solution was adjusted to 9 with hydroxide resin to provide 4-(4-bromo-pyrazol-1-yl)-piperidine.

To a solution of 4-(4-bromo-pyrazol-1 -yl)-piperidine (375 mg, 1.63 mmol) in DMF (3.26 mL) was added NEt₃ (230 μΙ, 1.63 mmol) and stirred for 5 minutes. Methyl iodide (Mel) (1.63 mL, 1 M Mel in DMF, made fresh) was added and the reaction stirred overnight at room temperature. To the reaction mixture was added water and the solution was extracted with EtOAc (4 x 10 mL). The organic solution was washed with brine, dried over Na₂SW₄, concentrated and dried in vacuo to provide 4-(4-bromo-pyrazol-1-yl)-1-methyl-pipendine (251 mg, 63% yield).

General Procedure 66:

<img file="ECSP077276A_D0169.tif" />

To a solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethox¡]-5-(1H-pyrazol-4-¡l)-p¡razin-2- ylamine (295 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added NaH (60% in mineral oil, 30.7 mg, 0.80 mmol). The mixture was stirred at room temperature under nitrogen for 0.5 h, then 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (223.5 mg, 0.80 mmol) was introduced. The reaction mixture was heated in an oil bath at 90^QC for 0.5 h under a nitrogen atmosphere and cooled to room temperature. To the mixture was slowly added water, and extracted with EtOAc, washed with brine, and dried over Na₂SW₄. The crude product was purified on a silica gel column to give 4-(4-{5-amino-6-[(ñ)-1 -(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid as a white solid (265 mg, 59% yield).

To a solution of 4-(4-{5-amino-6-[1-(2,6-d¡chloro-3-fluoro-phenyl)-ethoxy¡]p¡razin-2- acid tert-butyl ester ¡l}-p¡razol-1-yl)-piperidin-1-carboxylic acid (265 mg, 0.48 mmol) in CH₂IC₂ 4N HCl/dioxane (4 mL) was added. The mixture was stirred at room temperature for one hour. After evaporation, the residue was dissolved in methanol (2.5 mL) and purified on a reverse phase preparative HPLC C-18 column eluting with acetonitrile/water containing 0.1% acetic acid with a linear gradient. from 10%-40%. After lyophilization, 3-[(R)-1-(2,6-dichloro-3fluoro-phenyl)-ethoxy¡]-5-(1-piperidin-4-yl-1/7-p acetate was obtained Irazol-4-yl)-pyrazin-2-ylamine as a white solid (125 mg, 51% yield). General procedure 67:

h₃C.

<img file="ECSP077276A_D0170.tif" />

0-(7-Azabenzotriazol-1 -µl)-A/,/V,A/;/V-tetramethyluronium phosphorus pentafluoride (HATU) (66 mg, 0.17 mmol) was added to an acid solution 2 -(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3yl}-pyrazol-1-yl)-propionic acid (69 mg, 0. 16 mmol), triethylamine (0.024 mL, 0.17 mmol) and 3-dimethylaminopropylamine (0.022 mL, 0.17 mmol) in 1.6 mL DMF. After stirring for 3 hours, the reaction was concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of dichloromethane, methanol and ammonium hydroxide to give 2-(4-{6-amino-5-[1-(2,6-dichloro-

3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-A/-(3-dimethylamino-propyl)-propionamide. (41mg, 50%).

<td colspan="3">General procedure 68:</td>

<td></td><td>h₃c</td><td></td>

<td></td><td>N-Boc</td><td></td>

<td></td><td rowspan="2"></td><td>h₃c</td>

<td>N-NH</td><td>N-Boc</td>

<td rowspan="2">V</td><td>DEAD</td><td></td>

<td></td><td> )</td>

<td>Ϊ br</td><td>PPh₃THF</td><td>NN V</td>

<td></td><td></td><td>br</td>

Diethylazodicarboxylate (0.48 mL, 3.1 mmol) was added to a solution at 0²C of triphenylphosphine (0.80 g, 3.1 mmol) in THF (20 mL). After stirring for 5 minutes, 4-bromo-pyrazole (0.30 mg, 2.0 mmol) was added. After a further 5 minutes of stirring, (2-Hydroxyethyl)-methylcarbamic acid tert-butyl ester (0.45 g, 2.6 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was cooled to 0²C and filtered. The filtrate was concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of dichloromethane, ethyl acetate to give [2-(4-Bromo-pyrazol-1-yl)-ethyl]-methyl-carbamic acid tert-butyl ester (541mg, 87%). General Procedure 69:

<img file="ECSP077276A_D0171.tif" />

br

Sodium hydride (0.12 g, 4.9 mmol) was added to a solution of 4-bromo-4F/-pyrazole (0.60 g, 4.1 mmol) in DMF (10 mL). After stirring for 10 minutes, a solution of 2-chloropropionic acid methyl ester in DMF (4 mL) was added. After stirring for 4 hours, the reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO₄ and concentrated by rotary evaporator. The residue was purified by chromatography on silica gel using a gradient elution of ethyl acetate and hexanes to give 2-(4-bromo-pyrazol-1-yl)-propionic acid methyl ester (733 mg, 77%). General Procedure 70:

HgC

<img file="ECSP077276A_D0172.tif" />

LiOH, H₂EITHER

MeOH, THF

<img file="ECSP077276A_D0173.tif" />

A solution of LiOH (34 mg, 1.4 mmol) in water (0.4 mL) was added to a solution of 2-(4-{6-amino-5-[1-(2,6 -dichloro-3-fluoro-phenyl)-ethoxy¡]-pyridin-3-yl}-pyrazol-1-yl)-propionic acid (70 mg, 0.15 mmol) in a mixture of THF (1, 5ml) and MeOH (0.4ml). After stirring overnight, the reaction was partitioned between dichloromethane and half-saturated brine. A small amount of ethanol was added and the pH adjusted to 7 with 1 M HCl. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na₂SW₄, filtered and concentrated by rotary evaporator to give the acid 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl} -pyrazol-1-yl)propionic acid (69 mg, 100%). General procedure 71:

<img file="ECSP077276A_D0174.tif" />

To a stirred solution of 4-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-pyridin-3-[alic acid methyl ester CH₃NH₂ 2 M in THF (1.06 mL, 2.12 mmol) and the mixture was stirred and heated to 55⁵C for 18 hours. LCMS verified the reaction to be complete, the THF was removed and the residue was purified by prep. HPLC, leaving 4-(4-{6-amino-5-[1-(2,6-dichloro-3 -fluoro-phenyl)-ethoxy]-pyridin-3-yl}-p¡razol-1-yl)pyrrolidine-2-carboxylic acid (30 mg), 28.6% yield.

General procedure 72:

<img file="ECSP077276A_D0175.tif" />

x = Br,i

L=Br,OMs

<img file="ECSP077276A_D0176.tif" />

<img file="ECSP077276A_D0177.tif" />

tert-Butyl 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (21-1): Dicarbonate ert-butyl (7.2 molar equivalents), 4-(dimethylamino)pyrindine (0.84 molar equivalents) to 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl) solution -1,3,2-dioxaborolane (6 mmol) in 40 ml of DMF. The reaction mixture was stirred at room temperature for 12h. To the reaction mixture, water was added to quench the reaction. Then EtOAc was added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filtered off and the filtrate was evaporated to give a yellow brown oily residue as compound 21-1 (1.32 g, 4.56 mmol, 76%).¹H NMR (400 MHz, chloroform-D) δ ppm 1.32 (s, 12H) 1.63 (s, 9H) 7.91 (s, 1H) 8.37 (s, 1H). The residue was used in the next reaction step without further purification.

Compound 21-3, shown with the specific example of 3-[1-(2,6-dichloro-3-fluorophenyl)ethox¡]-5-(1Hpyrazol-4-¡l)p¡r¡d¡n-2 -amine (21-3a):

<img file="ECSP077276A_D0178.tif" />

Compound 21-1 (1.0 molar equivalent) was added to a solution of compound 21-2a (Compound 21-2, with R substituents, giving 2,6-dichloro-3-fluorophenyl) (1.92 mmol) in 20 ml of DME. The mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes, then dichloro£>/s(triphenylphosphino)palladium(II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalents) in 4 mL of H was added to the reaction mixture.₂O and the resulting solution was heated to 85⁹C for 12h. The alternative bases used were CsF and Cs2CO3 with 1 or 2 equivalents of boric ester and at room temperature (CsF) or at 80^yesC (all). To the reaction mixture, water was added to quench the reaction. Then EtOAc (150mL x 2) was added to extract the aqueous solution. Dry the EtOAc phase over Na2SO₄. The Na₂SW₄ filtered off and the filtrate evaporated to give a dark brown oily residue. The residue was purified by silica gel chromatography (eluting with 0—>10% MeOH in ethyl acetate) to give the desired product, compound 21-3a (2.05 g, 53.6% yield).¹H NMR (400 MHz, chloroform-D) δ ppm 1.60 (s, 1H) 1.84 (d, J = 6.57 Hz, 3H) 5.07 (s, 2H) 6.06 (c, J = 6.57 Hz, 1H) 6.89 (d, J = 1.77 Hz, 1H) 6.96-7.06 (m, 1H) 7.22 -7.33 (m, 1H) 7.67 (s, 2H) 7.80 (d, J=1.52Hz, 1H).

To make compounds of formula 21-4, the following illustrative procedure can be used: sodium hydride (1.2 molar equivalents) is added to a solution of compound 21-3 (0.87 mmol) in 10 mL of DMF. The mixture is stirred at room temperature under a nitrogen atmosphere for 30 min and then compound 21-6 (1 molar equivalent) is added. The resulting solution is heated to 85-90⁹C for 12h. To the reaction mixture is added water (20 ml) to quench the reaction. Then EtOAc (50 mL x 2) is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ it is filtered off and the filtrate is evaporated. The residue is purified by silica gel chromatography (eluting with EtOAc in hexanes) to give the desired product, compound 21-4 (2050% yield).

General procedure 73:

<img file="ECSP077276A_D0179.tif" />

<img file="ECSP077276A_D0180.tif" />

L = Br, Cl, COOH, COCI, OMs, ethylene carbonate, aldehyde

Compounds of formula 22-3 can be prepared by the following illustrative procedure: compound 22-2 (1.2 molar equivalents) is added to a solution of compound 22-1 (0.24 mmol) and base (3-5 molar equivalents). molars) and/or coupling reagent (1 molar equivalent) in 5 ml of DMF. The mixture is stirred under a nitrogen atmosphere for 12 h. To the reaction mixture is added water (20 ml) to quench the reaction. Then EtOAc (50 mL x 2) is added to extract the aqueous solution.

Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ it is filtered off and the filtrate is evaporated. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound 22-3.

General procedure 74:

The following procedure can be used to prepare pipedin-pyrazole-2-aminopyridine derivatives.

<img file="ECSP077276A_D0181.tif" />

23-1 a 23-1 b

<img file="ECSP077276A_D0182.tif" />

23-7a

tert-butyl 4-(4-vodo-1 H-pyrazole-1-¡l)p¡oer¡n-1-carboxylate (23-1 a)

NaH (1.2 equiv, 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 I) at 4^andC. The resulting mixture was stirred for 1 hour at 4⁹C and then compound 23-4 (1.1 equiv., 0.63 mmol) was added. The resulting mixture was heated to 100^yesC for 12h. The reaction was quenched with H₂O and extracted several times with EtOAc. The combined organic phases were dried, filtered and concentrated to give an orange oil. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound 23-1 a as a white solid (140 g, 66%).

tert-Butyl 4-14-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-1)-1H-pyrazole-1-Hlpiperidine-1-carboxylate (23-1 b )

t>/s(pinacolato)diboron (1.4 equiv, 134 g, 0.52 mol) and potassium acetate (4 equiv, 145 g, 1.48 mol) were added sequentially to a solution of compound 23-1 a (140 g, 0.37 mol) in 1.5 L DMSO. The mixture was purged several times with nitrogen and then dichlorob/s(t-phenylphosphino)palladio(II) (0.05 equiv., 12.9 g, 0.018 mol) was added. The resulting mixture was heated to 80⁵C for 2h. The reaction mixture was cooled to room temperature and filtered through a pad of celite and washed with EtOAc. The filtrate was washed with saturated NaCI (500 mL x 2), dried over Na₂SW₄, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes) to give compound 23-1b as a white solid (55 g, 40%).

Compound 23-2 (1.0 molar equivalent) was added to a solution of compound 23-1b (1.3 molar equivalent) in 15 mL of DME. The mixture was purged several times with nitrogen and then d¡chlorob/s(t~phenylphosphino)palladium(II) (0.05 molar equivalent) was added. Cesium carbonate (3 molar equivalents) in 4 mL of H was added to the reaction mixture.₂O and the resulting solution was heated to 85⁹C for 12h. To the reaction mixture, water (10 ml) was added to quench the reaction. Then EtOAc (150mL x 2) was added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ filtered off and the filtrate evaporated to give a dark brown oily residue. The residue was purified by silica gel chromatography (eluting with 75—>100% EtOAc in hexanes) to give compound 23-3a (61% yield).

Hydrochloride (19 equiv, 12 mmol) was added to a solution of compound 23-3a (0.63 mmol) in MeOH (4 mL). The mixture was stirred at room temperature for 12h. The solvent was evaporated and H was added.₂OR (10 mi). NaHCO was added₃ saturated (aq) to neutralize the solution to pH 7. Ethyl acetate (100 ml x 2) was added to extract the aqueous solution. The combined organic phase was dried over Na₂SW₄, filtered and evaporated to give compound 23-5a as a solid residue (0.6 mmol, 95% yield).

Compounds of formula 23-7 can be formed according to the following general procedure: Compound 23-8 (1.2 molar equivalents) is added to a solution of compound 23-5a (0.24 mmol) and base (3- 5 molar equivalents) and/or coupling reagent (1 molar equivalent) in 5 ml of DMF. The mixture is stirred under a nitrogen atmosphere for 12 h. To the reaction mixture is added water (20 ml) to quench the reaction. Then EtOAc (50 mL x 2) is added to extract the aqueous solution. Dry the EtOAc phase over Na₂SW₄. The Na₂SW₄ It is filtered off and the filtrate is evaporated, giving an oily residue. The residue is purified by chromatography on silica gel (eluting with CH₃oh, ch₂IC₂, EtOAc and hexanes), giving the desired product, compound 23-7a.

General Procedure 75:

<img file="ECSP077276A_D0183.tif" />

24-1

<img file="ECSP077276A_D0184.tif" />

The 3-methoxy1 compounds can be prepared from the corresponding 3-fluoro compounds by the following general procedure: To 4 mL of DMSO is added 0.124 mL of ethanol followed by 32 mg of NaH. After stirring for 30 minutes, 250 mg of 24-1 is added and the reaction is heated to 40⁹C. After three hours, the reaction is cooled and poured into water to precipitate. After neutralization to pH 6, the product 24-2 is isolated.

General procedure 76:

<img file="ECSP077276A_D0185.tif" />

<img file="ECSP077276A_D0186.tif" />

To a stirred solution of 3-[1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1 -(2,2-dimethyl-[1,3]dioxolan-4ylmethyl) -1/7-p¡razol-4-¡l]-p¡r¡d¡n-2-¡lam¡na (150 mg, 0.31 mmol) in THF (3 mL) and H₂OR (2 ml) TFA (2 ml) was added to 0⁹C, the mixture was stirred and warmed to room temperature and then heated to 50⁹C for hours. The reaction was checked by LCMS to be complete, the THF was removed and the residue was purified by

HPLC prep, leaving 3-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl) -propane1,2-diol (102 mg), 74.2% yield.

General Procedure 77:

Η

<img file="ECSP077276A_D0187.tif" />

+ χθ

NaH

br

DMF e

<img file="ECSP077276A_D0188.tif" />

br

To a stirred solution of 4-bromo-1H-pyrazole in DMF was added sodium hydride at room temperature. The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added and the mixture was stirred and slowly warmed to room temperature. The reaction was monitored by TLC. After the reaction was done, EtOAc was added, washed with NaHCO₃ saturated, water and brine, dried with Na₂SW₄, filtered and concentrated . The residue was purified by silica gel, eluents 10% EtOAc and DCM to give 2-(4Bromo-pyrazol-1-yl)-ethanol 0.22 g, 34% yield.¹H NMR (400 MHz, chloroform-D) δ ppm 7.49 (s, 1H) 7.46 (s, 1H) 4.18-4.23 (m, 2H) 3.93-3.98 (m, 2H) 3.09 (s, 1H).

Example 1: 5-Bromo-3-[(fi)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-p¡razin-2-ylam¡na

br

The title compound was prepared according to procedure 2, starting from (1 S)-1-(2,6-dichloro-3-fluorophenyl)ethanol.¹H NMR (400 MHz, DMSO-d_yes) δ 7.53 (s, 1H), 7.48 (m, 1H), 7.39 (t, 1H), 6.48 (s, 2H), 6.41 (c, 1H), 1.74 (d, 3H); LCMS: 381 [M+1 ]; K¡ of c-Met: 0.796 μΜ.

Example 2: 4-{5-amino-6-[(phy)-1 -(2,6-dichloro-3-fluoro-phen i I)-ethoxy]-pyrazin-2-yl}-benzoic acid

oh oh

<img file="ECSP077276A_D0189.tif" />

F

The title compound was prepared according to procedure 3,¹H NMR (400 MHz, DMSO-

<img file="ECSP077276A_D0190.tif" />

3H); LCMS: 422 [M+1]; k¡ of c-Met: 0.154 μΜ.

Example 3: (4-{5-Amino-6-[(R)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazin-1 -yl-methanone

<img file="ECSP077276A_D0191.tif" />

F

The title compound was prepared according to procedure 4,¹H NMR (400 MHz, DMSOd₆) δ 8.11 (s, 1H), 7.73 (d, 2H), 7.53 (m, 1H), 7.37 (t, 1H), 7.31 (d, 2H), 6.55 (m, 3H), 3.51 (a, 2H), 3.32 (a, 2H), 2.67 (a, 4H), 1.77 (d, 3H); LCMS: 490 [M+1]; c-Met ki: 0.027 μΜ.

Example 4: 4-(4-{5-amino-6-[(phy)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2 acid tert-butyl ester -yl}benzoyl)-piperaz¡n-1-carboxylic

<img file="ECSP077276A_D0192.tif" />

The title compound was prepared according to procedure 16 followed by 20,¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.72 (d, 2H), 7.50 (m, 1H), 7.33 (t, 3H), 6.55 (m, 3H), 3.51 (a, 2H),

3.39 (m, 3H), 3.32 (w, 3H), 1.77 (d, 3H), 1.40 (s, 9H); LCMS: 590 [M+1]; c-Met ki: 0.335 μΜ. Example 5: 3-[(1 R)-1 -(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-(piperazin-1-ylcarbonyl)phenyl]pyridin-2-amine

<img file="ECSP077276A_D0193.tif" />

The title compound was prepared according to procedure 20 followed by 21 as a racemic mixture with the corresponding S-enantiomer of Example 119, followed by separation by chiral chromatography. The title compound was also prepared as an enantiomerically pure compound starting from the chiral starting material.¹H NMR (400 MHz, DMSO-D_and) δppm

1.83 (d, J = 6.57 Hz, 3H) 3.35 (s, 4H) 3.69 (s, 4H) 6.24 (c, J = 6.57 Hz, 1H) 6.91- 7.08 (m, 2H) 7.10 (d, J = 1.26 Hz, 1H) 7.46 (t, J = 8.72 Hz, 1H) 7.50 (s, 4H) 7.58 ( dd, J = 8.97, 4.93 Hz, 1H) 7.91 (d, J = 1.77 Hz, 1H) 9.35 (s, 2H); LCMS: 490 [M+1 ]; c-Met ki: 0.01 μΜ.

Example 6: 4-{6-amino-5-[(1 fl)-1-(2,6-dichloro-3-fluorophenyl)ethoxy¡]p¡r¡d¡n-3-yl}-A/- [2-(dimethylamino)ethyl]-A/-

<img file="ECSP077276A_D0194.tif" />

The title compound was prepared according to procedure 20.¹H NMR (400 MHz, DMSOD₆) δ ppm 1.80 (d, J = 6.82 Hz, 3H) 1.97 (s, 3H) 2.19 (s, 3H) 2.30-2.42 (m, J = 1.77 Hz , 2H) 2.93 (s, 3H) 3.22-3.29 (m, 1H) 3.44-3.61 (m, 1H) 5.95 (s, 2H) 6.14 (c, J = 6.57 Hz, 1H) 6.98 (d, J = 1.01 Hz, 1H) 7.30-

7.39 (m, 2H) 7.40-7.47 (m, 3H) 7.51-7.62 (m, 1H) 7.87 (d, J=1.77 Hz, 1H); LCMS: 506 [M+1]; c-Met ki: 0.01 μΜ.

Example 7: (4-{6-amino-5-[(1 R)-1 -(2,6-dichloro-3-f luorophenyl)ethoxy]pyridin-3-ylJf en i I) methanol

<img file="ECSP077276A_D0195.tif" />

The title compound was prepared according to procedure 27.¹H NMR (400 MHz, DMSOD₆) δ ppm 1.84 (d, J = 6.57 Hz, 3H) 4.49 (d, J = 5.81 Hz, 2H) 5.20 (t, J = 5.81 Hz, 1H) 6, 25 (c, J = 6.57 Hz, 1H) 6.46-6.88 (m, 2H) 7.04 (d, J = 1.52 Hz, 1H) 7.34 (s, 4H) 7, 46 (t, J=8.72Hz, 1H) 7.59 (dd, J=8.97, 4.93Hz, 1H) 7.76 (d,J=1.52Hz, 1H); LCMS: 408 [M+1]; c-Met ki: 0.051 μΜ.

Example 8: 4-{6-amino-5-[(1 R)-1 -(2,6-dichloro-3-fluorophenyl)ethoxy¡]pyrid¡n-3-yl}-A/-[3 -(dimethylamino)propyl]-/Vmethylbenzamide

<img file="ECSP077276A_D0196.tif" />

The title compound was prepared according to procedure 27.¹H NMR (400 MHz, DMSOD_and) δ ppm 1.60-1.73 (m, 2H) 1.80 (d, J = 6.57 Hz, 3H) 1.94 (s, 3H) 2.13 (s, 3H) 2.20- 2.29 (m, 2H) 2.92 (s, 3H) 3.36-3.50 (m, 2H) 5.96 (s, 2H) 6.14 (c, J = 6.57 Hz, 1H ) 6.98 (s, 1H) 7.37 (s, 2H) 7.40-7.51 (m, 3H)

7.55 (dd, J=8.84, 4.80Hz, 1H) 7.86 (d, J=1.77Hz, 1H); LCMS: 520 [M+1 ]; c-Met ki: 0.01 μΜ. Example 9: 4-(4-{6-Amino-5-[(1 R)-1 -(2,6-dichloro-3-f luorofeni I)ethoxy]pyridin-3-yl}benzoyl)piperazin -1 - tere-butyl carboxylate

<img file="ECSP077276A_D0197.tif" />

The title compound was prepared according to procedure 20.¹H NMR (400 MHz, chloroform-D) δ ppm 1.46 (s, 9H) 1.86 (d, J = 6.82 Hz, 3H) 3.30-3.89 (m, 8H) 4 .90 (s, 2H) 6.11 (c, J =

6.57 Hz, 1H) 6.98 (d, J = 1.52 Hz, 1H) 7.01 -7.10 (m, 1H) 7.30 (dd, J = 8.97, 4.93 Hz , 1H) 7.35-7.43 (m, 4H)

7.88 (d, J=1.77Hz, 1H); LCMS: 590 [M+1 ]; c-Met ki: 0.03 μΜ.

Example 10: 3-[(R)-1-(2,6-Dichloro-3-fluoro-phen i I)-ethoxy]-5-[1 -(1-methyl-piperidin-4-yl)-1 R-pyrazol-4-yl]-pyridin-2ylamine

<img file="ECSP077276A_D0198.tif" />

The title compound was prepared according to procedure 62 using 3-[(R)-1 -(2,6dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine and 4-(4-bromopyrazol-1-yl)-1-methyl-piperidine (prepared according to General Procedure 11).¹H NMR (400 MHz, CDCIg) δ 7.65 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.31 (m, 1H), 7.06 (m , 1H), 6.87 (s, 1H), 6.08 (m, 1H), 5.50 (sa, 2H), 4.18 (m, 1H), 3.11 (m, 2H), 2 .40 (s, 3H), 2.30 (m, 2H), 2.20 (m, 4H), 2.07 (s, 3H), 1.86 (d, J = 8 Hz, 3H); LCMS: 464 [M+1]; k¡ dec-Met: 0.01 μΜ.

Example 11: 1 -[4-(4-{6-Amino-5-[(F?)-1 -(2,6-dichloro-3-fluoro-f enyl)-ethoxy]-pyridin-3 -yl}-pyrazol-1 -yl)-piperidi n-1 -

<img file="ECSP077276A_D0199.tif" />

The title compound was prepared according to procedure 63.¹H NMR (400 MHz, CDCI₃) δ 7.72 (s, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.31 (m, 1H), 7.06 (m, 1H), 6.86 (s, 1H), 6.08 (m, 1H), 5.00 (bs, 2H), 4.70 (m, 1H), 4.36 (m, 1H), 4.21 (s, 1H) , 3.70 (m, 1H), 3.18 (m, 1H), 3.00 (m, 1H), 2.223 (m, 2H), 2.01 (m, 2H), 1.86 (d, J=8Hz, 3H); LCMS: 508 [M+1]; k¡ of c-Met: 0.004 μΜ.

Example 12: 3-[(fi)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-iI-1H-pyrazol-4-yl)- p¡ridin-2-ilam¡na

<img file="ECSP077276A_D0200.tif" />

The title compound was prepared according to procedure 62 using 3-[(phy)-1-(2,6dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-¡l)-p¡r¡d¡n-2-ylam¡na and 4-(4-bromopyrazol-1-yl)-1-cyclopentyl-piperidine (prepared according to with general procedure 11 using bromocyclopentane as alkylation reagent).¹H NMR (400 MHz, CDCI₃) δ 7.73 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.31 (m, 1H), 7.07 (m, 1H), 6.88 (s, 1H), 6.08 (m, 1H), 4.64 (m, 1H), 2.04 (m, 2H), 1.98 (m, 2H), 1.86 (d, J = 8hz, 3H), 1.73 (m, 2H); LCMS: 435 [M+1 ]; k¡ of c-Met: 0.02 μΜ.

Example 13: 3-[(fi)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1 -piperid i n-4-i I-1 H-pyrazole-4- il)-p¡ ridin-2-ilam ¡na

<img file="ECSP077276A_D0201.tif" />

The title compound was prepared according to procedure 62.¹H NMR (400 MHz, CDCI₃) δ 7.69 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.32 (m, 1H), 7.07 (m, 1H), 6.87 (m, 1H), 6.07 (m, 1H), 5.25 (bs, 2H), 4.30 (m, 1H), 3.41 (m, 2H), 2.96 (m, 2H) , 2.26 (m, 2H), 2.12 (m, 2H), 1.86 (d, J = 8 Hz, 3H); LCMS: 450 [M+1]; k¡ of c-Met: 0.003 μΜ.

Example 14: 3-[(R)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1 -piperid i n-4-¡ I-1 H-pyrazole-4- il)-p¡ razin-2-ylamine

<img file="ECSP077276A_D0202.tif" />

The title compound was prepared according to procedure 66.¹H NMR (400 MHz, DMSOd₆) δ 7.86 (s, 1H), 7.76 (s, 1H), 7.63 (m, 2H), 7.54 (m, 1H), 7.37 (t, 1H), 6.46 (c, 1H), 6.15 (s, 1H), 4.10 (m, 1H), 3.01 (m, 2H), 1.95 (m, 2H), 1.85 (s, 2H) , 1.75(d, 3H), 1.67(dd, 1H); LCMS: 451 [M+1]; k¡ of c-Met: 0.010 μΜ.

Example 15: 3-[(ñ)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1/7-pyrazol-4-yl)-pyrazin-2-ylam¡ na

<img file="ECSP077276A_D0203.tif" />

The title compound was prepared according to procedure 3 using 5-bromo-3-[(phy)-1(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and ester ester 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid -butyl.¹H NMR (400 MHz, DMSO-de) δ 12.81 (s, 1H), 7.79 (s, 1H), 7.48 (m, 1H), 7.36 (t, 1H), 6.48 (c, 1H), 6.12 (s, 2H), 1.75 (d, 3H); LCMS: 368 [M+1 ]; c-Met ki: 0.065 μΜ. Example 16: 1 -[4-(4-{5-Amino-6-[(/3)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-i I}-p¡ razol -1 -i I)-piperidin1 -yl]-2-hydroxy-ethanone

<img file="ECSP077276A_D0204.tif" />

The title compound was prepared according to procedures 62 and 63, using 5-bromo-3[(/3)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin- 2-ylamine as starting material.¹H NMR (400 MHz, DMSO-de) δ 7.91 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.46 (c, 1H), 6.15 (s, 2H),

4.57 (w, 1H), 4.40 (m, 2H), 4.12 (w, 2H), 3.77 (m, 1H), 3.35 (m, 2H), 3.43 (m , 1H), 3.16 (m, 2H), 1.75 (d, 3H); LCMS: 509 [M+1]; c-Met ki: 0.015 μΜ.

Example 17: 3-[(R)-1-(2,6-Dichloro-3-fluoro-phen i I)-ethoxy]-5-[1 -(1-methyl-piperidin-4-yl)-1H -pyrazol-4-yl]-pyrazin 2-ylamine

<img file="ECSP077276A_D0205.tif" />

The title compound was prepared according to procedure 62 using 5-bromo-3-[(/3)-1(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4 -(4-bromo-pyrazol-1-yl)-1-methyl-piperidine (prepared according to General Procedure 11).¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.76 (s, 1H),

7.64 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.46 (c, 1H), 6.15 (s, 2H), 4.02 (m , 1H), 2.84 (m, 2H), 2.19 (s, 3H), 2.00 (m, 4H), 1.85 (m, 3H), 1.75 (d, 3H); LCMS: 465 [M+1 ]; c-Met ki: 0.03 μΜ.

Example 18: 1 -[4-(4-{5-Amino-6-[(/3)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-i I]-p¡ razol -1 -i I)-piperidin1 -yl]-2-dimethylam¡no-ethanone

<img file="ECSP077276A_D0206.tif" />

The title compound was prepared according to procedure 63 using 3-[(phy)-1-(2,6dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-i I- 1 Hpi razol-4-yl)-pyrazin-2-ylamine coupled with dimethylamino-acetic acid in the presence of HOBt/EDC/triethylamine in DMF as described in procedure 5 using 5-bromo-3-[(R )-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine as starting material.¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.47 (c, 1H), 6.15 (s, 2H), 4.39 (m, 1H), 4.16 (m, 1H), 3.16 (m, 2H), 3.02 (m, 1H) , 2.75 (m, 1H), 2.19 (s, 6H), 2.01 (m, 2H), 1.88 (s, 1H), 1.75 (d, 3H).; LCMS: 536 [M+1]; ki dec-Met: 0.015 μΜ.

Example 19: 3-[(R)-1 -(2-Chloro-3,6-dif I uoro-phenyl)-ethox¡]-5-(1-piperidin-4-yl-1 /7-pyrazol-4 -yl)-pyridin-2-ylam ¡na

<img file="ECSP077276A_D0207.tif" />

The title compound was prepared according to procedure 62 using 5-bromo-3-[(F?)-1(2-chloro-3,6-difluoro-phenyl)-ethoxy]-p¡r¡ d¡n-2-¡lam¡na as starting material (according to the procedures for the synthesis of 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethox ¡]-pyridin-2-¡lamine from (S)-1-(2-chloro-3,6-difluoro-phenyl)-ethanol, obtained from SynChem, Inc.).¹H NMR (400 MHz, DMSO-d_and) δ 7.88 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.38 (m, 1H), 7.25 (m, 1H), 6.99 (s, 1H), 5.88 (m, 1H), 5.48 (bs, 2H), 4.08 (m, 1H), 2.96 (m, 2H), 2.53 (m, 1H) , 2.45 (m, 1H), 1.89 (m, 1H), 1.80 (m, 4H), 1.67 (m, 4H); LCMS: 434 [M+1]; c-Met ki: 0.09 μΜ.

Biological Examples

It will be appreciated that, in any given series of compounds, a range of biological activities will be observed. In its presently preferred aspects, this invention relates to novel compounds capable of modulating, regulating and/or inhibiting protein kinase activity. The following assays can be used to select those compounds that demonstrate the optimum degree of desired activity.

Test Procedures

The following in vitro assay can be used to determine the level of activity and the effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed according to the same indications for any PK using techniques well known in the art. A bibliographical reference is provided. (Technikova-Dobrova Z, Sardanelli AM, Papa S FEBS

Lett. 1991 Nov. 4; 292:69-72).

The general procedure is as follows: kinase assay compounds and reagents are introduced into assay wells. The assay is started by the addition of the kinase enzyme. Enzyme inhibitors reduce measured enzyme activity.

In the continuous coupled spectrophotometric assay, the time-dependent production of ADP by the kinase is determined by analyzing the rate of consumption of NADH by measuring the decrease in absorbance at 340 nm. As the PK produces ADP, it is converted back to ATP by reaction with phosphoenolpyruvate and pyruvate kinase. Pyruvate is also produced in this reaction. Pyruvate is further converted to lactate by a lactate dehydrogenase reaction, which simultaneously converts NADH to NAD. NADH has a measurable absorbance at 340 nm while NAD does not.

The currently preferred protocol for performing continuous coupled spectrophotometric experiments for specific PKs is provided below. However, the adaptation of this protocol to determine the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art.

HGFR Continuous Coupled Spectrophotometric Assay

This assay analyzes HGFR tyrosine kinase activity on the peptide substrate Met-2, a peptide derived from the HGFR activation loop.

Materials and REACTIVES:

1. Upstate HGFR Enzyme (Met, Active) Cat. N⁹ 14-526

2. Met-2 peptide (HGFR activation loop) Ac-ARDMYDKEYYSVHNK (MW = 1960). Dissolve in 200 mM Hepes, pH 7.5 in a 10 mM stock solution.

3. 1 M PEP (phospho-enol-pyruvate) in 200 mM HEPES, pH 7.5

4. 100 mM NADH (B-Nicotinamide Adenine Dinucleotide, reduced form) in 200 mM HEPES, pH 7.5

5. MgCI₂ 4 M (Magnesium Chloride) to ddH₂EITHER

6. 1 M DTT (Dithiothreitol) in 200 mM HEPES, pH 7.5

7.15 Units/ml of LDH (Lactic Dehydrogenase)

8.15 Units/ml of PK (Pyruvate kinase)

9. 5 M NaCI dissolved in ddH₂EITHER

10. Tween-20 (Protein Quality) 10% solution

eleven. 1 M HEPES buffer: Sodium salt (/V-[2-hydroxyethyl]piperaz¡nA/-[2-ethanesulfon¡co] acid). Dissolve in ddH₂Or, adjust pH to 7.5, bring volume to 1 L. Filter at 0.1 pm.

12. HPLC quality water; Burdick and Jackson N.⁹ 365-4.1 x 4 liters (or equivalent)

13. DMSO 100% (SIGMA)

14. cost N⁹ 3880 - black transparent flat bottom half-area plates for determination of K¡ and % inhibition.

fifteen. cost N⁹ 3359 - 96-well polypropylene plates, round bottom for serial dilutions

16. cost N⁹ 3635 - UV transparent flat bottom plates for % inhibition

17. Beckman DU-650 with microcell holders

18. Microcellular cuvette in position 4 Beckman

Procedure:

Preparation of the dilution buffer (DB) for the enzyme (for 30 ml of prep).

1. The final concentration of DB is 2 mM DTT, 25 mM NaCI, MgCI₂ 5 mM, 0.01% Tween-20 and 50 mM HEPES buffer, pH 7.5.

2. Prepare 50 mM HEPES by adding 1.5 ml of 1 M HEPES in 28.1 ml of ddH2O. Add the rest of the reagents. In a 50 mL conical vial, add 60 μΙ of 1 M DTT, 150 μΙ of 5 M NaCI, 150 μΙ of MgCI₂1 M and 30 μΙ of 10% Tween-20 giving a total volume of 30 ml.

3. Vortex for 5 -10 seconds.

4. Withdraw an aliquot of DB at 1 mL/tube and label tubes as DB HGFR

5. Note: This can be made and stored ahead of time.

6. Freeze unused aliquots in microcentrifuge tubes in a freezer at -20⁹C. Preparation of compounds

1. For compound dilution plate, add 4 μΙ of 10 mM stock solution in column 1 of plate, and bring volume to 100 μΙ with 100% DMSO.

2. Set up the Precision 2000 dilution procedure. A final concentration of 200 μΜ compound in 50% DMSO, 100 mM HEPES (1:2 serial dilution).

Preparation of coupled enzyme buffer:

1. Final concentration in test:

<td>Reagent (Conc. of Stock Solution)</td><td>Final Conc. in Test</td>

<td>to. PEP (1M)</td><td>1mm</td>

<td>b. NADH (100mM)</td><td>300 μΜ</td>

<td>c. MgCI₂ (4M)</td><td>20mM</td>

<td>d. DTT (1M)</td><td>2mM</td>

<td>and. ATP (500mM)</td><td>300 μΜ</td>

<td>F. HEPES 200mM(pH 7.5)</td><td>100mM</td>

<td>g. Pyruvate Kinase (PK)</td><td>15 units/mL</td>

<td>h. Lactic dehydrogenase (LDH)</td><td>15 units/mL</td>

<td>Yo. Met-2 peptide (10 mM)</td><td>0.500mM</td>

<td>Yo. HGFR</td><td>50nM</td>

2. To 10 ml of a reaction buffer add 10 μΙ of 1 M PEP, 33 μΙ of 100 mM NADH, 50 μΙ of MgCI₂ 4 M, 20 µΙ 1 M DTT, 6 µΙ 500 mM ATP, and 500 µΙ 10 mM Met-2 peptide in 100 mM HEPES buffer, pH 7.5 and vortex/mix.

3. Add coupling enzymes, LDH and PK, into the reaction mixture. Mix by gentle inversion.

Sample processing:

1. Spectrophotometer Powers:

Yo. Absorbance Wavelength (λ): 340 nm ¡i. Incubation time: 10 min iii. Processing Time: 10 min iv. temperature 37⁵C.

2. Add 85 μΙ of the EC reaction mix to each well of the assay plate.

3. Add 5 μΙ of the diluted compound to one well of the assay plate.

4. Add 5 μΙ of 50% DMSO for the negative control in the last column of the assay plate.

5. Mix with a multichannel pipettor or orbital shaker.

6. Pre-incubate for 10 min at 37^Sc.

7. Add 10 μΙ of 500 nM HGFR to each well of the assay plate; the final concentration of HGFR is 50 nM in a total final volume of 100 μΙ.

8. Measure the activity for 10 min at λ = 340 nm at 37⁹c.

The following in vitro assays can be used to determine the level of activity and the effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed according to the same indications for any PK using techniques well known in the art.

The various assays described herein are performed in an ELISA (Enzyme-Linked Immunosorbent Sandwich Assay) format (Voller et al., 1980, Enzyme-Linked Immunosorbent Assay, Manual of Clinical Immunology, 2d. ed., Rose and Friedman, Am. Soc. Of Microbiology, Washington,

DC, pp. 359-371). The general procedure is as follows: a compound is introduced into cells expressing the test kinase, naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand is added that it is known to activate the receptor. The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody that recognizes the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the cell lysate are washed away and the amount of phosphorylation on the substrate is detected with a phosphotyrosine that specifically recognizes the antibody compared to control cells not in contact with a test compound.

The currently preferred protocols for performing ELISA experiments with respect to the

Specific PKs are provided below. However, adaptation of these protocols to determine the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art.

Other assays described herein measure the amount of DNA made in response to activation of a test kinase, which is a general measure of a proliferative response. The general procedure for this assay is as follows: a compound is introduced into cells expressing the test kinase, naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, it is added a ligand known to activate the receptor. After incubation for at least one night, a DNA labeling reagent such as 5-bromodeoxyuridine (BrdU) or H is added.³-thymidine. The amount of the labeled DNA is detected with an anti-BrdU antibody or by measuring radioactivity and compared to control cells not in contact with a test compound.

MET Transphosphorylation Assay

This assay is used to measure phosphotyrosine levels in a poly(glutamic acid:tyrosine, 4:1) substrate as a means of identifying agonists/antagonists of MET transphosphorylation of the substrate.

Materials and REACTIVES:

1. Corning 96-well ELISA Plates, Corning Catalog No.² 25805-96.

2. Poly(glu-tyr); 4:1, Sigma, Cat.N² P0275.

3. PBS, Gibco N Catalog⁹ 450-1300EB.

4. HEPES 50 mM.

5. Blocking buffer: dissolve 25 g of bovine serum albumin, Cat. Sigma N⁹ A-7888, in 500 mL of PBS, filter through a 4 μπι filter.

6. Purified GST fusion protein containing the kinase domain from Met, SUGEN, Inc.

7. TBST buffer.

8. 10% aqueous DMSO (MilliQue H₂EITHER).

9. 10 mM aqueous adenosine-5'-triphosphate (dH₂O), Sigma Cat. N⁹ A-5394.

10. 2X Kinase Dilution Buffer: For 100 mL, mix 10 mL 1 M HEPES pH 7.5 with 0.4 mL 5% BSA/PBS, 0.2 mL 0.1 M sodium orthovanadate, and 1 mL of 5 M sodium chloride in 88.4 mL of dH₂EITHER.

eleven. 4X ATP reaction mix: For 10 mL, mix 0.4 mL 1 M manganese chloride and 0.02 mL 0.1 M ATP in 9.56 mL dH₂EITHER.

12. 4X Negative Control Mix: For 10 mL, mix 0.4 mL 1 M Manganese Chloride in 9.6 mL dH₂EITHER.

13. NUNC 96-well V-bottom polypropylene plates, Applied Scientific Catalog N⁹ S72092.

14. 500mM EDTA.

fifteen. Antibody Dilution Buffer: For 100 mL, mix 10 mL 5% BSA/PBS, 0.5 mL 5% Instant Milk Carnation® in PBS, and 0.1 mL 0.1 M sodium orthovanadate in 88, 4ml TBST.

16. Rabbit Antiphosphotyrosine Polyclonal Antibody, SUGEN, Inc.

17. Horseradish peroxidase conjugated goat anti-rabbit antibody, Biosource, Inc.

18. ABTS solution: for 1 I, mix 19.21 g citric acid, 35.49 g Na₂HPO₄ and 500 mg of ABTS with sufficient dH₂Or to prepare 1 I.

19. ABTS/H₂EITHER₂: mix 15 ml of ABST solution with 2 μΙ of H₂EITHER₂ five minutes before use.

twenty. IHC 0.2M

Procedure:

1. Coat ELISA plates with 2 μρ of Poly(Glu-Tyr) in 100 μΙ PBS, hold overnight at 4²c.

2. Block the plate with 150 µΙ of 5% BSA/PBS for 60 min.

3. Wash the plate twice with PBS, then once with 50 mM Hepes buffer, pH 7.4.

4. Add 50 μΙ of the diluted kinase to all wells. (Purified kinase is diluted with kinase dilution buffer. Final concentration should be 10 ng/well).

5. Add to the plate 25 μΙ of the test compound (in 4% DMSO) or DMSO alone (4% in dH₂O) for controls.

6. Incubate the kinase/compound mixture for 15 minutes.

7. Add 25 μΙ of MnCI₂ 40 mM to the negative control wells.

8. Add 25 μΙ of the ATP/MnCI mix₂ to all other wells (except negative controls). Incubate for 5 minutes.

9. Add 25 μΙ of 500 mM EDTA to stop the reaction.

10. Wash the plate 3x with TBST.

eleven. Add 100 μΙ of rabbit anti-Ptyr polyclonal antibody diluted 1:10,000 in Test Buffer.

Antibody dilution to each well. Incubate, with shaking, at room temperature for one hour.

12. Wash the plate 3x with TBST.

13. Dilute Biosource HRP-conjugated anti-rabbit antibody 1:6,000 in Antibody Dilution Buffer. Add 100 μΙ per well and incubate at room temperature, shaking for one hour.

14. Wash the plate 1X with PBS.

fifteen. Add 100 μΙ of the ABTS/H solution₂EITHER₂ to each well.

16. If necessary, stop the development of the reaction with the addition of 100 μΙ of 0.2 M HCl per well.

17. Read the plates on a Dynatech MR7000 ELISA reader with the test filter at 410 nM and the reference filter at 630 nM.

BrdU INCORPORATION TRIALS

The following assays use cells engineered to express a selected receptor and then assess the effect of a compound of interest on ligand-induced DNA synthesis activity by determining the incorporation of BrdU into DNA.

The following materials, reagents, and procedures are general for each of the following BrdU incorporation assays. Changes are observed in specific trials. General materials and reagents:

1. the appropriate ligand.

2. The appropriate genetically engineered cells.

3. BrdU Labeling Reagent: 10 mM, in PBS, pH 7.4 (Roche Molecular Biochemicals, Indianapolis, IN).

4. FixDenat: fixation solution (Roche Molecular Biochemicals, Indianapolis, IN).

5. Anti-BrdU-POD: peroxidase-conjugated mouse monoclonal antibody (Chemicon, Temecula, CA).

6. TMB substrate solution: tetramethylbenzidine (TMB, ready to use, Roche Molecular Biochemicals, Indianapolis, IN).

7. PBS Wash Solution: 1X PBS, pH 7.4.

8. Bovine serum albumin (BSA), fraction V powder (Sigma Chemical Co., USA). General procedure:

1. Cells are seeded at 8000 cells/well in 10% CS, 2 mM Gln in DMEM, in a 96-well plate. Cells are incubated overnight at 37⁵C in CO₂ at 5%.

2. After 24 hours, cells are washed with PBS, and then maintained in serum-free medium (0% DMEM CS with 0.1% BSA) for 24 hours.

3. On day 3, the appropriate ligand and test compound are added to the cells simultaneously. Negative control wells receive serum-free DMEM with only 0.1% BSA; positive control cells receive the ligand but not the test compound. Test compounds are prepared in serum-free DMEM with ligand in a 96-well plate, and serially diluted to 7 assay concentrations.

4. After 18 hours of ligand activation, diluted BrdU labeling reagent (1:100 in DMEM, 0.1% BSA) is added and cells are incubated with BrdU (final concentration is 10 μΜ) for 1, 5 hours.

5. After incubation with labeling reagent, the medium is removed by decanting and tapping the plate inverted on blotting paper. FixDenat solution is added (50 μΙ/well) and the plates are incubated at room temperature for 45 minutes on a plate shaker.

6. The FixDenat solution is removed by decanting and tapping the plate inverted on blotting paper. Milk (5% dried milk in PBS, 200 μΙ/well) is added as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker.

7. The blocking solution is decanted off and the wells are washed once with PBS. Anti-BrdU-POD solution (1:200 dilution in PBS, 1% BSA, 50 μΙ/well) is added and the plate is incubated for 90 minutes at room temperature on a plate shaker.

8. The antibody conjugate is decanted off and the wells are rinsed five times with PBS, and the plate is dried by inverting and tapping on a blotting paper.

9. TMB Substrate Solution (100 μΙ/well) is added and incubated for 20 minutes at room temperature on a plate shaker until color development is sufficient for photometric detection.

10. The absorbance of the samples is measured at 410 nm (in dual wavelength mode with a filter reading at 490 nm, as a reference wavelength) on a Dynatech ELISA plate reader. HGF-Induced BrdU Incorporation Assay

Materials and REACTIVES:

1. Recombinant human HGF (Cat. N⁵ 249-HG, R&amp;D Systems, Inc. United States).

2. BxPC-3 cells (ATCC CRL-1687).

Remaining Materials and Reagents, as above.

Procedure:

1. Cells are seeded at 9000 cells/well in RPMI, 10% FBS in a 96-well plate. Cells are incubated overnight at 37^QC in CO₂ at 5%.

2. After 24 hours, cells are washed with PBS, and then maintained serum-free in 100 μΙ serum-free medium (RPMI with 0.1% BSA) for 24 hours.

3. On day 3, 25 μΙ containing ligand (prepared at 1 μg/ml in RPMI with 0.1% BSA; final HGF conc. is 200 ng/ml) and test compounds are added to cells. . Negative control wells receive 25 μΙ serum-free RPMI with 0.1% BSA only; positive control wells receive the ligand (HGF) but not the test compound. Test compounds are prepared at five times their final concentration in RPMI without liganded serum in a 96-well plate, serially diluted to give 7 assay concentrations. Typically, the highest final concentration of test compound is 100 μΜ, and 1:3 dilutions are used (ie, the final test compound concentration range is 0.137-100 μΜ).

4. After 18 hours of ligand activation, 12.5 μΙ of diluted BrdU labeling reagent (1:100 in RPMI, 0.1% BSA) is added to each well and cells are incubated with BrdU (final concentration is 10 μΜ) for 1 hour.

5. Same as in the general procedure.

6. Same as in the general procedure.

7. The blocking solution is decanted off and the wells are washed once with PBS. Anti-BrdU-POD solution (1:100 dilution in PBS, 1% BSA) is added (100 μΙ/well) and the plate is incubated for 90 minutes at room temperature on a plate shaker.

8. Same as in the general procedure.

9. Same as in the general procedure.

10. Same as in the general procedure.

Cellular HGFR Autophosphorylation Assay

A549 cells (ATCC) were used in this assay. Cells were seeded in the culture media (RPMI + 10% FBS) in 96-well plates and cultured overnight at 37⁹C for union. Cells were exposed to starvation media (RPMI + 0.05% BSA). Inhibitor dilutions were added to the plates and incubated at 37^gC for an hour. Cells were then stimulated by adding 40 ng/ml HGF for 15 minutes. Cells were washed once with 1 mM Na3VO4 in HBSS and then lysed. Lysates were diluted with 1 mM Na3VO41 in HBSS and transferred to a 96-well goat anti-rabbit antibody-coated plate (Pierce) that was pre-coated with anti-HGFR antibody (Zymed Laboratories). The plates were incubated overnight at 4^andC and washed with 1% Tween 20 in PBS 7 times. HRP-PY20 (Santa Cruz) was diluted and added to the plates during a 30 minute incubation. The plates were then washed again and TMB peroxidase substrate (Kirkegaard &amp; Perry) was added and incubated for 10 minutes. The reaction was then quenched by adding H2SO₄ 0.09 N. Plaques were measured at OD-450 nm using a spectrophotometer. IQ values₅₀ they were calculated by curve fitting using a four parameter analysis.

Compounds of the invention were measured for HGFR inhibition activity; data was shown in each example. K¡ data were obtained using HGFR continuous coupled spectrophotometric assay and CI data₅₀ they were obtained using the cellular HGFR autophosphorylation assay, which have been described above.

Although the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is not intended to be limited by the foregoing description, but is intended to be defined by the appended claims and their equivalents.

All references cited in this document, including any priority documents, are incorporated herein by reference in their entirety.