Compounds modulating c-fms and/or c-kit activity and uses therefor

FIELD OF THE INVENTION

0001This invention relates to ligands for c-fms and c-kit, and to methods for use thereof. The information provided is intended solely to assist the understanding of the reader. None of the information provided nor references cited is admitted to be prior art to the present invention.

BACKGROUND OF THE INVENTION

0002C-fms and c-kit are both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.

c-Fms

0003C-fms is a member of the family of genes originally isolated from the Susan McDonough strain of feline sarcoma viruses. The cellular proto-oncogene FMS (c-fms, <u>c</u>ellular <u>f</u>eline <u>M</u>cDonough <u>s</u>arcoma) codes for the receptor for the macrophage colony-stimulating factor (M-CSF). C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage, and upon binding of M-CSF to the extracellular domain of c-fms, the receptor dimerizes and trans-autophosphorylates cytoplasmic tyrosine residues.

0004M-CSF, first described by <nplcit id="ncit0001" npl-type="s"><text>Robinson and co-workers (Blood. 1969, 33:396-9</text></nplcit>), is a cytokine that controls the production, differentiation, and function of macrophages. M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes. Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production of additional factors in monocytes and macrophages. Examples of such additional factors include granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8). M-CSF stimulates hematopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism. Furthermore, M-CSF is important in pregnancy. Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (<nplcit id="ncit0002" npl-type="s"><text>Motoyoshi, Int J Hematol. 1998, 67:109-22</text></nplcit>). The elevated serum levels of M-CSF in early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (<nplcit id="ncit0003" npl-type="s"><text>Flanagan &amp; Lader, Curr Opin Hematol. 1998, 5:181-5</text></nplcit>).

0005Related to c-fms and c-kit are two <u>p</u>latelet-<u>d</u>erived growth <u>f</u>actor <u>r</u>eceptors, <u>a</u>lpha (i.e., pdgfra) and <u>b</u>eta (pdgfrb) (PDGF). The gene coding for pdgfra is located on chromosome 4q 11-q 12 in the same region of chromosome 4 as the oncogene coding for c-kit. The genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5. They are oriented head-to-tail with the 5-prime exon of the c-fms gene located only 500 bp from the last 3-prime exon of the gene coding for pdgfra. Most gastrointestinal stromal tumors (GIST) have activating mutations in c-kit, and most patients with GISTs respond well to Gleevec, which inhibits c-kit. <nplcit id="ncit0004" npl-type="s"><text>Heinrich et al. (Science 2003, 299:708-10</text></nplcit>) have shown that approximately 35% of GISTs lacking c-kit mutations have intragenic activation mutations in the gene encoding pdgfra, and that tumors expressing c-kit or pdgfra are indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, c-kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.

0006Similarly, the observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation points out a role for c-fms in diseases, such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of c-fms can ameliorate disease associated with increased levels of M-CSF.

c-Kit

0007The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of melanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded by the S1 locus, and has also been called "kit ligand" (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in <nplcit id="ncit0005" npl-type="s"><text>Tsujimura, Pathol Int 1996, 46:933-938</text></nplcit>; <nplcit id="ncit0006" npl-type="s"><text>Loveland, et al., J. Endocrinol 1997, 153:337-344</text></nplcit>; <nplcit id="ncit0007" npl-type="s"><text>Vliagoftis, et al., Clin Immunol 1997, 100:435-440</text></nplcit>; <nplcit id="ncit0008" npl-type="s"><text>Broudy, Blood 1997, 90:1345-1364</text></nplcit>; <nplcit id="ncit0009" npl-type="s"><text>Pignon, Hermatol Cell Ther 1997, 39:114-116</text></nplcit>; and <nplcit id="ncit0010" npl-type="s"><text>Lyman, et al., Blood 1998, 91:1101-1134</text></nplcit>.). Herein the abbreviation SCF refers to the physiological ligand for c-kit.

0008SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form a soluble, glycosylated protein which noncovalently dimerizes. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, sertoli cells and granulosa cells express SCF which regulates spermetogenesis by interaction with c-kit on germ cells.

RELATED PATENT APPLICATIONS

0009<patcit id="pcit0001" dnum="WO2006009755A2"><text>WO 2006/009755 A2</text></patcit> and <patcit id="pcit0002" dnum="WO2006009797A1"><text>WO 2006/009797 A1</text></patcit> both relate to compounds for modulating Kit activity, said compounds having an azaindole core structure.

SUMMARY OF THE INVENTION

0010The present invention relates to compounds active on c-fins, c-kit, or both c-fms and c-kit. In accordance with one aspect of the present invention, it has been discovered that in the treatment of diseases amenable to treatment by an effective amount of a modulator of either c-fms alone or c-kit alone, the efficacy of treatment can be enhanced if said compounds are dual inhibitors of both c-fms and c-kit. In another aspect of the present invention, compounds active on c-fms, c-kit, or both c-fms and c-kit are also active on one or more of TrkA, TrkB and HGK. Generally disclosed herein are compounds of Formula II, and all sub-generic formulae thereof (e.g. Formula IIa, IIb, IIe, IIg and IIp), Formula III, or additional compounds as described in the synthetic examples, as well as methods of using such compounds as described below. Subject matter of the present invention are compounds having the chemical structure of Formula III, wherein R⁸¹ is chloro. Further subject matter of the present invention is a composition comprising a pharmaceutically acceptable carrier and a compound according to the present invention, i.e. a compound having the chemical structure of Formula III, wherein R⁸¹ is chloro. Further subject matter of the present invention is a kit comprising the above composition. Further subject matter of the present invention is the use of a compound or composition, respectively, according to the present invention for treating a subject suffering from or at risk of a c-kit and/or c-fms mediated disease or condition, comprising administering to the subject an effective amount of the compound according to the present invention. Thus, the invention provides methods of using compounds that can be used therapeutically and/or prophylactically involving modulation of c-fms, c-kit, or both c-fms and c-kit, or involving one or more of TrkA, TrkB and HGK in addition to c-fms, c-kit, or both c-fms and c-kit.

0011The compounds of Formula II have the following structure: <chemistry id="chem0001" num="0001"><img file="EP2086972B1_D0001.tif" /></chemistry> all selts, prodrugs, tautomers, and isomers thereof, wherein: <ul id="ul0001" list-style="none" compact="compact"><li>D has a structure selected from the group consisting of <chemistry id="chem0002" num="0002"><img file="EP2086972B1_D0002.tif" /></chemistry><chemistry id="chem0003" num="0003"><img file="EP2086972B1_D0003.tif" /></chemistry> and <chemistry id="chem0004" num="0004"><img file="EP2086972B1_D0004.tif" /></chemistry> in which <chemistry id="chem0005" num="0005"><img file="EP2086972B1_D0005.tif" /></chemistry> indicates the attachment point of D to A₂ of Formula II;</li><li>A₂ is -CH₂- or -C(O)-;</li><li>B is selected from the group consisting of hydrogen, -CN, -OR⁴¹, -SR⁴¹, -NHR⁴¹, -NR⁴¹R⁴¹, -NR¹⁹C(O)R⁴¹, -NR³⁹S(O)₂R⁴¹, -C(O)NR³⁹R⁴¹, -C(O)R⁴¹, -S(O)NR³⁹R⁴¹, -S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as B, or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH₂, -CN, -NO₂, -S(O)₂NH₂, -C(O)NH₂, -OR⁴², -SR⁴², -NHR⁴², -NR⁴²R⁴², -NR³⁹C(O)R⁴², -NR³⁹S(O)₂R⁴², -S(O)₂R⁴², halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;</li><li>M₄ is -NR³⁹CH₂-, -NR³⁹CH(R⁴⁰)-, -NR³⁹CH₂CH₂-, or -NR³⁹C(O)-;</li><li>M_5. M_10. and M₁₈ are selected from the group consisting of a bond, -NR³⁹-, -S-, -O-, -NR³⁹CH₂-. -NR³⁹CH₂CH₂-, -NR³⁹CH(R⁴⁰)-, -SCH₂-, -OCH₂-, -C(O)NR³⁹-, -S(O)₂NR³⁹-, -CH₂NR³⁹-, -CH(R⁴⁰)NR³⁹-, -NR³⁹C(O)-, and -NR³⁹S(O)₂-;</li><li>M₈ is selected from the group consisting of a bond, -CH₂-, -CH₂C(O)-, -S(O)₂-, -S(O)₂CH₂-, -S(O)₂CH(CH₃)-, -S(O)₂CH₂CH₂-, -S(O)₃NR³⁹-. -S(O)₂NR³⁹CH₂-, -S(O)₂NR³⁹CH(CH₃)-, -S(O)₂NR³⁹CH₂CH₂-, -C(O)-, -C(O)CH₂-, -C(O)CH(CH₃)-, -C(O)CH₂CH₂-, -C(O)NR³⁹-, -C(O)NR³⁹CH₂-, -C(O)NR³⁹CH(CH₃)-, and -C(O)NR³⁹CH₂CH₂-;</li><li>Q¹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR⁴¹, -SR⁴¹, -S(O)R⁴¹, -S(O)₂R⁴¹, -NHR⁴¹, -NR⁴¹R⁴¹, -NR³⁹C(O)R⁴¹, -NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q'or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH₂, -CN, -NO₂, -S(O)₂NH₂, -C(O)NH₂, -OR⁴², -SR⁴², -NHR⁴², -NR⁴²R⁴², -NR³⁹C(O)R⁴², -NR³⁹S(O)₂R⁴², -S(O)₂R⁴², halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;</li><li>Q¹¹, Q⁴¹, Q⁶¹, and Q¹⁴¹ are lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein lower alkyl is optionally substituted with one or more fluoro, lower alkoxy, or fluoro substituted lower alkoxy, and wherein cyclaolkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR⁴¹, -SR⁴¹, -S(O)R⁴¹, -S(O)₂R⁴¹, -NHR⁴¹, -NR⁴¹R⁴¹, -NR³⁹C(O)R⁴¹, -NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q¹¹, Q⁴¹, Q⁶¹, or Q¹⁴¹, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH₂, -CN, -NO₂, -S(O)₂NH₂, -C(O)NH₂, -OR⁴², -SR⁴², -NHR⁴², -NR⁴²R⁴², -NR³⁹C(O)R⁴², -NR³⁹S(O)₂R⁴², -S(O)₂R⁴², halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;</li><li>Q¹² is fluoro, chloro or -CF₃;</li><li>Q¹³ and Q¹⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl;</li><li>Q²², Q²⁴, Q⁵², and Q⁵⁴ are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR⁴⁴R⁴⁴, -OR⁴⁴, and -SR⁴⁴, provided, however, that at least one of Q²² and Q² and at least one of Q⁵² and Q⁵⁴ is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl;</li><li>Q⁷⁴ and Q¹⁵² are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR⁴⁴R⁴⁴, -OR⁴⁴, or -SR⁴⁴;</li><li>Q⁷² is hydrogen, lower alkyl or fluoro substituted lower alkyl;</li><li>R³⁹ at each occurrence is independently hydrogen or lower alkyl;</li><li>R⁴⁰ is lower alkyl or fluoro substituted lower alkyl;</li><li>R⁴¹ at each occurrence is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R⁴¹ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH₂, -CN, -NO₂, -S(O)₂NH₂, -C(O)NH₂, -OR⁴², -SR⁴², -NHR⁴², -NR⁴²R⁴², -NR³⁹C(O)R⁴², -NR³⁹S(O)₂R⁴², -S(O)₂R⁴², halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;</li><li>R⁴² at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy; and</li><li>each R⁴⁴ is independently hydrogen, lower alkyl or fluoro substituted lower alkyl;</li><li>provided, however, that the compound is not <chemistry id="chem0006" num="0006"><img file="EP2086972B1_D0006.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP2086972B1_D0007.tif" /></chemistry><chemistry id="chem0008" num="0008"><img file="EP2086972B1_D0008.tif" /></chemistry><chemistry id="chem0009" num="0009"><img file="EP2086972B1_D0009.tif" /></chemistry><chemistry id="chem0010" num="0010"><img file="EP2086972B1_D0010.tif" /></chemistry></li></ul>

0012In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula IIa, <chemistry id="chem0011" num="0011"><img file="EP2086972B1_D0011.tif" /></chemistry> all salts, prodrugs, tautomers, and isomers thereof, wherein: <ul id="ul0002" list-style="none" compact="compact"><li>Q^1a is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, and -OR⁴¹;</li><li>Q⁵ is hydrogen, -CN, -OR⁴¹, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, and -OR⁴¹; and</li><li>A₂, M₄, Q¹², Q¹³, Q¹⁴ and R⁴¹ are as defined for Formula II;</li><li>provided, however, that the compound is not <chemistry id="chem0012" num="0012"><img file="EP2086972B1_D0012.tif" /></chemistry></li></ul>

0013In one embodiment of compounds of Formula IIa, A₂ is -CH₂- and M₄ is -NHCH₂-. In one embodiment A₂ is -C(O)- and M₄ is -NHCH₂-. In one embodiment A₂ is -C(O)- and M₄ is -NHC(O)-. In one embodiment A₂ is -CH₂- and M₄ is -NHC(O)-.

0014In one embodiment of compounds of Formula IIa, A₂ is -CH₂-, M₄ is -NHCH₂-, Q⁵ is -OR⁴¹, -CN, C_1-3alkyl, fluoro substituted C_1-3alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q¹³ and Q¹⁴ are hydrogen.

0015In one embodiment of compounds of Formula IIa, A₂ is -C(O)-, M₄ is -NHCH₂-, Q⁵ is -OR⁴¹, -CN, C_1-3 alkyl, fluoro substituted C_1-3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q¹³ and Q¹⁴ are hydrogen.

0016In one embodiment of compounds of Formula IIa, A₂ is -C(O)-, M₄ is -NHC(O)-, Q⁵ is -OR⁴¹, -CN, C_1-3 alkyl, fluoro substituted C_1-3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q¹³ and Q¹⁴ are hydrogen.

0017In one embodiment of compounds of Formula IIa, A₂ is -CH₂-, M₄ is -NHC(O)-, Q⁵ is -OR⁴¹, -CN, C_1-3 alkyl, fluoro substituted C_1-3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q¹³ and Q¹⁴ are hydrogen.

0018In one embodiment, further to any of the embodiments of Formula IIa above, R⁴¹ is R⁴² as defined for Formula II.

0019In one embodiment, further to any of the embodiments of Formula IIa above, Q^1a is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with I or 2 substituents selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy; A₂ is -CH₂-; M₄ is -NHCH₂-; and Q⁵ is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. In one embodiment, further to any of the embodiments of Formula IIa above, Q^1a is phenyl mono substituted with chloro, preferably at the 4-position; A₂ is -CH₂-; M₄ is -NHCH₂-; and Q⁵ is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. In one embodiment, further to any of the embodiments of Formula IIa, Q^1a is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position; A₂ is -CH₂-; M₄ is -NHCH₂-; Q⁵ is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.

0020In one embodiment of compounds of Formula IIa, A₂ is -CH₂-; M₄ is -NHCH₂-; Q^1a is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy; Q⁵ is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CN, or 1-methyl-1H-pyrazole4-yl; Q¹² is fluoro or chloro; and Q¹³ and Q¹⁴ are hydrogen. In one embodiment, A₂ is -CH₂-; M₄ is -NHCH₂-; Q^1a is phenyl mono substituted with chloro, preferably at the 4-position; Q⁵ is hydrogen, chloro, methyl, methoxy, or -CN; Q¹² is fluoro or chloro; and Q¹³ and Q¹⁴ are hydrogen. In one embodiment, A₂ is -CH₂-; M₄ is -NHCH₂-; Q^1a is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position; Q⁵ is hydrogen, chloro, methyl, methoxy, -CN, or 1-methyl-1H-pyrazole-4-yl; Q¹² is fluoro or chloro; and Q¹³ and Q¹⁴ are hydrogen.

0021In one embodiment of compounds of Formula IIa, the compound is selected from the group consisting of: <ul id="ul0003" list-style="none" compact="compact"><li>(4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amine <b>(P-0132),</b></li><li>(4-Chloro-benyl)-[6-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0161),</li><li>[6-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0174),</b></li><li>[6-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0176),</b></li><li>{6-Chloro-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0179),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0186),</b></li><li>[6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0187),</b></li><li>[6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0188).</b></li><li>3-{2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0232).</b></li><li>[6-Chloro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl. pyridin-3-ylmethyl)-amine <b>(P-0233),</b></li><li>[6-Chloro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0234),</b></li><li>[6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmelhyl)-amine <b>(P-0378),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0379),</b></li><li>(5-Fluoro-pyridin-3-ylmethyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0414),</b></li><li>3-{2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0415)</b>,</li><li>3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0432),</b> and</li><li>all salts, prodrugs, tautomers, and isomers thereof.</li></ul>

0022In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula IIb, <chemistry id="chem0013" num="0013"><img file="EP2086972B1_D0013.tif" /></chemistry> all salts, prodrugs, tautomers, and isomers thereof, wherein: <ul id="ul0004" list-style="none" compact="compact"><li>A₃ is -CH₂- or -C(O)-;</li><li>Q¹⁵ is hydrogen, -CN, -OR⁴¹, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, and -OR⁴¹; and</li><li>M₅, Q¹¹, Q²², Q²⁴, and R⁴¹, are as defined for Formula II.</li></ul>

0023In one embodiment of compounds of Formula IIb, M₅ is -NR³⁹CH₂-, -NR³⁹CH(R⁴⁰)-, -NR³⁹CH₂CH₂-, or -NR³⁹C(O)-; A₃ is -CH₂- or -C(O)-, preferably -CH₂-; Q¹¹ is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; Q¹⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q²² and Q²⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen, fluoro, chloro, or -CF₃, more preferably both Q²² and Q²⁴ are hydrogen; wherein R⁴¹ is as defined for Formula II.

0024In one embodiment, further to any of the embodiments of Formula IIb above, R⁴¹ is R⁴² as defined for Formula II.

0025In one embodiment of compounds of Formula IIb, M₅ is -NHCH₂CH₂-, -NHCH₂--N(CH₃)CH₂-, or -NHCH(CH₃)-, preferably -NHCH₂-; A₃ is -CH₂-; Q¹¹ is cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, wherein phenyl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, di-alkylamino, and heterocycloalkyl; Q¹⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; and Q²² and Q²⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen, fluoro, chloro, or -CF₃, more preferably both Q²² and Q²⁴ are hydrogen.

0026In one embodiment of compounds of Formula IIb, M₅ is -NHCH₂-; A₃ is -CH₂-; Q¹¹ is phenyl substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q¹⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, preferably hydrogen or chloro; and Q²² and Q²⁴ are hydrogen.

0027In one embodiment of compounds of Formula IIb, the compound is selected from the group consisting of: <ul id="ul0005" list-style="none" compact="compact"><li>(4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0260),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine <b>(P-0261),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0262),</b></li><li>(2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0263),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-benzyl)-amine <b>(P-0264),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-amine <b>(P-0265),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine <b>(P-0266),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzyl)-amine <b>(P-0267),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-amine <b>(P-0268),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoromethylbenzyl)-amine <b>(P-0289),</b></li><li>(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0291),</b></li><li>(2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0292),</li><li>(2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0293),</b></li><li>(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0294),</b></li><li>(3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0295),</li><li>(2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0300),</li><li>(2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0301),</li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0302),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine <b>(P-0303),</b></li><li>(5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0304),</b></li><li>(2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0305),</li><li>(2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0306),</li><li>(4-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0307),</li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine <b>(P-0308),</b></li><li>(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0309),</b></li><li>(2,5-Dichloro-benzyl)-[5-(H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0310),</li><li>(3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0311),</b></li><li>(2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0312),</b></li><li>(2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0313),</li><li>(4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0314),</b></li><li>(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0315),</b></li><li>(2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0316),</b></li><li>(5-Chloro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0317),</b></li><li>(5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0318),</b></li><li>(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0319),</b></li><li>(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0320),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-amine <b>(P-0390),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethyl-benzyl)-amine <b>(P-0391),</b></li><li>(3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0392),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethylbenzyl)-amine <b>(P-0393),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethylbenzyl)-amine <b>(P-0394),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,3-difluoro-benzyl)-amine <b>(P-0395),</b></li><li>(2-Chloro-4-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0396),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine <b>(P-0402),</b></li><li>(2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0407),</b></li><li>(2-Chloro-5-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0408),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmethyl-amine <b>(P-0416).</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-pyrrolidin-1-yl-ethyl)-amine <b>(P-0417),</b></li><li>Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0418),</b></li><li>Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine <b>(P-0419),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-benzyl)-amine <b>(P-0420),</b></li><li>(3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0421),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine <b>(P-0422),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amine <b>(P-0423).</b></li><li>(3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methylamine <b>(P-0424),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3,5-difluoro-benzyl)-amine <b>(P-0425),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(2-fluoro-phenyl)-ethyl]-amine <b>(P-0426),</b></li><li>[1-(4-Chloro-phenyl)-ethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0427),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-1-(4-fluoro-phenyl)-ethyl]-amine <b>(P-0428),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0429),</b></li><li>(2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methylamine <b>(P-0430),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methyl-benzyl)-amine <b>(P-0431),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-amine <b>(P-0433),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine <b>(P-0434),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexylmethyl-amine <b>(P-0435),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-amine <b>(P-0436),</b></li><li>[2-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0437),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-benzyl)-amine <b>(P-0438),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methoxy-benzyl)-amine <b>(P-0439),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine <b>(P-0440),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-ethyl)-amine <b>(P-0441),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-amine <b>(P-0442),</b></li><li>(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0443),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-ethoxy-benzyl)-amine <b>(P-0444),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl)-amine <b>(P-0445),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)-amine <b>(P-0446),</b></li><li>(4-Chloro-3-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0447),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(3-fluoro-phenyl)-ethyl]-amine <b>(P-0448),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-benzyl)-amine <b>(P-0449),</b> and</li><li>all salts, prodrugs, tautomers, and isomers thereof.</li></ul>

0028In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula IIe, <chemistry id="chem0014" num="0014"><img file="EP2086972B1_D0014.tif" /></chemistry> all salts, prodrugs, tautomers, and isomers thereof, wherein: <ul id="ul0006" list-style="none" compact="compact"><li>A₆ is -CH₂- or -C(O)-;</li><li>M_8a is -CH₂-, -CH₂C(O)-, -C(O)NR³⁹CH₂-, -C(O)NR³⁹CH(R⁴⁰)-, or -C(O)NR³⁹CH₂CH₂-;</li><li>Q⁴⁵ is hydrogen, -CN, -OR⁴¹, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, and -OR⁴¹; and</li><li>Q⁴¹, Q⁵², Q⁵⁴, R³⁹, R⁴⁰, and R⁴¹ are as defined for Formula II;</li><li>provided, however, that the compound is not <chemistry id="chem0015" num="0015"><img file="EP2086972B1_D0015.tif" /></chemistry><chemistry id="chem0016" num="0016"><img file="EP2086972B1_D0016.tif" /></chemistry></li></ul>

0029In one embodiment of compounds of Formula IIe, M_8a is -C(O)NR³⁹CH₂-, -C(O)NR³⁹CH(CH₃)-, or -C(O)NR³⁹(CH₂)₂-; A₆ is -CH₂- or -C(O)-, preferably -CH₂-; Q⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; Q⁴⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q⁵² and Q⁵⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q⁵² and Q⁵⁴ are independently hydrogen, fluoro, chloro, methyl, or -CF₃; wherein R⁴¹ is as defined in Formula II.

0030In one embodiment, further to any of the embodiments of Formula IIe above, R⁴¹ is R⁴² as defined for Formula II.

0031In one embodiment of compounds of Formula IIe, M_8a is -C(O)NHCH₂-, -C(O)NHCH(CH₃)- or -C(O)NH(CH₂)₂-; A₆ is -CH₂- or -C(O)-, preferably -CH₂-; Q⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q⁴⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen or chloro; and Q⁵² and Q⁵⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q⁵² and Q⁵⁴ are methyl.

0032In one embodiment of compounds of Formula IIe, the compound is selected from the group consisting of: <ul id="ul0007" list-style="none" compact="compact"><li>3-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (P-0133),</li><li>2-[3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazol-1-yl]-1-phenyl-ethanone <b>(P-0134),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-methoxy-benzylamide <b>(P-0135),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-chloro-benzylamide <b>(P-0136),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-fluoro-benzylamide <b>(P-0137),</b></li><li>3-[3,5-Dimethyl-1-(5-trifluoromethyl-furan-2-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine <b>(P-0138),</b></li><li>3-[3,5-Dimethyl-1-(5-methyl-isoxazol-3-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine <b>(P-0139),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-chloro-benzylamide <b>(P-0140),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-amide <b>(P-0141),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 3-methoxy-benzylamide <b>(P-0142),</b></li><li>3-{3,5-Dimethyl-1-[4-methyl-2-(4-triftuoromethy)-phenyl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylmethyl}-1H-pyrrolo[2,3-b]pyridine <b>(P-0143),</b></li><li>3-[3,5-Dimethyl-1-(4-methyl-2-phenyl-thiazol-5-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine <b>(P-0144),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-methoxy-benzylamide <b>(P-0145),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(2,4-dichloro-phenyl)-ethyl]-amide <b>(P-0146),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(4-fluoro,-phenyl)-ethyl]-amide <b>(P-0147),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(2-fluorophenyl)-ethyl]-amide <b>(P-0148),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid ((S)-1-phenylethyl)-amide <b>(P-0149),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 3-fluoro-benzylamide <b>(P-0150),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-fluoro-benzylamide <b>(P-0151),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-methyl-benzylamide <b>(P-0152),</b></li><li>3,5-Dimethyl4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-methyl-benzylamide <b>(P-0153),</b></li><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide <b>(P-0157),</b></li><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid 4-fluoro-benzylamide <b>(P-0158),</b></li><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid 4-chloro-benzylamide <b>(P-0159),</b></li><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide <b>(P-0160)</b>, and</li><li>all salts, prodrugs, tautomers, and isomers thereof.</li></ul>

0033In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula IIg, <chemistry id="chem0017" num="0017"><img file="EP2086972B1_D0017.tif" /></chemistry> all salts, prodrugs, tautomers, and isomers thereof, wherein: <ul id="ul0008" list-style="none" compact="compact"><li>A₈ is -CH₂-, or -C(O)-;</li><li>Q⁶⁵ is hydrogen, -CN, -OR⁴¹, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, and -OR⁴¹; and</li><li>M₁₀, Q⁶¹, Q⁷², Q⁷⁴, and R⁴¹ are as defined for Formula II.</li></ul>

0034In one embodiment of compounds of Formula IIg, M₁₀ is -NR³⁹CH₂- or -NR³⁹-(CH₂)₂-; A₈ is -CH₂- or -C(O)-, preferably -CH₂-; Q⁶¹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; Q⁶⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q⁷⁴ is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R⁴¹ is as defined for Formula II.

0035In one embodiment, further to any of the embodiments of Formula IIg above, R⁴¹ is R⁴² as defined for Formula II.

0036In one embodiment of compounds of Formula IIg, M₁₀ is -NHCH₂-; A₈ is -CH₂-; Q⁶¹ is phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; Q⁶⁵ is hydrogen, fluoro, -CN, or 1-methyl-pyrazol-4-yl; Q⁷² is lower alkyl or fluoro substituted lower alkyl; and Q⁷⁴ is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, M₁₀ is -NHCH₂-; A₈ is -CH₂-; Q⁶¹ is 4-fluoro-phenyl; Q⁶⁵ is hydrogen, chloro, -CN, or 1-methyl-pyrazol-4-yl; Q⁷² is methyl or ethyl; and Q⁷⁴ is hydrogen or chloro.

0037In one embodiment, the compound of Formula IIg is selected from the group consisting of: <ul id="ul0009" list-style="none" compact="compact"><li>[1-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>(P-0165),</b></li><li>(4-Fluoro-benzyl)-[1-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-amine <b>(P-0169),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>(P-0170),</b></li><li>(4-Fluoro-benzyl)- {1-methyl-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-pyrazol-3-yl}-amine <b>(P-0180),</b></li><li>(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanone <b>(P-0184),</b></li><li>[5-(5-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>(P-0185),</b></li><li>3-[5-(4-Fluoro-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0191),</b></li><li>(3-Chloro-benzyl)-[5-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine <b>(P-0410),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2,5-difluoro-benzyl)-amine <b>(P-0411),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2-fluoro-benzyl)-amine <b>(P-0413),</b> and</li><li>all salts, prodrugs, tautomers, and isomers thereof.</li></ul>

0038In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula IIp, <chemistry id="chem0018" num="0018"><img file="EP2086972B1_D0018.tif" /></chemistry> all salts, prodrugs, tautomers, and isomers thereof, wherein: <ul id="ul0010" list-style="none" compact="compact"><li>A₁₆ is -CH₂- or -C(O)-;</li><li>Q¹⁴⁵ is hydrogen, -CN, -OR⁴¹, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, and -OR⁴¹;</li><li>Q¹⁵² is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and</li><li>M₁₈, Q¹⁴¹, and R⁴¹, are as defined for Formula II;</li><li>provided, however, that the compound is not <chemistry id="chem0019" num="0019"><img file="EP2086972B1_D0019.tif" /></chemistry> or <chemistry id="chem0020" num="0020"><img file="EP2086972B1_D0020.tif" /></chemistry></li></ul>

0039In one embodiment of compounds of Formula IIp, M₁₈ is -NR³⁹CH₂- or -NR³⁹-(CH₂)₂-; A₁₆ is -CH₂- or -C(O)-, preferably -CH₂-; Q¹⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; Q¹⁴⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and Q¹⁵² is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl; wherein R⁴¹ is as defined for Formula II.

0040In one embodiment of compounds of Formula IIp, M₁₈ is -NH-CH₂- or -NH-(CH₂)₂-, preferably -NH-CH₂-; A₁₆ is -CH₂- or -C(O)-, preferably -CH₂-; Q¹⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with I or 2 substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, and heterocycloalkyl; Q¹⁴⁵ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, -CN, or chloro; and Q¹⁵² is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen or chloro, more preferably chloro.

0041In one embodiment, the compound of Formula Ih is selected from the group consisting of [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine <b>(P-0156),</b> [4-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine (P-0162), (4-Fluoro-benzyl)-[4-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>(P-0163),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine <b>(P-0164),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine <b>(P-0167),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine <b>(P-0168),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine <b>(P-0171),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(1,5-dimethyl-1H-pyrazol-3-ylmethyl)-amine <b>(P-0172),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0173),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amine<b>(P-0175),</b> [2-(4-Fluoro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone <b>(P-0177),</b> {2-[(4-Chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0178), [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-thiazol-2-ylmethyl-amine <b>(P-0189),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0190),</b> Benzyl-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>(P-0192),</b> (4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-methoxy-benzyl)-amine <b>(P-0193),</b> (4-Chloro-benzyl)-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>(P-0194),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine <b>(P-0195),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine <b>(P-0196),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmcthyl)-amine <b>(P-0197),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-2H-pyrazol-3-ylmethyl)-amine <b>(P-0198),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2-ylmethyl)-amine <b>(P-0199),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-ylmethyl)-amine <b>(P-0200),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-thiazol-4-ylmethyl)-amine <b>(P-0201),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-methyl-thiazol-5-ylmethyl)-amine <b>(P-0202),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2-ylmethyl)-amine <b>(P-0203),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine <b>(P-0204),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amine <b>(P-0205),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine <b>(P-0206),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0207),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimethyl-thiophen-2-ylmethyl)-amine <b>(P-0208),</b> [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-thiophen-3-ylmethyl)-amine <b>(P-0209),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>(P-0231),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine <b>(P-0236),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine <b>(P-0237),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-chloro-pyridin-4-ylmethyl)-amine <b>(P-0238),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(1-ethyl-1H-pyrazol-4-ylmethyl)-amine <b>(P-0239),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine <b>(P-0240),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0241),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0242),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-fluorobenzyl)-amine <b>(P-0243),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-amine <b>(P-0244),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-difluoro-benzyl)-amine <b>(P-0245),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-benzyl)-amine <b>(P-0246),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0247),</b> (2-Chloro-benzyl)-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>(P-0248),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)-amine <b>(P-0249),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro-benzyl)-amine <b>(P-0250),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2-ylmethyl)-amine <b>(P-0251),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-morpholin-4-yl-pyridin-2-ylmethyl)-amine <b>(P-0252),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4-ylmethyl)-amine <b>(P-0253),</b> (4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0254),</b> [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine <b>(P-0255),</b> [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine <b>(P-0290),</b> and all salts, prodrugs, tautomers, and isomers thereof.

0042Subject matter of the present invention are compounds according to Formula III, wherein R⁸¹ is chloro, or a salt, tautomer or stereoisomer thereof.

0043Generally disclosed herein, however, are compounds of Formula III having the following structure: <chemistry id="chem0021" num="0021"><img file="EP2086972B1_D0021.tif" /></chemistry> all salts, prodrugs, tautomers, and isomers thereof, wherein: <ul id="ul0011" list-style="none" compact="compact"><li>L₄ is -CH₃-. -CH₂CH₂-, -CH(R⁴⁰)-, -C(O)- or -C(O)NH-;</li><li>R⁸¹ is selected from the group consisting of hydrogen, -OR⁴¹, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹;</li><li>R⁸² is selected from the group consisting of hydrogen, C_1-3 alkyl, fluoro substituted C_2-3 alkyl, OH, C_1-3 alkoxy, and fluoro substituted C_1-3 alkoxy;</li><li>R⁶³ is heterocycloalkyl, heteroaryl, or <chemistry id="chem0022" num="0022"><img file="EP2086972B1_D0022.tif" /></chemistry> in which <chemistry id="chem0023" num="0023"><img file="EP2086972B1_D0023.tif" /></chemistry> indicates the attachment point of R⁸³ to L₄ of Formula III, wherein heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹;</li><li>R⁹², R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHS(O)₂R⁴¹, -NHC(O)R⁴¹, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹; and</li><li>R⁴⁰, R⁴¹ and R⁴² are as defined for Formula II;</li><li>provided, however, that the compound is not <chemistry id="chem0024" num="0024"><img file="EP2086972B1_D0024.tif" /></chemistry><chemistry id="chem0025" num="0025"><img file="EP2086972B1_D0025.tif" /></chemistry><chemistry id="chem0026" num="0026"><img file="EP2086972B1_D0026.tif" /></chemistry><chemistry id="chem0027" num="0027"><img file="EP2086972B1_D0027.tif" /></chemistry><chemistry id="chem0028" num="0028"><img file="EP2086972B1_D0028.tif" /></chemistry><chemistry id="chem0029" num="0029"><img file="EP2086972B1_D0029.tif" /></chemistry><chemistry id="chem0030" num="0030"><img file="EP2086972B1_D0030.tif" /></chemistry><chemistry id="chem0031" num="0031"><img file="EP2086972B1_D0031.tif" /></chemistry><chemistry id="chem0032" num="0032"><img file="EP2086972B1_D0032.tif" /></chemistry><chemistry id="chem0033" num="0033"><img file="EP2086972B1_D0033.tif" /></chemistry><chemistry id="chem0034" num="0034"><img file="EP2086972B1_D0034.tif" /></chemistry></li></ul>

0044In one embodiment of compounds of Formula III, L₄ is -CH₂-, -CH₂CH₂-, -CH(CH₃)- or -C(O)-; R⁸¹ is hydrogen, fluoro, chloro, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; R⁸² is hydrogen; R⁸³ is <chemistry id="chem0035" num="0035"><img file="EP2086972B1_D0035.tif" /></chemistry> wherein R⁹², R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are independently hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that when R⁹⁴ is fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, at least one of R⁹², R⁹³, R⁹⁵, and R⁹⁶ is fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.

0045In one embodiment of compounds of Formula III, L₄ is -CH₂-, -CH₂CH₂-, -CH(CH₃)- or -C(O)-; R⁸¹ is hydrogen, fluoro, chloro, -CN, methyl, or methoxy, preferably hydrogen, chloro, -CN, or methyl; R⁸² is hydrogen; R⁸³ is <chemistry id="chem0036" num="0036"><img file="EP2086972B1_D0036.tif" /></chemistry> wherein R⁹², R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are independently hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy, preferably hydrogen, chloro, methyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy, provided, however, that when R⁹⁴ is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy, at least one of R⁹², R⁹³, R⁹⁵, and R⁹⁶ is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

0046In one embodiment of compounds of Formula III, L₄ is -CH₂-; R⁸¹ is fluoro, chloro, -CN, methyl, or methoxy, preferably chloro, -CN, or methyl; R⁸² is hydrogen; R⁸³ is <chemistry id="chem0037" num="0037"><img file="EP2086972B1_D0037.tif" /></chemistry> wherein R⁹⁴ is hydrogen and R⁹², R⁹³, R⁹⁵, and R⁹⁶ are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

0047In one embodiment of compounds of Formula III, L₄ is -CH₂-, -CH₂CH₂-, -C(O)-, or -CH(CH₃)-, preferably -CH₂- or -C(O)-; R⁸¹ is hydrogen or flouro; R⁸² is hydrogen; R⁸³ is <chemistry id="chem0038" num="0038"><img file="EP2086972B1_D0038.tif" /></chemistry> wherein R⁹² is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methyl, or trifluoromethyl, and R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, preferably hydrogen or fluoro. In one embodiment, L₄ is -CH₂-, -C(O)-, or -CH(CH₃)-; R⁸¹ is hydrogen; R⁸² is hydrogen; R⁹² is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl; and R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are hydrogen. In one embodiment, L₄ is -CH₂-, -C(O)-, or -CH(CH₃)-; R⁸¹ is hydrogen; R⁸² is hydrogen; R⁹² is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl; R⁹⁴, R⁹⁵, and R⁹⁶ are hydrogen; and R⁹³ is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, trifluoromethyl or methoxy, more preferably fluoro. In one embodiment, L₄ is -CH₂-, -C(O)-, or -CH(CH₃)-; R⁸¹ is hydrogen; R⁸² is hydrogen; R⁹² is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl; R⁹³, R⁹⁵, and R⁹⁶ are hydrogen; and R⁹⁴ is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methyl or trifluoromethyl, more preferably fluoro. In one embodiment, L₄ is -CH₂CH₂- or -C(O)-; R⁸¹ is hydrogen; R⁸² is hydrogen; R⁹², R⁹⁵, and R⁹⁶ are hydrogen; R⁹³ is hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, more preferably fluoro, chloro, trifluoromethyl or methoxy; and R⁹⁴ is hydrogen, fluoro, or chloro; provided, however, that when L₄ is -C(O)- and R⁹⁴ is fluoro or chloro, R⁹³ is not hydrogen. In one embodiment, L₄ is -CH₂CH₂-; R⁸¹ is hydrogen; R⁸² is hydrogen; R⁹², R⁹⁴, R⁹³, and R⁹⁶ are hydrogen; and R⁹³ is hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro. In one embodiment, L₄ is -C(O)-; R⁸¹ is hydrogen; R⁸² is hydrogen; R⁹², R⁹⁵, and R⁹⁶ are hydrogen; R⁹³ is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, trifluoromethyl or methoxy, and R⁹⁴ is hydrogen, fluoro, or chloro.

0048In one embodiment of compounds of Formula III, R⁸³ is pyrrolidine, morpholine, pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazol, or benzimidazole, wherein R⁸³ is optionally substituted with one or more substituents independently selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR⁴¹, -NR⁴¹R⁴¹, -OR⁴¹ and -S(O)₂R⁴¹, preferably wherein R⁸³ is optionally substituted with 1 or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino, more preferably fluoro, chloro, methyl, trifluoromethyl, methoxy or morpholine.

0049In one embodiment of compounds of Formula III, L₄ is -CH₂-, -CH₂CH₂-, -CH(CH₃)- or -C(O)-, preferably -CH₂-, -CH₂CH₂-, or -C(O)-; R⁸¹ is hydrogen, fluoro, chloro, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, chloro, methyl or -CN; R⁸² is hydrogen; and R⁸³ is pyrrolidine, morpholine, pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazole, or benzimidazole, wherein R⁸³ is optionally substituted with 1 or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino, preferably fluoro, chloro, methyl, trifluoromethyl, methoxy or morpholine.

0050In one embodiment of compounds of Formula III, the compound is selected from the group consisting of: <ul id="ul0012" list-style="none" compact="compact"><li>Pyridin-3-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0094),</li><li>(5-Methyl-isoxazol-3-ylmelhyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0095),</b></li><li>(2-Pyrrolidin-1-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0096),</li><li>[1-(4-Methanesulfonyl-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0097),</b></li><li>(2-Morpholin-4-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0099),</b></li><li>3,4-Dichloro-N-(5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0100),</b></li><li>2-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0101),</b></li><li>2.5-Dimethy)-2H-pyrazole-3-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0102),</b></li><li>Thiophene-2-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0103),</b></li><li>2-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide <b>(P-0104),</b></li><li>N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide <b>(P-0105),</b></li><li>Pyrazine-2-carboxylic acid [5-(1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0106),</b></li><li>Pyridine-2-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0107),</b></li><li>6-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-nicotinamide <b>(P-0108),</b></li><li>4-Fluoro-3-methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0109),</b></li><li>5-Methyl-pyrazine-2-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl)-amide <b>(P-0110),</b></li><li>3-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0111),</b></li><li>4-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide <b>(P-0112),</b></li><li>N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethoxy-benzamide <b>(P-0113),</b></li><li>N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide <b>(P-0114),</b></li><li>3-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0115),</b></li><li>3,4-Difluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0116),</b></li><li>2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0117),</b></li><li>5-Fluoro-2-methyl-N-(5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0118),</b></li><li>2-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0119),</b></li><li>3-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0120),</b></li><li>3-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0121),</b></li><li>3-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0122),</b></li><li>2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide <b>(P-0123),</b></li><li>((R)-1-Phenyl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0125),</b></li><li>(3-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl)-amine <b>(P-0126),</b></li><li>[1-(2-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0127),</b></li><li>[2-(3-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0128),</b></li><li>(3-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0129),</b></li><li>(1-Methyl-1H-imidazol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0130),</b></li><li>(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0131),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0181),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0182),</b></li><li>(3-Chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0183),</b></li><li>(2-Chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0210),</b></li><li>Phenethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0211),</b></li><li>(2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0212),</b></li><li>(2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0213),</b></li><li>(3-Bromo-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0214),</b></li><li>(2-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0215),</b></li><li>(2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0216),</b></li><li>(2-Methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0217),</b></li><li>(1-Methyl-1H-benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0218),</b></li><li>(6-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0219),</b></li><li>(1H-Benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0220),</b></li><li>(2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0221),</b></li><li>(5-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0222),</b></li><li>(3-Fluoro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0223),</b></li><li>(6-Methoxy-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0224),</b></li><li>(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc <b>(P-0225),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl)-(2-trifluoromethyl-benzyl)-amine <b>(P-0226),</b></li><li>(3,5-Dichloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0227),</b></li><li>(6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0228),</b></li><li>(3-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0229),</b></li><li>(5-Fluoro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0230),</b></li><li>(3-Chloro-pyridin4-ylmethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0235),</b></li><li>3-{6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0256),</b></li><li>3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0257),</b></li><li>Propane-1-sulfonic acid (2,4-difluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide <b>(P-0258),</b></li><li>Propane-1-sulfonic acid (3-{[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-2,4-difluoro-phenyl)-amide <b>(P-0259),</b></li><li>3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0269),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine <b>(P-0270),</b></li><li>3-[6-(2-Fluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0271),</b></li><li>(2-Fluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0272),</b></li><li>3-{6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0273),</b></li><li>3-[6-(2-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0274),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0275),</b></li><li>[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0276),</b></li><li>3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0277),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine <b>(P-0278),</b></li><li>(2-Chloro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0279),</b></li><li>(2-Chlotro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0280),</b></li><li>3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0281),</b></li><li>(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0282),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0283),</b></li><li>3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0284),</b></li><li>(2-Metboxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0285),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0286),</b></li><li>3-{6-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0287),</b></li><li>(2-Ethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0288),</b></li><li>(2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0296),</b></li><li>(2,5-Difluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0297),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,5-difluoro-benzyl)-amine <b>(P-0298),</b></li><li>3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0299),</b></li><li>3-[6-(2-Trifluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0321),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethoxy-benzyl)-amine <b>(P-0322),</b></li><li>3-[6-(2-Ethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0323),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>(P-0324),</b></li><li>[5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0325),</b></li><li>[5-(5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0326),</b></li><li>(2-Chloro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0327),</b></li><li>(2-Chloro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0328),</b></li><li>(2,5-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0329),</b></li><li>(2,5-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0330),</b></li><li>[5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0331),</b></li><li>(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0332),</b></li><li>(2,6-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0333),</b></li><li>(2,6-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0334),</b></li><li>(2-Methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0336),</b></li><li>3-[6-(2-Methoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0337),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-difluoromethoxy-benzyl)-aminc <b>(P-0338),</b></li><li>3-[6-(2-Difluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0339),</b></li><li>(2,6-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0340),</b></li><li>(2,6-Difluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0341),</b></li><li>(2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0342),</b></li><li>(3-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0343),</b></li><li>(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0344),</b></li><li>(4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0345),</b></li><li>(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0346),</b></li><li>(2-Morpholin-4-yl-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0347),</b></li><li>(4-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0348),</b></li><li>(2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0349),</b></li><li>(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0350),</b></li><li>(2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0351),</b></li><li>(2-Fluoro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0352),</b></li><li>Dimethyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine <b>(P-0353),</b></li><li>(3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl)-amine <b>(P-0354),</b></li><li>(5-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0355),</b></li><li>(3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0356),</b></li><li>(2-Propoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0357),</b></li><li>(2-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0358),</b></li><li>(2-Chloro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0359),</b></li><li>(2-Fluoro-6-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0360),</b></li><li>[2-(2-Morpholin-4-yl-ethoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0361),</b></li><li>(2,3-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0362),</li><li>(2-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0363),</b></li><li>(2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0364),</b></li><li>(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0365),</b></li><li>(5-Fluoro-2-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0366),</b></li><li>(2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0367),</b></li><li>(2-Fluoro-4-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0368),</b></li><li>[2-(3-Dimethylamino-propoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0369),</b></li><li>(2,6-Dimethoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0370),</b></li><li>(2-Fluoro-5-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0371</b>),</li><li>(4-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0372),</b></li><li>(3-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0373),</b></li><li>(6-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0374),</b></li><li>(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0375),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine <b>(P-0376),</b></li><li>Propane-1-sulfonic acid (2-fluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide <b>(P-0377),</b></li><li>(2,5-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0380),</b></li><li>Pyrimidin-5-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0381),</b></li><li>(5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0382),</b></li><li>(2-Ethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0383),</b></li><li>2,2-Dimethyl-N-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-propionamide <b>(P-0384),</b></li><li>Methyl-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine <b>(P-0385),</b></li><li>Methyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine <b>(P-0386),</b></li><li>(2-Chloro-4-methanesulfonyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0387),</b></li><li><b>Possibly to be added (P-0388),</b></li><li>(5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0397),</b></li><li>Dimethyl-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine <b>(P-0399),</b></li><li>(5-Chloro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0400),</b></li><li>(2-Methoxy-pyrimidin-5-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0401),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine <b>(P-0409),</b></li><li>1-(3-Fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea <b>(P-0412),</b> and all salts, prodrugs, tautomers, and isomers thereof.</li></ul>

0051In one embodiment, a compound is: <ul id="ul0013" list-style="none" compact="compact"><li>(4-Chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amine <b>(P-0092),</b></li><li>(4-Morpholin-4-ylmethyl-benzyl)-[5-(1H-pyrrolo[2,3,b]pyridin-3-ylmethyl)-pyridin-2-yl]-mine <b>(P-0093),</b></li><li>(2-Methoxy-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0098),</li><li>[4-Chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amine <b>(P-0166),</b></li><li>((2,2-Difluoro-benzo[1,3]dioxol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0398);</b> or</li><li>any salts, prodrugs, tautomers, and isomers thereof.</li></ul>

0052In certain embodiments of the above compounds, compounds are excluded where N (except where N is a heteroaryl ring atom), O, or S is bound to a carbon that is also bound to N (except where N is a heteroaryl ring atom), O, or S, except where the carbon forms a double bond with one of the heteroatoms, such as in an amide, carboxylic acid, and the like; or where N (except where N is a heteroaryl ring atom), O, C(S), C(O), or S(O)_n (n is 0-2) is bound to an alkene carbon of an alkenyl group or bound to an alkyne carbon of an alkynyl group; accordingly, in certain embodiments compounds which include linkages such as the following are excluded: -NR-CH₂-NR-, -O-CH₂-NR-, -S-CH₂-NR-, -NR-CH₂-O-, -O-CH₂-O-, -S-CH₂-O-,-NR-CH₂-S-, -O-CH₂-S-, -S-CH₂-S-, -NR-CH=CH-, -CH=CH-NR-, -NR-C ≡C-, -C≡C-NR-, -O-CH=CH-, -CH=CH-O-, -O-C≡C-, -C ≡C-O-, -S(O)_0-2-CH=CH-, -CH=CH-S(O)_0-2-, -S(O)_0-2-C ≡C-, -C ≡C-S(O)_0-2-, -C(O)-CH=CH-, -CH=CH-C(O)-, -C ≡C-C(O)-, or -C(O)-C ≡C-, -C(S)-CH=CH-, -CH=CH-C(S)-, -C≡C-C(S)-, or -C(S)-C≡C-,

0053In reference to compounds herein, specification of a compound or group of compounds includes pharmaceutically acceptable salts of such compound(s), and all stereoisomers, unless clearly indicated to the contrary. In reference to compounds of Formula <b>II,</b> it is understood that such reference includes compounds of Formulae IIa, IIb, IIe, IIg and IIp, and all sub-embodiments thereof.

0054In another aspect, the invention provides compounds and compositions for use in methods of treating a c-kit-mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal c-kit activity (e.g. kinase activity). Invention uses involve administering to the subject suffering from or at risk of a c-kit-mediated disease or condition an effective amount of a compound of Formula II or Formula III, and all sub-embodiments thereof. The c-kit mediated disease is selected from the group consisting of malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myclocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.

0055In a related aspect, compounds of Formula II or Formula III, and all sub-embodiments thereof, can be used in the preparation of a medicament for the treatment of a c-kit-mediated disease or condition selected from the group consisting of malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic lcukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.

0056In a further aspect, the invention provides compounds and compositions for use in methods of treating a c-fms-mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal c-fms activity (e.g. kinase activity). Invention uses involve administering to the subject suffering from or at risk of a c-fms-mediated disease or condition an effective amount of compound of Formula II or Formula III, and all sub-embodiments thereof. In one embodiment, the c-fms mediated disease is selected from the group consisting of immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection; inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative colitis. Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure, mineralization and bone formation and resorption, including osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, and metastasis of cancer to bone; kidney and genitourinary diseases, including endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the central nervous system, including multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease; inflammatory and chronic pain, including bone pain; and cancers, including multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis.

0057In a related aspect, compounds of Formula <b>II</b> or Formula III, and all sub-embodiments thereof, can be used in the preparation of a medicament for the treatment of a c-fms-mediated disease or condition selected from the group consisting of immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection; inflammatory diseases including osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure, mineralization and bone formation and resorption, including osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), peri-prosthelic or wear-debris-mediated osteolysis, and metastasis of cancer to bone; kidney and genitourinary diseases, including endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the central nervous system, including multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease; inflammatory and chronic pain, including bone pain; and cancers, including multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis.

0058In a further aspect, the invention provides compounds and compositions for use in methods of treating, in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), a disease or condition mediated by c-fms and c-kit, e.g., a disease or condition characterized by abnormal c-fms activity and c-kit activity (e.g. kinase activity). Invention uses involve administering to the subject suffering from or at risk of a disease or condition mediated by c-fms and c-kit an effective amount of compound of Formula II or Formula III, and all sub-embodiments thereof. In one embodiment, the condition mediated by c-fms and c-kit is selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors, metastasis of cancer to bone or other tissues, chronic myeloproliferative diseases such as myelofibrosis, renal hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. ostcomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, endometriosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease, Parkinson's disease, inflammatory pain, chronic pain, and bone pain.

0059In a related aspect, compounds of Formula II or Formula III, and all sub-embodiments thereof, can be used in the preparation of a medicament for the treatment of a disease or condition mediated by c-fms and c-kit selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors, metastasis of cancer to bone or other tissues, chronic myeloproliferative diseases such as myelofibrosis, renal hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosinophilia, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, endometriosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease, Parkinson's disease, inflammatory pain, chronic pain, and bone pain.

0060In particular embodiments, the compound has an IC₅₀ of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay. In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on Ret, PDGF, or both Ret and PDGF. In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on c-fms. In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-fms than on c-kit. In certain embodiments, the compound has in combination each pairing of activity (e.g. IC₅₀) and/or selectivity as specified in this paragraph.

0061In particular embodiments, the compound has an IC₅₀ of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinase activity. In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit, c-fms, or both c-kit and c-fms than on Ref, PDGF, or both Ret and PDGF.

0062In particular embodiments, the compound has an IC₅₀ of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinase activity, and further has an IC₅₀ of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for at least one of HGK, TrkA, or TrkB kinase activity.

0063An additional aspect of this invention relates to compositions that include a therapeutically effective amount of a compound of Formula II or Formula III and all sub-embodiments thereof and at least one pharmaceutically acceptable carrier, excipient, and/or diluent, including combinations of any two or more compounds of Formula II or Formula III. The composition can further include one or more different pharmacologically active compounds, which can include one or more compounds of Formula II or Formula III.

0064In one aspect, the invention provides for treating a cancer by administering to the subject an effective amount of a composition including a compound of Formula II or Formula III, in combination with one or more other therapies or medical procedures effective in treating the cancer. Other therapies or medical procedures include suitable anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant). In one aspect, the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g. x-ray, γ-ray, or electron, proton, neutron, or α particle beam), hyperthermia heating (e.g. microwave, ultrasound, radiofrequency ablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g. aminolevulinic acid, motexafin lutetium), surgery, and bone marrow and stem cell transplantation.

0065In one aspect, the invention provides for treating a cancer by administering to the subject an effective amount of a composition including a compound of Formula II or Formula III, in combination with one or more suitable chemotherapeutic agents. In one aspect, the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; an antibiotic, including, but not limited to, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; an antimetabolite, including, but not limited to, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; a hormone or hormone antagonist, including, but not limited to, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including, but not limited to, DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; a retinoid, including, but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid, including, but not limited to, etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; an antiangiogenic agent, including, but not limited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a topoisomerase inhibitor, including, but not limited to, amsacrine, edotecarin, exatecan, irinotecan (also active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan, and 9-aminocamptothecin; a kinase inhibitor, including, but not limited to, erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate; AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), and vatalanib; a targeted signal transduction inhibitor including, but not limited to bortezomib, geldanamycin, and rapamycin; a biological response modifier, including, but not limited to, imiquimod, interferon-α, and interleukin-2; and other chemotherapeutics, including, but not limited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone). aminoglutethimide, asparaginase, bryostatin-1, cilengitide, E7389, ixabepilone, procarbazine, sulindac, temsirolimus, tipifarnib. Preferably, the method of treating a cancer involves administering to the subject an effective amount of a composition of Formula II, Formula III or Formula IV in combination with a chemotherapeutic agent selected from 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, or erlotinib.

0066In another aspect, the invention provides for treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of a compound of Formula II or Formula III<b>,</b> a prodrug of such compound, or a pharmaceutically acceptable salt of such compound. The compound can be alone or can be part of a composition.

0067In a related aspect, the invention provides kits that include a composition as described herein. In particular embodiments, the composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the composition is approved by the U.S. Food and Drug Administration or similar regulatory agency for administration to a mammal, e.g., a human; the composition is approved for administration to a mammal, e.g., a human, for a c-kit- and/or c-fms-mediated disease or condition; the kit of the invention includes written instructions on use and/or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a c-kit- and/or c-fms-mediated disease or condition; the composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.

0068In another aspect, the present invention also provides for modulating c-kit or c-fms activity by contacting c-kit or c-fms with an effective amount of a compound of Formula <b>II</b> or Formula III and all sub-embodiments thereof active on c-kit and/or c-fms (such as compounds developed using methods described herein). The compound is preferably provided at a level sufficient to modulate the activity of the c-kit or c-fms by at least 10%, more preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater than 90%. In many embodiments, the compound will be at a concentration of about 1 µM, 100 µM, or 1 mM, or in a range of 1-100 nM, 100-500 nM, 500-1000 nM, 1-100 µM, 100-500 µM, or 500-1000 µM. In particular embodiments, the contacting is carried out <i>in vitro.</i>

0069Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims.

DETAILED

DESCRIPTION OF THE PREFERRED

EMBODIMENTS

0070As used herein the following definitions apply:

0071"Halo" and "halogen" refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).

0072"Hydroxyl" and "hydroxy" refer to the group -OH.

0073"Thiol" refers to the group -SH.

0074"Lower alkyl" alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. "Optionally substituted lower alkyl" denotes lower alkyl that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound. For example "fluoro substituted lower alkyl" denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as - OR, -NHR, -C(O)NHR, and the like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any -O-, -S-, or -N- of the moiety (except where -N- is a heteroaryl ring atom) excludes substituents that would result in any -O-, -S-, or -N- of the substituent (except where -N- is a heteroaryl ring atom) being bound to the alkyl carbon bound to any -O-, -S-, or -N-of the moiety.

0075"Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. A "substituted cycloalkyl" is a cycloalkyl that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound.

0076"Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from I to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which one of the ring carbons is oxo substituted, i.e. the ring carbon is a carbonyl group, such as lactones and lactams. The point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. A "substituted heterocycloalkyl" is a heterocycloalkyl that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound.

0077"Aryl" alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members. A "substituted aryl" is an aryl that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound.

0078"Heteroaryl" alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, and indolyl. "Nitrogen containing heteroaryl" refers to heteroaryl wherein any heteroatoms are N. A "substituted heteroaryl" is a heteroaryl that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound.

0079"Lower alkoxy" denotes the group -OR^z, where R^z is lower alkyl. "Substituted lower alkoxy" denotes lower alkoxy in which R^z is lower alkyl substituted with one or more substituents as indicated herein attached at any available atom to produce a stable compound. Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example "fluoro substituted lower alkoxy" denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkoxy are attached at any available atom to produce a stable compound, substitution of alkoxy is such that -O-, -S-, or -N- (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy -O-. Further, where alkoxy is described as a substituent of another moiety, the alkoxy oxygen is not bound to a carbon atom that is bound to an -0-, -S-, or -N- of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.

0080"Lower alkylthio" denotes the group -SR^aa, where R^aa is lower alkyl. "Substituted lower alkylthio" denotes lower alkylthio in which R^aa is lower alkyl substituted with one or more substituents as indicated herein attached at any available atom to produce a stable compound. Preferably, substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example "fluoro substituted lower alkylthio" denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkylthio are attached at any available atom to produce a stable compound, substitution of alkylthio is such that -O-, -S-, or -N- (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkylthio -S-. Further, where alkylthio is described as a substituent of another moiety, the alkylthio sulfur is not bound to a carbon atom that is bound to an -0-, -S-, or -N- of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.

0081"Mono-alkylamino" denotes the group -NHR^bb where R^bb is lower alkyl. "Di-alkylamino" denotes the group -NR^bbR^cc, where R^bb and R^cc are independently lower alkyl. "Cycloalkylamino" denotes the group -NR^ddR^ee, where R^dd and R^cc combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as -0-, -N-, or -S-, and may also be further substituted with lower alkyl. Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. While it is understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on other moieties that are attached at any available atom to produce a stable compound, the nitrogen of mono-alkylamino, di-alkylamino, or cycloalkylamino as substituents is not bound to a carbon atom that is bound to an -O-, -S-, or -N- of the other moiety.

0082As used herein, the term c-kit-mediated disease or condition refers to a disease or condition in which the biological function of c-kit affects the development and/or course of the disease or condition, and/or in which modulation of c-kit alters the development, course, and/or symptoms. For example, mutations in the c-kit gene such as the W42, Wv, and W41 mutations reported by <nplcit id="ncit0011" npl-type="s"><text>Herbst et al al (J. Biol. Chem., 1992, 267: 13210-13216</text></nplcit>) confer severe, intermediate, and mild phenotypic characteristics, respectively. These mutations attenuate the intrinsic tyrosine kinase activity of the receptor to different degrees and are models for the effect of modulation of c-kit activity. A c-kit mediated disease or condition includes a disease or condition for which c-kit inhibition provides a therapeutic benefit, e.g. wherein treatment with c-kit inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.

0083As used herein, the term c-fms-mediated disease or condition refers to a disease or condition in which the biological function of c-fms affects the development and/or course of the disease or condition, and/or in which modulation of c-fms alters the development, course, and/or symptoms. For example, the <i>Csflr^-</i>/<i>Csflr^-</i> mutant mouse of<nplcit id="ncit0012" npl-type="s"><text> Dai et al (Blood, 2002, 99: 111-120</text></nplcit>) which lacks c-fms is an animal model for diseases or conditions wherein c-fms activity has been abolished. A c-fms mediated disease or condition includes a disease or condition for which c-fms inhibition provides a therapeutic benefit, e.g. wherein treatment with c-fms inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.

0084As used herein, the term "composition" refers to a formulation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

0085The term "pharmaceutically acceptable" indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles.

0086In the present context, the terms "therapeutically effective" and "effective amount" indicate that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.

0087As used herein, the term "modulating" or "modulate" refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as c-kit or c-fms. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, <i>e.g.,</i> an enzyme.

0088The term "c-kit activity" refers to a biological activity of c-kit, particularly including kinase activity. The term "c-fms activity" refers to a biological activity of c-fms, particularly including kinase activity.

I. General

0089In one aspect, the present invention concerns compounds of Formula III, wherein R⁸¹ is chloro and all sub-embodiments thereof, that are inhibitors of c-kit, c-fms, or both c-kit and c-fms, and the use of the compounds in treating diseases that are mediated by c-kit, c-fms, or both c-kit and c-fms.

Exemplary Diseases Associated with c-Kit.

0090The compounds described herein are useful for treating disorders related to c-kit e.g., diseases related to unregulated kinase signal transduction, including cell proliferative disorders, fibrotic disorders and metabolic disorders, among others. As described in more detail below and in <patcit id="pcit0003" dnum="US20040002534A"><text>Lipson ct al., U.S. 20040002534 </text></patcit>(<patcit id="pcit0004" dnum="US60086803A" dnum-type="L"><text>U.S. application 10/600, 868, filed June 23, 2003</text></patcit>), cell proliferative disorders which can be treated by the present invention include cancers, and mast cell proliferative disorders.

0091The presence of c-kit has also been associated with a number of different types of cancers. In addition, the association between abnormalities in c-kit and disease are not restricted to cancer. As such, c-kit has been associated with malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.

Exemplary diseases associated with c-fms

0092The presence of c-fms has been associated with a number of different types of diseases. As such, c-fms has been associated with immune disorders, including, but not limited to, rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection; inflammatory diseases including, but not limited to, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g., osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis, and metastasis of cancer to bone; kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g. diapetic nephropathy), and renal hypertrophy; disorders of the central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease; inflammatory and chronic pain, including, but not limited to, bone pain; and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis.

Exemplary diseases associated with TrkA and TrkB

0093<b><u>TrkA:</u></b> Target kinase TrkA (i.e., <u>neurotrophic tyrosine kinase, receptor, type 1)</u> is a 140 kDa tyrosine kinase encoded by chromosome 1q21-q22 (symbol: NTRK1). TrkA inhibitors may be useful in treating pain (e.g. chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lung cancer, myeloid leukemia, pancreatic cancer), arthritis, allergic disorders (e.g. asthma), diabetic retinopathy, macular degeneration and psoriasis.

0094<b><u>TrkB:</u></b> Target kinase <b>TrkB</b> (i.e., <u>neurotrophic tyrosine kinase, receptor, type 2</u>) is a 145 kDa tyrosine kinase encoded by chromosome 9q22.1 (symbol: NTRK2). TrkB inhibitors may be useful in treating various cancers and their metastases (e.g. prostate cancer, lung cancer, Wilm's tumors, neuroblastoma, and pancreatic cancer), and various neuropathies (e.g. stroke, multiple sclerosis, transverse myelitis, and encephalitis).

Exemplary diseases associated with HGK

0095<b><u>HGK</u>:</b> Target kinase <b>HGK</b> (i.e., Hematopoietic progenitor kinase/Geminal center kinase-like Kinase, aka mitogen-activated protein kinase kinase kinase kinase 4) is a 130 kDa scrine/threonine kinase encoded by chromosome 2q11.2-q12 (symbol: MAP4K4). HGK inhibitors may be useful in treating metabolic indications, including re-sensitizing fat and muscle cells to insulin, ameliorating the pathology in adipocytes, ameliorating the pathology in muscle cells, and type II diabetes; a broad range of oncology indications, including blocking the migration, invasion and metastasis in many different tumor types; and T-cell mediated autoimmune diseases.

V. Organic Synthetic Techniques

0096A wide array of organic synthetic techniques exist in the art to meet the challenge of constructing potential modulators. Many of these organic synthetic methods are described in detail in standard reference sources utilized by those skilled in the art. One example of suh a reference is <nplcit id="ncit0013" npl-type="b"><text>March, 1994, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, New York, McGraw Hill</text></nplcit>. Thus, the techniques useful to synthesize a potential modulator of kinase function are readily available to those skilled in the art of organic chemical synthesis.

VI. Alternative Compound Forms or Derivatives

0097Alternative forms or derivatives, such as (a) Isomers, Prodrugs, and Active Metabolites (b) Tautomers, Stereoisomers, Regioisomers, and Solvated Forms (c) Prodrugs and Metabolites (d) Pharmaceutically acceptable salts and (e) Polymorphic forms, are described, for example, in US Patent Application Publication number <patcit id="pcit0005" dnum="US20070032519A"><text>US 2007/0032519</text></patcit>.

VII. Administration

0098The methods and compounds will typically be used in therapy for human subjects. However, they may also be used to treat similar or identical indications in other animal subjects. In this context, the terms "subject," "animal subject," and the like refer to human and non-human vertebrates, e.g. mammals, such as non-human primates, sports and commercial animals, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines. A description of possible methods and routes of administration may be found, for example, in US Patent Application Publication number <patcit id="pcit0006" dnum="US20070032519A"><text>US 2007/0032519</text></patcit>.

EXAMPLES

0099A number of examples, both illustrative of and not according to the present invention are described below. In most cases, alternative techniques could also be used. The examples are intended to be illustrative. Unless specifically noted to the contrary, in cases where a compound number is not proceeded by a "P-" (e.g., "P-0001") in the Examples section, compound naming and/or enumeration is not related to naming and/or enumeration employed in other sections of this application. Similarly, structure and substituent naming and enumeration within the Examples are independent of structure and substituent naming and enumeration in above sections of this application unless clearly indicated otherwise.

0100In the following Examples, it is understood that the solvents and reagents used or suggested are not limiting, and can be substituted appropriately with solvents and reagents known to those of skill in the art. Reaction products may be isolated by means known in the art, such as extraction with a suitable solvent, precipitation from a suitable solvent, chromatography using a suitable solvent system, including silica gel column chromatography, HPLC, preparative TLC, and the like. Exemplary methods for synthesis of compounds of the present invention may be found in US Patent Application Publication number <patcit id="pcit0007" dnum="US20070032519A"><text>US 2007/0032519</text></patcit>. The 1H-pyrrolo[2,3-b]pyridine core of compounds described in the <b>examples may also be referred to as 7-azaindole in the examples.</b>

Example 1: Synthesis

of

[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amine (P-0038)

0101[5-(5-Bromo-1H-pyrroto[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amine <b>P-0038</b> was synthesized in 5 steps from commercially available 2-Amino-5-bromopyridine 15 as shown in Scheme 19. <chemistry id="chem0039" num="0039"><img file="EP2086972B1_D0039.tif" /></chemistry>

Step 1- Synthesis of (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine

(41)

0102To 2-Amino-5-bromopyridine (15, 6.10 g, 0.0352 mol) in toluene (90.0 mL) were added 4-chlorobenzaldehyde (40, 5.00 g, 0.0356 mol), trifluoroacetic acid (8.0 mL, 0.10 mol) and triethylsilane (16.5 mL, 0.103 mol). The reaction was heated to reflux for 48 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude residue was crystallized with ethyl acetate to give compound (<b>41,</b> 6.8 g, 65.4%).

Step 2 - Synthesis of 6-(4-Chloro-benzylamino)pyridine-3-carbaldehyde

(42)

0103To (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine <b>(41,</b> 10.00 g, 0.03360 mol) in tetrahydrofuran (400.0 mL) under an atmosphere of nitrogen at -78 °C was added n-butyllithium (17.5 mL, 2.00 M in cyclohexane). After 90 minutes, tert-butyllithium (42.00 mL, 1.70 M in hexane) was added to the reaction. After 80 minutes, N,N-dimethylformamide (6.9 mL, 0.089 mol) was added to the reaction. The reaction mixture was stirred at -78 °C for 2 hours, then allowed to warm to room temperature for I hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude compound, which was crystallized from <i>tert</i>-butoxyl methyl ether to provide compound (<b>42,</b> 7.66 g, 92.2%).

Step 3 - Synthesis of (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (43)

0104To 6-(4-Chloro-benzylamino)-pyridine-3-carbaldehyde (<b>42,</b> 2.00 g, 8.11 mmol) in dichloromethane (20.0 mL) were added triethylamine (1.70 mL, 12.2 mmol), di-tert-butyldicarbonate (2.00 g, 9.16 mmol) and 4-dimethylaminopyridine (52.3 mg, 0.43 mmol). The reaction was stirred at room temperature for 48 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give compound (<b>43,</b> 2.50 g, 89.3%).

Step 4 - Synthesis of {5-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester (45)

0105To 5-bromo-7-azaindole <b>(44,</b> 198.0 mg, 1.01 mmol) in methanol (30.0 mL, 0.741 mol) were added (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (43, 355.0 mg, 1.02 mmol) and potassium hydroxide (80.0 mg, 1.42 mmol). The reaction was stirred at room temperature 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 8% methanol in dichloromethane to give compound <b>(45,</b> 200.0 mg, 36.8%).

Step 5 - Synthesis of [5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amine

(P-0038)

0106To {5-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(4-chloro-benzyl)-carbamic acid tert-butyl ester (<b>45,</b> 180.0 mg, 0.33 mmol) in acetonitrile (30.0 mL) were added trifluoroacetic acid (2.0 mL, 0.026 mol) and triethylsilane (4.0 mL, 0.025 mol). The reaction was heated to reflux for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound <b>(P-0038,</b> 120 mg, 85.2%). MS(ESI)[M+H⁺]⁺ = 427.2, 429.2.

0107Additional compounds were prepared following the protocol of Scheme 19, optionally replacing 4-chlorobenzaldehyde <b>40</b> with an appropriate aldehyde in Step 1 and optionally replacing 5-bromo-7-azaindole <b>44</b> with an appropriate azaindole in Step 4. The following compounds were made following this procedure: <ul id="ul0014" list-style="none" compact="compact"><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0181),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0182),</b></li><li>3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0257).</b></li><li>3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0269),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine <b>(P-0270),</b></li><li>3-[6-(2-Fluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0271),</b></li><li>(2-Fluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0272),</b></li><li>3-{6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0273),</b></li><li>3-[6-(2-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0274),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0275),</b></li><li>[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0276),</b></li><li>3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0277),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine <b>(P-0278),</b></li><li>(2-Chloro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0279),</b></li><li>(2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0280),</b></li><li>3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo(2,3-b]pyridine-5-carbonitrile <b>(P-0281),</b></li><li>(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0282),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0283),</b></li><li>3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0284),</b></li><li>(2-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0285),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0286),</b></li><li>3- {6-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0287),</b></li><li>(2-Ethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0288),</b></li><li>(2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0296),</b></li><li>(2,5-Difluoro-benzyl)-(5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0297),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,5-difluoro-benzyl)-amine <b>(P-0298),</b></li><li>3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0299),</b></li><li>3-[6-(2-Trifluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0321),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethoxy-benzyl)-amine <b>(P-0322),</b></li><li>3-[6-(2-Ethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0323),</b></li><li>[5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0325),</b></li><li>[5-(5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0326),</b></li><li>(2-Chloro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0327),</b></li><li>(2-Chloro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0328),</b></li><li>(2,5-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0329),</b></li><li>(2,5-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0330),</b></li><li>[5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0331),</b></li><li>(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0332),</b></li><li>(2,6-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0333),</b></li><li>(2,6-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0334),</b></li><li>(2-Methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0336),</li><li>3-[6-(2-Methoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0337),</b></li><li>(2,6-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0340), and</li><li>(2,6-Difluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0341).</b></li></ul> The following table indicates the aldehyde used in Step 1 in Column 3 and the azaindole used in Step 4 in Column 2 to provide the compound of Column 4. Column I provides the compound number and Column 5 the measured mass spectrometry result. <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="5"><colspec colnum="1" colname="col1" colwidth="32mm" /><colspec colnum="2" colname="col2" colwidth="32mm" /><colspec colnum="3" colname="col3" colwidth="30mm" /><colspec colnum="4" colname="col4" colwidth="52mm" /><colspec colnum="5" colname="col5" colwidth="21mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Azaindole in Step 4</entry><entry align="center" valign="middle">Aldehyde in Step 1</entry><entry align="center" valign="middle">Compound structure Compound</entry><entry align="center" valign="middle">MS [M+H⁺]⁺</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0181</entry><entry align="center" valign="middle"><chemistry id="chem0040" num="0040"><img file="EP2086972B1_D0040.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0041" num="0041"><img file="EP2086972B1_D0041.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0042" num="0042"><img file="EP2086972B1_D0042.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">418.2</entry></row><row><entry align="center" valign="middle">P-0182</entry><entry align="center" valign="middle"><chemistry id="chem0043" num="0043"><img file="EP2086972B1_D0043.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0044" num="0044"><img file="EP2086972B1_D0044.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0045" num="0045"><img file="EP2086972B1_D0045.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">384.2</entry></row><row><entry align="center" valign="middle">P-0257</entry><entry align="center" valign="middle"><chemistry id="chem0046" num="0046"><img file="EP2086972B1_D0046.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0047" num="0047"><img file="EP2086972B1_D0047.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0048" num="0048"><img file="EP2086972B1_D0048.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">374.2</entry></row><row><entry align="center" valign="middle">P-0269</entry><entry align="center" valign="middle"><chemistry id="chem0049" num="0049"><img file="EP2086972B1_D0049.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0050" num="0050"><img file="EP2086972B1_D0050.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0051" num="0051"><img file="EP2086972B1_D0051.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">408.7</entry></row><row><entry align="center" valign="middle">P-0270</entry><entry align="center" valign="middle"><chemistry id="chem0052" num="0052"><img file="EP2086972B1_D0052.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0053" num="0053"><img file="EP2086972B1_D0053.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0054" num="0054"><img file="EP2086972B1_D0054.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.0</entry></row><row><entry align="center" valign="middle">P-0271</entry><entry align="center" valign="middle"><chemistry id="chem0055" num="0055"><img file="EP2086972B1_D0055.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0056" num="0056"><img file="EP2086972B1_D0056.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0057" num="0057"><img file="EP2086972B1_D0057.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">358.0</entry></row><row><entry align="center" valign="middle">P-0272</entry><entry align="center" valign="middle"><chemistry id="chem0058" num="0058"><img file="EP2086972B1_D0058.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0059" num="0059"><img file="EP2086972B1_D0059.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0060" num="0060"><img file="EP2086972B1_D0060.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.0</entry></row><row><entry align="center" valign="middle">P-0273</entry><entry align="center" valign="middle"><chemistry id="chem0061" num="0061"><img file="EP2086972B1_D0061.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0062" num="0062"><img file="EP2086972B1_D0062.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0063" num="0063"><img file="EP2086972B1_D0063.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">409.4</entry></row><row><entry align="center" valign="middle">P-0274</entry><entry align="center" valign="middle"><chemistry id="chem0064" num="0064"><img file="EP2086972B1_D0064.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0065" num="0065"><img file="EP2086972B1_D0065.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0066" num="0066"><img file="EP2086972B1_D0066.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">408.5</entry></row><row><entry align="center" valign="middle">P-0275</entry><entry align="center" valign="middle"><chemistry id="chem0067" num="0067"><img file="EP2086972B1_D0067.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0068" num="0068"><img file="EP2086972B1_D0068.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0069" num="0069"><img file="EP2086972B1_D0069.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">417.0</entry></row><row><entry align="center" valign="middle">P-0276</entry><entry align="center" valign="middle"><chemistry id="chem0070" num="0070"><img file="EP2086972B1_D0070.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0071" num="0071"><img file="EP2086972B1_D0071.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0072" num="0072"><img file="EP2086972B1_D0072.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">397.6</entry></row><row><entry align="center" valign="middle">P-0277</entry><entry align="center" valign="middle"><chemistry id="chem0073" num="0073"><img file="EP2086972B1_D0073.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0074" num="0074"><img file="EP2086972B1_D0074.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0075" num="0075"><img file="EP2086972B1_D0075.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">376.5</entry></row><row><entry align="center" valign="middle">P-0278</entry><entry align="center" valign="middle"><chemistry id="chem0076" num="0076"><img file="EP2086972B1_D0076.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0077" num="0077"><img file="EP2086972B1_D0077.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0078" num="0078"><img file="EP2086972B1_D0078.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">385.0</entry></row><row><entry align="center" valign="middle">P-0279</entry><entry align="center" valign="middle"><chemistry id="chem0079" num="0079"><img file="EP2086972B1_D0079.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0080" num="0080"><img file="EP2086972B1_D0080.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0081" num="0081"><img file="EP2086972B1_D0081.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">363.0</entry></row><row><entry align="center" valign="middle">P-0280</entry><entry align="center" valign="middle"><chemistry id="chem0082" num="0082"><img file="EP2086972B1_D0082.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0083" num="0083"><img file="EP2086972B1_D0083.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0084" num="0084"><img file="EP2086972B1_D0084.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">383.3</entry></row><row><entry align="center" valign="middle">P-0281</entry><entry align="center" valign="middle"><chemistry id="chem0085" num="0085"><img file="EP2086972B1_D0085.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0086" num="0086"><img file="EP2086972B1_D0086.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0087" num="0087"><img file="EP2086972B1_D0087.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">374.0</entry></row><row><entry align="center" valign="middle">P-0282</entry><entry align="center" valign="middle"><chemistry id="chem0088" num="0088"><img file="EP2086972B1_D0088.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0089" num="0089"><img file="EP2086972B1_D0089.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0090" num="0090"><img file="EP2086972B1_D0090.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">360.8</entry></row><row><entry align="center" valign="middle">P-0283</entry><entry align="center" valign="middle"><chemistry id="chem0091" num="0091"><img file="EP2086972B1_D0091.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0092" num="0092"><img file="EP2086972B1_D0092.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0093" num="0093"><img file="EP2086972B1_D0093.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">380.0</entry></row><row><entry align="center" valign="middle">P-0284</entry><entry align="center" valign="middle"><chemistry id="chem0094" num="0094"><img file="EP2086972B1_D0094.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0095" num="0095"><img file="EP2086972B1_D0095.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0096" num="0096"><img file="EP2086972B1_D0096.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">371.5</entry></row><row><entry align="center" valign="middle">P-0285</entry><entry align="center" valign="middle"><chemistry id="chem0097" num="0097"><img file="EP2086972B1_D0097.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0098" num="0098"><img file="EP2086972B1_D0098.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0099" num="0099"><img file="EP2086972B1_D0099.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">360.1</entry></row><row><entry align="center" valign="middle">P-0286</entry><entry align="center" valign="middle"><chemistry id="chem0100" num="0100"><img file="EP2086972B1_D0100.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0101" num="0101"><img file="EP2086972B1_D0101.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0102" num="0102"><img file="EP2086972B1_D0102.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">380.0</entry></row><row><entry align="center" valign="middle">P-0287</entry><entry align="center" valign="middle"><chemistry id="chem0103" num="0103"><img file="EP2086972B1_D0103.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0104" num="0104"><img file="EP2086972B1_D0104.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0105" num="0105"><img file="EP2086972B1_D0105.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">371.0</entry></row><row><entry align="center" valign="middle">P-0288</entry><entry align="center" valign="middle"><chemistry id="chem0106" num="0106"><img file="EP2086972B1_D0106.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0107" num="0107"><img file="EP2086972B1_D0107.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0108" num="0108"><img file="EP2086972B1_D0108.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">359.6</entry></row><row><entry align="center" valign="middle">P-0296</entry><entry align="center" valign="middle"><chemistry id="chem0109" num="0109"><img file="EP2086972B1_D0109.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0110" num="0110"><img file="EP2086972B1_D0110.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0111" num="0111"><img file="EP2086972B1_D0111.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">351.6</entry></row><row><entry align="center" valign="middle">P-0297</entry><entry align="center" valign="middle"><chemistry id="chem0112" num="0112"><img file="EP2086972B1_D0112.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0113" num="0113"><img file="EP2086972B1_D0113.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0114" num="0114"><img file="EP2086972B1_D0114.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">365.5</entry></row><row><entry align="center" valign="middle">P-0298</entry><entry align="center" valign="middle"><chemistry id="chem0115" num="0115"><img file="EP2086972B1_D0115.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0116" num="0116"><img file="EP2086972B1_D0116.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0117" num="0117"><img file="EP2086972B1_D0117.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">385.9</entry></row><row><entry align="center" valign="middle">P-0299</entry><entry align="center" valign="middle"><chemistry id="chem0118" num="0118"><img file="EP2086972B1_D0118.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0119" num="0119"><img file="EP2086972B1_D0119.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0120" num="0120"><img file="EP2086972B1_D0120.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">376.4</entry></row><row><entry align="center" valign="middle">P-0321</entry><entry align="center" valign="middle"><chemistry id="chem0121" num="0121"><img file="EP2086972B1_D0121.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0122" num="0122"><img file="EP2086972B1_D0122.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0123" num="0123"><img file="EP2086972B1_D0123.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">424.6</entry></row><row><entry align="center" valign="middle">P-0322</entry><entry align="center" valign="middle"><chemistry id="chem0124" num="0124"><img file="EP2086972B1_D0124.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0125" num="0125"><img file="EP2086972B1_D0125.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0126" num="0126"><img file="EP2086972B1_D0126.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">399.5</entry></row><row><entry align="center" valign="middle">P-0323</entry><entry align="center" valign="middle"><chemistry id="chem0127" num="0127"><img file="EP2086972B1_D0127.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0128" num="0128"><img file="EP2086972B1_D0128.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0129" num="0129"><img file="EP2086972B1_D0129.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">384.7</entry></row><row><entry align="center" valign="middle">P-0325</entry><entry align="center" valign="middle"><chemistry id="chem0130" num="0130"><img file="EP2086972B1_D0130.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0131" num="0131"><img file="EP2086972B1_D0131.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0132" num="0132"><img file="EP2086972B1_D0132.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.5</entry></row><row><entry align="center" valign="middle">P-0326</entry><entry align="center" valign="middle"><chemistry id="chem0133" num="0133"><img file="EP2086972B1_D0133.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0134" num="0134"><img file="EP2086972B1_D0134.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0135" num="0135"><img file="EP2086972B1_D0135.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">413.4</entry></row><row><entry align="center" valign="middle">P-0327</entry><entry align="center" valign="middle"><chemistry id="chem0136" num="0136"><img file="EP2086972B1_D0136.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0137" num="0137"><img file="EP2086972B1_D0137.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0138" num="0138"><img file="EP2086972B1_D0138.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.2</entry></row><row><entry align="center" valign="middle">P-0328</entry><entry align="center" valign="middle"><chemistry id="chem0139" num="0139"><img file="EP2086972B1_D0139.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0140" num="0140"><img file="EP2086972B1_D0140.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0141" num="0141"><img file="EP2086972B1_D0141.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">379.0</entry></row><row><entry align="center" valign="middle">P-0329</entry><entry align="center" valign="middle"><chemistry id="chem0142" num="0142"><img file="EP2086972B1_D0142.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0143" num="0143"><img file="EP2086972B1_D0143.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0144" num="0144"><img file="EP2086972B1_D0144.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">369.7</entry></row><row><entry align="center" valign="middle">P-0330</entry><entry align="center" valign="middle"><chemistry id="chem0145" num="0145"><img file="EP2086972B1_D0145.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0146" num="0146"><img file="EP2086972B1_D0146.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0147" num="0147"><img file="EP2086972B1_D0147.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">381.6</entry></row><row><entry align="center" valign="middle">P-0331</entry><entry align="center" valign="middle"><chemistry id="chem0148" num="0148"><img file="EP2086972B1_D0148.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0149" num="0149"><img file="EP2086972B1_D0149.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0150" num="0150"><img file="EP2086972B1_D0150.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">364.5</entry></row><row><entry align="center" valign="middle">P-0332</entry><entry align="center" valign="middle"><chemistry id="chem0151" num="0151"><img file="EP2086972B1_D0151.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0152" num="0152"><img file="EP2086972B1_D0152.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0153" num="0153"><img file="EP2086972B1_D0153.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">376.4</entry></row><row><entry align="center" valign="middle">P-0333</entry><entry align="center" valign="middle"><chemistry id="chem0154" num="0154"><img file="EP2086972B1_D0154.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0155" num="0155"><img file="EP2086972B1_D0155.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0156" num="0156"><img file="EP2086972B1_D0156.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">369.6</entry></row><row><entry align="center" valign="middle">P-0334</entry><entry align="center" valign="middle"><chemistry id="chem0157" num="0157"><img file="EP2086972B1_D0157.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0158" num="0158"><img file="EP2086972B1_D0158.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0159" num="0159"><img file="EP2086972B1_D0159.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">381.6</entry></row><row><entry align="center" valign="middle">P-0336</entry><entry align="center" valign="middle"><chemistry id="chem0160" num="0160"><img file="EP2086972B1_D0160.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0161" num="0161"><img file="EP2086972B1_D0161.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0162" num="0162"><img file="EP2086972B1_D0162.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.7</entry></row><row><entry align="center" valign="middle">P-0337</entry><entry align="center" valign="middle"><chemistry id="chem0163" num="0163"><img file="EP2086972B1_D0163.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0164" num="0164"><img file="EP2086972B1_D0164.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0165" num="0165"><img file="EP2086972B1_D0165.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">370.7</entry></row><row><entry align="center" valign="middle">P-0340</entry><entry align="center" valign="middle"><chemistry id="chem0166" num="0166"><img file="EP2086972B1_D0166.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0167" num="0167"><img file="EP2086972B1_D0167.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0168" num="0168"><img file="EP2086972B1_D0168.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">351.5</entry></row><row><entry align="center" valign="middle">P-0341</entry><entry align="center" valign="middle"><chemistry id="chem0169" num="0169"><img file="EP2086972B1_D0169.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0170" num="0170"><img file="EP2086972B1_D0170.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0171" num="0171"><img file="EP2086972B1_D0171.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">365.5</entry></row></tbody></tgroup></table></tables>

0108Additional compounds were prepared following the protocol of Scheme 19, Steps 4 and 5, replacing (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>43</b> with an appropriate protected aldehyde and 5-bromo-7-azaindole <b>44</b> with an appropriate azaindole in Step 4. Aldehydes were prepared as described in Example 60. The following compounds were made following this procedure: <ul id="ul0015" list-style="none" compact="compact"><li>3- {2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0232),</b></li><li>[6-Chloro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0233),</b></li><li>[6-Chloro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0234),</b></li><li>(3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0235),</b></li><li>3-{6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0256),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-difluaromethoxy-benzyl)-amine <b>(P-0338),</b></li><li>3-[6-(2-Difluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0339),</b></li></ul> The following table indicates the aldehyde used in Column 2 and the azaindole used in Column 3 to provide the compound of Column 4. Column I provides the compound number and Column 5 the measured mass spectrometry result. <tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="5"><colspec colnum="1" colname="col1" colwidth="26mm" /><colspec colnum="2" colname="col2" colwidth="38mm" /><colspec colnum="3" colname="col3" colwidth="31mm" /><colspec colnum="4" colname="col4" colwidth="52mm" /><colspec colnum="5" colname="col5" colwidth="20mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Aldehyde</entry><entry align="center" valign="middle">Azaindole</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS [M+H]⁺</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0232</entry><entry align="center" valign="middle"><chemistry id="chem0172" num="0172"><img file="EP2086972B1_D0172.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0173" num="0173"><img file="EP2086972B1_D0173.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0174" num="0174"><img file="EP2086972B1_D0174.tif" /></chemistry></entry><entry align="center" valign="middle">443.0</entry></row><row><entry align="center" valign="middle">P-0233</entry><entry align="center" valign="middle"><chemistry id="chem0175" num="0175"><img file="EP2086972B1_D0175.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0176" num="0176"><img file="EP2086972B1_D0176.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0177" num="0177"><img file="EP2086972B1_D0177.tif" /></chemistry></entry><entry align="center" valign="middle">[M-H⁺]^- = 446.1</entry></row><row><entry align="center" valign="middle">P-0234</entry><entry align="center" valign="middle"><chemistry id="chem0178" num="0178"><img file="EP2086972B1_D0178.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0179" num="0179"><img file="EP2086972B1_D0179.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0180" num="0180"><img file="EP2086972B1_D0180.tif" /></chemistry></entry><entry align="center" valign="middle">430.1</entry></row><row><entry align="center" valign="middle">P-0235</entry><entry align="center" valign="middle"><chemistry id="chem0181" num="0181"><img file="EP2086972B1_D0181.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0182" num="0182"><img file="EP2086972B1_D0182.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0183" num="0183"><img file="EP2086972B1_D0183.tif" /></chemistry></entry><entry align="center" valign="middle">383.9</entry></row><row><entry align="center" valign="middle">P-0256</entry><entry align="center" valign="middle"><chemistry id="chem0184" num="0184"><img file="EP2086972B1_D0184.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0185" num="0185"><img file="EP2086972B1_D0185.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0186" num="0186"><img file="EP2086972B1_D0186.tif" /></chemistry></entry><entry align="center" valign="middle">375.2</entry></row><row><entry align="center" valign="middle">P-0338</entry><entry align="center" valign="middle"><chemistry id="chem0187" num="0187"><img file="EP2086972B1_D0187.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0188" num="0188"><img file="EP2086972B1_D0188.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0189" num="0189"><img file="EP2086972B1_D0189.tif" /></chemistry></entry><entry align="center" valign="middle">415.0</entry></row><row><entry align="center" valign="middle">P-0339</entry><entry align="center" valign="middle"><chemistry id="chem0190" num="0190"><img file="EP2086972B1_D0190.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0191" num="0191"><img file="EP2086972B1_D0191.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0192" num="0192"><img file="EP2086972B1_D0192.tif" /></chemistry></entry><entry align="center" valign="middle">406.6</entry></row></tbody></tgroup></table></tables>

Example 2: Synthesis of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carboldehyde 47.

0109Compound 47 was synthesized in 2 steps from 7-azaindole <b>1</b> as described in Scheme 20. <chemistry id="chem0193" num="0193"><img file="EP2086972B1_D0193.tif" /></chemistry>

Step 1 -

Preparation of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

(46):

0110To 1H-Pyrrolo[2,3-b]pyridine (1, 16.0 g, 135 mmol) in water (110 mL), were added hexamethylenetetramine (26.0 g, 185 mmol), and acetic acid (55.0 mL, 967 mmol). The reaction was refluxed for 12 hours. Water (329 mL) was added and the reaction was cooled to room temperature. The reaction was filtrated and washed with water to give compound (46, 15.0 g, 76%). MS(ESI)[M+H⁺]⁺ = 147.

Step 2 -

Preparation of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

(47)

:

0111To 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (46, 4.05 g, 27.71 mmol) in tetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil, 1.5 g, 38 mmol) and triisopropylsilyl chloride (8.0 mL, 38 mmol) under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10 % ethyl acetate in hexane to give compound (<b>47,</b> 3.0 g, 36%). MS(ESI)[M+H⁺]⁺ = 303.

01121-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine <b>66</b><chemistry id="chem0194" num="0194"><img file="EP2086972B1_D0194.tif" /></chemistry> was prepared following the protocol of Scheme 20 Step 2, substituting 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde 46 with 3-iodo-1H-pyrrolo[2,3-b]pyridine and triisopropylsilyl chloride with tert-Butyl-dimethyl-silyl chloride.

01131-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde 55 <chemistry id="chem0195" num="0195"><img file="EP2086972B1_D0195.tif" /></chemistry> was prepared following the protocol of Scheme 20, substituting triisopropylsilyl chloride with benzenesulfonyl chloride in Step 2.

Example 3: Synthesis of 5 substituted 7-azaindole intermediates

01145-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine 79 was synthesized in 1 Step from commercially available 5-bromo-azaindole as shown in Scheme 31. <chemistry id="chem0196" num="0196"><img file="EP2086972B1_D0196.tif" /></chemistry>

Step 1 - 5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine (79):

0115To 4-morpholineethanol (30 mL, 0.2 mol) in N, N-dimethylformamide (30 mL) was slowly added sodium hydride (7 g, 60% dispersion in mineral oil, 0.2 mol). After the solution turned clear, a solution of 5-bromo-7-azaindole <b>(44,</b> 1.0 g, 0.0051 mol) in N,N-dimethylformamide (5 mL) and copper(I) bromide (1.4 g, 0.0098 mol) were added. The reaction mixture was stirred at 120 °C under nitrogen for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with a solution of ammonium chloride and ammonium hydroxide (4:1), brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (79, 0.62 g, 50%). MS (ESI) [M+H⁺]⁺ = 248.25.

0116Additional 5-substituted 7-azaindoles were prepared following the protocol of Scheme 31, replacing 4-morpholineethanol with either 2-diethylamino-ethanol, 3-diethylamino-propan-1-ol, 2-piperidin-1-yl-ethanol, or 2-pyrrolidin-1-yl-ethanol to provide diethyl-[2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-ethyl]-amine, Diethyl-[3-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-propyl]-amine, 5-(2-piperidin-1-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine, and 5-(2-pyrrolidin-1-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine, respectively.

Example 4: Synthesis of 3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid benzylamide P-0084

01173,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid benzylamide P-0084 was synthesized in 6 steps from dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 2 as shown in Scheme 158. <chemistry id="chem0197" num="0197"><img file="EP2086972B1_D0197.tif" /></chemistry>

Step 1: Preparation of 3-Dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (511)

0118To dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine (2, 2.50 g, 14.3 mmol,) in tetrahydrofuran (200.0 mL) was added sodium hydride (0.685 g, 60% in mineral oil, 17.1 mmol). After 10 minutes, di-<i>tert</i>-butyldicarbonate (3.74 g, 17.1 mmol) was added to the reaction. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give as a white solid (<b>511,</b> 3.80 g, 96.7%).

Step 2: Preparation of 3-Chloromethyl-pyrrolo[2.3-b]pyridine-1-carboxylic acid tert-butyl ester (512)

0119To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(511,</b> 2.60 g, 9.44 mmol) in toluene (50.00 mL) was added isopropyl chloroformate (11.3 mL, 1.0 M in toluene) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 2.0 g, 79.4%).

Step 3 - Preparation of 3-(2-Acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(513):</b>

0120To acetylacetone (0.563 g, 5.62 mmol) in dimethyl sulfoxide (29.0 mL) was added sodium hydride (0.225 g, 60% in mineral oil, 5.62 mmol). After 20 minutes, 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (512, 1.00 g, 3.75 mmol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a colorless oil (513, 0.59 g, 48.0%). MS (ESI) [M+H⁺]⁺ = 331.4.

Step 4 - Preparation of 3-(3,5-Dimethyl-1H-pyrazol-4-ylmethyl)pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (514)

0121To 3-(2-acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (513, 1.20 g, 3.63 mmol) in methanol (15.0 mL), cooled to -20 °C under an atmosphere of nitrogen, was added hydrazine (0.128 g, 4.00 mmol) in dichloromethane (6.0 mL). The reaction was stirred for 2 hours. The reaction was concentrated to remove the solvents, and the residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 60% ethyl acetate in hexane to give a white solid (<b>514,</b> 1.0 g, 84.4%). MS (ESI) [M+H⁺]⁺= 327.4.

Step 5 - Preparation of 3-(1-Benzylcarbamoyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(515)</b>

0122To 3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (<b>514,</b> 60.0 mg, 0.18 mmol) in dichloromethane (6.0 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL, 0.220 mmol) and benzyl isocyanate (29.4 mg, 0.220 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give crude compound (515, approx. 50 mg) that was used in the next step directly. MS (ESI) [M+H⁺]⁺ = 460.5.

Step 6 - 3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid benzylamide <b>(P-0084)</b>

0123To 3-(1-benzylcarbamoyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(515,</b> 50.0 mg, 0.11 mmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (0.20 mL, 2.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 20 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid <b>(P-0084</b>, 11.0 mg, 28.1%). MS (ESI) [M+H⁺]⁺ = 360.5.

01243-(3,5-Dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine <b>P-0124</b><chemistry id="chem0198" num="0198"><img file="EP2086972B1_D0198.tif" /></chemistry> was prepared from 3-(3,5-Dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(514,</b> 15.0 mg, 0.046 mmol) by dissolving in dichloromethane (10.0 mL) to which trifluoroacetic acid (0.10 mL, 1.3 mmol) was added. The reaction was stirred at room temperature for I hour, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate in hexane to give an off-white solid <b>(P-0124,</b> 7.5 mg, 72.0%). MS (ESI) [M+H⁺]⁺ = 227.3.

0125Additional compounds were prepared following the protocol of Scheme 158, replacing dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 2 with (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-dimethyl-amine (prepared as described in Example 10, Scheme 164, isolated after step 1) in Step 1 and replacing benzyl isocyanate with an appropriate electrophile in Step 5. The following compounds were made following this procedure: <ul id="ul0016" list-style="none" compact="compact"><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide <b>(P-0157),</b></li><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid 4-fluoro-benzylamide <b>(P-0158),</b></li><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid 4-chloro-benzylamide <b>(P-0159),</b> and</li><li>4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide <b>(P-0160).</b></li></ul>

0126The electrophile used in place of benzyl isocyanate in Step 5 is indicated in Column 2 of the following table, with the compound structure given in Column 3. Column I provides the compound number and Column 4 the experimental mass spectrometry result. <tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="15mm" /><colspec colnum="2" colname="col2" colwidth="34mm" /><colspec colnum="3" colname="col3" colwidth="61mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle" /><entry align="center" valign="middle">Electrophile</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0157</entry><entry align="center" valign="middle"><chemistry id="chem0199" num="0199"><img file="EP2086972B1_D0199.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0200" num="0200"><img file="EP2086972B1_D0200.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">426.2</entry></row><row><entry align="center" valign="middle">P-0158</entry><entry align="center" valign="middle"><chemistry id="chem0201" num="0201"><img file="EP2086972B1_D0201.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0202" num="0202"><img file="EP2086972B1_D0202.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">412.2</entry></row><row><entry align="center" valign="middle">P-0159</entry><entry align="center" valign="middle"><chemistry id="chem0203" num="0203"><img file="EP2086972B1_D0203.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0204" num="0204"><img file="EP2086972B1_D0204.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">428.2</entry></row><row><entry align="center" valign="middle">P-0160</entry><entry align="center" valign="middle"><chemistry id="chem0205" num="0205"><img file="EP2086972B1_D0205.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0206" num="0206"><img file="EP2086972B1_D0206.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">426.2</entry></row></tbody></tgroup></table></tables>

Example 5: Synthesis of [4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine P-0168

0127[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine <b>P-0168</b> was synthesized in 5 steps as shown in Scheme 159. <chemistry id="chem0207" num="0207"><img file="EP2086972B1_D0207.tif" /></chemistry>

Step 1 - Preparation of 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517):

0128To a solution of 4-(aminomethyl)pyridine (516, 1.16 mL, 11.5 mmol) and N,N-diisopropylethylamine (3.8 mL, 22 mmol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde <b>(93,</b> 2.0 g, 11.0 mmol) in tetrahydrofuran (5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The crude compound 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde <b>(517)</b> was used for the next step without purification.

Step 2 - Preparation of (4-chloro-5-formyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester <b>(518):</b>

0129A mixture of 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde <b>(517,</b> 3.28 g, 11.0 mmol), di-tert-butyldicarbonate (4.0 g, 18 mol) and triethylamine (10 mL, 74 mmol) in dichloromethane (120 mL) was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid <b>(518,</b> 564 mg, 15%). MS (ESI) [M+H⁺]⁺= 354.1.

Step 3 - Preparation of {4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-buyl ester <b>(519):</b>

0130To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>(96,</b> 0.44 g, 1.1 mmol) in tetrahydrofuran (20 mL) at -20 °C, isopropylmagnesium chloride (2 M in tetrahydrofuran, 0.6 mL, 1.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0 °C in 10 minutes. The reaction mixture was then cooled to -40 °C. A solution of (4-chloro-5-formyl-thiazol-2-yl)-pyridin4-ylmethyl-carbamic acid tert-butyl ester <b>(518,</b> 0.26 g, 0.73 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to -10 °C over 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid <b>(519,</b> 397 mg, 86%). MS (ESI) [M+H⁺]⁺ = 628.3.

Step 4 - Preparation of [4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-carbamic acid tert-butyl ester <b>(520):</b>

0131A mixture of {4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester <b>(519,</b> 0.397 g, 0.57 mmol), triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid <b>(520,</b> 126 mg, 49%). MS (ESI) [M+H⁺]⁺ = 456.2.

Step 5 - Preparation of [4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine <b>(P-0168):</b>

0132To a solution of [4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-carbamic acid tert-butyl ester <b>(520,</b> 126 mg, 0.000276 mol) in dichloromethane (2 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into cold sodium bicarbonate solution, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After removal of solvents, the residue was washed with ethyl acetate to provide the desired compound as a light yellow solid <b>(P-0168,</b> 68.4 mg, 70%). MS (ESI) [M+H⁺]⁺ = 356.2.

0133Additional compounds were prepared following the protocol of Scheme 159, replacing 4-(aminomethyl)pyridine <b>516</b> with an appropriate amine. The following compounds were made following this procedure: <ul id="ul0017" list-style="none" compact="compact"><li>[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine <b>(P-0164),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-<i>b</i>]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine <b>(P-0167),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-<i>b</i>]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine <b>(P-0171),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-<i>b</i>]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0173),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-<i>b</i>]pyridin-3-ylmethyl)-thiazol-2-yl]-(1,5-dimethyl-1H-pyrazol-3-ylmethyl)-amine <b>(P-0172),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-<i>b</i>]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amine <b>(P-0175),</b> and</li><li>[4-Chloro-5-(1H-pyrrolo[2,3-<i>b</i>]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine (<b>P-0156).</b></li></ul> The following table indicates the amine (Column 2) used in Scheme 159 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the observed mass. <tables id="tabl0004" num="0004"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="34mm" /><colspec colnum="3" colname="col3" colwidth="49mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Amine</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0164</entry><entry align="center" valign="middle"><chemistry id="chem0208" num="0208"><img file="EP2086972B1_D0208.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0209" num="0209"><img file="EP2086972B1_D0209.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">356.1</entry></row><row><entry align="center" valign="middle">P-0167</entry><entry align="center" valign="middle"><chemistry id="chem0210" num="0210"><img file="EP2086972B1_D0210.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0211" num="0211"><img file="EP2086972B1_D0211.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">356.1</entry></row><row><entry align="center" valign="middle">P-0171</entry><entry align="center" valign="middle"><chemistry id="chem0212" num="0212"><img file="EP2086972B1_D0212.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0213" num="0213"><img file="EP2086972B1_D0213.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">370.2</entry></row><row><entry align="center" valign="middle">P-0173</entry><entry align="center" valign="middle"><chemistry id="chem0214" num="0214"><img file="EP2086972B1_D0214.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0215" num="0215"><img file="EP2086972B1_D0215.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">424.2</entry></row><row><entry align="center" valign="middle">P-0172</entry><entry align="center" valign="middle"><chemistry id="chem0216" num="0216"><img file="EP2086972B1_D0216.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0217" num="0217"><img file="EP2086972B1_D0217.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">373.2</entry></row><row><entry align="center" valign="middle">P-0175</entry><entry align="center" valign="middle"><chemistry id="chem0218" num="0218"><img file="EP2086972B1_D0218.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0219" num="0219"><img file="EP2086972B1_D0219.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">373.2</entry></row><row><entry align="center" valign="middle">P-0156</entry><entry align="center" valign="middle"><chemistry id="chem0220" num="0220"><img file="EP2086972B1_D0220.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0221" num="0221"><img file="EP2086972B1_D0221.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">373.1</entry></row></tbody></tgroup></table></tables>

Example 6: Synthesis of [4-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine P-0162 and (4-fluoro-benzyl)-[4-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine P-0162

0134[4-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine <b>P-0162</b> was synthesized in 1 step from [4-chloro-5-(1H-pyrrolo[2, 3-b] pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine <b>P-0156</b> as shown in Scheme 160. <chemistry id="chem0222" num="0222"><img file="EP2086972B1_D0222.tif" /></chemistry>

Step 1 - Preparation of [4-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine (P-0162):

0135Into a round bottom flask, under an atmosphere of nitrogen, [1,1'-bis(diphenyl phosphino) ferrocene] dichloro palladium (II), complex with dichloromethane (1:1), was placed with toluene (15 mL, 140 mmol). [4-Chloro-5-(1H-pyrrolo[2,3-b] pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine <b>(P-0156,</b> 145 mg, 0.4 mmol) was added in 5 ml of toluene at room temperature. The mixture was stirred for 10 minutes. To the stirring reaction, a solution of 3.13 M ethyl magnesium bromide in ether (1.86 mL) was added dropwise at room temperature. The opaque solution was heated to 60 °C. Tetrahydrofuran (10 mL) was added to the warm solution. The mixture was heated to reflux for an additional two hours. After cooling to 0 °C, the reaction was quenched with a solution of citric acid at pH 4-5 in ice-water and stirred to room temperature. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Purification with flash chromatography, eluting with a gradient of ethyl acetate:hexanes (20:100), gave a yellow solid that was further washed with ethyl acetate to give <b>P-0162</b> (15 mg,10%) as an off-white solid. MS (ESI) [M+H⁺]⁺ = 367.2.

0136(4-Fluoro-benzyl)-[4-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>P-0163</b><chemistry id="chem0223" num="0223"><img file="EP2086972B1_D0223.tif" /></chemistry> was prepared using the protocol of Scheme 160, substituting the 3.13 M ethyl magnesium bromide in ether solution with 1.4 M of methylmagnesium bromide in tetrahydrofuran. MS (ESI) [M+H⁺]⁺ = 353.2.

Example 7: Synthesis of (4-Chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amine P-0092

0137(4-Chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amine <b>P-0092</b> was synthesized in 3 steps as shown in Scheme 161. <chemistry id="chem0224" num="0224"><img file="EP2086972B1_D0224.tif" /></chemistry>

Step 1 - Synthesis of (6-bromo-pyridazin-3-yl)-(4-chloro-benzyl)-amine <b>(522)</b>:

0138To 6-bromo-pyridazin-3-ylamine <b>(521,</b> 0.85 g, 0.0049 mol) in acetonitrile (30.0 mL) were added 4-chlorobenzaldehyde (40, 0.82 g, 0.0058 mol), triethylsilane (4.0 mL, 0.025 mol) and trifluoroacetic acid (2.0 mL, 0.026 mol). The reaction was heated to reflux for 4 hours, then poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and washed with ethyl acetate to give a white solid <b>(522,</b> 1.0 g). MS (ESI) [M+H⁺]⁺= 298.3, 300.2.

Step 2

-

Preparation of 3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(523):</b>

0139To (6-bromo-pyridazin-3-yl)-(4-chloro-benzyl)-amine <b>(522,</b> 0.560 g, 1.88 mmol) in tetrahydrofuran (45.0 mL), under an atmosphere of nitrogen at -78 °C, was added n-butyllithium (2.50 M in hexane, 0.760 mL) slowly. After 10 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.201 g, 0.94 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction mixture was allowed to stir at room temperature for 3 hours. The reaction was cooled to -78 °C, followed by addition of 1.70 M of tert-butyllithium in hexane (1.20 mL) slowly. The reaction was stirred for 20 minutes, followed by addition of a solution of CuCN.2LiCl (0.6 M in tetrahydrofuran, 3.00 mL) and 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(512,</b> 0.47 g, 1.8 mol) in tetrahydrofuran (10.0 mL). After 30 minutes, the reaction was allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was treated with trifluoroacetic acid (1.0 mL) dissolved in dichloromethane (10.0 mL) for 10 minutes. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 60% ethyl acetate in hexane to give the desired compound <b>(523,</b> 0.10 g, 23.8%). MS (ESI) [M+H⁺]⁺ = 450.1.

Step 3 - Preparation of (4-chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-y

/

]-amine (P-0092):

0140To 3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(523,</b> 50.0 mg, 0.111 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid <b>(P-0092,</b> 7.3 mg, 19.0%). MS (ESI) [M+H⁺]⁺ = 350.1.

Example 8: Synthesis of [1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine P-0165

0141[1-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>P-0165</b> was synthesized in 7 steps as shown in Scheme 162. <chemistry id="chem0225" num="0225"><img file="EP2086972B1_D0225.tif" /></chemistry>

Step 1 - Preparation of 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester <b>(525)</b>:

0142To 5-nitro-2H-pyrazole-3-carboxylic acid <b>(524,</b> 10.0 g, 0.0637 mol) in methanol (100.0 mL) was added concentrated sulfuric acid (1.00 mL, 0.0180 mol). The reaction was stirred at room temperature overnight. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid <b>(525,</b> 1.5 g, 13.8%).

Step 2 - Preparation of 2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester <b>(526)</b>:

0143To 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester <b>(525,</b> 2.50 g, 0.0146 mol) in N,N-dimethylformamide (62.5 mL) were added iodoethane (1.2 mL, 0.016 mol) and potassium carbonate (4.17 g, 0.0301 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(526,</b> 1.3 g, 44.7%).

Step 3 - Preparation of 5-amino-2-ethyl-2H-pyrazole-3-carboxylic acid methyl ester <b>(527)</b>:

0144To 2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester <b>(526,</b> 1.30 g, 6.53 mmol) in methanol (60.0 mL) was added 20% Pd(OH)₂/C (0.1 g). The reaction was stirred under an atmosphere of hydrogen overnight. The reaction was filtered and concentrated to give a light yellow solid <b>(527,</b> 1.0 g, 90.6%).

Step 4 - Preparation of 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methyl ester <b>(529)</b>:

0145To 5-amino-2-ethyl-2H-pyrazole-3-carboxylic acid methyl ester <b>(527,</b> 1.00 g, 5.91 mmol) in acetonitrile (27.5 mL) were added 4-fluorobenzaldehyde <b>(528,</b> 0.660 mL, 6.26 mmol), triethylsilane (4.77 mL, 0.0298 mol) and trifluoroacetic acid (2.38 mL, 0.0310 mol). The reaction was stirred at 80 °C for 4 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(529,</b> 1.00 g, 61%).

Step 5 - Preparation of 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde <b>(530):</b>

0146To 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methyl ester <b>(529,</b> 1.00 g, 3.61 mol) in tetrahydrofuran (70.0 mL) under an atmosphere of nitrogen at room temperature, lithium tetrahydroaluminate (1.00 M of in tetrahydrofuran, 10.00 mL) was slowly added. The reaction was stirred at room temperature overnight, followed by slowly adding sodium sulfate decahydrate (15.0 g). After 2 hours, the reaction was filtered, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow oil <b>(530,</b> 0.16 g, 18%). MS (ESI) [M+H⁺]⁺ = 248.2.

Step 6- Preparation of 1-ethyl-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-1H-pyrazol-3-yl-(4-fluoro-benzyl)-amine <b>(531):</b>

0147To 1H-Pyrrolo[2,3-b]pyridine (1, 54.0 mg, 0.46 mmol) in methanol (15.0 mL) were added 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde <b>(530,</b> 110.0 mg, 0.44 mmol) and potassium hydroxide (0.60 g, 0.011 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a white solid <b>(531,</b> 0.12 g, 71.1%). MS (ESI) [M-H⁺]^- = 378.2.

Step 7 - Preparation of [1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>(P-0165):</b>

0148To 1-ethyl-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-1H-pyrazol-3-yl-(4-fluoro-benzyl)-amine <b>(531,</b> 0.12 g, 0.32 mmol) in acetonitrile (10.0 mL, 0.191 mol) were added triethylsilane (0.60 mL, 0.0038 mol) and trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at 80 °C for 2 hours. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give crude compound. ¹H NMR indicated that the reaction was incomplete. The crude compound was dissolved in dichloromethane (15.0 mL), trifluoroacetic acid (0.30 mL) and triethylsilane (0.60 mL). The reaction was stirred at 43 °C for 72 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid (P-0165, 18.7 mg, 17%). MS (ESI) [M+H⁺]⁺ = 350.3.

0149(4-Fluoro-benzyl)-[1-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-amine <b>P-0169</b><chemistry id="chem0226" num="0226"><img file="EP2086972B1_D0226.tif" /></chemistry> was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethane in Step 2. MS (ESI) [M+H⁺]⁺ = 336.3.

0150[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>P-0170</b><chemistry id="chem0227" num="0227"><img file="EP2086972B1_D0227.tif" /></chemistry> was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethane in step 2 and 1H-pyrrolo[2,3-b]pyridine 1 with 5-chloro-1H-pyrrolo[2,3-b]pyridine in step 6. MS (ESI) [M+H⁺]⁺ = 370.3

0151(4-Fluoro-benzyl)-{1-methyl-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-pyrazol-3-yl}-amine <b>P-0180</b><chemistry id="chem0228" num="0228"><img file="EP2086972B1_D0228.tif" /></chemistry> was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethane in step 2 and 1H-Pyrrolo[2,3-b]pyridine <b>1</b> with 5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (prepared as described in Example 18, Scheme 172) in step 6. MS (ESI) [M+H⁺]⁺ = 416.2.

01523-[5-(4-Fluoro-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>P-0191</b><chemistry id="chem0229" num="0229"><img file="EP2086972B1_D0229.tif" /></chemistry> was prepared using the protocol of Scheme 162, substituting 1H-Pyrrolo[2,3-b]pyridine 1 with I H-Pyrrolo[2,3-b]pyridine-5-carbonitrile in Step 6. MS (ESI) [M+H⁺]⁺ = 361.5.

Example 9: Synthesis of [4-chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amine P-0166

0153[4-chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amine <b>P-0166</b> was synthesized in I step as shown in Scheme 163. <chemistry id="chem0230" num="0230"><img file="EP2086972B1_D0230.tif" /></chemistry>

Step I - Preparation of [4-chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amine <b>(P-0166)</b>:

0154To [1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>(P-0165,</b> 10.1 mg, 0.0289 mmol, prepared as described in Example 8, Scheme 162) in acetonitrile (8.0 mL) was added N-chloro-succinimide (4.18 mg, 0.0318 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(P-0166,</b> 1.1 mg). MS (ESI) [M+H⁺]⁺ = 382.1.

Example 10: Synthesis of 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester

01555-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester was synthesized in 3 steps as shown in Scheme 164. <chemistry id="chem0231" num="0231"><img file="EP2086972B1_D0231.tif" /></chemistry>

Step 1 - Preparation of (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-dimethyl-amine <b>(533)</b>:

0156To 5-Chloro-1H-pyrrolo[2,3-b]pyridine <b>(532,</b> 8.00 g, 0.0524 mol) in isopropyl alcohol (250.0 mL) were added dimethylamine hydrochloride (4.79 g, 0.0587 mol) and formaldehyde (1.77 g, 0.0589 mol). The reaction was stirred at room temperature overnight, followed by refluxing for 4 hours. The reaction was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound <b>(533,</b> 10.0 g, 91%), that was used directly in the next step.

Step 2 and 3 - Preparation of 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxy

/

ic acid tert-butyl ester <b>(535):</b>

01575-Chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>535</b> was prepared following the protocol of Scheme 158 (Example 4) steps 1 and 2, substituting dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine <b>2</b> with (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-dimethyl-amine <b>533</b> in step 1.

Example 11: Synthesis of (4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amine P-0132

0158(4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amine <b>P-0132</b> was synthesized in 3 steps as shown in Scheme 165. <chemistry id="chem0232" num="0232"><img file="EP2086972B1_D0232.tif" /></chemistry><chemistry id="chem0233" num="0233"><img file="EP2086972B1_D0233.tif" /></chemistry>

Step 1 - Preparation of (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine <b>(536)</b>:

0159To 2,6-difluoropyridine <b>(58,</b> 9.85 g, 0.0856 mol) in N-methylpyrrolidinone (50.0 mL) were added p-chlorobenzylamine <b>(61,</b> 10.5 mL, 8.63 mmol) and N,N-diisopropylethylamine (30.0 mL, 0.172 mol). The reaction was stirred at 90 °C overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane, then washed with ethyl acetate/hexane to give a white solid <b>(536,</b> 10 g, 50%).

Step 2 - Preparation of (5-bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-amine <b>(537)</b>:

0160To (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine <b>(536,</b> 1.03 g, 4.35 mmol) in acetonitrile (30.0 mL), under an atmosphere of nitrogen, N-bromosuccinimide (0.820 g, 4.61 mol) was added slowly. After 2 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate and hexane to give a white solid <b>(537,</b> 1.10 g, 80.1 %).

Step 3 - Preparation of (4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-0132):

0161To (5-bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-amine <b>(537,</b> 2.76 g, 8.75 mol) in tetrahydrofuran (90.0 mL), under an atmosphere of nitrogen at -78 °C, n-butyllithium (2.50 M in hexane, 3.64 mL) was added slowly. After 60 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.942 g, 4.38 mol) in tetrahydrofuran (8.0 mL) was added to the reaction. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction was cooled to -78 °C, followed by addition of tert-butyllithium (1.70 M in hexane, 10.50 mL). The reaction was stirred for 30 minutes, followed by addition of 0.65 M of CuCN.2LiCl in tetrahydrofuran (14.0 mL). The reaction was stirred at -35 °C for 10 minutes, followed by addition of 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(535,</b> 1.70 g, 5.64 mol, prepared as described in Example 10, Scheme 164) in tetrahydrofuran (10.0 mL). The reaction was allowed to warm to room temperature for 1 hour and 2 N HCl (30 mL) was added to the reaction mixture, then stirred for 30 minutes. The reaction was poured into aqueous ammonia and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the desired compound <b>(P-0132,</b> 0.75 g, 33.1%). MS (ESI) [M+H⁺]⁺= 401.1.

Example 12: Synthesis of 5-chloro-3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine P-0155

01625-Chloro-3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>P-0155</b> was synthesized in I step as shown in Scheme 166. <chemistry id="chem0234" num="0234"><img file="EP2086972B1_D0234.tif" /></chemistry>

Step 1 - Preparation of 5-chloro-3-(2,6-difluoro-pyridin-3-ylmethy

/

)-1H-pyrrolo[2,3-b]pyridine <b>(P-0135)</b>:

0163To 2,6-Difluoropyridine <b>(58,</b> 3.40 g, 0.0295 mol) in tetrahydrofuran (200.0 mL), under an atmosphere of nitrogen at -78 °C, 2.50 M of n-butyllithium in hexane (12.0 mL) was added slowly. After 60 minutes, CuCN.2LiCl (0.75 M in tetrahydrofuran, 40.0 mL) was added to the reaction mixture. After 5 minutes, 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(535,</b> 4.20 g, 0.0139 mol, prepared as described in Example 10, Scheme 164) in tetrahydrofuran (20 mL) was added to the reaction. The reaction was stirred at -78 °C overnight, then poured into water and ammonia (10 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% ethyl acetate in hexane to give a white solid <b>(P-0155,</b> 300 mg, 7.7%). MS (ESI) [M-H⁺]^- = 278.1.

Example 13: Synthesis of 3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine P-0154

01643-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>P-0154</b> was synthesized in I step as shown in Scheme 167. <chemistry id="chem0235" num="0235"><img file="EP2086972B1_D0235.tif" /></chemistry>

Step 1 - Preparation of 3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (P-0154):

0165To 3-(2,6-difluoro-pyridin-3-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (536, 0.35 g, 1.0 mmol, prepared as described in Example 10, Scheme 164, replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 532 with 1H-pyrrolo[2,3-b]pyridine in step 1) in N-methylpyrrolidinone (3.00 mL) were added p-chlorobenzylamine (0.20 mL, 1.6 mmol) and N,N-diisopropylethylamine (0.30 mL, 0.0017 mol). The reaction was stirred at 50 °C for 72 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude intermediate was dissolve in dichloromethane (15.0 mL) and trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% ethyl acetate in hexane to give a white solid (<b>P-0154,</b> 0.18 g, 72%). MS (ESI) [M+H⁺]⁺ = 246.2.

Example 14: Synthesis of 5-((1H-pyrrolo[2,3-b]pyridio-3-yl)methyl)-N-(4-chlorobenzyl)-6-chloropyridin-2-amine P-0161

01665-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-hlorobenzyl)-6-chloropyridin-2-amine <b>P-0161</b> was synthesized in 6 steps as shown in Scheme 168. <chemistry id="chem0236" num="0236"><img file="EP2086972B1_D0236.tif" /></chemistry><chemistry id="chem0237" num="0237"><img file="EP2086972B1_D0237.tif" /></chemistry>

Step 1 - Preparation of (4-ch

/

oro-benzy

/

)-(6-chloro-pyridin-2-y

/

)-amine (538):

0167To 6-chloro-pyridin-2-ylamine <b>(537,</b> 5.60 g, 0.0436 mol) in acetonitrile (300 mL) were added 4-chlorobenzaldehyde <b>(40,</b> 6.7 g, 0.048 mol), trifluoroacetic acid (13 mL, 0.17 mol) and triethylsilane (21 mL, 0.13 mol). The reaction was heated to reflux for 4 hours, then concentrated, poured into water, extracted with ethyl acetate, and washed with sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The filtrate was purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(538,</b> 6.5 g, 59%). MS (ESI) [M+H⁺]⁺ = 255.1.

Step 2 - Preparation of (5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine <b>(539):</b>

0168To (4-chloro-benzyl)-(6-chloro-pyridin-2-yl)-amine <b>(538,</b> 4.00 g, 0.0158 mol) in acetonitrile (66.7 mL, 1.28 mol) under an atmosphere of nitrogen, N-bromosuccinimide (2.81 g, 0.0158 mol) in acetonitrile (20 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate in hexane to give a white solid <b>(539,</b> 2.60 g, 95.3%).

Step 3 - Preparation of 2-chloro-6-(4-chloro-benzylamino)-pyridine-3-carbaldehyde <b>(540):</b>

0169To (5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine <b>(539,</b> 2.60 g, 7.83 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at -78 °C, isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 4.20 mL) was added over 10 minutes. The reaction was stirred at -78 °C for 20 minutes, then allowed to warm to room temperature for 10 minutes. The reaction was cooled to -78 °C. tert-Butyllithium (1.70 M in hexane, 10.2 mL) was added to the reaction over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.80 mL, 0.0232 mol) was added to the reaction. The reaction was stirred at -78 °C for 40 minutes, then allowed to warm to room temperature for another 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid <b>(540,</b> 1.0 g, 45.4%). MS (ESI) [M-H⁺]^- = 279.0.

Step 4 - Preparation of (4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>(541):</b>

0170To 2-chloro-6-(4-chloro-benzylamino)-pyridine-3-carbaldehyde <b>(540,</b> 0.40 g, 1.42 mmol) in dichloromethane (10.0 mL) were added 4-dimethylaminopyridine (10.0 mg, 0.082 mmol), di-tert-butyldicarbonate (0.693 g, 3.17 mmol) and triethylamine (0.50 mL, 0.0036 mol). The reaction was stirred at room temperature overnight, then concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(541,</b> 0.45 g, 83.0%).

Step 5 - Preparation of (4-chloro-benzyl)-6-chloro-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester <b>(542):</b>

0171To 1H-Pyrrolo[2,3-b]pyridine <b>(1,</b> 465 mg, 3.93 mmol) in methanol (50 mL) were added sodium hydroxide (0.630 g, 0.0157 mol) and (4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>(541,</b> 1.5 g, 0.0039 mol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(542,</b> 1.0g, 51%). MS (ESI) [M+H⁺]⁺ = 499.1.

Step 6 - Preparation of 5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chlorobenzy

/

)-6-chloropyridin-2-amine (P-0161):

0172To (4-chloro-benzyl)-6-chloro-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester <b>(542,</b> 1.00 g, 2.00 mmol) in acetonitrile (130.0 mL) were added triethylsilane (11.5 mL, 0.0720 mol) and trifluoroacetic acid (5.5 mL, 0.071 mol). The reaction was heated to reflux for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give a light yellow solid <b>(P-0161,</b> 480 mg, 62%). MS (ESI) [M+H⁺]⁺ = 383.1, 385.1.

0173[6-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>P-0174</b><chemistry id="chem0238" num="0238"><img file="EP2086972B1_D0238.tif" /></chemistry> was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with 6-trifluoromethyl-pyridine-3-carbaldehyde in step 1. MS (ESI) [M+H⁺]⁺ = 418.2.

0174[6-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>P-0176</b><chemistry id="chem0239" num="0239"><img file="EP2086972B1_D0239.tif" /></chemistry> was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde <b>40</b> with 6-trifluoromethyl-pyridine-3-carbaldehyde in step 1 and 1H-Pyrrolo[2,3-b]pyridine <b>1</b> with 5-chloro-1H-pyrrolo[2,3-b]pyridine in step 5. MS (ESI) [M+H⁺]⁺ = 452.0.

0175{6-Chloro-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>P-0179</b><chemistry id="chem0240" num="0240"><img file="EP2086972B1_D0240.tif" /></chemistry> was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with 6-trifluoromethyl-pyridine-3-carbaldehyde in step I and 1H-Pyrrolo[2,3-b]pyridine <b>1</b> with 5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (prepared as described in Example 18, Scheme 172) in step 5. MS (ESI) [M+H⁺]⁺ = 498.0.

Example 15: Synthesis of (3-chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyrridin-3-ylmethyl)-pyridin-2-yl]-amine P-0129

0176(3-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>P-0129</b> was synthesized in 1 step as shown in Scheme 169. <chemistry id="chem0241" num="0241"><img file="EP2086972B1_D0241.tif" /></chemistry><chemistry id="chem0242" num="0242"><img file="EP2086972B1_D0242.tif" /></chemistry>

Step 1 - Preparation of (3-chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0129):</b>

01773-(6-bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6a, 10 mg, 0.023 mmol) was combined with 3-chlorobenzyl amine <b>(543,</b> 13 mg, 0.093 mmol) in dioxane (0.3 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg) and sodium tert-butoxide (15 mg) were added. The mixture was heated at 100 °C overnight. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO and purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50mm x 10mm ID), eluting with water with 0.1 % trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound <b>P-0129.</b> MS (ESI) [M+H⁺]⁺ = 349.1.

0178Additional compounds were prepared following the protocol of Scheme 169, replacing 3-chlorobenzyl amine <b>543</b> with an appropriate amine. The following compounds were made following this procedure: <ul id="ul0018" list-style="none" compact="compact"><li>(4-Morpholin-4-ylmethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0093),</b></li><li>Pyridin-3-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0094),</b></li><li>(5-Methyl-isoxazol-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0095),</b></li><li>(2-Pyrrolidin-1-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0096),</b></li><li>[1-(4-Methanesulfonyl-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0097),</b></li><li>(2-Methoxy-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0098),</b></li><li>(2-Morpholin-4-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0099),</b></li><li>((R)-1-Phenyl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0125),</b></li><li>(3-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0126).</b></li><li>[1-(2-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0127),</b></li><li>[2-(3-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0128),</b></li><li>(1-Methyl-1H-imidazol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0130),</b> and</li><li>(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0131)</b>.</li></ul>

0179The following table indicates the amine (Column 2) used in Scheme 169 to provide the compounds (Column 3). Column 1 provides the compound number and column 4 the observed mass. <tables id="tabl0005" num="0005"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="34mm" /><colspec colnum="3" colname="col3" colwidth="55mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Amine</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0093</entry><entry align="center" valign="middle"><chemistry id="chem0243" num="0243"><img file="EP2086972B1_D0243.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0244" num="0244"><img file="EP2086972B1_D0244.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">414.3</entry></row><row><entry align="center" valign="middle">P-0094</entry><entry align="center" valign="middle"><chemistry id="chem0245" num="0245"><img file="EP2086972B1_D0245.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0246" num="0246"><img file="EP2086972B1_D0246.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">316.3</entry></row><row><entry align="center" valign="middle">P-0095</entry><entry align="center" valign="middle"><chemistry id="chem0247" num="0247"><img file="EP2086972B1_D0247.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0248" num="0248"><img file="EP2086972B1_D0248.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">319.9</entry></row><row><entry align="center" valign="middle">P-0096</entry><entry align="center" valign="middle"><chemistry id="chem0249" num="0249"><img file="EP2086972B1_D0249.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0250" num="0250"><img file="EP2086972B1_D0250.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">322.3</entry></row><row><entry align="center" valign="middle">P-0097</entry><entry align="center" valign="middle"><chemistry id="chem0251" num="0251"><img file="EP2086972B1_D0251.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0252" num="0252"><img file="EP2086972B1_D0252.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.1</entry></row><row><entry align="center" valign="middle">P-0098</entry><entry align="center" valign="middle"><chemistry id="chem0253" num="0253"><img file="EP2086972B1_D0253.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0254" num="0254"><img file="EP2086972B1_D0254.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">283.5</entry></row><row><entry align="center" valign="middle">P-0099</entry><entry align="center" valign="middle"><chemistry id="chem0255" num="0255"><img file="EP2086972B1_D0255.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0256" num="0256"><img file="EP2086972B1_D0256.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">338.3</entry></row><row><entry align="center" valign="middle">P-0125</entry><entry align="center" valign="middle"><chemistry id="chem0257" num="0257"><img file="EP2086972B1_D0257.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0258" num="0258"><img file="EP2086972B1_D0258.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">329.1</entry></row><row><entry align="center" valign="middle">P-0126</entry><entry align="center" valign="middle"><chemistry id="chem0259" num="0259"><img file="EP2086972B1_D0259.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0260" num="0260"><img file="EP2086972B1_D0260.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">400.3</entry></row><row><entry align="center" valign="middle">P-0127</entry><entry align="center" valign="middle"><chemistry id="chem0261" num="0261"><img file="EP2086972B1_D0261.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0262" num="0262"><img file="EP2086972B1_D0262.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0128</entry><entry align="center" valign="middle"><chemistry id="chem0263" num="0263"><img file="EP2086972B1_D0263.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0264" num="0264"><img file="EP2086972B1_D0264.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0130</entry><entry align="center" valign="middle"><chemistry id="chem0265" num="0265"><img file="EP2086972B1_D0265.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0266" num="0266"><img file="EP2086972B1_D0266.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">319.1</entry></row><row><entry align="center" valign="middle">P-0131</entry><entry align="center" valign="middle"><chemistry id="chem0267" num="0267"><img file="EP2086972B1_D0267.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0268" num="0268"><img file="EP2086972B1_D0268.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">333.1</entry></row></tbody></tgroup></table></tables>

Example 16: Synthesis of 3-chloro-N-[5-(1H-pyrrolo[2,3-b]pyridn-3-ylmethyl)-pyridin-2-yl]-benzamide P-0111

01803-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>P-0111</b> was synthesized in 1 step as shown in Scheme 170. <chemistry id="chem0269" num="0269"><img file="EP2086972B1_D0269.tif" /></chemistry>

Step 1 - Preparation of 3-chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0111)</b>:

01813-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6a, 10 mg, 0.023 mmol) was combined with 3-chloro-benzamide <b>(544,</b> 15 mg, 0.096 mmol) in dioxane (0.4 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg), and sodium <i>tert</i>-butoxide (15 mg) were added. Cesium carbonate (20 mg) was added and the mixture was heated at 100°C overnight. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO (0.2 mL) and purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50mm x 10mm ID), eluting with water with 0.1 % trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound <b>P-0111.</b> MS (ESI) [M+H⁺]⁺= 363.1.

0182Additional compounds were prepared following the protocol of Scheme 170, replacing 3-chloro-benzamide <b>544</b> with an appropriate amide. The following compounds were made following this procedure: <ul id="ul0019" list-style="none" compact="compact"><li>3,4-Dichloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0100),</b></li><li>2-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0101)</b>,</li><li>2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0102),</b></li><li>Thiophene-2-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0103)</b>,</li><li>2-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide <b>(P-0104),</b></li><li>N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide <b>(P-0105)</b>,</li><li>Pyrazine-2-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0106)</b>,</li><li>Pyridine-2-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-</b>0107),</li><li>6-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-nicotinamide <b>(P-0108),</b></li><li>4-Fluoro-3-methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0109)</b>,</li><li>5-Methyl-pyrazine-2-carboxylic acid [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide <b>(P-0110),</b></li><li>4-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide <b>(P-0112)</b>,</li><li>N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethoxy-benzamide <b>(P-0113),</b></li><li>N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide <b>(P-0114)</b>,</li><li>3-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0115)</b>,</li><li>3,4-Difluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0116)</b>,</li><li>2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0117),</b></li><li>5-Fluoro-2-methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0118)</b>,</li><li>2-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0119)</b>,</li><li>3-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0120),</b></li><li>3-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0121),</b></li><li>3-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide <b>(P-0122),</b> and</li><li>2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide <b>(P-0123).</b></li></ul>

0183The following table indicates the amide (Column 2) used in Scheme 170 to provide the compounds (Column 3). Column I provides the compound number and Column 4 the observed mass. <tables id="tabl0006" num="0006"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="30mm" /><colspec colnum="3" colname="col3" colwidth="55mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Amide</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0100</entry><entry align="center" valign="middle"><chemistry id="chem0270" num="0270"><img file="EP2086972B1_D0270.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0271" num="0271"><img file="EP2086972B1_D0271.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">397.1</entry></row><row><entry align="center" valign="middle">P-0101</entry><entry align="center" valign="middle"><chemistry id="chem0272" num="0272"><img file="EP2086972B1_D0272.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0273" num="0273"><img file="EP2086972B1_D0273.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">381.1</entry></row><row><entry align="center" valign="middle">P-0102</entry><entry align="center" valign="middle"><chemistry id="chem0274" num="0274"><img file="EP2086972B1_D0274.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0275" num="0275"><img file="EP2086972B1_D0275.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0103</entry><entry align="center" valign="middle"><chemistry id="chem0276" num="0276"><img file="EP2086972B1_D0276.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0277" num="0277"><img file="EP2086972B1_D0277.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">335.1</entry></row><row><entry align="center" valign="middle">P-0104</entry><entry align="center" valign="middle"><chemistry id="chem0278" num="0278"><img file="EP2086972B1_D0278.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0279" num="0279"><img file="EP2086972B1_D0279.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">360.3</entry></row><row><entry align="center" valign="middle">P-0105</entry><entry align="center" valign="middle"><chemistry id="chem0280" num="0280"><img file="EP2086972B1_D0280.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0281" num="0281"><img file="EP2086972B1_D0281.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">329.9</entry></row><row><entry align="center" valign="middle">P-0106</entry><entry align="center" valign="middle"><chemistry id="chem0282" num="0282"><img file="EP2086972B1_D0282.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0283" num="0283"><img file="EP2086972B1_D0283.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">331.1</entry></row><row><entry align="center" valign="middle">P-0107</entry><entry align="center" valign="middle"><chemistry id="chem0284" num="0284"><img file="EP2086972B1_D0284.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0285" num="0285"><img file="EP2086972B1_D0285.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">329.9</entry></row><row><entry align="center" valign="middle">P-0108</entry><entry align="center" valign="middle"><chemistry id="chem0286" num="0286"><img file="EP2086972B1_D0286.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0287" num="0287"><img file="EP2086972B1_D0287.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">344.3</entry></row><row><entry align="center" valign="middle">P-0109</entry><entry align="center" valign="middle"><chemistry id="chem0288" num="0288"><img file="EP2086972B1_D0288.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0289" num="0289"><img file="EP2086972B1_D0289.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">361.1</entry></row><row><entry align="center" valign="middle">P-0110</entry><entry align="center" valign="middle"><chemistry id="chem0290" num="0290"><img file="EP2086972B1_D0290.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0291" num="0291"><img file="EP2086972B1_D0291.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.1</entry></row><row><entry align="center" valign="middle">P-0112</entry><entry align="center" valign="middle"><chemistry id="chem0292" num="0292"><img file="EP2086972B1_D0292.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0293" num="0293"><img file="EP2086972B1_D0293.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">415.1</entry></row><row><entry align="center" valign="middle">P-0113</entry><entry align="center" valign="middle"><chemistry id="chem0294" num="0294"><img file="EP2086972B1_D0294.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0295" num="0295"><img file="EP2086972B1_D0295.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">413.1</entry></row><row><entry align="center" valign="middle">P-0114</entry><entry align="center" valign="middle"><chemistry id="chem0296" num="0296"><img file="EP2086972B1_D0296.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0297" num="0297"><img file="EP2086972B1_D0297.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">397.1</entry></row><row><entry align="center" valign="middle">P-0115</entry><entry align="center" valign="middle"><chemistry id="chem0298" num="0298"><img file="EP2086972B1_D0298.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0299" num="0299"><img file="EP2086972B1_D0299.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">381.1</entry></row><row><entry align="center" valign="middle">P-0116</entry><entry align="center" valign="middle"><chemistry id="chem0300" num="0300"><img file="EP2086972B1_D0300.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0301" num="0301"><img file="EP2086972B1_D0301.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">365.1</entry></row><row><entry align="center" valign="middle">P-0117</entry><entry align="center" valign="middle"><chemistry id="chem0302" num="0302"><img file="EP2086972B1_D0302.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0303" num="0303"><img file="EP2086972B1_D0303.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">363.1</entry></row><row><entry align="center" valign="middle">P-0118</entry><entry align="center" valign="middle"><chemistry id="chem0304" num="0304"><img file="EP2086972B1_D0304.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0305" num="0305"><img file="EP2086972B1_D0305.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">361.1</entry></row><row><entry align="center" valign="middle">P-0119</entry><entry align="center" valign="middle"><chemistry id="chem0306" num="0306"><img file="EP2086972B1_D0306.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0307" num="0307"><img file="EP2086972B1_D0307.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0120</entry><entry align="center" valign="middle"><chemistry id="chem0308" num="0308"><img file="EP2086972B1_D0308.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0309" num="0309"><img file="EP2086972B1_D0309.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">359.1</entry></row><row><entry align="center" valign="middle">P-0121</entry><entry align="center" valign="middle"><chemistry id="chem0310" num="0310"><img file="EP2086972B1_D0310.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0311" num="0311"><img file="EP2086972B1_D0311.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0122</entry><entry align="center" valign="middle"><chemistry id="chem0312" num="0312"><img file="EP2086972B1_D0312.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0313" num="0313"><img file="EP2086972B1_D0313.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">343.1</entry></row><row><entry align="center" valign="middle">P-0123</entry><entry align="center" valign="middle"><chemistry id="chem0314" num="0314"><img file="EP2086972B1_D0314.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0315" num="0315"><img file="EP2086972B1_D0315.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">364.3</entry></row></tbody></tgroup></table></tables>

Example 17: Synthesis of 3,5-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-methoxy-benzylamide P-0135

01843,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-methoxy-benzylamide <b>P-0135</b> was synthesized in 1 step as shown in Scheme 171. <chemistry id="chem0316" num="0316"><img file="EP2086972B1_D0316.tif" /></chemistry>

Step 1 - Preparation of 3,5-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-methoxy-benzylamide <b>(P-0135):</b>

01853-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(514,</b> 10 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). 1,8-Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04 mmol) was added. 1-Isocyanatomethyl-4-methoxybenzene <b>(545,</b> 6.5 mg, 0.04 mmol) was added. The reaction was allowed to proceed at room temperature for 30 minutes. Acetic acid (0.2 mL) was added to the reaciton. The solvents were removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0.2 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ID), eluting with water with 0.1 % trifluoroacetic acid and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound <b>P-0135.</b> MS (ESI) [M+H⁺]⁺ = 390.3.

0186Additional compounds were prepared following the protocol of Scheme 171, replacing 1-isocyanatomethyl-4-methoxy-benzene <b>545</b> with an appropriate isocyanate or bromide. The following compounds were made following this procedure: <ul id="ul0020" list-style="none" compact="compact"><li>3-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>(P-0133),</b></li><li>2-[3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylpyrazol-1-yl]-1-phenyl-ethanone <b>(P-0134),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-chloro-benzylamide <b>(P-0136),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-fluoro-benzylamide <b>(P-0137),</b></li><li>3-[3,5-Dimethyl-1-(5-trifluoromethyl-furan-2-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine <b>(P-0138),</b></li><li>3-[3,5-Dimethyl-1-(5-methyl-isoxazol-3-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine <b>(P-0139),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-chloro-benzylamide <b>(P-0140),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(4-ethoxy-phenyl)-ethyl]-amide <b>(P-0141),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 3-methoxy-benzylamide <b>(P-0142),</b></li><li>3-{3,5-Dimethyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylmethyl}-1H-pyrrolo[2,3-b]pyridine <b>(P-0143)</b>,</li><li>3-[3,5-Dimethyl-1-(4-methyl-2-phenyl-thiazol-5-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine <b>(P-0144)</b>,</li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-methoxy-benzylamide <b>(P-0145)</b>,</li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(2,4-dichloro-phenyl)-ethyl]-amide <b>(P-0146),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide <b>(P-0147),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide <b>(P-0148)</b>,</li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid ((S)-1-phenyl-ethyl)-amide <b>(P-0149),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 3-fluoro-benzylamide <b>(P-0150)</b>,</li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-fluoro-benzylamide <b>(P-0151),</b></li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 4-methyl-benzylamide <b>(P-0152),</b> and</li><li>3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic acid 2-methyl-benzylamide <b>(P-0153).</b></li></ul>

0187The following table indicates the isocyanate or bromide (Column 2) used in Scheme 171 to provide the compounds (Column 3). Column I provides the compound number and Column 4 the observed mass. <tables id="tabl0007" num="0007"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="36mm" /><colspec colnum="3" colname="col3" colwidth="48mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Isocyanate or bromide</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0133</entry><entry align="center" valign="middle"><chemistry id="chem0317" num="0317"><img file="EP2086972B1_D0317.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0318" num="0318"><img file="EP2086972B1_D0318.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">317.1</entry></row><row><entry align="center" valign="middle">P-0134</entry><entry align="center" valign="middle"><chemistry id="chem0319" num="0319"><img file="EP2086972B1_D0319.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0320" num="0320"><img file="EP2086972B1_D0320.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.1</entry></row><row><entry align="center" valign="middle">P-0136</entry><entry align="center" valign="middle"><chemistry id="chem0321" num="0321"><img file="EP2086972B1_D0321.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0322" num="0322"><img file="EP2086972B1_D0322.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">394.3</entry></row><row><entry align="center" valign="middle">P-0137</entry><entry align="center" valign="middle"><chemistry id="chem0323" num="0323"><img file="EP2086972B1_D0323.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0324" num="0324"><img file="EP2086972B1_D0324.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">378.3</entry></row><row><entry align="center" valign="middle">P-0138</entry><entry align="center" valign="middle"><chemistry id="chem0325" num="0325"><img file="EP2086972B1_D0325.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0326" num="0326"><img file="EP2086972B1_D0326.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">375.1</entry></row><row><entry align="center" valign="middle">P-0139</entry><entry align="center" valign="middle"><chemistry id="chem0327" num="0327"><img file="EP2086972B1_D0327.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0328" num="0328"><img file="EP2086972B1_D0328.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">322.3</entry></row><row><entry align="center" valign="middle">P-0140</entry><entry align="center" valign="middle"><chemistry id="chem0329" num="0329"><img file="EP2086972B1_D0329.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0330" num="0330"><img file="EP2086972B1_D0330.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">393.9</entry></row><row><entry align="center" valign="middle">P-0141</entry><entry align="center" valign="middle"><chemistry id="chem0331" num="0331"><img file="EP2086972B1_D0331.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0332" num="0332"><img file="EP2086972B1_D0332.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">404.3</entry></row><row><entry align="center" valign="middle">P-0142</entry><entry align="center" valign="middle"><chemistry id="chem0333" num="0333"><img file="EP2086972B1_D0333.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0334" num="0334"><img file="EP2086972B1_D0334.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">390.3</entry></row><row><entry align="center" valign="middle">P-0143</entry><entry align="center" valign="middle"><chemistry id="chem0335" num="0335"><img file="EP2086972B1_D0335.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0336" num="0336"><img file="EP2086972B1_D0336.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">482.3</entry></row><row><entry align="center" valign="middle">P-0144</entry><entry align="center" valign="middle"><chemistry id="chem0337" num="0337"><img file="EP2086972B1_D0337.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0338" num="0338"><img file="EP2086972B1_D0338.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">414.3</entry></row><row><entry align="center" valign="middle">P-0145</entry><entry align="center" valign="middle"><chemistry id="chem0339" num="0339"><img file="EP2086972B1_D0339.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0340" num="0340"><img file="EP2086972B1_D0340.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">390.3</entry></row><row><entry align="center" valign="middle">P-0146</entry><entry align="center" valign="middle"><chemistry id="chem0341" num="0341"><img file="EP2086972B1_D0341.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0342" num="0342"><img file="EP2086972B1_D0342.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">442.3</entry></row><row><entry align="center" valign="middle">P-0147</entry><entry align="center" valign="middle"><chemistry id="chem0343" num="0343"><img file="EP2086972B1_D0343.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0344" num="0344"><img file="EP2086972B1_D0344.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">392.3</entry></row><row><entry align="center" valign="middle">P-0148</entry><entry align="center" valign="middle"><chemistry id="chem0345" num="0345"><img file="EP2086972B1_D0345.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0346" num="0346"><img file="EP2086972B1_D0346.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">392.3</entry></row><row><entry align="center" valign="middle">P-0149</entry><entry align="center" valign="middle"><chemistry id="chem0347" num="0347"><img file="EP2086972B1_D0347.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0348" num="0348"><img file="EP2086972B1_D0348.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">374.3</entry></row><row><entry align="center" valign="middle">P-0150</entry><entry align="center" valign="middle"><chemistry id="chem0349" num="0349"><img file="EP2086972B1_D0349.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0350" num="0350"><img file="EP2086972B1_D0350.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">378.3</entry></row><row><entry align="center" valign="middle">P-0151</entry><entry align="center" valign="middle"><chemistry id="chem0351" num="0351"><img file="EP2086972B1_D0351.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0352" num="0352"><img file="EP2086972B1_D0352.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">378.3</entry></row><row><entry align="center" valign="middle">P-0152</entry><entry align="center" valign="middle"><chemistry id="chem0353" num="0353"><img file="EP2086972B1_D0353.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0354" num="0354"><img file="EP2086972B1_D0354.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">374.3</entry></row><row><entry align="center" valign="middle">P-0153</entry><entry align="center" valign="middle"><chemistry id="chem0355" num="0355"><img file="EP2086972B1_D0355.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0356" num="0356"><img file="EP2086972B1_D0356.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">374.3</entry></row></tbody></tgroup></table></tables>

Example 18: Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 547.

01885-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine <b>547</b> was synthesized in 1 step from 5-bromo-1H-pyrrolo[2,3-b]pyridine <b>44</b> as shown in Scheme 172. <chemistry id="chem0357" num="0357"><img file="EP2086972B1_D0357.tif" /></chemistry>

Step 1 - Preparation of 5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine

(547)

:

0189To 5-bromo-7-azaindole <b>(44,</b> 1.04 g, 5.28 mmol) in 1.00 M potassium carbonate in water (15.8 mL) and tetrahydrofuran (50.0 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole <b>(546,</b> 1.65 g, 7.92 mmol), Tetrakis(triphenylphosphine)palladium(O) (0.305 mg, 0.26 mmol) and tetra-n-butylammonium iodide (0.20 g, 0.53 mmol). The reaction mixture was stirred at 70 °C overnight. The reaction mixture was poured into water and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide a light yellow solid <b>(547,</b> 670 mg, 64.0%). MS(ESI)[M+H⁺]⁺ = 199.4.

Example 19: Synthesis of [2-(4-fluoro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0177.

0190[2-(4-Fluoro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone <b>P-0177</b> was synthesized in 2 steps as shown in Scheme 173. <chemistry id="chem0358" num="0358"><img file="EP2086972B1_D0358.tif" /></chemistry>

Step 1 - Preparation of (4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-thiazol-2-yl]-carbamic acid tert-butyl ester <b>(549)</b>:

0191A mixture of {4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester <b>(548,</b> 0.397 g, 0.57 mmol, prepared according to the protocol of Scheme 159, Example 5, replacing 4-(aminomethyl)pyridine <b>516</b> with 4-fluoro-benzylamine in step 1, isolated after step 3), triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid <b>(549,</b> 0.11 g, 9%). MS (ESI) [M-H⁺]⁺=451.10.

Step 2 - Preparation of [2-(4-fluoro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone <b>(P-0177):</b>

0192To a solution of (4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-thiazol-2-yl]-carbamic acid tert-butyl ester <b>(549,</b> 0.11g, 0.2 mmol) in dichloromethane (2 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into cold sodium bicarbonate solution, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After removal of solvents, the residue was washed with ethyl acetate to provide the desired compound as a yellow solid <b>(P-0177,</b> 9 mg, 10%). MS (ESI) [M+H⁺]⁺= 353.12.

Example 20: Synthesis of {2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0178.

0193{2-[(4-Chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone <b>P-0178</b> was synthesized in 3 steps as shown in Scheme 174. <chemistry id="chem0359" num="0359"><img file="EP2086972B1_D0359.tif" /></chemistry>

Step 1 - Preparation of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde <b>(551):</b>

0194To a solution of (4-chloro-benzyl)-methyl-amine <b>(550,</b> 2 g, 0.01 mol) and N,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde <b>(93, 3</b> g, 0.01 mmmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was collected by filtration and washed with hexanes to provide the desired compound as a light-yellow solid <b>(551,</b> 3.6 g, 90%).

Step 2 - Preparation of {4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(552):</b>

0195To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at -20 °C, isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0 °C in 10 minutes. The reaction mixture was then cooled to -40 °C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde <b>(551</b>, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to -10 °C in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid <b>(552,</b> 0.5 g, 60%). MS (ESI) [M+H⁺]⁺= 575.29.

Step 3 - Preparation of {2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2.3-b]pyridin-3-yl)-methanone <b>(P-0178):</b>

0196A mixture of {4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(552, 1</b> g, 2 mmol), triethylsilane (2 mL, 12 mmol), and trifluoroacetic acid (1 mL, 13 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid <b>(P-0178,</b> 0.17 g, 30%). MS (ESI) [M+H⁺]⁺ = 383.09.

Example 21: Synthesis of aldehyde intermediates.

0197(3-Chloro-pyridin-4-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>558</b> was synthesized in 4 steps from 6-amino-nicotinic acid methyl ester 553 as shown in Scheme 175. <chemistry id="chem0360" num="0360"><img file="EP2086972B1_D0360.tif" /></chemistry>

Step 1 - Synthesis of 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester <b>(555):</b>

0198To 6-amino-nicotinic acid methyl ester <b>(553,</b> 2.15 g, 0.014 mol) in acetonitrile (60.0 mL) were added 3-chloro-pyridine-4-carbaldehyde (554, 2.00 g, 0.014 mol), triethylsilane (11.00 mL, 0.069 mol) and trifluoroacetic acid (5.00 mL, 0.065 mol). The reaction was stirred at 80 °C overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(555,</b> 1.5 g, 38.2%). MS (ESI) [M+H⁺]⁺ = 278.9.

Step 2 - Synthesis of 6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-yl-methanol <b>(556):</b>

0199To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester <b>(555,</b> 1.00 g, 3.60 mmol) in tetrahydrofuran (120 mL) was added a solution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 5.00 mL) under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature overnight, followed with addition of sodium sulfate decahydrate. After I hour, the reaction mixture was filtered, concentrated, and purified with silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound as a white solid <b>(556,</b> 0.5 g, 56%). MS (ESI) [M+H⁺]⁺ = 250.1.

Step 3 - Synthesis of 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridine-3-carbaldehyde <b>(557)</b>:

0200To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-yl-methanol <b>(556</b>, 0.50 g, 2.00 mmol) in tetrahydrofuran (20.0 mL) was added Dess-Martin periodinane (1.02 g, 2.40 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound <b>(557,</b> 0.45 g, 91%) that was used in the next step without further purification.

Step 4 - Synthesis of (3-chloro-pyridin-4-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>(558):</b>

0201To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridine-3-carbaldehyde <b>(557,</b> 0.45 g, 1.80 mmol) in dichloromethane (20.0 mL) were added di-tert-butyldicarbonate (0.65 g, 3.00mmol), 4-dimethylaminopyridine (0.012 g, 0.010 mmol) and triethylamine (0.28 mL, 2.00 mmol). The reaction was stirred at room temperature overnight, then concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(558,</b> 250 mg, 40.0%).

0202(2-Difluoromethoxy-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>559</b><chemistry id="chem0361" num="0361"><img file="EP2086972B1_D0361.tif" /></chemistry> was prepared following the protocol of Scheme 175, substituting 3-chloro-pyridine-4-carbaldehyde <b>554</b> with 2-difluoromethoxy-benzaldehyde in Step 1.

0203[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>560</b><chemistry id="chem0362" num="0362"><img file="EP2086972B1_D0362.tif" /></chemistry> was prepared following the protocol of Scheme 175, substituting 3-chloro-pyridine-4-carbaldehyde <b>554</b> with propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide in Step 1. MS (ESI) [M+H⁺]⁺ = 470.3.

0204(6-Fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>565</b> was synthesized in 4 steps from 2,6-Difluoro-nicotinic acid methyl ester <b>60</b> as shown in Scheme 176. <chemistry id="chem0363" num="0363"><img file="EP2086972B1_D0363.tif" /></chemistry>

Step 1 - Synthesis of 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinic acid methyl ester <b>(562):</b>

0205To 2,6-difluoro-nicotinic acid methyl ester <b>(60,</b> 1.82 g, 0.0105 mol) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at -40 °C, C-(6-trifluoromethyl-pyridin-3-yl)-methylamine <b>(561,</b> 1.00 g, 5.68 mmol) was added. The reaction was stirred at -40 °C, then allowed to warm to room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a white solid <b>(562,</b> 1.40 g, 74.9). MS (ESI) [M+H⁺]⁺ = 330.1.

Step 2 - Synthesis of 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanol (563):

0206To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinic acid methyl ester <b>(562,</b> 1.40 g, 4.25 mmol) in tetrahydrofuran (100.0 mL) under an atmosphere of nitrogen at room temperature, a solution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 10.0 mL) was added slowly. The reaction was stirred at room temperature overnight, followed by addition of an appropriate amount of sodium sulfate decahydrate. After 1 hour, the reaction mixture was filtered and concentrated to give crude compound <b>(563,</b> 1.2 g, 93.7%) that was used in the next step without further purification.

Step 3 - Synthesis of 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde (564):

0207To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanol <b>(563,</b> 1.20 g, 3.98 mmol) in dichloromethane (40.0 mL) was added Dess-Martin periodinane (1.86 g, 4.38 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous sodium thiosulfate and potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(564,</b> 0.28 g, 23.5%).

Step 4 - Synthesis of (6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(565):</b>

0208To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde <b>(564,</b> 0.28 g, 0.94 mmol) in tetrahydrofuran (10.0 mL) were added di-tert-butyldicarbonate (0.245 g, 1.12 mmol) and 4-dimethylaminopyridine (0.050 g, 0.41 mmol). The reaction was stirred at room temperature overnight, then concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (565, 0.22 g, 59%).

0209(6-Chloro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>570</b> was synthesized in 4 steps from 6-chloro-pyridin-2-ylamine <b>537</b> as shown in Scheme 177. <chemistry id="chem0364" num="0364"><img file="EP2086972B1_D0364.tif" /></chemistry>

Step 1 - Synthesis of (6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(567)</b>:

0210To 6-chloro-pyridin-2-ylamine <b>(537,</b> 0.760 g, 5.91 mmol) in acetonitrile (30.0 mL), 6-trifluoromethyl-pyridine-3-carbaldehyde <b>(566,</b> 1.06 g, 6.05 mmol), trifluoroacetic acid (3.00 mL, 0.0389 mol) and triethylsilane (6.00 mL, 0.0376 mol) were added. The reaction was heated to reflux for 4 hours. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(567,</b> 1.60 g, 94.1 %).

Step 2 - Synthesis of (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(568)</b>:

0211To (6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(567,</b> 4.50 g, 0.0156 mol) in acetonitrile (120.0 mL) under an atmosphere of nitrogen, N-bromosuccinimide (3.03 g, 0.0170 mol) in acetonitrile (50 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give a white solid <b>(568,</b> 6.20 g, 80.2%).

Step 3 - Synthesis of 2-chloro-6-[(6-trifluoromelhyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde (569):

0212To (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(568,</b> 4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at -78 °C, isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 6.44 mL) was added over 10 minutes. The reaction was stirred at -78 °C for 20 minutes, and then allowed to warm to room temperature for 10 minutes. The reaction was cooled to -78 °C, followed by adding tert-butyllithium (1.70 M in hexane, 15.3 mL) over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.23 mL, 0.0158 mol) was added and the reaction was stirred at -78 °C for 40 minutes, then allowed to warm to room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid <b>(569,</b> 2.84 g, 71.7%).

Step 4 - Synthesis of (6-chloro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(570)</b>

0213To a solution of 2-chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde <b>(569,</b> 0.545 g, 1.73 mmol) in tetrahydrofuran (10 mL), N,N-diisopropylethylamine (0.60 mL, 3.40 mmol), 4-dimethylaminopyridine (20 mg, 0.10 mmol), and a solution of di-tert-butyldicarbonate (0.41 g, 0.0019 mol) were added. The reaction mixture was stirred at room temperature overnight, then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography cluting with 20% to 100% ethyl acetate in hexane to give the desired compound (570, 0.60 g, 83.6%).

0214(5-Bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine <b>571</b><chemistry id="chem0365" num="0365"><img file="EP2086972B1_D0365.tif" /></chemistry> was prepared following the protocol of Steps 1 and 2 of Scheme 177, substituting 6-chloro-pyridin-2-ylamine 537 and 6-trifluoromethyl-pyridine-3-carbaldehyde <b>566</b> with 6-fluoro-pyridin-2-ylamine and 2-chloro-benzaldehyde, respectively in Step 1.

0215(6-Fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>572</b><chemistry id="chem0366" num="0366"><img file="EP2086972B1_D0366.tif" /></chemistry> was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine <b>537</b> and 6-trifluoromethyl-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin-2-ylamine and 6-methoxy-pyridine-3-carbaldehyde, respectively in Step 1.

0216(5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>631</b><chemistry id="chem0367" num="0367"><img file="EP2086972B1_D0367.tif" /></chemistry> was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine <b>537</b> and 6-trifluoromethyl-pyridine-3-carbaldehyde <b>566</b> with 6-fluoro-pyridin-2-ylamine and 5-fluoro-pyridine-3-carbaldehyde, respectively in Step 1, without Step 3 (i.e. the product of Step 2 is reacted according to Step 4).

0217(5-Bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester <b>637</b><chemistry id="chem0368" num="0368"><img file="EP2086972B1_D0368.tif" /></chemistry> was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine <b>537</b> and 6-trifluoromethyl-pyridine-3-carbaldehyde <b>566</b> with 6-fluoro-pyridin-2-ylamine and 5-chloro-benzaldehyde, respectively in Step 1, without Step 3 (i.e. the product of Step 2 is reacted according to Step 4).

Example 22: Synthesis of propane-1-sulfonic acid (2,4-difluoro-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino)-methyl-phenyl)-amide P-0258

0218Propane-1-sulfonic acid (2,4-difluoro-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl-phenyl)-amide <b>P-0258</b> was synthesized in 2 steps from 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>96</b> as shown in Scheme 178. <chemistry id="chem0369" num="0369"><img file="EP2086972B1_D0369.tif" /></chemistry>

Step 1 -Synthesis of [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester <b>(574):</b>

0219To a solution of 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>(96,</b> 0.644 g, 1.61 mmol) in tetrahydrofuran (10.0 mL) at -40 °C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.80 mL) was added slowly. The reaction was allowed to warm to 15 °C over 100 minutes, then cooled to -40 °C, followed by adding [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>(560,</b> 0.100 g, 0.21 mmol, prepared as described in Example 21, Scheme 175) in tetrahydrofuran (2.0 mL). The reaction was allowed to warm to 5 °C over 2 hours, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid <b>(574,</b> 75 mg, 47%). MS (ESI) [M+H⁺]⁺ = 744.7.

Step 2 - Synthesis of Propane-1-sulfonic acid (2,4-difluoro-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl-phenyl)-amide <b>(P-0258):</b>

0220To [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester <b>(574,</b> 75.0 mg, 0.10 mmol) in acetonitrile (10.0 mL) were added triethylsilane (0.40 mL, 2.5 mmol) and trifluoroacetic acid (0.20 mL, 2.6 mmol). The reaction was stirred at 80 °C for 4 hours. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give an off-white solid <b>(P-0258,</b> 29.3 mg, 61.6%). MS (ESI) [M+H⁺]⁺ = 472.4.

0221Propane-1-sulfonic acid (3-{[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-2,4-difluoro-phenyl)-amide <b>(P-0259),</b> [6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0378)</b>, and [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0379)</b>, <chemistry id="chem0370" num="0370"><img file="EP2086972B1_D0370.tif" /></chemistry> respectively, were prepared following the protocol of Scheme 178. <b>P-0259</b> was prepared by replacing 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 96 with 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine in Step 1 (MS [M+H⁺]⁺ = 506.1). <b>P-0378</b> was prepared by replacing [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>560</b> with (6-Fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>572</b> (prepared as described in Example 21, Scheme 177) in Step 1 (MS [M+H⁺]⁺ = 364.1). <b>P-0379</b> was prepared by replacing both azaindole <b>96</b> with 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine and aldehyde <b>560</b> with aldehyde <b>572</b> in Step 1 (MS [M+H⁺]⁺ = 400.0).

Example 23: Synthesis of [6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine P-0187

0222[6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>P-0187</b> was synthesized in 3 steps from 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine <b>575</b> as shown in Scheme 179. <chemistry id="chem0371" num="0371"><img file="EP2086972B1_D0371.tif" /></chemistry>

Step 1 - Synthesis of 5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[1,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(576):</b>

0223To 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine <b>(575,</b> 0.326 g, 0.000788 mol) in tetrahydrofuran (3.00 mL) at -45 °C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.380 mL) was added slowly. The reaction was allowed to warm to -25 °C in 30 minutes, and then cooled to -45 °C followed by adding (6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(565,</b> 80.0 mg, 0.20 mmol, prepared as described in Example 21, Scheme 176) in tetrahydrofuran (1.0 mL). The reaction was allowed to warm to room temperature over 2 hours. The reaction was poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(576,</b> 0.080 g, 60%). MS (ESI) [M+H⁺]⁺ = 688.1.

Step 2 - Synthesis of [5-(1-Benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(577)</b>

:

0224To 5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(576,</b> 0.100 g, 0.15 mmol) in acetonitrile (12.6 mL) were added triethylsilane (0.34 mL, 2.10 mmol) and trifluoroacetic acid (0.17 mL, 2.20 mmol). The reaction was heated to 80 °C for 2 hours. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude compound <b>(577,</b> 90 mg, 100%) that was used in the next step without further purification.

Step 3 - Synthesis of [6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0187):</b>

0225To [5-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(577,</b> 0.08 g, 0.13 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.110 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give an off-white solid <b>(P-0187,</b> 8.1 mg, 10%). MS (ESI) [M+H⁺]⁺ = 431.9.

0226[6-Fluoro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>P-0186</b> and [6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>P-0188,</b><chemistry id="chem0372" num="0372"><img file="EP2086972B1_D0372.tif" /></chemistry> respectively, were prepared following the protocol of Scheme 179, substituting 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine <b>575</b> with 1-benzenesulfonyl-3-iodo-5-chloro-1H-pyrrolo[2,3-b]pyridine or 1-Benzenesulfonyl-3-iodo-1H-pprolo[2,3-b]pyridine, respectively, in Step 1. MS (ESI) [M+H⁺]⁺ = 435.7 and 401.6, respectively.

Example 24: Synthesis of [6-(2-fluoro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0403

0227Synthesis of [6-(2-fluoro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone <b>P-0403</b> was synthesized in 2 steps from 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>96</b> as shown in Scheme 180. <chemistry id="chem0373" num="0373"><img file="EP2086972B1_D0373.tif" /></chemistry>

Step 1 - (2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic

acid tert-butyl ester <b>(580):</b>

0228To 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>(96,</b> 0.550 g, 1.37 mmol) in tetrahydrofuran (15.0 mL) at -40 °C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.65 mL) was added slowly. The reaction was allowed to warm to 5 °C over 70 minutes, then cooled to -40 °C, followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>(579,</b> prepared according to the protocol of Example 1, Scheme 19, Steps 1-3, replacing 4-chlorobenzaldehyde 40 with 2-fluoro-benzaldehyde in Step 1) in tetrahydrofuran (4.0 mL). The reaction was allowed to warm to room temperature over I hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(580,</b> 0.14 g, 26%). MS (ESI) [M+H⁺]⁺ = 447.0.

Step 2 - Synthesis of [6-(2-Fluoro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone <b>(P-0403)</b>:

0229To (2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester <b>(580,</b> 0.080 g, 0.18 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction was stirred at room temperature overnight, then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15 % methanol in dichloromethane to give the desired compound <b>(P-0403,</b> 15.0 mg, 23.0%). MS (ESI) [M+H⁺]⁺ = 347.5.

Example 25: Synthesis of (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)pyridin-3-yl]-methanone P-0404

0230(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)-pyridin-3-yl]-methanone <b>P-0404</b> was synthesized in 4 steps from 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine <b>581</b> as shown in Scheme 181. <chemistry id="chem0374" num="0374"><img file="EP2086972B1_D0374.tif" /></chemistry>

Step 1 - Synthesis of 5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2.3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(2-fluoro-benzy

/

)-carbamic acid tert-butyl ester <b>(582)</b>

0231To a solution of 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine <b>(581,</b> 0.420 g, 1.00 mmol) in tetrahydrofuran (15.0 mL) at -40 °C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.49 mL) was added slowly. The reaction was allowed to warm to 5 °C over 70 minutes, then cooled to -40 °C, followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester <b>579</b> in tetrahydrofuran (6.0 mL). The reaction was allowed to warm to room temperature over I hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(582,</b> 0.25 g, 41%). MS (ESI) [M+H⁺]⁺ = 623.1.

Step 2 - Synthesis of [5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridlne-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester <b>(583)</b>:

0232To 5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(2-fluoro-benzyl)-carbamic acid tert-butyl ester <b>(582,</b> 0.25 g, 0.40 mmol) in dichloromethane (5.0 mL) was added Dess-Martin periodinane (0.20 g, 0.48 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(583,</b> 0.060 g., 24%).

Step 3 - Synthesis of [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-1-yl]-(2-fluorobenzyl)-carbamic acid tert-butyl ester (584):

0233To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester <b>(583,</b> 60.0 mg, 0.097 mmol) in tetrahydrofuran (1.0 mL) was added aqueous potassium carbonate (1.0 M, 1.0 mL). The reaction was irradiated with microwave on 300 watts, 100°C for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound <b>(584,</b> 0.040 g, 64%) that was used in the next step without further purification.

Step 4 - Synthesis of (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)-pyridin-3-yl]-methanone <b>(P-0404):</b>

0234To [5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester <b>(584,</b> 0.030 g, 0.062 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction was stirred at room temperature overnight, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound <b>(P-0404,</b> 2.8 mg, 12%). MS (ESI) [M+H⁺]⁺ = 381.0.

Example 26: Synthesis of (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanone P-0405

0235(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanone <b>P-0405</b> was synthesized in 3 steps from 5-Chloro-1H-pyrrolo[2,3-b]pyridine <b>532</b> as shown in Scheme 182. <chemistry id="chem0375" num="0375"><img file="EP2086972B1_D0375.tif" /></chemistry>

Step 1 - Synthesis of 5-[(5-chloro-1H-pyrrolo[2.3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (586):

0236To 5-chloro-1H-pyrrolo[2,3-b]pyridine <b>(532,</b> 0.092 g, 0.60 mmol) in methanol (15.0 mL) were added (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(585,</b> 0.240 g, 0.70 mmol, prepared according to the protocol of Example 1, Scheme 19, Steps 1-3, replacing 4-chlorobenzaldehyde <b>40</b> with 6-methoxy-pyridine-3-carbaldehyde in Step 1) and potassium hydroxide (1.2 g, 0.021 mol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(586,</b> 0.110 g, 37%).

Step 2 - Synthesis of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(587):</b>

0237To 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(586,</b> 0.060 g, 0.12 mmol) in dichloromethane (10.0 mL) was added Dess-Martin periodinane (0.062 g, 0.15 mmol). The reaction was stirred at room temperature for 10 minutes. The reaction was concentrated and purified with a silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(587,</b> 0.020 g, 33%).

Step 3 - Synthesis of (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanone <b>(P-0405):</b>

0238To [5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(587,</b> 0.020 g, 0.040 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature for 2 hours, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(P-0405,</b> 5.5 mg, 34%). MS (ESI) [M+H⁺]⁺<b>=</b> 394.3.

0239{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone <b>P-0406</b><chemistry id="chem0376" num="0376"><img file="EP2086972B1_D0376.tif" /></chemistry> was prepared following the protocol of Scheme 182, substituting 5-chloro-1H-pyrrolo[2,3-b]pyridine <b>532</b> with 5-methoxy-1H-pyrrolo[2,3-b]pyridine in step 1. MS (ESI) [M+H⁺]⁺ = 390.1.

Example 27: Synthesis of intermediate 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine 592

02405-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine <b>592</b> was synthesized in 4 steps from 2-amino-4-chloro-thiazole-5-carbaldehyde <b>588</b> as shown in Scheme 183. <chemistry id="chem0377" num="0377"><img file="EP2086972B1_D0377.tif" /></chemistry>

Step 1 - Synthesis of (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester <b>(589):</b>

0241To 2-amino-4-chloro-thiazole-5-carbaldehyde (588, 5.00 g, 0.0308 mol) in tetrahydrofuran (122 mL) were added di-tert-butyldicarbonate (7.38 g, 0.0338 mol) and 4-dimethylaminopyridine (0.35 g, 0.0029 mol). The reaction was stirred at 58 °C for 2 hours, then concentrated and purified with silica gel column chromatography eluting with 20% to 80% ethyl acetate in hexane to give a yellow solid <b>(589,</b> 7.0 g, 87%).

Step 2 - Synthesis of 5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-chloro-thiazol-2-yl-carbamic acid tert-butyl ester <b>(590):</b>

0242To a solution of 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine <b>(581,</b> 4.40 g, 10.5 mmol) in tetrahydrofuran (30.0 mL) at -45 °C under nitrogen, a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.4 mL) was added slowly over 10 minutes. The reaction was allowed to warm to -25 °C over 30 minutes. The reaction was cooled to -65 °C, followed by adding the cold deprotonated (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester <b>589,</b> which was prepared in situ by adding isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.0 mL) to (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester <b>(589,</b> 2.51 g, 9.55 mmol) in tetrahydrofuran (23.0 mL) at -78 °C under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature in 2 hours, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25%to 100% ethyl acetate in hexane to give the desired compound <b>(590,</b> 3.70 g, 60.3%). MS (ESI) [M+H⁺]⁺ = 554.2.

Step 3 - Synthesis of [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-carbamic acid tert-butyl ester (591):

0243To 5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-chloro-thiazol-2-yl-carbamic acid tert-butyl ester <b>(590,</b> 0.200 g, 0.32 mmol) in dichloromethane (15.0 mL) were added triethylsilane (0.600 mL, 376 mmol) and trifluoroacetic acid (0.300 mL, 3.89 mmol). The reaction was stirred at room temperature for 3 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25%to 100% ethyl acetate in hexane to give the desired compound <b>(591,</b> 0.155 g, 88.7%). MS (ESI) [M+H⁺]⁺ = 538.9.

Step 4 - Synthesis of 5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-1-ylamine (592):

0244To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-carbamic acid tert-butyl ester <b>(591,</b> 4.30 g, 7.97 mmol) in dichloromethane (70.0 mL) was added a solution of hydrogen chloride (4.00 M in 1,4-dioxane, 42.0 mL). The reaction was stirred at room temperature for 2 days, then concentrated, and titrated with ethyl ether and ethyl acetate to give the desired compound <b>(592,</b> 2.60 g, 74.2%). MS (ESI) [M+H⁺]⁺ = 439.0.

02455-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine <b>593</b><chemistry id="chem0378" num="0378"><img file="EP2086972B1_D0378.tif" /></chemistry> was prepared following the protocol of Scheme 183, substituting 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine <b>581</b> with 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine in Step 2. MS (ESI) [M+H⁺]⁺ = 404.4.

Example 28: Synthesis of [4-Chloro-5-(5-chloro-1H-pyrroto[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine P-0231

0246[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>P-0231</b> was synthesized in 2 steps from 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine <b>592</b> as shown in Scheme 184. <chemistry id="chem0379" num="0379"><img file="EP2086972B1_D0379.tif" /></chemistry>

Step 1 - Synthesis of [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl-ylmethyl)-4-chloro-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>(595):</b>

0247To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine <b>(592,</b> 50.0 mg, 0.11 mmol, prepared as described in Example 27, Scheme 183) in ethanol (1.60 mL) and acetic acid (0.08 mL) were added 5-fluoro-pyridine-3-carbaldehyde <b>(594,</b> 43 mg, 0.34 mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.180 g). The reaction was irradiated with microwave on 300 watts, 100°C for 7 minutes. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound <b>(595,</b> 0.030 g, 48%).

Step 2 - Synthesis of [4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>(P-0231):</b>

0248To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmelhyl)-amine <b>(595,</b> 0.030 g, 0.055 mmol) in tetrahydrofuran (6.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.034 g, 0.11 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(P-0231</b>, 1.5 mg, 6.7%). MS (ESI) [M+H⁺]⁺ = 408.1.

Example 29: Synthesis of 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 599

02495-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 599 was synthesized in 4 steps from 5-chloro-1H-pyrrolo[2,3-b]pyridine 532 as shown in Scheme 185. <chemistry id="chem0380" num="0380"><img file="EP2086972B1_D0380.tif" /></chemistry>

Step 1 - Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde <b>(596):</b>

0250To 5-chloro-1H-pyrrolo[2,3-b]pyridine (532, 10.0 g, 65.5 mmol) in acetic acid (28.3 mL) were added hexamethylenetetramine (11.9 g, 85.2 mmol) and water (56.7 mL). The reaction was refluxed overnight, followed by addition of 200 mL of water. After 30 minutes, the reaction was filtered to recover the solid, then dried under air to give the desired compound (596, 7.0 g. 59%).

Step 2 - Synthesis of 1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (<b>597</b>):

0251To 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (596, 3.60 g, 0.0199 mol) in dichloromethane (100 mL) were added a solution of potassium hydroxide (9 M in water, 50 mL), tetrabutylammonium hydrogen sulfate (400 mg, 0.001 mol) and benzenesulfonyl chloride (2.9 mL, 0.023 mol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate to give a white solid (597, 2.3 g, 36.0%).

Step 3 - Synthesis of (6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(598):</b>

0252To 2-amino-5-bromopyridine (<b>15,</b> 3.10 g, 17.9 mmol) in tetrahydrofuran (80.0 mL) under an atmosphere of nitrogen at -78 °C, a solution n-butyllithium (2.50 M in hexane, 7.10 mL) was added slowly. After 30 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (3.90 g dissolved in tetrahydrofuran 20.0 mL, 18.1 mmol) was added to the reaction mixture slowly, and then allowed to warm to room temperature for 1 hour. The reaction was cooled to -78 °C followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.10 mL). The reaction mixture was stirred at -78 °C for 30 minutes, then allowed to warm to room temperature for 60 minutes. The reaction mixture was cooled to -78 °C, followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.50 mL) slowly. After 60 minutes, 1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (597, 1.90 g in 30 mL tetrahydrofuran, 5.92 mmol) was added to the reaction mixture. The reaction mixture was stirred at -78 °C for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound <b>(598,</b> 1.25 g, 50.9%). MS (ESI) [M+H⁺]⁺ = 415.2.

Step 4 - Synthesis of 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine <b>(599):</b>

0253To (6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(598,</b> 1.00 g, 0.00241 mol) in dichloromethane (25.0 mL) were added triethylsilane (3.00 mL, 0.0188 mol) and trifluoroacetic acid (1.50 mL, 0.0195 mol). The reaction was stirred at room temperature overnight, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(599,</b> 0.70 g, 73%).

02545-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine <b>600</b><chemistry id="chem0381" num="0381"><img file="EP2086972B1_D0381.tif" /></chemistry> was prepared following the protocol of Scheme 185, substituting 5-chloro-1H-pyrrolo[2,3-b]pyridine <b>532</b> with 1H-pyrrolo[2,3-b]pyridine in Step 1. MS (ESI) [M+H⁺]⁺ = 365.2.

Example 30: Synthesis of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine P-0324

0255[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>P-0324</b> was synthesized in 2 steps from 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine <b>599</b> as shown in Scheme 186. <chemistry id="chem0382" num="0382"><img file="EP2086972B1_D0382.tif" /></chemistry>

Step 1 - Synthesis of [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>(601):</b>

0256To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (599, 80.0 mg, 0.20 mmol, prepared as described in Example 29, Scheme 185) in ethanol (2.0 mL) and acetic acid (0.10 mL, 0.0018 mol) were added 5-fluoro-pyridine-3-carbaldehyde (594, 62.7 mg, 0.50 mmol) and sodium cyanoborohydride on silica gel (1.200 mmol/g loading; 0.251 g, 0.30 mmol). The reaction was irradiated with microwave on 300 watts, 100 °C for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (601, 0.060 g, 59%).

Step 2 - Synthesis of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>(P-0324):</b>

0257To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (601, 0.060 g, 0.12 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.11 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(P-0324,</b> 13.5mg, 31%). MS (ESI) [M+H⁺]⁺ = 368.0.

Example 31: Synthesis of (3-Chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-0183

0258(3-Chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>P-0183</b> was synthesized in 2 steps from 5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 600 as shown in Scheme 187. <chemistry id="chem0383" num="0383"><img file="EP2086972B1_D0383.tif" /></chemistry>

Step 1 - Synthesis of [5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyridin-2-yl]-(4-chloro-pyridin-3-ylmethyl)-amine <b>(602):</b>

0259To 5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 120.0 mg, 0.33 mmol, prepared as described in Example 29, Scheme 185) in acetonitrile (10.0 mL) were added 3-chloro-pyridine-4-carbaldehyde (554, 51.3 mg, 0.36 mmol), trifluoroacetic acid (0.30 mL, 0.0039 mol) and triethylsilane (0.60 mL, 0.0038 mol). The reaction was heated to reflux overnight, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% to 100% ethyl acetate in hexane to give the desired compound (602, 80 mg, 49.6%). MS [M+H⁺]⁺= 490.2.

Step 2 - Synthesis of (3-chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0183</b>):

0260To [5-(1-benzenesulfony]-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-pyridin-3-ylmethyl)-amine (602, 0.08 g, 0.16 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid (<b>P-0183</b>, 4.0 mg, 7%). MS (ESI) [M+H⁺]⁺ = 350.2.

Example 32: Synthesis of [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine P-0409

0261[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine <b>P-0409</b> was synthesized in 2 steps from 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine <b>599</b> as shown in Scheme 188. <chemistry id="chem0384" num="0384"><img file="EP2086972B1_D0384.tif" /></chemistry>

Step 1 - Synthesis of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyridin-2-yl]-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine (<b>P-0409</b>):

0262To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3,b]pyridin-3-ylmethyl)-pyridin-2-ylamine <b>(599,</b> 124.1 mg, 0.31 mmol, prepared as described in Example 29, Scheme 185) in ethanol (3.00 mL) and acetic acid (0.2 mL) were added 6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbaldehyde <b>(603,</b> 164.0 mg, 0.80 mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.700 g). The reaction was irradiated with microwave on 300 watts, 100°C for 150 minutes. To the reaction was added a solution of potassium hydroxide (9.0 M in water, 1.0 mL). The reaction was irradiated with microwave on 300 watts, 100 °C for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (<b>P-0409</b>, 10.6 mg, 7.6%). MS ESI) [M+H⁺]⁺ =448.4.

Example 33: Synthesis of 1-(3-fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea P-0412

02631-(3-Fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea <b>P-0412</b> was synthesized in 2 steps from 5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 600 as shown in Scheme 189. <chemistry id="chem0385" num="0385"><img file="EP2086972B1_D0385.tif" /></chemistry>

Step 1 - Synthesis of 1-[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea <b>(605):</b>

0264To 5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 150.0 mg, 0.41 mmol, prepared as described in Example 29, Scheme 185) in acetonitrile (12.5 mL) were added 3-fluoro-isocyanato-benzene (604, 61.6 mg, 0.45 mmol), 4-dimethylaminopyridine (10.0 mg, 0.082 mmol) and triethylamine (0.25 mL, 0.0018 mol). The reaction mixture was heated at 70 °C overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (605, 0.100 g, 48.4%).

Step 2 - Synthesis of 1-(3-Fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea (<b>P-0412</b>):

0265To 1-[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea (<b>605</b>, 0.100 g, 0.20 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature for 5 hours, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(P-0412,</b> 17.9 mg, 24.8%). MS (ESI) [M+H⁺]⁺ = 362.2.

Example 34: Synthesis of (2-chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-0335

0266(2-Chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>P-0335</b> was synthesized in 2 steps from (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine 571 as shown in Scheme 190. <chemistry id="chem0386" num="0386"><img file="EP2086972B1_D0386.tif" /></chemistry>

Step 1 - Synthesis of [6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(606):</b>

0267To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (<b>571</b>, 0.635 g, 2.01 mmol, prepared as described in Example 21, Scheme 177) in tetrahydrofuran (25.0 mL) under an atmosphere of nitrogen at -78 °C, a solution of n-butyllithium (2.50 M in hexane, 0.80 mL) was added slowly. After 20 minutes, tert-butyllithium (1.7 M in hexane, 2.40 mL) was added to the reaction and after 30 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (<b>47</b>, 0.575 g, 1.90 mmol) in tetrahydrofuran (8.0 mL) was added to the reaction. The reaction mixture was stirred at -78 °C for 60 minutes, then allowed to warm to room temperature for another 10 minutes. The reaction mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (606, 0.180 g, 17.6%). MS (ESI) [M+H⁺]⁺ = 539.2.

Step 2 - Synthesis of (2-chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0335</b>):

0268To [6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(606,</b> 180.0 mg, 0.33 mmol) in acetonitrile (15.0 mL) were added triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.50 mL, 6.50 mmol). The reaction was heated to reflux for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (<b>P-0335</b>, 24.9 mg, 19.4%). MS (ESI) [M+H⁺]⁺ = 367.0.

Example 35: Synthesis of 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine 610

02691-Benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>610</b> was synthesized in 3 steps from 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine <b>581</b> as shown in Scheme 191. <chemistry id="chem0387" num="0387"><img file="EP2086972B1_D0387.tif" /></chemistry>

Step 1 - Synthesis of (1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol <b>(608):</b>

0270To a solution of 1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine <b>(581,</b> 4.36 g, 10.4 mmol) in tetrahydrofuran (100.0 mL) at -40 °C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran. 5.06 mL) was added slowly. The reaction was allowed to warm to 5 °C over 60 minutes, then cooled to -40 °C, followed by adding 2-methylsulfanyl-pyrimidine-5-carbaldchyde (607, 1.30 g, 8.43 mmol, dissolved in tetrahydrofuran 15.0 mL). The reaction was allowed to warm to 10 °C over 2 hours. The reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound (608, 3.00 g, 79.6%). MS (ESI) [M+H⁺]⁺ = 447.2.

Step 2

-

Synthesis of 1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>(609):</b>

0271To (1-benzesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol <b>(608,</b> 0.35 g, 0.78 mmol) in dichloromethane (15.0 mL) were added triethylsilane (2.00 mL, 12.52 mmol) and trifluoroacetic acid (1.00 mL, 13.0 mmol). The reaction was stirred at 35 °C overnight, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(609,</b> 0.25 g, 74%). MS (ESI) [M+H⁺]^+* = 430.9.

Step 3 - Synthesis of 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (610) and 1-benzenesulfonyl-5-chloro-3-(2-methanesufonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>(611):</b>

0272To 1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>(609,</b> 0.500 g, 1.16 mmol) in dichloromethane (15.0 mL) was added metachloroperoxybenzoic acid (max. 77%, 0.572 g, 2.55 mmol) at 0 °C. The reaction was stirred at 0 °C for 70 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compounds (<b>610</b>, 0.310 g, 57.7%), MS (ESI) [M+H⁺]⁺ = 463.1; and (611, 0.200 g, 38.6%), MS (ESI) [M+H⁺]⁺ = 447.2.

02731-Benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>612</b><chemistry id="chem0388" num="0388"><img file="EP2086972B1_D0388.tif" /></chemistry> was prepared following the protocol of Scheme 191, substituting 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 581 with 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine in Step 1.

Example 36: Synthesis of (4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine P-0260

0274(4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>P-0260</b> was synthesized in 2 steps from 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>610</b> as shown in Scheme 192. <chemistry id="chem0389" num="0389"><img file="EP2086972B1_D0389.tif" /></chemistry>

Step 1 - Synthesis of [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-chloro-benzyl)-amine (<b>613</b>):

0275To 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>(610,</b> 0.060 g, 0.13 mmol, prepared as described in Example 35, Scheme 191) in N-methylpyrrolidinone (1.80 mL) was added p-chlorobenzylamine <b>(61</b>, 0.20 g, 1.4 mmol). The reaction was irradiated with microwave on 300 watts, 150 °C for 15 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(613,</b> 0.05 g, 74%). MS (ESI) [M+H⁺]⁺ = 524.3.

Step 2 - Synthesis of (4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0260</b>):

0276To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-chloro-benzyl)-amine <b>(613,</b> 0.050 g, 0.095 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.20 g, 0.63 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate in hexane to give an off-white solid (<b>P-0260</b>, 16.9 mg, 46%). MS (ESI) [M+H⁺]⁺ = 385.9.

0277Additional compounds were prepared following the protocol of Scheme 192, substituting p-chlorobenzylamine <b>61</b> with a suitable amine in Step 1. The following compounds were prepared following this protocol: <ul id="ul0021" list-style="none" compact="compact"><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine <b>(P-0261),</b></li><li>[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine (<b>P-0262</b>),</li><li>(2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0263),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-benzyl)-amine (<b>P-0264</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-amine (<b>P-0265</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine (<b>P-0266</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzyl)-amine (<b>P-0267</b>), and</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-amine <b>(P-0268).</b></li></ul> The following table indicates the amine (Column 2) used in Scheme 192 to provide the compounds (Column 3). Column I provides the compound number and Column 4 the experimental mass spectrometry result. <tables id="tabl0008" num="0008"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="38mm" /><colspec colnum="3" colname="col3" colwidth="53mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Amine in Step 1</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS (ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0261</entry><entry align="center" valign="middle"><chemistry id="chem0390" num="0390"><img file="EP2086972B1_D0390.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0391" num="0391"><img file="EP2086972B1_D0391.tif" /></chemistry></entry><entry align="center" valign="middle">384.1</entry></row><row><entry align="center" valign="middle">P-0262</entry><entry align="center" valign="middle"><chemistry id="chem0392" num="0392"><img file="EP2086972B1_D0392.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0393" num="0393"><img file="EP2086972B1_D0393.tif" /></chemistry></entry><entry align="center" valign="middle">418.9</entry></row><row><entry align="center" valign="middle">P-0263</entry><entry align="center" valign="middle"><chemistry id="chem0394" num="0394"><img file="EP2086972B1_D0394.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0395" num="0395"><img file="EP2086972B1_D0395.tif" /></chemistry></entry><entry align="center" valign="middle">384.2</entry></row><row><entry align="center" valign="middle">P-0264</entry><entry align="center" valign="middle"><chemistry id="chem0396" num="0396"><img file="EP2086972B1_D0396.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0397" num="0397"><img file="EP2086972B1_D0397.tif" /></chemistry></entry><entry align="center" valign="middle">368.2</entry></row><row><entry align="center" valign="middle">P-0265</entry><entry align="center" valign="middle"><chemistry id="chem0398" num="0398"><img file="EP2086972B1_D0398.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0399" num="0399"><img file="EP2086972B1_D0399.tif" /></chemistry></entry><entry align="center" valign="middle">386.2</entry></row><row><entry align="center" valign="middle">P-0266</entry><entry align="center" valign="middle"><chemistry id="chem0400" num="0400"><img file="EP2086972B1_D0400.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0401" num="0401"><img file="EP2086972B1_D0401.tif" /></chemistry></entry><entry align="center" valign="middle">418.9</entry></row><row><entry align="center" valign="middle">P-0267</entry><entry align="center" valign="middle"><chemistry id="chem0402" num="0402"><img file="EP2086972B1_D0402.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0403" num="0403"><img file="EP2086972B1_D0403.tif" /></chemistry></entry><entry align="center" valign="middle">[M-H⁺]^- = 384.0</entry></row><row><entry align="center" valign="middle">P-0268</entry><entry align="center" valign="middle"><chemistry id="chem0404" num="0404"><img file="EP2086972B1_D0404.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0405" num="0405"><img file="EP2086972B1_D0405.tif" /></chemistry></entry><entry align="center" valign="middle">419.2</entry></row></tbody></tgroup></table></tables>

Example 37: Synthesis of (2-fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine P-0291

0278(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>P-0291</b> was synthesized in 1 step from 1-benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>612</b> as shown in Scheme 193. <chemistry id="chem0406" num="0406"><img file="EP2086972B1_D0406.tif" /></chemistry>

Step 1 - Synthesis of (2-fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0291</b>):

0279To 1-benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>(612,</b> 0.080 g, 0.19 mmol, prepared as described in Example 35, Scheme 191) in N-methylpyrrolidinone (1.00 mL) was added 2-fluoro-5-trifluoromethyl-benzylamine <b>(614,</b> 0.20 g, 1.0 mmol). The reaction was irradated with microwave on 300 watts, 150°C for 15 minutes. Potassium hydroxide in water (1.00 M, 2.00 mL) was added to the reaction. The reaction was irradiated with microwave on 300 watts, 90°C for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (<b>P-0291</b>, 37.4 mg, 50%). MS (ESI) [M+H⁺]⁺ = 402.6.

0280Additional compounds were prepared following the protocol of Scheme 193, substituting 2-fluoro-5-trifluoromethyl-benzylamine <b>614</b> with a suitable amine. The following compounds were prepared following this protocol: <ul id="ul0022" list-style="none" compact="compact"><li>(2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0292),</b></li><li>(2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0293),</b></li><li>(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0294</b>),</li><li>(3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0295</b>),</li><li>(2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0300),</b></li><li>(2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0301</b>),</li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine (<b>P-0302</b>),</li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine (<b>P-0303</b>),</li><li>(5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0304),</b></li><li>(2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0305</b>),</li><li>(2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0306</b>),</li><li>(4-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0307),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine (<b>P-0308</b>),</li><li>(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0309),</b></li><li>(2,5-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0310</b>),</li><li>(3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0311</b>),</li><li>(2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0312</b>),</li><li>(2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0313),</b></li><li>(4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0314</b>),</li><li>(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0315</b>),</li><li>(2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0316</b>),</li><li>(5-Chloro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0317</b>),</li><li>(5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0318),</b></li><li>(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0319),</b></li><li>(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0320</b>), and</li><li>(2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0407).</b></li></ul> The following table indicates the amine (Column 2) used in Scheme 193 to provide the compounds (Column 3). Column I provides the compound number and Column 4 the experimental mass spectrometry result. <tables id="tabl0009" num="0009"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="39mm" /><colspec colnum="3" colname="col3" colwidth="46mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Amine</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS (ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0292</entry><entry align="center" valign="middle"><chemistry id="chem0407" num="0407"><img file="EP2086972B1_D0407.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0408" num="0408"><img file="EP2086972B1_D0408.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">352.3</entry></row><row><entry align="center" valign="middle">P-0293</entry><entry align="center" valign="middle"><chemistry id="chem0409" num="0409"><img file="EP2086972B1_D0409.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0410" num="0410"><img file="EP2086972B1_D0410.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">418.2</entry></row><row><entry align="center" valign="middle">P-0294</entry><entry align="center" valign="middle"><chemistry id="chem0411" num="0411"><img file="EP2086972B1_D0411.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0412" num="0412"><img file="EP2086972B1_D0412.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">402.5</entry></row><row><entry align="center" valign="middle">P-0295</entry><entry align="center" valign="middle"><chemistry id="chem0413" num="0413"><img file="EP2086972B1_D0413.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0414" num="0414"><img file="EP2086972B1_D0414.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">352.3</entry></row><row><entry align="center" valign="middle">P-0300</entry><entry align="center" valign="middle"><chemistry id="chem0415" num="0415"><img file="EP2086972B1_D0415.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0416" num="0416"><img file="EP2086972B1_D0416.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">334.5</entry></row><row><entry align="center" valign="middle">P-0301</entry><entry align="center" valign="middle"><chemistry id="chem0417" num="0417"><img file="EP2086972B1_D0417.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0418" num="0418"><img file="EP2086972B1_D0418.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">349.9</entry></row><row><entry align="center" valign="middle">P-0302</entry><entry align="center" valign="middle"><chemistry id="chem0419" num="0419"><img file="EP2086972B1_D0419.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0420" num="0420"><img file="EP2086972B1_D0420.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">384.0</entry></row><row><entry align="center" valign="middle">P-0303</entry><entry align="center" valign="middle"><chemistry id="chem0421" num="0421"><img file="EP2086972B1_D0421.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0422" num="0422"><img file="EP2086972B1_D0422.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">400.5</entry></row><row><entry align="center" valign="middle">P-0304</entry><entry align="center" valign="middle"><chemistry id="chem0423" num="0423"><img file="EP2086972B1_D0423.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0424" num="0424"><img file="EP2086972B1_D0424.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.9</entry></row><row><entry align="center" valign="middle">P-0305</entry><entry align="center" valign="middle"><chemistry id="chem0425" num="0425"><img file="EP2086972B1_D0425.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0426" num="0426"><img file="EP2086972B1_D0426.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">383.9</entry></row><row><entry align="center" valign="middle">P-0306</entry><entry align="center" valign="middle"><chemistry id="chem0427" num="0427"><img file="EP2086972B1_D0427.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0428" num="0428"><img file="EP2086972B1_D0428.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">352.4</entry></row><row><entry align="center" valign="middle">P-0307</entry><entry align="center" valign="middle"><chemistry id="chem0429" num="0429"><img file="EP2086972B1_D0429.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0430" num="0430"><img file="EP2086972B1_D0430.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">352.0</entry></row><row><entry align="center" valign="middle">P-0308</entry><entry align="center" valign="middle"><chemistry id="chem0431" num="0431"><img file="EP2086972B1_D0431.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0432" num="0432"><img file="EP2086972B1_D0432.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">384.0</entry></row><row><entry align="center" valign="middle">P-0309</entry><entry align="center" valign="middle"><chemistry id="chem0433" num="0433"><img file="EP2086972B1_D0433.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0434" num="0434"><img file="EP2086972B1_D0434.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">402.5</entry></row><row><entry align="center" valign="middle">P-0310</entry><entry align="center" valign="middle"><chemistry id="chem0435" num="0435"><img file="EP2086972B1_D0435.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0436" num="0436"><img file="EP2086972B1_D0436.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">389.0</entry></row><row><entry align="center" valign="middle">P-0311</entry><entry align="center" valign="middle"><chemistry id="chem0437" num="0437"><img file="EP2086972B1_D0437.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0438" num="0438"><img file="EP2086972B1_D0438.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">368.0</entry></row><row><entry align="center" valign="middle">P-0312</entry><entry align="center" valign="middle"><chemistry id="chem0439" num="0439"><img file="EP2086972B1_D0439.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0440" num="0440"><img file="EP2086972B1_D0440.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">382.5</entry></row><row><entry align="center" valign="middle">P-0313</entry><entry align="center" valign="middle"><chemistry id="chem0441" num="0441"><img file="EP2086972B1_D0441.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0442" num="0442"><img file="EP2086972B1_D0442.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">385.0</entry></row><row><entry align="center" valign="middle">P-0314</entry><entry align="center" valign="middle"><chemistry id="chem0443" num="0443"><img file="EP2086972B1_D0443.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0444" num="0444"><img file="EP2086972B1_D0444.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.9</entry></row><row><entry align="center" valign="middle">P-0315</entry><entry align="center" valign="middle"><chemistry id="chem0445" num="0445"><img file="EP2086972B1_D0445.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0446" num="0446"><img file="EP2086972B1_D0446.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">402.4</entry></row><row><entry align="center" valign="middle">P-0316</entry><entry align="center" valign="middle"><chemistry id="chem0447" num="0447"><img file="EP2086972B1_D0447.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0448" num="0448"><img file="EP2086972B1_D0448.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">368.2</entry></row><row><entry align="center" valign="middle">P-0317</entry><entry align="center" valign="middle"><chemistry id="chem0449" num="0449"><img file="EP2086972B1_D0449.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0450" num="0450"><img file="EP2086972B1_D0450.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">364.8</entry></row><row><entry align="center" valign="middle">P-0318</entry><entry align="center" valign="middle"><chemistry id="chem0451" num="0451"><img file="EP2086972B1_D0451.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0452" num="0452"><img file="EP2086972B1_D0452.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">348.6</entry></row><row><entry align="center" valign="middle">P-0319</entry><entry align="center" valign="middle"><chemistry id="chem0453" num="0453"><img file="EP2086972B1_D0453.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0454" num="0454"><img file="EP2086972B1_D0454.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">402.5</entry></row><row><entry align="center" valign="middle">P-0320</entry><entry align="center" valign="middle"><chemistry id="chem0455" num="0455"><img file="EP2086972B1_D0455.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0456" num="0456"><img file="EP2086972B1_D0456.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">402.5</entry></row><row><entry align="center" valign="middle">P-0407</entry><entry align="center" valign="middle"><chemistry id="chem0457" num="0457"><img file="EP2086972B1_D0457.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0458" num="0458"><img file="EP2086972B1_D0458.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">368.3</entry></row></tbody></tgroup></table></tables>

Example 38: Synthesis of [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-amine P-0390

0281[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxybenzyl)-amine <b>P-0390</b> was synthesized in 1 step from 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethylp)-1H-pyrrolo[2,3-b]pyridine 610 as shown in Scheme 194. <chemistry id="chem0459" num="0459"><img file="EP2086972B1_D0459.tif" /></chemistry>

Step 1-Synthesis of [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-amine (P-0390)

0282To 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine <b>(610,</b> 0.060 g, 0.13 mmol, prepared as described in Example 35, Scheme 191) in N-methylpyrrolidinone (1.40 mL) was added 2-difluoromethoxy-benzylamine <b>(615,</b> 0.200 g, 1.16 mmol). The reaction was irradiated with microwave on 300 watts, 150 °C for 15 minutes. Potassium hydroxide in water (1.00 M, 2.00 mL) was added to the reaction. The reaction was irradiated with microwave on 300 watts, 90 °C for 10 minutes, then poured into ethyl acetate and water. The organic layer was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(P-0390,</b> 10.9 mg, 20%). MS (ESI) [M+H⁺]⁺ = 418.0.

0283Additional compounds were prepared following the protocol of Scheme 194, substituting 2-difluoromethoxy-benzylamine <b>615</b> with a suitable amine. The following compounds were prepared following this protocol: <ul id="ul0023" list-style="none" compact="compact"><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoromethylbenzyl)-amine <b>(P-0289),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethylbenzyl)-amine <b>(P-0391),</b></li><li>(3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine <b>(P-0392),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethylbenzyl)-amine <b>(P-0393),</b></li><li>[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethylbenzyl)-amine (<b>P-0394</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-y]-(2,3-difluoro-benzyl)-amine (<b>P-0395</b>),</li><li>(2-Chloro-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl)-amine (<b>P-0396</b>),</li><li>[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine (<b>P-0402</b>),</li><li>(2-Chloro-5-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0408</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmethyl-amine <b>(P-0416),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-pyrrolidin-1-yl-ethyl)-amine <b>(P-0417),</b></li><li>Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0418</b>),</li><li>Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine <b>(P-0419),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-benzyl)-amine <b>(P-0420),</b></li><li>(3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0421</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine <b>(P-0422),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amine <b>(P-0423),</b></li><li>(3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methylamine <b>(P-0424),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3,5-difluoro-benzyl)-amine (<b>P-0425</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(2-fluoro-phenyl)-ethyl]-amine (<b>P-0426</b>),</li><li>[1-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0427</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-1-(4-fluoro-phenyl)-ethyl]-amine <b>(P-0428),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (<b>P-0429</b>),</li><li>(2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methylamine <b>(P-0430),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methyl-benzyl)-amine <b>(P-0431),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-amine <b>(P-0433),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine <b>(P-0434),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexylmethyl-amine <b>(P-0435),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-amine (<b>P-0436</b>),</li><li>[2-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-aminc <b>(P-0437),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-benzyl)-amine <b>(P-0438),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methoxy-benzyl)-amine <b>(P-0439),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine <b>(P-0440),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-ethyl)-amine <b>(P-0441),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-bcnzyl)-aminc <b>(P-0442),</b></li><li>(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0443</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-thoxy-benzyl)-amine <b>(P-0444),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl)-amine <b>(P-0445),</b></li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)-amine <b>(P-0446),</b></li><li>(4-Chloro-3-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (<b>P-0447</b>),</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(3-fluoro-phenyl)-ethyl]-amine (<b>P-0448</b>), and</li><li>[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-benzyl)-amine <b>(P-0449).</b></li></ul> The following table indicates the amine (Column 2) used in Scheme 194 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result. <tables id="tabl0010" num="0010"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="37mm" /><colspec colnum="3" colname="col3" colwidth="51mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Amine</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS (ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0289</entry><entry align="center" valign="middle"><chemistry id="chem0460" num="0460"><img file="EP2086972B1_D0460.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0461" num="0461"><img file="EP2086972B1_D0461.tif" /></chemistry></entry><entry align="center" valign="middle">436.0</entry></row><row><entry align="center" valign="middle">P-0391</entry><entry align="center" valign="middle"><chemistry id="chem0462" num="0462"><img file="EP2086972B1_D0462.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0463" num="0463"><img file="EP2086972B1_D0463.tif" /></chemistry></entry><entry align="center" valign="middle">436.0</entry></row><row><entry align="center" valign="middle">P-0392</entry><entry align="center" valign="middle"><chemistry id="chem0464" num="0464"><img file="EP2086972B1_D0464.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0465" num="0465"><img file="EP2086972B1_D0465.tif" /></chemistry></entry><entry align="center" valign="middle">402.0</entry></row><row><entry align="center" valign="middle">P-0393</entry><entry align="center" valign="middle"><chemistry id="chem0466" num="0466"><img file="EP2086972B1_D0466.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0467" num="0467"><img file="EP2086972B1_D0467.tif" /></chemistry></entry><entry align="center" valign="middle">[M-H⁺]^- = 434.1</entry></row><row><entry align="center" valign="middle">P-0394</entry><entry align="center" valign="middle"><chemistry id="chem0468" num="0468"><img file="EP2086972B1_D0468.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0469" num="0469"><img file="EP2086972B1_D0469.tif" /></chemistry></entry><entry align="center" valign="middle">437.3</entry></row><row><entry align="center" valign="middle">P-0395</entry><entry align="center" valign="middle"><chemistry id="chem0470" num="0470"><img file="EP2086972B1_D0470.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0471" num="0471"><img file="EP2086972B1_D0471.tif" /></chemistry></entry><entry align="center" valign="middle">386.0</entry></row><row><entry align="center" valign="middle">P-0396</entry><entry align="center" valign="middle"><chemistry id="chem0472" num="0472"><img file="EP2086972B1_D0472.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0473" num="0473"><img file="EP2086972B1_D0473.tif" /></chemistry></entry><entry align="center" valign="middle">402.0</entry></row><row><entry align="center" valign="middle">P-0402</entry><entry align="center" valign="middle"><chemistry id="chem0474" num="0474"><img file="EP2086972B1_D0474.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0475" num="0475"><img file="EP2086972B1_D0475.tif" /></chemistry></entry><entry align="center" valign="middle">434.3</entry></row><row><entry align="center" valign="middle">P-0408</entry><entry align="center" valign="middle"><chemistry id="chem0476" num="0476"><img file="EP2086972B1_D0476.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0477" num="0477"><img file="EP2086972B1_D0477.tif" /></chemistry></entry><entry align="center" valign="middle">402.0</entry></row><row><entry align="center" valign="middle">P-0416</entry><entry align="center" valign="middle"><chemistry id="chem0478" num="0478"><img file="EP2086972B1_D0478.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0479" num="0479"><img file="EP2086972B1_D0479.tif" /></chemistry></entry><entry align="center" valign="middle">351.1</entry></row><row><entry align="center">P-0417</entry><entry align="center"><chemistry id="chem0480" num="0480"><img file="EP2086972B1_D0480.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0481" num="0481"><img file="EP2086972B1_D0481.tif" /></chemistry></entry><entry align="center">357.1</entry></row><row><entry align="center">P-0418</entry><entry align="center"><chemistry id="chem0482" num="0482"><img file="EP2086972B1_D0482.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0483" num="0483"><img file="EP2086972B1_D0483.tif" /></chemistry></entry><entry align="center">350.3</entry></row><row><entry align="center">P-0419</entry><entry align="center"><chemistry id="chem0484" num="0484"><img file="EP2086972B1_D0484.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0485" num="0485"><img file="EP2086972B1_D0485.tif" /></chemistry></entry><entry align="center">364.3</entry></row><row><entry align="center">P-0420</entry><entry align="center"><chemistry id="chem0486" num="0486"><img file="EP2086972B1_D0486.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0487" num="0487"><img file="EP2086972B1_D0487.tif" /></chemistry></entry><entry align="center">434.3</entry></row><row><entry align="center">P-0421</entry><entry align="center"><chemistry id="chem0488" num="0488"><img file="EP2086972B1_D0488.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0489" num="0489"><img file="EP2086972B1_D0489.tif" /></chemistry></entry><entry align="center">383.9</entry></row><row><entry align="center">P-0422</entry><entry align="center"><chemistry id="chem0490" num="0490"><img file="EP2086972B1_D0490.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0491" num="0491"><img file="EP2086972B1_D0491.tif" /></chemistry></entry><entry align="center">351.1</entry></row><row><entry align="center">P-0423</entry><entry align="center"><chemistry id="chem0492" num="0492"><img file="EP2086972B1_D0492.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0493" num="0493"><img file="EP2086972B1_D0493.tif" /></chemistry></entry><entry align="center">368.3</entry></row><row><entry align="center">P-0424</entry><entry align="center"><chemistry id="chem0494" num="0494"><img file="EP2086972B1_D0494.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0495" num="0495"><img file="EP2086972B1_D0495.tif" /></chemistry></entry><entry align="center">398.3</entry></row><row><entry align="center">P-0425</entry><entry align="center"><chemistry id="chem0496" num="0496"><img file="EP2086972B1_D0496.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0497" num="0497"><img file="EP2086972B1_D0497.tif" /></chemistry></entry><entry align="center">386.3</entry></row><row><entry align="center">P-0426</entry><entry align="center"><chemistry id="chem0498" num="0498"><img file="EP2086972B1_D0498.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0499" num="0499"><img file="EP2086972B1_D0499.tif" /></chemistry></entry><entry align="center">382.3</entry></row><row><entry align="center">P-0427</entry><entry align="center"><chemistry id="chem0500" num="0500"><img file="EP2086972B1_D0500.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0501" num="0501"><img file="EP2086972B1_D0501.tif" /></chemistry></entry><entry align="center">398.3</entry></row><row><entry align="center">P-0428</entry><entry align="center"><chemistry id="chem0502" num="0502"><img file="EP2086972B1_D0502.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0503" num="0503"><img file="EP2086972B1_D0503.tif" /></chemistry></entry><entry align="center">382.3</entry></row><row><entry align="center">P-0429</entry><entry align="center"><chemistry id="chem0504" num="0504"><img file="EP2086972B1_D0504.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0505" num="0505"><img file="EP2086972B1_D0505.tif" /></chemistry></entry><entry align="center">419.1</entry></row><row><entry align="center">P-0430</entry><entry align="center"><chemistry id="chem0506" num="0506"><img file="EP2086972B1_D0506.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0507" num="0507"><img file="EP2086972B1_D0507.tif" /></chemistry></entry><entry align="center">397.9</entry></row><row><entry align="center">P-0431</entry><entry align="center"><chemistry id="chem0508" num="0508"><img file="EP2086972B1_D0508.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0509" num="0509"><img file="EP2086972B1_D0509.tif" /></chemistry></entry><entry align="center">364.3</entry></row><row><entry align="center">P-0433</entry><entry align="center"><chemistry id="chem0510" num="0510"><img file="EP2086972B1_D0510.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0511" num="0511"><img file="EP2086972B1_D0511.tif" /></chemistry></entry><entry align="center">380.3</entry></row><row><entry align="center">P-0434</entry><entry align="center"><chemistry id="chem0512" num="0512"><img file="EP2086972B1_D0512.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0513" num="0513"><img file="EP2086972B1_D0513.tif" /></chemistry></entry><entry align="center">373.1</entry></row><row><entry align="center">P-0435</entry><entry align="center"><chemistry id="chem0514" num="0514"><img file="EP2086972B1_D0514.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0515" num="0515"><img file="EP2086972B1_D0515.tif" /></chemistry></entry><entry align="center">356.3</entry></row><row><entry align="center">P-0436</entry><entry align="center"><chemistry id="chem0516" num="0516"><img file="EP2086972B1_D0516.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0517" num="0517"><img file="EP2086972B1_D0517.tif" /></chemistry></entry><entry align="center">351.1</entry></row><row><entry align="center">P-0437</entry><entry align="center"><chemistry id="chem0518" num="0518"><img file="EP2086972B1_D0518.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0519" num="0519"><img file="EP2086972B1_D0519.tif" /></chemistry></entry><entry align="center">397.9</entry></row><row><entry align="center">P-0438</entry><entry align="center"><chemistry id="chem0520" num="0520"><img file="EP2086972B1_D0520.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0521" num="0521"><img file="EP2086972B1_D0521.tif" /></chemistry></entry><entry align="center">416.3</entry></row><row><entry align="center">P-0439</entry><entry align="center"><chemistry id="chem0522" num="0522"><img file="EP2086972B1_D0522.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0523" num="0523"><img file="EP2086972B1_D0523.tif" /></chemistry></entry><entry align="center">380.3</entry></row><row><entry align="center">P-0440</entry><entry align="center"><chemistry id="chem0524" num="0524"><img file="EP2086972B1_D0524.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0525" num="0525"><img file="EP2086972B1_D0525.tif" /></chemistry></entry><entry align="center">364.3</entry></row><row><entry align="center">P-0441</entry><entry align="center"><chemistry id="chem0526" num="0526"><img file="EP2086972B1_D0526.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0527" num="0527"><img file="EP2086972B1_D0527.tif" /></chemistry></entry><entry align="center">317.9</entry></row><row><entry align="center">P-0442</entry><entry align="center"><chemistry id="chem0528" num="0528"><img file="EP2086972B1_D0528.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0529" num="0529"><img file="EP2086972B1_D0529.tif" /></chemistry></entry><entry align="center">368.3</entry></row><row><entry align="center">P-0443</entry><entry align="center"><chemistry id="chem0530" num="0530"><img file="EP2086972B1_D0530.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0531" num="0531"><img file="EP2086972B1_D0531.tif" /></chemistry></entry><entry align="center">401.9</entry></row><row><entry align="center">P-0444</entry><entry align="center"><chemistry id="chem0532" num="0532"><img file="EP2086972B1_D0532.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0533" num="0533"><img file="EP2086972B1_D0533.tif" /></chemistry></entry><entry align="center">393.9</entry></row><row><entry align="center">P-0445</entry><entry align="center"><chemistry id="chem0534" num="0534"><img file="EP2086972B1_D0534.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0535" num="0535"><img file="EP2086972B1_D0535.tif" /></chemistry></entry><entry align="center">435.1</entry></row><row><entry align="center">P-0446</entry><entry align="center"><chemistry id="chem0536" num="0536"><img file="EP2086972B1_D0536.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0537" num="0537"><img file="EP2086972B1_D0537.tif" /></chemistry></entry><entry align="center">416.3</entry></row><row><entry align="center">P-0447</entry><entry align="center"><chemistry id="chem0538" num="0538"><img file="EP2086972B1_D0538.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0539" num="0539"><img file="EP2086972B1_D0539.tif" /></chemistry></entry><entry align="center">402.3</entry></row><row><entry align="center">P-0448</entry><entry align="center"><chemistry id="chem0540" num="0540"><img file="EP2086972B1_D0540.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0541" num="0541"><img file="EP2086972B1_D0541.tif" /></chemistry></entry><entry align="center">382.3</entry></row><row><entry align="center">P-0449</entry><entry align="center"><chemistry id="chem0542" num="0542"><img file="EP2086972B1_D0542.tif" /></chemistry></entry><entry align="center"><chemistry id="chem0543" num="0543"><img file="EP2086972B1_D0543.tif" /></chemistry></entry><entry align="center">393.1</entry></row></tbody></tgroup></table></tables>

Example 39: Synthesis of (2-chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-0210

0284(2-Chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>P-0210</b> was synthesized in 2 steps from 5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine <b>600</b> as shown in Scheme 195. <chemistry id="chem0544" num="0544"><img file="EP2086972B1_D0544.tif" /></chemistry>

Step 1 - Preparation of [5-(1-benzenesulfonyl-1Hpyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6-fluoro-benzyl)-amine (617):

02855-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 30 mg, 0.083 mmol, prepared as described in Example 29, Scheme 185) was combined with 2-chloro-6-fluoro-benzaldehyde (<b>616</b>, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol:acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100 °C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give compound 617, which was used in the next step without further purification.

Step 2 - Preparation of (2-chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0210</b>):

0286[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6-fluoro-benzyl)-amine 617 was combined with methanol:potassium hydroxide (1M) (1:1, 0.5 mL). The mixture was heated at 80 °C for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ID) eluting with 0.1 % trifluoroacetic acid in water and 20-100 % acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound <b>P-0210.</b> MS (ESI) [M+H⁺]⁺ = 367.1.

0287Additional compounds were prepared following the protocol of Scheme 195, replacing 2-chloro-6-fluoro-benzaldehyde <b>616</b> with an appropriate aldehyde in Step 1. The following compounds were made following this procedure: <ul id="ul0024" list-style="none" compact="compact"><li>Phenethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0211</b>),</li><li>(2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0212</b>),</li><li>(2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0213</b>),</li><li>(3-Bromo-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0214),</b></li><li>(2-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0215</b>),</li><li>(2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0216),</b></li><li>(2-Methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0217</b>),</li><li>(1-Methyl-1H-benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0218),</b></li><li>(6-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0219</b>),</li><li>(1H-Benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0220),</b></li><li>(2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0221),</b></li><li>(5-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0222</b>),</li><li>(3-Fluoro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0223),</b></li><li>(6-Methoxy-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0224</b>),</li><li>(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0225),</b></li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0226),</b></li><li>(3,5-Dichloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0227),</b></li><li>(6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0228),</b></li><li>(3-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0229),</b></li><li>(5-Fluoro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0230),</b></li><li>(2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0342</b>),</li><li>(3-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0343</b>),</li><li>(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0344),</b></li><li>(4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0345),</b></li><li>(3-Fluoro-5-trifluoromelhyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0346),</b></li><li>(2-Morpholin-4-yl-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0347),</b></li><li>(4-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0348</b>),</li><li>(2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0349</b>),</li><li>(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0350),</b></li><li>(2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0351</b>),</li><li>(2-Fluoro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0352</b>),</li><li>Dimethyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine <b>(P-0353),</b></li><li>(3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0354),</b></li><li>(5-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0355),</b></li><li>(3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0356),</b></li><li>(2-Propoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0357),</b></li><li>(2-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0358),</b></li><li>(2-Chloro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0359</b>),</li><li>(2-Fluoro-6-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0360</b>),</li><li>[2-(2-Morpholin-4-yl-ethoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0361),</b></li><li>(2,3-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0362),</b></li><li>(2-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0363</b>),</li><li>(2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0364),</b></li><li>(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0365),</b></li><li>(5-Fluoro-2-methoxy-benzyl)-[5-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0366),</b></li><li>(2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0367),</b></li><li>(2-Fluoro-4-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0368),</b></li><li>[2-(3-Dimethylamino-propoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0369</b>),</li><li>(2,6-Dimethoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0370),</b></li><li>(2-Fluoro-5-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0371),</b></li><li>(4-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0372),</b></li><li>(3-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0373),</b></li><li>(6-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0374),</b></li><li>(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0375</b>),</li><li>[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine <b>(P-0376),</b></li><li>Propane-1-sulfonic acid (2-fluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide (<b>P-0377</b>),</li><li>(2,5-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0380)</b>,</li><li>Pyrimidin-5-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0381),</b></li><li>(5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0382),</b></li><li>(2-Ethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0383</b>),</li><li>2,2-Dimethyl-N-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-propionamide <b>(P-0384),</b></li><li>Methyl-(3-{(5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine (<b>P-0385</b>),</li><li>Methyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine <b>(P-0386),</b></li><li>(2-Chloro-4-methanesulfonyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0387</b>),</li><li>(5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0397</b>),</li><li>(2,2-Difluoro-benzo[1,3]dioxol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0398),</b></li><li>Dimethyl-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine <b>(P-0399),</b></li><li>(5-Chloro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>(P-0400),</b> and</li><li>(2-Methoxy-pyrimidin-5-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (<b>P-0401</b>).</li></ul> The following table indicates the aldehyde (Column 2) used in Step 1 of Scheme 195 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result. <tables id="tabl0011" num="0011"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="38mm" /><colspec colnum="3" colname="col3" colwidth="50mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Aldehyde</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0211</entry><entry align="center" valign="middle"><chemistry id="chem0545" num="0545"><img file="EP2086972B1_D0545.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0546" num="0546"><img file="EP2086972B1_D0546.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">329.1</entry></row><row><entry align="center" valign="middle">P-0212</entry><entry align="center" valign="middle"><chemistry id="chem0547" num="0547"><img file="EP2086972B1_D0547.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0548" num="0548"><img file="EP2086972B1_D0548.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">351.1</entry></row><row><entry align="center" valign="middle">P-0213</entry><entry align="center" valign="middle"><chemistry id="chem0549" num="0549"><img file="EP2086972B1_D0549.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0550" num="0550"><img file="EP2086972B1_D0550.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">338.1</entry></row><row><entry align="center" valign="middle">P-0214</entry><entry align="center" valign="middle"><chemistry id="chem0551" num="0551"><img file="EP2086972B1_D0551.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0552" num="0552"><img file="EP2086972B1_D0552.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">395.9</entry></row><row><entry align="center" valign="middle">P-0215</entry><entry align="center" valign="middle"><chemistry id="chem0553" num="0553"><img file="EP2086972B1_D0553.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0554" num="0554"><img file="EP2086972B1_D0554.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.9</entry></row><row><entry align="center" valign="middle">P-0216</entry><entry align="center" valign="middle"><chemistry id="chem0555" num="0555"><img file="EP2086972B1_D0555.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0556" num="0556"><img file="EP2086972B1_D0556.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">349.1</entry></row><row><entry align="center" valign="middle">P-0217</entry><entry align="center" valign="middle"><chemistry id="chem0557" num="0557"><img file="EP2086972B1_D0557.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0558" num="0558"><img file="EP2086972B1_D0558.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">329.1</entry></row><row><entry align="center" valign="middle">P-0218</entry><entry align="center" valign="middle"><chemistry id="chem0559" num="0559"><img file="EP2086972B1_D0559.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0560" num="0560"><img file="EP2086972B1_D0560.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">369.1</entry></row><row><entry align="center" valign="middle">P-0219</entry><entry align="center" valign="middle"><chemistry id="chem0561" num="0561"><img file="EP2086972B1_D0561.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0562" num="0562"><img file="EP2086972B1_D0562.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.9</entry></row><row><entry align="center" valign="middle">P-0220</entry><entry align="center" valign="middle"><chemistry id="chem0563" num="0563"><img file="EP2086972B1_D0563.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0564" num="0564"><img file="EP2086972B1_D0564.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">355.1</entry></row><row><entry align="center" valign="middle">P-0221</entry><entry align="center" valign="middle"><chemistry id="chem0565" num="0565"><img file="EP2086972B1_D0565.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0566" num="0566"><img file="EP2086972B1_D0566.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.1</entry></row><row><entry align="center" valign="middle">P-0222</entry><entry align="center" valign="middle"><chemistry id="chem0567" num="0567"><img file="EP2086972B1_D0567.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0568" num="0568"><img file="EP2086972B1_D0568.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.9</entry></row><row><entry align="center" valign="middle">P-0223</entry><entry align="center" valign="middle"><chemistry id="chem0569" num="0569"><img file="EP2086972B1_D0569.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0570" num="0570"><img file="EP2086972B1_D0570.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">334.3</entry></row><row><entry align="center" valign="middle">P-0224</entry><entry align="center" valign="middle"><chemistry id="chem0571" num="0571"><img file="EP2086972B1_D0571.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0572" num="0572"><img file="EP2086972B1_D0572.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.9</entry></row><row><entry align="center" valign="middle">P-0225</entry><entry align="center" valign="middle"><chemistry id="chem0573" num="0573"><img file="EP2086972B1_D0573.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0574" num="0574"><img file="EP2086972B1_D0574.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0226</entry><entry align="center" valign="middle"><chemistry id="chem0575" num="0575"><img file="EP2086972B1_D0575.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0576" num="0576"><img file="EP2086972B1_D0576.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">383.1</entry></row><row><entry align="center" valign="middle">P-0227</entry><entry align="center" valign="middle"><chemistry id="chem0577" num="0577"><img file="EP2086972B1_D0577.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0578" num="0578"><img file="EP2086972B1_D0578.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">383.9</entry></row><row><entry align="center" valign="middle">P-0228</entry><entry align="center" valign="middle"><chemistry id="chem0579" num="0579"><img file="EP2086972B1_D0579.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0580" num="0580"><img file="EP2086972B1_D0580.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0229</entry><entry align="center" valign="middle"><chemistry id="chem0581" num="0581"><img file="EP2086972B1_D0581.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0582" num="0582"><img file="EP2086972B1_D0582.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">334.3</entry></row><row><entry align="center" valign="middle">P-0230</entry><entry align="center" valign="middle"><chemistry id="chem0583" num="0583"><img file="EP2086972B1_D0583.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0584" num="0584"><img file="EP2086972B1_D0584.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">334.3</entry></row><row><entry align="center" valign="middle">P-0342</entry><entry align="center" valign="middle"><chemistry id="chem0585" num="0585"><img file="EP2086972B1_D0585.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0586" num="0586"><img file="EP2086972B1_D0586.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">383.1</entry></row><row><entry align="center" valign="middle">P-0343</entry><entry align="center" valign="middle"><chemistry id="chem0587" num="0587"><img file="EP2086972B1_D0587.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0588" num="0588"><img file="EP2086972B1_D0588.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">333.1</entry></row><row><entry align="center" valign="middle">P-0344</entry><entry align="center" valign="middle"><chemistry id="chem0589" num="0589"><img file="EP2086972B1_D0589.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0590" num="0590"><img file="EP2086972B1_D0590.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0345</entry><entry align="center" valign="middle"><chemistry id="chem0591" num="0591"><img file="EP2086972B1_D0591.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0592" num="0592"><img file="EP2086972B1_D0592.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.1</entry></row><row><entry align="center" valign="middle">P-0346</entry><entry align="center" valign="middle"><chemistry id="chem0593" num="0593"><img file="EP2086972B1_D0593.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0594" num="0594"><img file="EP2086972B1_D0594.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0347</entry><entry align="center" valign="middle"><chemistry id="chem0595" num="0595"><img file="EP2086972B1_D0595.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0596" num="0596"><img file="EP2086972B1_D0596.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0348</entry><entry align="center" valign="middle"><chemistry id="chem0597" num="0597"><img file="EP2086972B1_D0597.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0598" num="0598"><img file="EP2086972B1_D0598.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">417.1</entry></row><row><entry align="center" valign="middle">P-0349</entry><entry align="center" valign="middle"><chemistry id="chem0599" num="0599"><img file="EP2086972B1_D0599.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0600" num="0600"><img file="EP2086972B1_D0600.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">417.1</entry></row><row><entry align="center" valign="middle">P-0350</entry><entry align="center" valign="middle"><chemistry id="chem0601" num="0601"><img file="EP2086972B1_D0601.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0602" num="0602"><img file="EP2086972B1_D0602.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0351</entry><entry align="center" valign="middle"><chemistry id="chem0603" num="0603"><img file="EP2086972B1_D0603.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0604" num="0604"><img file="EP2086972B1_D0604.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">383.1</entry></row><row><entry align="center" valign="middle">P-0352</entry><entry align="center" valign="middle"><chemistry id="chem0605" num="0605"><img file="EP2086972B1_D0605.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0606" num="0606"><img file="EP2086972B1_D0606.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">363.1</entry></row><row><entry align="center" valign="middle">P-0353</entry><entry align="center" valign="middle"><chemistry id="chem0607" num="0607"><img file="EP2086972B1_D0607.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0608" num="0608"><img file="EP2086972B1_D0608.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">360.3</entry></row><row><entry align="center" valign="middle">P-0354</entry><entry align="center" valign="middle"><chemistry id="chem0609" num="0609"><img file="EP2086972B1_D0609.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0610" num="0610"><img file="EP2086972B1_D0610.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.1</entry></row><row><entry align="center" valign="middle">P-0355</entry><entry align="center" valign="middle"><chemistry id="chem0611" num="0611"><img file="EP2086972B1_D0611.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0612" num="0612"><img file="EP2086972B1_D0612.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">334.3</entry></row><row><entry align="center" valign="middle">P-0356</entry><entry align="center" valign="middle"><chemistry id="chem0613" num="0613"><img file="EP2086972B1_D0613.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0614" num="0614"><img file="EP2086972B1_D0614.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">351.1</entry></row><row><entry align="center" valign="middle">P-0357</entry><entry align="center" valign="middle"><chemistry id="chem0615" num="0615"><img file="EP2086972B1_D0615.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0616" num="0616"><img file="EP2086972B1_D0616.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">373.1</entry></row><row><entry align="center" valign="middle">P-0358</entry><entry align="center" valign="middle"><chemistry id="chem0617" num="0617"><img file="EP2086972B1_D0617.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0618" num="0618"><img file="EP2086972B1_D0618.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">400.3</entry></row><row><entry align="center" valign="middle">P-0359</entry><entry align="center" valign="middle"><chemistry id="chem0619" num="0619"><img file="EP2086972B1_D0619.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0620" num="0620"><img file="EP2086972B1_D0620.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">379.1</entry></row><row><entry align="center" valign="middle">P-0360</entry><entry align="center" valign="middle"><chemistry id="chem0621" num="0621"><img file="EP2086972B1_D0621.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0622" num="0622"><img file="EP2086972B1_D0622.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0361</entry><entry align="center" valign="middle"><chemistry id="chem0623" num="0623"><img file="EP2086972B1_D0623.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0624" num="0624"><img file="EP2086972B1_D0624.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">444.3</entry></row><row><entry align="center" valign="middle">P-0362</entry><entry align="center" valign="middle"><chemistry id="chem0625" num="0625"><img file="EP2086972B1_D0625.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0626" num="0626"><img file="EP2086972B1_D0626.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">351.1</entry></row><row><entry align="center" valign="middle">P-0363</entry><entry align="center" valign="middle"><chemistry id="chem0627" num="0627"><img file="EP2086972B1_D0627.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0628" num="0628"><img file="EP2086972B1_D0628.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">417.1</entry></row><row><entry align="center" valign="middle">P-0364</entry><entry align="center" valign="middle"><chemistry id="chem0629" num="0629"><img file="EP2086972B1_D0629.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0630" num="0630"><img file="EP2086972B1_D0630.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.1</entry></row><row><entry align="center" valign="middle">P-0365</entry><entry align="center" valign="middle"><chemistry id="chem0631" num="0631"><img file="EP2086972B1_D0631.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0632" num="0632"><img file="EP2086972B1_D0632.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0366</entry><entry align="center" valign="middle"><chemistry id="chem0633" num="0633"><img file="EP2086972B1_D0633.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0634" num="0634"><img file="EP2086972B1_D0634.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">363.1</entry></row><row><entry align="center" valign="middle">P-0367</entry><entry align="center" valign="middle"><chemistry id="chem0635" num="0635"><img file="EP2086972B1_D0635.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0636" num="0636"><img file="EP2086972B1_D0636.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">381.1</entry></row><row><entry align="center" valign="middle">P-0368</entry><entry align="center" valign="middle"><chemistry id="chem0637" num="0637"><img file="EP2086972B1_D0637.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0638" num="0638"><img file="EP2086972B1_D0638.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0369</entry><entry align="center" valign="middle"><chemistry id="chem0639" num="0639"><img file="EP2086972B1_D0639.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0640" num="0640"><img file="EP2086972B1_D0640.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">416.3</entry></row><row><entry align="center" valign="middle">P-0370</entry><entry align="center" valign="middle"><chemistry id="chem0641" num="0641"><img file="EP2086972B1_D0641.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0642" num="0642"><img file="EP2086972B1_D0642.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">376.3</entry></row><row><entry align="center" valign="middle">P-0371</entry><entry align="center" valign="middle"><chemistry id="chem0643" num="0643"><img file="EP2086972B1_D0643.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0644" num="0644"><img file="EP2086972B1_D0644.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">363.1</entry></row><row><entry align="center" valign="middle">P-0372</entry><entry align="center" valign="middle"><chemistry id="chem0645" num="0645"><img file="EP2086972B1_D0645.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0646" num="0646"><img file="EP2086972B1_D0646.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0373</entry><entry align="center" valign="middle"><chemistry id="chem0647" num="0647"><img file="EP2086972B1_D0647.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0648" num="0648"><img file="EP2086972B1_D0648.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.1</entry></row><row><entry align="center" valign="middle">P-0374</entry><entry align="center" valign="middle"><chemistry id="chem0649" num="0649"><img file="EP2086972B1_D0649.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0650" num="0650"><img file="EP2086972B1_D0650.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">400.3</entry></row><row><entry align="center" valign="middle">P-0375</entry><entry align="center" valign="middle"><chemistry id="chem0651" num="0651"><img file="EP2086972B1_D0651.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0652" num="0652"><img file="EP2086972B1_D0652.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">401.1</entry></row><row><entry align="center" valign="middle">P-0376</entry><entry align="center" valign="middle"><chemistry id="chem0653" num="0653"><img file="EP2086972B1_D0653.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0654" num="0654"><img file="EP2086972B1_D0654.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">413.9</entry></row><row><entry align="center" valign="middle">P-0377</entry><entry align="center" valign="middle"><chemistry id="chem0655" num="0655"><img file="EP2086972B1_D0655.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0656" num="0656"><img file="EP2086972B1_D0656.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">453.9</entry></row><row><entry align="center" valign="middle">P0380</entry><entry align="center" valign="middle"><chemistry id="chem0657" num="0657"><img file="EP2086972B1_D0657.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0658" num="0658"><img file="EP2086972B1_D0658.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">383.1</entry></row><row><entry align="center" valign="middle">P-0381</entry><entry align="center" valign="middle"><chemistry id="chem0659" num="0659"><img file="EP2086972B1_D0659.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0660" num="0660"><img file="EP2086972B1_D0660.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">317.2</entry></row><row><entry align="center" valign="middle">P-0382</entry><entry align="center" valign="middle"><chemistry id="chem0661" num="0661"><img file="EP2086972B1_D0661.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0662" num="0662"><img file="EP2086972B1_D0662.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">367.1</entry></row><row><entry align="center" valign="middle">P-0383</entry><entry align="center" valign="middle"><chemistry id="chem0663" num="0663"><img file="EP2086972B1_D0663.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0664" num="0664"><img file="EP2086972B1_D0664.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">343.1</entry></row><row><entry align="center" valign="middle">P-0384</entry><entry align="center" valign="middle"><chemistry id="chem0665" num="0665"><img file="EP2086972B1_D0665.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0666" num="0666"><img file="EP2086972B1_D0666.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">415.2</entry></row><row><entry align="center" valign="middle">P-0385</entry><entry align="center" valign="middle"><chemistry id="chem0667" num="0667"><img file="EP2086972B1_D0667.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0668" num="0668"><img file="EP2086972B1_D0668.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.4</entry></row><row><entry align="center" valign="middle">P-0386</entry><entry align="center" valign="middle"><chemistry id="chem0669" num="0669"><img file="EP2086972B1_D0669.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0670" num="0670"><img file="EP2086972B1_D0670.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">345.2</entry></row><row><entry align="center" valign="middle">P-0387</entry><entry align="center" valign="middle"><chemistry id="chem0671" num="0671"><img file="EP2086972B1_D0671.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0672" num="0672"><img file="EP2086972B1_D0672.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">427.1</entry></row><row><entry align="center" valign="middle">P-0397</entry><entry align="center" valign="middle"><chemistry id="chem0673" num="0673"><img file="EP2086972B1_D0673.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0674" num="0674"><img file="EP2086972B1_D0674.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row><row><entry align="center" valign="middle">P-0398</entry><entry align="center" valign="middle"><chemistry id="chem0675" num="0675"><img file="EP2086972B1_D0675.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0676" num="0676"><img file="EP2086972B1_D0676.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">396.1</entry></row><row><entry align="center" valign="middle">P-0399</entry><entry align="center" valign="middle"><chemistry id="chem0677" num="0677"><img file="EP2086972B1_D0677.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0678" num="0678"><img file="EP2086972B1_D0678.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">359.1</entry></row><row><entry align="center" valign="middle">P-0400</entry><entry align="center" valign="middle"><chemistry id="chem0679" num="0679"><img file="EP2086972B1_D0679.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0680" num="0680"><img file="EP2086972B1_D0680.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">350.3</entry></row><row><entry align="center" valign="middle">P-0401</entry><entry align="center" valign="middle"><chemistry id="chem0681" num="0681"><img file="EP2086972B1_D0681.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0682" num="0682"><img file="EP2086972B1_D0682.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">347.1</entry></row></tbody></tgroup></table></tables>

Example 40: Synthesis of

[

4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine P-0190

0288<b>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxypyridin-3-ylmethyl)-amine P-0190 was synthesized in 2 steps from 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine 592 as shown in Scheme 196.</b><chemistry id="chem0683" num="0683"><img file="EP2086972B1_D0683.tif" /></chemistry>

<b>Step</b> I <b>- Preparation of [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (619):</b>

0289<b>5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine (592, 30 mg, 0.083 mmol, prepared as described in Example 27, Scheme 183) was combined with 6-methoxy-pyridine-3-carbaldehyde (618, 26.2 mg, 0.165 mmol) in a 2 mL</b> microwave reaction vial. The mixture was dissolved in ethanol: acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100 °C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give the desired compound <b>619,</b> which was used without further purification.

<i>Step II - Preparation of [4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-0190):</i>

0290[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-3-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine <b>619</b> was combined with methanol: potassium hydroxide (1M) (1:1, 0.5 mL). The mixture was heated at 80 °C for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ID) eluting with 0.1% trifluoroacetic acid in water and 20-100 % acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound <b>P-0190.</b> MS (ESI) [M+H⁺]⁺= 419.9.

0291Additional compounds were prepared following the protocol of Scheme 196, replacing 6-methoxy-pyridine-3-carbaldehyde <b>618</b> with a suitable aldehyde in Step 1. The following compounds were made following this procedure: <ul id="ul0025" list-style="none" compact="compact"><li>(4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-thiazol-2-ylmethyl-amine <b>(P-0189),</b></li><li>Benzyl-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>(P-0192),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-methoxy-benzyl)-amine <b>(P-0193),</b></li><li>(4-Chloro-benzyl)-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>(P-0194),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine <b>(P-0195),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine <b>(P-0196),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amine <b>(P-0197),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-2H-pyrazol-3-ylmethyl)-amine <b>(P-0198),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2-ylmethyl)-amine <b>(P-0199),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-ylmethyl)-amine <b>(P-0200),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-thiazol-4-ylmethyl)-amine <b>(P-0201),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl)-(4-methyl-thiazol-5-ylmethyl)-amine <b>(P-0202),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2-ylmethyl)-amine <b>(P-0203),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine <b>(P-0236),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine <b>(P-0237),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-chloro-pyridin-4-ylmethyl)-amine <b>(P-0238),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(1-ethyl-1H-pyrazol-4-ylmethyl)-amine <b>(P-0239),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine <b>(P-0240),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0241),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine <b>(P-0242),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-fluoro-benzyl)-amine <b>(P-0243),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-amine <b>(P-0244),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-difluoro-benzyl)-amine <b>(P-0245),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-benzyl)-amine <b>(P-0246),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0247),</b></li><li>(2-Chloro-benzyl)-(4-chloro-5-(5-chloro-1H-pynrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl)-amine <b>(P-0248),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)-amine <b>(P-0249),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro-benzyl)-amine <b>(P-0250),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2-ylmethyl)-amine <b>(P-0251),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-morpholin-4-yl-pyridin-2-ylmethyl)-amine <b>(P-0252),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4-ylmethyl)-amine <b>(P-0253),</b></li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-trifluoromethyl-benzyl)-amine <b>(P-0254),</b> and</li><li>[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine <b>(P-0255).</b></li></ul> The following table indicates the aldehyde (Column 2) used in Step 1 of Scheme 196 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result. <tables id="tabl0012" num="0012"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="34mm" /><colspec colnum="3" colname="col3" colwidth="51mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Aldehyde</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0189</entry><entry align="center" valign="middle"><chemistry id="chem0684" num="0684"><img file="EP2086972B1_D0684.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0685" num="0685"><img file="EP2086972B1_D0685.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">395.9</entry></row><row><entry align="center" valign="middle">P-0192</entry><entry align="center" valign="middle"><chemistry id="chem0686" num="0686"><img file="EP2086972B1_D0686.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0687" num="0687"><img file="EP2086972B1_D0687.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">389.1</entry></row><row><entry align="center" valign="middle">P-0193</entry><entry align="center" valign="middle"><chemistry id="chem0688" num="0688"><img file="EP2086972B1_D0688.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0689" num="0689"><img file="EP2086972B1_D0689.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">419.1</entry></row><row><entry align="center" valign="middle">P-0194</entry><entry align="center" valign="middle"><chemistry id="chem0690" num="0690"><img file="EP2086972B1_D0690.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0691" num="0691"><img file="EP2086972B1_D0691.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">425.1</entry></row><row><entry align="center" valign="middle">P-0195</entry><entry align="center" valign="middle"><chemistry id="chem0692" num="0692"><img file="EP2086972B1_D0692.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0693" num="0693"><img file="EP2086972B1_D0693.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.1</entry></row><row><entry align="center" valign="middle">P-0196</entry><entry align="center" valign="middle"><chemistry id="chem0694" num="0694"><img file="EP2086972B1_D0694.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0695" num="0695"><img file="EP2086972B1_D0695.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">423.9</entry></row><row><entry align="center" valign="middle">P-0197</entry><entry align="center" valign="middle"><chemistry id="chem0696" num="0696"><img file="EP2086972B1_D0696.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0697" num="0697"><img file="EP2086972B1_D0697.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">421.1</entry></row><row><entry align="center" valign="middle">P-0198</entry><entry align="center" valign="middle"><chemistry id="chem0698" num="0698"><img file="EP2086972B1_D0698.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0699" num="0699"><img file="EP2086972B1_D0699.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.1</entry></row><row><entry align="center" valign="middle">P-0199</entry><entry align="center" valign="middle"><chemistry id="chem0700" num="0700"><img file="EP2086972B1_D0700.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0701" num="0701"><img file="EP2086972B1_D0701.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">419.9</entry></row><row><entry align="center" valign="middle">P-0200</entry><entry align="center" valign="middle"><chemistry id="chem0702" num="0702"><img file="EP2086972B1_D0702.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0703" num="0703"><img file="EP2086972B1_D0703.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.9</entry></row><row><entry align="center" valign="middle">P-0201</entry><entry align="center" valign="middle"><chemistry id="chem0704" num="0704"><img file="EP2086972B1_D0704.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0705" num="0705"><img file="EP2086972B1_D0705.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">409.9</entry></row><row><entry align="center" valign="middle">P-0202</entry><entry align="center" valign="middle"><chemistry id="chem0706" num="0706"><img file="EP2086972B1_D0706.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0707" num="0707"><img file="EP2086972B1_D0707.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">409.9</entry></row><row><entry align="center" valign="middle">P-0203</entry><entry align="center" valign="middle"><chemistry id="chem0708" num="0708"><img file="EP2086972B1_D0708.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0709" num="0709"><img file="EP2086972B1_D0709.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">423.9</entry></row><row><entry align="center" valign="middle">P-0236</entry><entry align="center" valign="middle"><chemistry id="chem0710" num="0710"><img file="EP2086972B1_D0710.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0711" num="0711"><img file="EP2086972B1_D0711.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">390.3</entry></row><row><entry align="center" valign="middle">P-0237</entry><entry align="center" valign="middle"><chemistry id="chem0712" num="0712"><img file="EP2086972B1_D0712.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0713" num="0713"><img file="EP2086972B1_D0713.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">390.3</entry></row><row><entry align="center" valign="middle">P-0238</entry><entry align="center" valign="middle"><chemistry id="chem0714" num="0714"><img file="EP2086972B1_D0714.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0715" num="0715"><img file="EP2086972B1_D0715.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">425.9</entry></row><row><entry align="center" valign="middle">P-0239</entry><entry align="center" valign="middle"><chemistry id="chem0716" num="0716"><img file="EP2086972B1_D0716.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0717" num="0717"><img file="EP2086972B1_D0717.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.1</entry></row><row><entry align="center" valign="middle">P-0240</entry><entry align="center" valign="middle"><chemistry id="chem0718" num="0718"><img file="EP2086972B1_D0718.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0719" num="0719"><img file="EP2086972B1_D0719.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.9</entry></row><row><entry align="center" valign="middle">P-0241</entry><entry align="center" valign="middle"><chemistry id="chem0720" num="0720"><img file="EP2086972B1_D0720.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0721" num="0721"><img file="EP2086972B1_D0721.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">419.9</entry></row><row><entry align="center" valign="middle">P-0242</entry><entry align="center" valign="middle"><chemistry id="chem0722" num="0722"><img file="EP2086972B1_D0722.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0723" num="0723"><img file="EP2086972B1_D0723.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">458.3</entry></row><row><entry align="center" valign="middle">P-0243</entry><entry align="center" valign="middle"><chemistry id="chem0724" num="0724"><img file="EP2086972B1_D0724.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0725" num="0725"><img file="EP2086972B1_D0725.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">443.1</entry></row><row><entry align="center" valign="middle">P-0244</entry><entry align="center" valign="middle"><chemistry id="chem0726" num="0726"><img file="EP2086972B1_D0726.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0727" num="0727"><img file="EP2086972B1_D0727.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">403.1</entry></row><row><entry align="center" valign="middle">P-0245</entry><entry align="center" valign="middle"><chemistry id="chem0728" num="0728"><img file="EP2086972B1_D0728.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0729" num="0729"><img file="EP2086972B1_D0729.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">424.7</entry></row><row><entry align="center" valign="middle">P-0246</entry><entry align="center" valign="middle"><chemistry id="chem0730" num="0730"><img file="EP2086972B1_D0730.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0731" num="0731"><img file="EP2086972B1_D0731.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.1</entry></row><row><entry align="center" valign="middle">P-0247</entry><entry align="center" valign="middle"><chemistry id="chem0732" num="0732"><img file="EP2086972B1_D0732.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0733" num="0733"><img file="EP2086972B1_D0733.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">419.9</entry></row><row><entry align="center" valign="middle">P-0248</entry><entry align="center" valign="middle"><chemistry id="chem0734" num="0734"><img file="EP2086972B1_D0734.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0735" num="0735"><img file="EP2086972B1_D0735.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">424.7</entry></row><row><entry align="center" valign="middle">P-0249</entry><entry align="center" valign="middle"><chemistry id="chem0736" num="0736"><img file="EP2086972B1_D0736.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0737" num="0737"><img file="EP2086972B1_D0737.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">403.1</entry></row><row><entry align="center" valign="middle">P-0250</entry><entry align="center" valign="middle"><chemistry id="chem0738" num="0738"><img file="EP2086972B1_D0738.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0739" num="0739"><img file="EP2086972B1_D0739.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">441.1</entry></row><row><entry align="center" valign="middle">P-0251</entry><entry align="center" valign="middle"><chemistry id="chem0740" num="0740"><img file="EP2086972B1_D0740.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0741" num="0741"><img file="EP2086972B1_D0741.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">407.9</entry></row><row><entry align="center" valign="middle">P-0252</entry><entry align="center" valign="middle"><chemistry id="chem0742" num="0742"><img file="EP2086972B1_D0742.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0743" num="0743"><img file="EP2086972B1_D0743.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">475.1</entry></row><row><entry align="center" valign="middle">P-0253</entry><entry align="center" valign="middle"><chemistry id="chem0744" num="0744"><img file="EP2086972B1_D0744.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0745" num="0745"><img file="EP2086972B1_D0745.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">459.9</entry></row><row><entry align="center" valign="middle">P-0254</entry><entry align="center" valign="middle"><chemistry id="chem0746" num="0746"><img file="EP2086972B1_D0746.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0747" num="0747"><img file="EP2086972B1_D0747.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">457.1</entry></row><row><entry align="center" valign="middle">P-0255</entry><entry align="center" valign="middle"><chemistry id="chem0748" num="0748"><img file="EP2086972B1_D0748.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0749" num="0749"><img file="EP2086972B1_D0749.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">404.3</entry></row></tbody></tgroup></table></tables>

0292Additional compounds were prepared following the protocol of Scheme 196, replacing 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine <b>592</b> with 5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine <b>593</b> (prepared as described in Example 27, Scheme 183) in addition to replacing 6-methoxy-pyridine-3-carbaldehyde <b>618</b> with a suitable aldehyde in Step 1. The following compounds were made following this procedure: <ul id="ul0026" list-style="none" compact="compact"><li>[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine <b>(P-0204),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amine <b>(P-0205),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine <b>(P-0206),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine <b>(P-0207),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimethyl-thiophen-2-ylmethyl)-amine <b>(P-0208),</b></li><li>[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-thiophen-3-ylmethyl)-amine <b>(P-0209),</b></li></ul> The following table indicates the aldehyde (Column 2) used in Step 1 of Scheme 196 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result. <tables id="tabl0013" num="0013"><table frame="all"><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="30mm" /><colspec colnum="3" colname="col3" colwidth="45mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="middle">Compound number</entry><entry align="center" valign="middle">Aldehyde</entry><entry align="center" valign="middle">Compound</entry><entry align="center" valign="middle">MS(ESI) [M+H⁺]⁺ observed</entry></row></thead><tbody><row><entry align="center" valign="middle">P-0204</entry><entry align="center" valign="middle"><chemistry id="chem0750" num="0750"><img file="EP2086972B1_D0750.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0751" num="0751"><img file="EP2086972B1_D0751.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">390.3</entry></row><row><entry align="center" valign="middle">P-0205</entry><entry align="center" valign="middle"><chemistry id="chem0752" num="0752"><img file="EP2086972B1_D0752.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0753" num="0753"><img file="EP2086972B1_D0753.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">387.1</entry></row><row><entry align="center" valign="middle">P-0206</entry><entry align="center" valign="middle"><chemistry id="chem0754" num="0754"><img file="EP2086972B1_D0754.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0755" num="0755"><img file="EP2086972B1_D0755.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">373.9</entry></row><row><entry align="center" valign="middle">P-0207</entry><entry align="center" valign="middle"><chemistry id="chem0756" num="0756"><img file="EP2086972B1_D0756.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0757" num="0757"><img file="EP2086972B1_D0757.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">386.3</entry></row><row><entry align="center" valign="middle">P-0208</entry><entry align="center" valign="middle"><chemistry id="chem0758" num="0758"><img file="EP2086972B1_D0758.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0759" num="0759"><img file="EP2086972B1_D0759.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">389.1</entry></row><row><entry align="center" valign="middle">P-0209</entry><entry align="center" valign="middle"><chemistry id="chem0760" num="0760"><img file="EP2086972B1_D0760.tif" /></chemistry></entry><entry align="center" valign="middle"><chemistry id="chem0761" num="0761"><img file="EP2086972B1_D0761.tif" /></chemistry></entry><entry valign="middle" align="char" char=".">389.1</entry></row></tbody></tgroup></table></tables>

Example 41: Synthesis of 5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine P-0388

02935-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine <b>P-0388</b> was synthesized from (5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine 17 as shown in Scheme 197. <chemistry id="chem0762" num="0762"><img file="EP2086972B1_D0762.tif" /></chemistry>

Step 1 - Preparation of 1-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-ethanone (620):

0294(5-Bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17, 3.00 g, 9.06 mmol) was dissolved in tetrahydrofuran (80 mL). The reaction was cooled at -78 °C under an atmosphere of argon. 2.5 M n-butyllithium in hexane (10.9 mL) was added. The reaction was stirred at -78 °C for 60 minutes. N-Methoxy-N-methylacetamide (1.93 mL, 18.1 mmol) was added to the reaction, which was allowed to warm to room temperature. The reaction was poured into 1 M ammonium chloride and brine and extracted with ethyl acetate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (ethyl acetate:hexanes) to provide the desired compound as an oil that crystallized to a white solid <b>(620,</b> 1.328 g, 50%), consistent with the compound structure by ¹H-NMR and MS(ESI): (M+H⁺]⁺=295.3.

Step 2 - Preparation of (5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (621):

0295To 1-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-ethanone <b>(620,</b> 1.30 g, 4.42 mmol) in tetrahydrofuran (15.0 mL) were added di-tert-butyldicarbonate (1.10 g, 5.04 mmol), 4-dimethylaminopyridine (0.0259 g, 0.21 mmol) and N,N-diisopropylethylamine (0.888 mL, 5.10 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 days. The mixture was extracted with ethyl acetate and saturated sodium bicabonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (0-15% ethyl acetate:hexanes) to provide the desired compound as an oil that solidified to a white solid (621, 1.29g, 74%), consistent with the compound structure by ¹H-NMR.

Step 3 - Preparation of 1-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-1-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanol <b>(622)</b>

:

02963-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 485.9 mg, 1.21 mmol) was dissolved in tetrahydrofuran (8 mL) at -20 °C under an atmosphere of nitrogen. 2.0 M isopropylmagnesium chloride in tetrahydrofuran (0.655 mL) was added. The reaction was stirred at -20 °C for 1 hour. Into the reaction was added (5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (621, 300.0 mg, 0.76 mmol) in tetrahydrofuran (6 mL) The reaction was allowed to warm to room temperature overnight. The mixture was extracted with ethyl acetate and saturated sodium bicabonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography on the (ethyl acetate:hexanes), to provide the desired compound as an oil (622, 125 mg, 29%), consistent with the compound structure by ¹H-NMR.

Step 4 - Preparation of 5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine (623):

02971-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-yl]-1-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanol (622, 125.0 mg, 0.22 mmol) was dissolved in acetonitrile (11.7 mL) and trifluoroacetic acid (0.175 mL, 2.3 mmol) and triethylsilane (0.292 mL, 1.8 mmol) were added. The reaction was heated to reflux overnight. The reaction was concentrated, then washed with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (0-60% ethyl acetate:hexanes) to provide the desired compound (623, 43 mg, 50%), consistent with the compound structure by ¹H-NMR.

Step 5 - Preparation of 5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine <b>(P-0388):</b>

02985-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine <b>(623,</b> 0.043 g, 0.00011 mol) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL). The reaction was shaken under an atmosphere of hydrogen (30 psi) overnight. The reaction was filtered through Celite and the filtrate adsorbed onto silica and purified by silica gel column chromatography (ethyl acetate:hexanes) to provide the desired compound as a white solid <b>(P-0388,</b> 2.1 mg, 5%), consistent with compound structure by ¹H-NMR and MS(ESI): [M+H⁺]⁺=397.6.

Example 42: Synthesis of [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine P-0290

0299l<b>5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine P-0290 was synthesized in four steps from (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester 624 as shown in Scheme 198.</b><chemistry id="chem0763" num="0763"><img file="EP2086972B1_D0763.tif" /></chemistry>

Step 1 - Preparation of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester <b>(625):</b>

0300To a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (624, 1 g, 2.70 mmol, prepared as described in Example 5, Scheme 159, Step 2, where 4-(aminomethyl)pyridine <b>516</b> is replaced with p-ftuorobenzylamine, i.e. intermediate in preparing compound <b>P-0156)</b> in methanol (100 mL) was added Pd/C (100 mg, 50% water wet) and sodium acetate (660 mg, 8.09 mmol) and the mixture was shaken under an atmosphere of hydrogen (50 psi) overnight observing ∼50% conversion by LC/MS. The mixture was filtered over a bed of Celite and the solvent was removed <i>in vacuo</i> and purified by silica gel chromatography (ethyl acetate/heptane) to provide the desired compound as an off-white solid (450 mg, 50 %), consistent with compound structure by ¹H-NMR.

Step 2 - Preparation of {5-[(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamic acid tert-butyl ester <b>(627)</b>:

0301To a solution of 5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine <b>(626,</b> 300 mg, 0.69 mmol) in tetrahydrofuran (10 mL) at -20 °C was added dropwise iso-propyl-magnesium chloride (2M in tetrahydrofuran, 0.44 mL, 0.88 mmol). The reaction mixture was allowed to warm to 0 °C over 10 minutes and then cooled to -40 °C. To this reaction mixture was added a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (<b>625</b>, 211 mg, 0.63 mmol) in tetrahydrofuran (5 mL). The reaction mixture was allowed to warm to 0 °C over 30 minutes and then quenched with brine (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over sodium sulfate and evaporated <i>in vacuo</i> to give the crude material which was purified by silica gel column chromatography (0-30% ethyl acetate/heptane) to provide the desired compound as a foam (120 mg, 30%), consistent with structure by ¹H-NMR.

Step 3 - Preparation of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester <b>(628):</b>

0302To a solution of {5-[(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (627, 120 mg, 0.186 mmol) in acetonitrile (3 mL) was added trifluoroacetic acid (0.14 mL, 1.86 mmol) and triethylsilane (0.30 mL, 1.86 mmol). The resulting mixture was stirred for 2 hours at 40 °C. The solvent was then removed in <i>vacuo</i> and the residue was used directly in the next step.

Step 4: Preparation of [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro benzyl)-amine <b>(P-0290):</b>

0303To the solution of crude [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester <b>(628,</b> 0.186 mmol theory) in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (1 mL) and the reaction was allowed to stir overnight. The solvent was removed <i>in vacuo</i> and the residue taken up in ethyl acetate and then washed with saturated aqueous potassium carbonate making sure basicity was reached. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated <i>in vacuo</i> to give the crude compound which was purified by silica gel chromatography (0-10% methanol/ethyl acetate). The solvent was removed <i>in vacuo</i> and the material was triturated with dichloromethane to give the desired compound as an off-white solid (20 mg, 29 % over 2 steps) consistent with compound structure by ¹H-NMR and MS(ESI): [M+H⁺]⁺=372.9.

0304(4-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine <b>P-0389</b><chemistry id="chem0764" num="0764"><img file="EP2086972B1_D0764.tif" /></chemistry> was synthesized following the protocol of Scheme <b>198,</b> replacing 5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine <b>626</b> with 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>96,</b> to provide the desired compound, consistent with structure by 1H-NMR and MS(ESI): [M+H⁺]⁺=339.0.

Example 43: Synthesis of (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanone P-0184

0305(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanone <b>P-0184</b> was synthesized from 5-chloro-1H-pyrrolo[2,3-b]pyridine <b>532</b> in 1 step as shown in Scheme 199. <chemistry id="chem0765" num="0765"><img file="EP2086972B1_D0765.tif" /></chemistry>

Step 1 - Synthesis of (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanone <b>(P-0184):</b>

03065-Chloro-1H-pyrrolo[2,3-b]pyridine <b>(532,</b> 0.068 g, 0.44 mmol) was combined with methanol (10 mL) and potassium hydroxide (0.16 g, 2.8 mmol). The mixture was stirred for 50 minutes, then 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde <b>(530,</b> 0.100 g, 0.40 mmol, prepared as described in Example 8, Scheme 162, Step 5) was added and the reaction was stirred overnight at room temperature and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexanes provided the desired compound (0.0033 g, 2%). MS (ESI) [M+H⁺]⁺ = 398.1.

Example 44: Synthesis of

[

5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine P-0185

0307[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluorobenzyl)-amine <b>P-0185</b> was synthesized from 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>629</b> in 2 steps as shown in Scheme 200. <chemistry id="chem0766" num="0766"><img file="EP2086972B1_D0766.tif" /></chemistry>

Step 1 - Synthesis of (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanol <b>(630):</b>

03085-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (<b>629,</b> 0.15 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL, 40 mmol) and the solution was cooled to -20 °C. 2 M isopropylmagnesium chloride in tetrahydrofuran (200 µL) was added dropwise and the reaction was stirred and allowed to warm to -5 °C. After the reaction was cooled to -20 °C, 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde <b>(530,</b> 0.043g, 0.17 mmol, prepared as described in Example 8, Scheme 162, Step 5) in tetrahydrofuran (4 mL) was added to the mixture. The reaction was stirred and allowed to warm to -5 °C, then concentrated, ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexanes gave the desired compound <b>(630,</b> 0.038 g, 40%).

Step 2 - Synthesis of 5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine <b>(P-0185):</b>

0309(5-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluorobenzylamino)-2H-pyrazol-3-yl]-methanol <b>(630,</b> 0.045 g, 0.081 mmol) was dissolved in acetonitrile (5 mL) and triethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroacetic acid (0.2 mL, 2.0 mmol). The reaction was stirred at room temperature for 45 minutes, then stirred at 60 °C for 45 minutes. The solvent was removed under reduced pressure, ethyl acetate was added and the organic was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (40-100%) in hexanes gave the desired compound <b>(P-0185,</b> 0.0068 g, 22%). MS (ESI) [M+H⁺]⁺= 384.1.

Example 45: Synthesis of 3-2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile P-0415

03103-2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>P-0415</b> was synthesized in 5 steps from 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile 632 as shown in Scheme 201. <chemistry id="chem0767" num="0767"><img file="EP2086972B1_D0767.tif" /></chemistry>

Step 1 - Synthesis of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(633):</b>

0311To 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(632,</b> 3.00 g, 0.0210 mol) in isopropyl alcohol (120 mL) were added dimethylamine hydrochloride (1.91 g, 0.0235 mol) and formaldehyde (0.708 g, 0.0236 mol). The reaction was heated to reflux overnight, then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% to 30% methanol in dichloromethane containing 0.3% triethyl amine to give the desired compound (633, 2.0 g, 48%).

Step 2 - Synthesis of 5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (634):

0312To 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(633,</b> 2.0 g, 0.010 mol) in tetrahydrofuran (60.0 mL) were added di-tert-butyldicarbonate (2.62 g, 0.0120 mol), 4-dimethylaminopyridine (0.12 g, 0.0010 mol) and triethylamine (4.0 mL, 0.029 mol). The reaction was stirred at 45 °C over a weekend, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 30% methanol in dichloromethane in hexane to give the desired compound <b>(634,</b> 2.50 g, 83%).

Step 3

-

Synthesis of 3-chloromethyl-5-cyano-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(635):</b>

0313To 5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(634,</b> 2.60 g, 8.66 mmol) in toluene (60.0 mL) under an atmosphere of nitrogen was added ethyl chloroformate (0.828 mL, 8.66 mmol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid <b>(635, 400</b> mg, 16%).

Step 4

-

Synthesis of [5-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(636)</b>:

0314To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>(631,</b> 0.600 g, 1.50 mmol, prepared as described in Example 21) in tetrahydrofuran (10.0 mL) at -25 °C under an atmosphere of nitrogen, was added a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.730 mL). The reaction was allowed to warm to 5 °C over 1 hour. The reaction was cooled to -35 °C, followed by addition of a solution of CuCN.2LiCl (0.65 M in tetrahydrofuran, 2.4 mL). After 5 minutes, 3-chloromethyl-5-cyano-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester <b>(635,</b> 0.086 g, 0.29 mmol) in tetrahydrofuran (4.0 mL) was added to the reaction. The reaction was allowed to warm to room temperature over 1 hour, then poured into a diluted ammonia solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound <b>(636</b>, 0.13 g, 92%). MS (ESI) [M+H⁺]⁺ = 477.4.

Step 5

-

Synthesis of 3-2-fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>(P-0415):</b>

0315To [5-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (636, 0.130 g, 0.27 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.00 mL, 0.0130 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give a white solid <b>(P-0415,</b> 85.6 mg, 83.4%). MS (ESI) [M+H⁺]⁺ = 377.0.

0316(5-Fluoro-pyridin-3-ylmethyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine <b>P-0414</b><chemistry id="chem0768" num="0768"><img file="EP2086972B1_D0768.tif" /></chemistry> was prepared following the protocol of Scheme 201, substituting 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile <b>632</b> with 1H-Pyrrolo[2,3-b]pyridine in Step 1. MS (ESI) [M+H⁺]⁺ = 352.5.

03173-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile <b>P-0432</b><chemistry id="chem0769" num="0769"><img file="EP2086972B1_D0769.tif" /></chemistry> was prepared following the protocol of Scheme 201, replacing 5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester <b>631</b> with (5-Bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester <b>637</b> (prepared as described in Example 21) in Step 4. MS (ESI) [M+H⁺]⁺ = 391.9.

Example 46: Synthesis of (3-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine P-0410

0318(3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine <b>P-0410</b> was synthesized in 11 steps from 1H-pyrazole-3,5-dicarboxylic acid monohydrate <b>638</b> as shown in Scheme 202. <chemistry id="chem0770" num="0770"><img file="EP2086972B1_D0770.tif" /></chemistry>

Step 1 - Preparation of 1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (639):

03191H-Pyrazole-3,5-dicarboxylic acid monohydrate <b>(638,</b> 21.1 g, 121.0 mmol) was combined with methanol (350 mL) and hydrogen chloride (10 mL). The reaction was stirred at reflux overnight and then concentrated. The resulting solid was washed with ethyl acetate and hexanes and dried under reduced pressure. The obtained compound <b>639</b> was used without further purification. MS (ESI) [M+H⁺]⁺= 185.0.

Step 2 - Preparation of 1-methyl-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (640):

03201H-Pyrazole-3,5-dicarboxylic acid dimethyl ester <b>(639,</b> 9.1 g, 49.0 mmol) was combined with acetone (400 mL) and potassium carbonate (10.2 g, 74.1 mmol). The mixture was stirred for 40 minutes under an atmosphere of nitrogen. To the stirring suspension, methyl iodide (3.4 mL, 54.0 mmol) was added dropwise. The reaction was stirred at room temperature overnight and then the solvent was evaporated under reduced pressure. The resulting solid was washed with water and filtered. After toluene was added, the solvent was removed under reduced pressure. The resulting compound <b>640</b> was used without further purification.

Step 3 - Preparation of 1-methyl-1H-pyrazole-3,5-dicarboxylic acid 5-methyl ester (641):

03211-Methyl-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester <b>(640,</b> 3.7 g, 19.0 mmol) was combined with 1,4-dioxane (20 mL) and water (60 mL). Concentrated sulfuric acid (1.0 mL) in 2 mL of water was added to the solution. After the reaction was stirred at reflux overnight, it was cooled to room temperature and concentrated until precipitation began. The obtained mixture was left standing overnight. The resulting solid was filtered and dried under reduced pressure. The collected aqueous fractions were extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and concentrated. Additional solid was crystallized from ethyl acetate to give the desired compound <b>(641,</b> 2.33 g, 68%). MS (ESI) [M+H⁺]⁺ = 185.0, melting point 175 °C.

Step 4 - Preparation of 5-azidocarbonyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (642):

03221-Methyl-1H-pyrazole-3,5-dicarboxylic acid 5-methyl ester <b>(641,</b> 3.2 g, 17.0 mmol) was combined with thionyl chloride (5 mL). The reaction was heated to reflux for 40 minutes and then concentrated twice from toluene. The resulting solid was dried under reduced pressure overnight. The product was dissolved into acetone (20 mL) and sodium azide (3.5 g, 54.0 mmol) was added in water (10 mL) rapidly at once. The obtained solution was stirred for one minute and then poured into ice-water (50mL). The precipitate was filtered and dried under reduced pressure. The final compound was used without further purification <b>(642,</b> 2.8 g, 77%).

Step 5 - Preparation of 5-benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (643):

03235-Azidocarbonyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester <b>(642,</b> 2.8 g, 13.0 mmol) was combined with toluene (35 mL) and benzyl alcohol (2.1 mL, 20.0 mmol). The reaction was heated to reflux for 45 minutes and then the solvent was removed under reduced pressure. The compound <b>(643,</b> 2.4 g, 62%) was washed with methanol and dried under vacuum. MS (ESI) [M+H⁺]⁺ = 290.3.

Step 6 - Preparation of 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester <b>(644):</b>

03245-Benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester <b>(643,</b> 2.2 g, 7.6 mmol) was combined with methanol (50 mL) and 10% palladium on carbon (500 mg). The mixture was stirred under an atmosphere of hydrogen for three hours. The mixture was filtered through Celite and the solvent was removed under reduced pressure to give the desired compound (<b>644</b>, 1.2g, 98%). (ESI) [M+H⁺]⁺ = 156.1.

Step 7 - Preparation of 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (646):

03255-Amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester <b>(644,</b> 1.3 g, 8.0 mmol) was combined with 3-chlorobenzaldehyde <b>(645,</b> 0.95 mL, 8.4 mmol) and acetonitrile (40 mL). Trifluoroacetic acid (3.2 mL, 42.0 mmol) was added followed by triethylsilane (6.7 mL, 42.0 mmol). The reaction was heated to reflux overnight and then concentrated. Ethyl acetate was added and the solution was washed with 1N potassium carbonate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated. The compound <b>(646,</b> 0.944 g, 42%) was crystallized from a mixture of ethyl acetate: hexane.

Step 8 - Preparation of [5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-methanol <b>(647):</b>

03265-(3-Chloro-benzylamino)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester <b>(646,</b> 0.944 g, 3.37 mmol) was combined with tetrahydrofuran (20 mL) and the solution was cooled to -40 °C. 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.7 mL) was added and the reaction was stirred for 45 min at -20 °C. 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.7 mL) was added at -40 °C and the reaction was stirred to 10°C. Sodium sulfate decahydrate was added in small portions and the mixture was stirred for two hours at room temperature, then filtered through Celite and concentrated. The resulting compound <b>(647,</b> 0.821 g, 97%) was washed with a mixture of ethyl acetate: hexanes and dried under reduced pressure.

Step 9- Preparation of 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde <b>(648):</b>

0327[5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-methanol (<b>647</b>, 0.821 g, 3.26 mmol) was combined with dichloromethane (70 mL) and manganese(IV) oxide (4 g). The reaction was stirred at room temperature overnight under an atmosphere of nitrogen. The mixture was filtered through Celite and concentrated. Purification by silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexane gave the desired aldehyde <b>(648,</b> 0.482 g, 60%).

<b>Step</b> 10 - Preparation of [5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(649):</b>

03285-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine <b>(629,</b> 0.19 g, 0.44 mmol) was dissolved in tetrahydrofuran (0.9 mL). The solution was cooled to -20 °C. 2M isopropylmagnesium chloride in tetrahydrofuran (200 µL) was added dropwise to the mixture, then stirred to -5 °C. After the reaction was cooled to -20 °C, 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde <b>(648,</b> 0.050 g, 0.20 mmol) in 2 mL of tetrahydrofuran was added at once to the mixture. The reaction was stirred to 0 °C and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexane gave the desired compound <b>(649,</b> 0.033 g, 30%). (ESI) [M+H⁺]⁺ = 558.3, 560.9.

Step 11 - Preparation of (3-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine <b>(P-0410):</b>

0329[5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol <b>(649,</b> 0.033 g, 0.059 mmol) was combined with dichloromethane (5 mL, 0.08 mol) and triethylsilane (200 µL, 1.0 mmol) was added, followed by trifluoroacetic acid (100 µL, 1.0 mmol). The reaction was stirred at room temperature overnight and then concentrated. Ethyl acetate was added and the organic portion was washed with 1 M potassium carbonate, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography eluting with a gradient of methanol (2-20%) and dichloromethane followed by washes with a mixture of ethyl acetate:hexane gave the desired compound <b>(P-0410,</b> 0.0039 g, 17%). (ESI) [M+H⁺]⁺= 387.30.

0330[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2,5-difluoro-benzyl)-amine <b>P-0411</b> and [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2-fluoro-benzyl)-amine <b>P-0413,</b><chemistry id="chem0771" num="0771"><img file="EP2086972B1_D0771.tif" /></chemistry> respectively, were prepared following the protocol of Scheme 202, replacing 3-chlorobenzaldehyde 645 with 2,5-difluorobenzaldehyde and 2-fluorobenzaldehyde, respectively, in Step 7. (ESI) [M+H⁺]⁺= 389.95 <b>(P-0411)</b> and 370.20 <b>(P-0413).</b>

Example 47: Enzyme activity assays

0331Assays for the activity of c-Kit or c-Fms are known in the art, for example as described in US Patent Application Publication number <patcit id="pcit0008" dnum="US20070032519A"><text>US 2007/0032519</text></patcit>. Similar assays may be used to assess the activity of TrkA, TrkB, and HGK.

0332Additional cell based assays can be correlated to the Fms activity of compounds disclosed herein. For example, the ability of osteoclast precursor cells (commercially available from Lonza) to differentiate into mature osteoclasts, due to stimulation by M-CSF and RANKL, in the presence of compounds, can be measured using a method analogous to that previously reported (<nplcit id="ncit0014" npl-type="s"><text>Hudson et al., Journal of Urology, 1947, 58:89-92</text></nplcit>), where the amount of acid phosphatase in the supernatant (i.e. TRAP5b excreted by mature osteoclasts) is proportional to the number of mature osteoclasts present. In another example, the ability of M-CSF-dependent murine macrophage cells (BAC1.2F5) to proliferate in the presence of compounds can be measured by culturing cells as previously described (<nplcit id="ncit0015" npl-type="s"><text>Morgan et al., Journal of Cellular Physiology, 1987, 130:420-427</text></nplcit>) and determining cell viability by analysis of ATP levels in the cell culture (<nplcit id="ncit0016" npl-type="s"><text>Crouch et al., Journal of Immunological Methods, 1993, 160:81-8</text></nplcit>).

0333Compounds P-0092, P-0093, P-0094, P-0095, P-0096, P-0097, P-0098, P-0099, P-0100, P-0101, P-0102, P-0103, P-0104, P-0105, P-0107, P-0108, P-0109, P-0111, P-0112, P-0113, P-0114, P-0115, P-0116, P-0118, P-0120, P-0121, P-0122, P-0123, P-0125, P-0126, P-0127, P-0128, P-0129, P-0131, P-0132, P-0138, P-0143, P-0144, P-0145, P-0148, P-0154, P-0156, P-0157, P-0159, P-0161, P-0163, P-0170, P-0171, P-0173, P-0174, P-0176, P-0177, P-0179, P-0180, P-0181, P-0182, P-0186, P-0187, P-0188, P-0190, P-0192, P-0193, P-0194, P-0195, P-0197, P-0199, P-0201, P-0203, P-0205, P-0206, P-0208, P-0211, P-0212, P-0213, P-0214, P-0215, P-0216, P-0217, P-0218, P-0219, P-0221, P-0222, P-0224, P-0225, P-0226, P-0228, P-0234, P-0237, P-0239, P-0240, P-0242, P-0243, P-0244, P-0245, P-0246, P-0252, P-0253, P-0255, P-0257, P-0258, P-0259, P-0260, P-0262, P-0263, P-0264, P-0265, P-0266, P-0267, P-0268, P-0269, P-0270, P-0271, P-0272, P-0273, P-0274, P-0275, P-0276, P-0277, P-0278, P-0279, P-0280, P-0281, P-0282, P-0283, P-0284, P-0285, P-0286, P-0287, P-0288, P-0289, P-0290, P-0291, P-0294, P-0297, P-0298, P-0301, P-0302, P-0303, P-0305, P-0306, P-0307, P-0308, P-0309, P-0311, P-0312, P-0313, P-0314, P-0316, P-0319, P-0320, P-0321, P-0322, P-0323, P-0324, P-0325, P-0326, P-0327, P-0328, P-0329, P-0330, P-0331, P-0332, P-0334, P-0336, P-0337, P-0338, P-0339, P-0340, P-0341, P-0342, P-0343, P-0344, P-0345, P-0346, P-0347, P-0348, P-0350, P-0351, P-0352, P-0354, P-0355, P-0356, P-0357, P-0358, P-0359, P-0361, P-0362, P-0363, P-0365, P-0366, P-0367, P-0368, P-0369, P-0370, P-0371, P-0372, P-0373, P-0375, P-0376, P-0377, P-0378, P-0379, P-0382, P-0383, P-0385, P-0387, P-0390, P-0392, P-0393, P-0394, P-0395, P-0396, P-0402, P-0404, P-0406, P-0407, P-0408, P-0409, and P-0412 demonstrated an IC₅₀ of less than 1 µM in at least one of the c-kit assays described in US Patent Application Publication number <patcit id="pcit0009" dnum="US20070032519A"><text>US 2007/0032519</text></patcit>.

0334Compounds P-0092, P-0093, P-0094, P-0095, P-0096, P-0097, P-0098, P-0099, P-0100, P-0101, P-0102, P-0103, P-0104, P-0105, P-0106, P-0107, P-0108, P-0109, P-0110, P-0111, P-0112, P-0113, P-0114, P-0115, P-0116, P-0117, P-0118, P-0119, P-0120, P-0121, P-0122, P-0123, P-0125, P-0126, P-0127, P-0128, P-0129, P-0130, P-0131, P-0132, P-0134, P-0135, P-0136, P-0137, P-0140, P-0141, P-0142, P-0143, P-0144, P-0145, P-0146, P-0147, P-0148, P-0149, P-0150, P-0151, P-0152, P-0153, P-0154, P-0156, P-0157, P-0158, P-0159, P-0160, P-0161, P-0163, P-0164, P-0165, P-0167, P-0168, P-0169, P-0170, P-0171, P-0172, P-0173, P-0174, P-0175, P-0176, P-0179, P-0180, P-0181, P-0182, P-0183, P-0185, P-0186, P-0187, P-0188, P-0189, P-0190, P-0191, P-0192, P-0193, P-0194, P-0195, P-0196, P-0197, P-0198, P-0199, P-0200, P-0201, P-0202, P-0203, P-0204, P-0205, P-0206, P-0207, P-0208, P-0209, P-0210, P-0211, P-0212, P-0213, P-0214, P-0215, P-0216, P-0217, P-0218, P-0219, P-0220, P-0221, P-0222, P-0223, P-0224, P-0225, P-0226, P-0227, P-0228, P-0229, P-0230, P-0231, P-0232, P-0233, P-0234, P-0235, P-0236, P-0237, P-0238, P-0239, P-0240, P-0241, P-0242, P-0243, P-0244, P-0245, P-0246, P-0247, P-0248, P-0249, P-0250, P-0251, P-0252, P-0253, P-0254, P-0255, P-0256, P-0257, P-0258, P-0259, P-0260, P-0261, P-0262, P-0263, P-0264, P-0265, P-0266, P-0267, P-0268, P-0269, P-0270, P-0271, P-0272, P-0273, P-0274, P-0275, P-0276, P-0277, P-0278, P-0279, P-0280, P-0281, P-0282, P-0283, P-0284, P-0285, P-0286, P-0287, P-0288, P-0289, P-0290, P-0291, P-0292, P-0293, P-0294, P-0295, P-0296, P-0297, P-0298, P-0299, P-0300, P-0301, P-0302, P-0303, P-0304, P-0305, P-0306, P-0307, P-0308, P-0309, P-0310, P-0311, P-0312, P-0313, P-0314, P-0315, P-0316, P-0317, P-0318, P-0319, P-0320, P-0321, P-0322, P-0323, P-0324, P-0325, P-0326, P-0327, P-0328, P-0329, P-0330, P-0331, P-0332, P-0333, P-0334, P-0335, P-0336, P-0337, P-0338, P-0339, P-0340, P-0341, P-0342, P-0343, P-0344, P-0345, P-0346, P-0347, P-0348, P-0349, P-0350, P-0351, P-0352, P-0353, P-0354, P-0355, P-0356, P-0357, P-0358, P-0359, P-0360, P-0361, P-0362, P-0363, P-0364, P-0365, P-0366, P-0367, P-0368, P-0369, P-0370, P-0371, P-0372, P-0373, P-0374, P-0375, P-0376, P-0377, P-0378, P-0379, P-0380, P-0381, P-0382, P-0383, P-0384, P-0385, P-0386, P-0387, P-0390, P-0391, P-0392, P-0393, P-0394, P-0395, P-0396, P-0402, P-0403, P-0404, P-0405, P-0406, P-0407, P-0408, P-0409, and P-0412 had IC₅₀ of less than 1 µM in at least one of the Fms assays described in US Patent Application Publication number <patcit id="pcit0010" dnum="US20070032519A"><text>US 2007/0032519</text></patcit>.

0335Compounds were similarly assayed to determine IC₅₀ values with respect to inhibition of TrkA kinase activity, for which compounds P-0157, P-0171, P-0179, P-0180, P-0303 and P-0412 had IC₅₀ of less than 1 µM. in this TrkA assay. Compounds were similarly assayed to determine IC₅₀ values with respect to inhibition of HGK kinase activity, for which compounds P-0156, P-0177, P-0179, P-0195, P-0201, P-0203, P-0206, P-0207, P-0231, P-0240, P-0241, P-0255, P-0324, P-0341, and P-0403 had IC₅₀ of less than I µM.

0336All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains.

0337One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The uses, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed by the scope of the claims.

0338It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope of the invention. For example, variations can be made to provide additional compounds of Formulae II or III and/or various methods of administration can be used. Thus, such additional embodiments are within the scope of the present invention and the following claims.

0339The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those stalled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

0340In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

0341Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention.

0342Thus, additional embodiments are within the scope of the invention and within the following claims.