US20100216779A1 - Imidazopyridine Kinase Inhibitors - Google Patents

Imidazopyridine Kinase Inhibitors Download PDF

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Publication number
US20100216779A1
US20100216779A1 US12/602,289 US60228908A US2010216779A1 US 20100216779 A1 US20100216779 A1 US 20100216779A1 US 60228908 A US60228908 A US 60228908A US 2010216779 A1 US2010216779 A1 US 2010216779A1
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alkyl
cancer
canceled
formula
compound
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Eric W. Baum
Kyle Allen Emmitte
Kevin Wayne Kuntz
Robert Anthony Mook, Jr.
Kristen Elizabeth Nailor
James Michael Salovich
John Brad Shotwell
Stephon Cornell Smith
Kirk Lawrence Stevens
David Edward Uehling
Alex Gregory Waterson
Mui Cheung
Ganesh S. Moorthy
Brian John Wilson
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GlaxoSmithKline LLC
SmithKline Beecham Corp
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GlaxoSmithKline LLC
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Priority to US12/602,289 priority Critical patent/US20100216779A1/en
Assigned to SMITHKLINE BEECHAM CORPORATION reassignment SMITHKLINE BEECHAM CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MOOK JR., ROBERT ANTHONY, NAILOR, KRISTEN ELIZABETH, BAUM, ERICH W, CHEUNG, MUI, EMMITTE, KYLE ALLEN, KUNTZ, KEVIN WAYNE, MOORTHY, GANESH S, SALOVICH, JAMES MICHAEL, SHOTWELL, JOHN BRAD, SMITH, STEPHON CORNELL, STEVENS, KIRK LAWRENCE, UEHLING, DAVID EDWARD, WATERSON, ALEX GREGORY, WILSON, BRIAN JOHN
Publication of US20100216779A1 publication Critical patent/US20100216779A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to imidazopyridine compounds, compositions containing the same, as well as processes for the preparation and methods of using such compounds and compositions.
  • Receptor tyrosine kinases have been implicated in cellular signaling pathways that control various cellular functions, including cell division, growth, metabolism, differentiation and survival, through reversible phosphorylation of the hydroxyl groups of tyrosine residues in proteins.
  • Extracellular signals are transduced via activation of the cell surface receptors, with amplification and propagation using a complex choreography of cascades of protein phosphorylation and protein dephosphorylation events to avoid uncontrolled signaling.
  • These signaling pathways are highly regulated, often by complex and intermeshed kinase pathways where each kinase may itself be regulated by one or more other kinases and protein phosphatases. The biological importance of these finely tuned systems is such that a variety of cell proliferative disorders have been linked to defects in one or more of the various cell signaling pathways mediated by tyrosine or serine/threonine kinases.
  • Receptor tyrosine kinases catalyze phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which govern cell growth, proliferation and differentiation.
  • IGF-1R Insulin-like growth factor-1 receptor
  • the IGF signaling axis is made up of multiple ligands (IGF-1, IGF-2 and Insulin), at least six high affinity ligand binding proteins and proteases, multiple receptors (IGF-1R & IGF-2R, IR and IRR), and many other down stream signaling proteins (Pollak, M N et al., Nature Reviews Cancer (2004) 4(7):505-518).
  • IGF-1R & IGF-2R multiple receptors
  • IR and IRR multiple receptors
  • the structure and function of the IGF-1R has been reviewed by Adams et al., Cell. Mol. Life. Sci. (2000) 57:1050-1093 and Benito, M et al., Int J Biochem Cell Biol (1996) 28(5):499-510.
  • the receptor is activated by the ligands IGF-1 and IGF-2, which are mitogenic proteins that signal through the IGF-1R and IR in an endocrine, paracrine or autocrine manner. Activation of the IGF-1 receptor tyrosine kinase elicits cellular responses which include cellular proliferation and protection of cells from apoptosis.
  • IGF-1 and IGF-2 are mitogenic proteins that signal through the IGF-1R and IR in an endocrine, paracrine or autocrine manner.
  • IGF-1 receptor tyrosine kinase elicits cellular responses which include cellular proliferation and protection of cells from apoptosis.
  • Over expression of IGF-1R leads to malignant transformation of cultured cells, while down regulation can reverse the transformed phenotype of tumor cells and potentially render them susceptible to apoptosis.
  • IR-A human insulin receptor isoform A
  • IRR Insulin receptor-related receptor tyrosine kinase
  • IGF-1R is a hetero-tetrameric, transmembrane, cell surface receptor tyrosine kinase.
  • An IGF-1 binding domain is part of the extracellular alpha-chain of IGF-1R, whereas the intracellular beta-chain contains the tyrosine kinase domain.
  • Three tyrosine residues represent autophosphorylation sites, specifically Tyr 1131 , Tyr 1135 , and Tyr 1136 , within the activation loop of the IGF-1R beta catalytic domain (Li, W et al., J. Biol. Chem. (2006) 281(33):23785-23791).
  • Phosphorylation of all three is required for full receptor activation, and precedes phosphorylation of juxtamembrane tyrosines and carboxy terminus serines.
  • the insulin receptor has three similar autophosphorylation sites on the activation loop and juxtamembrane region. Activation and autophoshorylation results in the recruitment of multiple docking proteins and the generation of intracellular signaling (Benito, Int J Biochem Cell Biol (1996)).
  • IGF-1R and IR can phosphorylate or interact directly with a number of intracellular protein substrates, including IRS-1, IRS-2, Grb2, Grb10, Grb14, Shc, SOC, 14.3.3, FAK, or indirectly with other proteins like PI3K and MAPK (Benito, M et al. Int J Biochem Cell Biol (1996) 28(5):499-510) (Brown, G C et al., Biochem. J. (1992) 284:1-13; Bruning, J C et al., Mol. Cell. (1998) 2(5):559-569).
  • Focal adhesion kinase (FAK) is of particular interest because of its role as a regulator of cell survival, proliferation, migration and invasion.
  • FAK is activated by growth factor receptors such as IGF-1R, by binding through its N-terminal domain and autophosphorylation at Tyr 397 .
  • Activated or over expressed FAK is common in a wide variety of cancers, and may play a role in human carcinogenesis (van Nimwegen, M J et al., Biochem. Pharmacol. (2007) 73(5):597-609).
  • IGF-1R In addition to its role in cancers, the IGF receptor plays important and diverse roles in growth and development (Benito, M et al. Int J Biochem Cell Biol (1996) 28(5):499-510). IGF-1R has been implicated in several metabolic, and immunological diseases (Walenkamp, M J et al., Horm. Res. (2006) 66(5):221-230; Kurmasheva, R. T et al., Biochim. Biophys. Acta—Rev on Cancer (2006) 1766(1):1-22; Bateman, J M et al., Cell. Mol. Life. Sci. (2006) 63(15):1701-1705, LeRoith, D, et al., Can. Lett. (2003) 195:127-137 and Samani A, et al., Endocrine Reviews 28(1):20-47.)
  • IGF/IGF-1R signaling system The role of the IGF/IGF-1R signaling system in cancer has been thoroughly examined over the last 15 years.
  • the implication of IGF-1R in human cancer stems from its roles in stimulating mitogenesis, mobility and metastasis and in protecting against apoptosis.
  • IGF-1R has been identified as the major survival factor that protects from oncogene induced cell death (Harrington et al., EMBO J. (1994) 13( ):3286-3295). IGF-1R is expressed in a large number and variety of tumors and the IGFs amplify the tumor growth through their interaction with the receptor.
  • IGF-1R Intracellular factor-1 receptor
  • Studies using monoclonal antibodies directed towards the receptor which inhibit the proliferation of numerous cell lines in culture and in vivo can be found in studies using monoclonal antibodies directed towards the receptor which inhibit the proliferation of numerous cell lines in culture and in vivo (Arteaga C et al., Cancer Res. (1989) 49(22):6237-6241; Li et al., Biochem. Biophys. Res. Com. (1993) 196(1):92-98; Scotlandi K et al., Cancer Res. (1998) 58(18):4127-4131).
  • Dominant negative IGF-1R is capable of inhibiting tumor proliferation (Jiang et al., Oncogene (1999) 18(44):6071-6077).
  • the IGF signaling axis is implicated in various tumor types including:
  • ErbB family tyrosine kinases includes EGFR, ErbB2, ErbB3 and ErbB4.
  • Aberrant activity in the ErbB family kinases has been implicated in a range of hyperproliferative disorders including psoriasis, rheumatoid arthritis, bronchitis and several cancers.
  • the biological role of ErbB family RTKs and their implication in different disease states has been widely discussed (Ullrich, A., et al., Cell (Apr. 20, 1990) 61: 203-212; Aaronson, S., Science (1991) 254:1146-1153; Salomon, D., et al., Crit. Rev.
  • elevated EGFR activity has been implicated in non-small cell lung, squamous cell lung, breast, bladder, head and neck squamous cell, esophageal, gastric, colorectal, pancreatic, thyroid, glial, cervical and ovarian cancers (Salomon (1995) supra; Woodburn (1999) supra; Normanno (2005) supra; Hynes (2005) supra).
  • overexpression and/or mutation of ErbB2 has been implicated in non-small cell lung, breast, ovarian, esophageal, gastric, colorectal, glial, pancreatic and cervical cancers (Salomon (1995) supra; Normanno (2005) supra; Hynes (2005) supra).
  • W 1 is —(CR 4 R 5 )—(CR 6 R 7 )—, —CR 5 ⁇ CR 7 —, —N ⁇ CR 7 —, —S(O) m — or —O—;
  • R 1 and R 0 is 4-Pyridyl or C 1-4 alkyl-4-pyridyl, provided that when R 1 is C 1-4 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of R 1 and R 0 is
  • W 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 and R 9 are as defined herein; provided that: 1) when W 1 is —(CR 4 R 5 )—(CR 6 R 7 )— then
  • PCT Publication No. WO 01/14375 to AstraZeneca AB relates to imidazo[1,2-a]pyridine and pyrazolo[2,3-a]pyridine derivatives of formula (I)
  • Ring A is a imidazo[1,2-a]pyridine or pyrazolo[2,3-a]pyrid-3-yl; R 2 is as defined therein, m is 0-5; wherein the values of R 2 may be the same or different; R 1 is as defined therein; n is 0 to 2, wherein the values of R 1 may be the same or different; Ring B is phenyl or phenyl fused to a C 5-7 cycloalkyl ring; R 3 is as defined therein; p is 0-4; wherein the values of R 3 may be the same or different; R 4 is as defined therein; q is 0-2; wherein the values of R 4 may be the same or different; and wherein p+q ⁇ 5; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
  • the use of the compounds of formula (I) in the inhibition of cell cycle kinases CDK2, CDK4 and CDK6 are also described.
  • Selected compounds of the formula (I) include:
  • the present invention provides N-(2,6-difluorophenyl)-3-[3-(2- ⁇ [4- ⁇ 4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl ⁇ -2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide and pharmaceutically acceptable salts thereof.
  • the present invention provides N-(2,6-difluorophenyl)-3-(3- ⁇ 2-[(2-(methyloxy)-4- ⁇ 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)benzamide and pharmaceutically acceptable salts thereof.
  • the present invention provides 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1-yl)-2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide and pharmaceutically acceptable salts thereof.
  • the present invention provides N-(2,6-difluorophenyl)-5-(3- ⁇ 2-[(2-(ethyloxy)-5-methyl-4- ⁇ 4-[2-(methylsulfonyl)ethyl]-1-piperidinyl ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide and pharmaceutically acceptable salts thereof.
  • the present invention provides N-(2,6-difluorophenyl)-5-(3- ⁇ 2-[(5-ethyl-2-(methyloxy)-4- ⁇ 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide and pharmaceutically acceptable salts thereof.
  • the compound is as the monocitric acid (citrate) salt.
  • the compound is the free base.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • a method of treating a susceptible neoplasm in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating breast cancer in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating sarcoma in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating lung cancer in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating non-small cell lung carcinoma in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating prostate cancer in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating colorectal cancer in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating pancreatic cancer in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating a hematologic cancer in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating multiple myeloma in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating head and neck cancer in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating ovarian cancer in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a susceptible neoplasm (e.g., breast cancer, sarcomas, lung cancer (including non-small cell lung carcinoma), prostate cancer, colorectal cancer, renal cancer, pancreatic cancer, hematologic cancers (including multiple myeloma), neuroblastomas, primary CNS tumors, secondary CNS tumors, head and neck cancer, thyroid cancer, hepatocarcinoma, ovarian cancer, vulval cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) or skin cancer (including melanoma), in a mammal (e.g., human) in need thereof.
  • a susceptible neoplasm e.g., breast cancer, sarcomas, lung cancer (including non-small cell lung carcinoma), prostate cancer, colorectal
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of breast cancer, sarcomas, lung cancer, non-small cell lung carcinoma, prostate cancer, colorectal cancer, pancreatic cancer, hematologic cancers, multiple myeloma, head and neck cancer or ovarian cancer, in a mammal (e.g., human) in need thereof.
  • a susceptible neoplasm e.g., breast cancer, sarcomas, lung cancer (including non-small cell lung carcinoma), prostate cancer, colorectal cancer, renal cancer, pancreatic cancer, hematologic cancers (including multiple myeloma), neuroblastomas, primary CNS tumors, secondary CNS tumors, head and neck cancer, thyroid cancer, hepatocarcinoma, ovarian cancer, vulval cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) or skin cancer (including melanoma), in a mammal (e.g., human) in need thereof.
  • a susceptible neoplasm e.g., breast cancer, sarcomas, lung cancer (including non-small cell lung carcinoma), prostate cancer, colorectal cancer, renal cancer, pancreatic cancer, hematologic cancers (including multiple myel
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in the treatment of breast cancer, sarcoma, lung cancer, non-small cell lung carcinoma, prostate cancer, colorectal cancer, pancreatic cancer, hematologic cancers, multiple myeloma, head and neck cancer or ovarian cancer, in a mammal (e.g., human) in need thereof.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a susceptible neoplasm (e.g., breast cancer, sarcomas, lung cancer (including non-small cell lung carcinoma), prostate cancer, colorectal cancer, renal cancer, pancreatic cancer, hematologic cancers (including multiple myeloma), neuroblastomas, primary CNS tumors, secondary CNS tumors, head and neck cancer, thyroid cancer, hepatocarcinoma, ovarian cancer, vulval cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) or skin cancer (including melanoma), in a mammal (e.g., human) in need thereof.
  • a susceptible neoplasm e.g., breast cancer, sarcomas, lung cancer (including non-small cell lung carcinoma), prostate
  • IGF-1R family tyrosine kinase refers to IGF-1R tyrosine kinase (herein “IGF-1R”), insulin receptor tyrosine kinase (herein “IR”) and Insulin receptor-related receptor tyrosine kinase (herein “IRR”).
  • IGF-1R IGF-1R tyrosine kinase
  • IR insulin receptor tyrosine kinase
  • IRR Insulin receptor-related receptor tyrosine kinase
  • ErbB family kinase refers to ErbB kinases and their dimerization partners including EGFR (also known as ErbB1), ErbB2, ErbB3 and ErbB4.
  • compound(s) of formula (I) means any compound having the structural formula (I) as defined by the variable definitions provided, solvate, hydrate, and amorphous and crystalline forms, including one or more polymorphic forms, and mixtures thereof.
  • the compounds may be in the form of a racemic mixture, or one or more isomerically enriched or pure stereoisomers, including enantiomers and disastereomers thereof.
  • “compound(s) of formula (I)” includes the racemic form as well as the enriched or pure enantiomers and diasteriomers.
  • Enantiomerically enriched or pure compounds will be designated using conventional nomenclature, including the designations +, ⁇ , R, S, d, I, D and L, according to the predominant isomer present.
  • a compound of the invention contains an alkenyl or alkenylene group
  • cis (E) and trans (Z) isomerism may also occur.
  • compound(s) of formula (I) includes the individual stereoisomers of the compound, which will be indicated using conventional, cis/trans nomenclature. It should also be understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and alternative tautomeric forms are also included within “compound(s) of formula (I).”
  • compound(s) of the invention means a compound of formula (I) (as defined above) in any version, i.e., as the free base or as a pharmaceutically acceptable salt thereof.
  • the compound as any version may be in any form, including solvates, hydrates, amorphous or crystalline forms, including specific polymorphic forms, or mixture of forms.
  • alkyl refers to linear or branched hydrocarbon chains having from 1 to 8 carbon atoms (i.e., C 1-8 alkyl), unless a different number of atoms is specified.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl and tert-butyl.
  • alkylene refers to linear or branched divalent hydrocarbon chains containing from 1 to 8 carbon atoms, unless a different number of atoms is specified. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, propylene, butylene and isobutylene.
  • cycloalkyl refers to a saturated monocyclic carbocyclic ring having from 3 to 8 carbon atoms, unless a different number of atoms is specified. “Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Halo “halo” or “halogen” are synonymous and refer to fluoro, chloro, bromo and iodo. “Halo” is specifically used to identify a particular substituent of formula (I) designated as such.
  • haloalkyl refers to an alkyl, as defined above, substituted by one or more halogen atoms, fluoro, chloro, bromo or iodo. Where the haloalkyl group has fewer than 8 carbon atoms, the number of carbon atoms in the group is indicated as, for example, haloC 1-3 alkyl. Examples of haloalkyl as used herein include, but are not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl and the like.
  • oxo refers to the group ⁇ O attached directly to a carbon atom of a hydrocarbon ring (e.g., cyclohexyl), or a C, N or S of a heterocyclic or heteroaryl ring to result in oxides, —N-oxides, sulfones and sulfoxides.
  • heterocycle and “heterocyclic” are synonymous and refer to monocyclic saturated or unsaturated non-aromatic groups, fused or bridged bicyclic saturated or unsaturated non-aromatic groups and spiro systems, each having from 5 to 10 members (unless a different number of members is specified) including 1, 2, 3 or 4 heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified.
  • the heterocycle includes 2 or more heteroatoms
  • the heteroatoms may be the same or different and are independently selected from N, O and S.
  • the compound of formula (I) includes two or more heterocyclic groups
  • the heterocyclic groups may be the same or different and are independently selected.
  • heterocyclic groups include but are not limited to tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene and the like.
  • N-heterocycle refers to monocyclic saturated or unsaturated non-aromatic groups, fused or bridged bicyclic saturated or unsaturated non-aromatic groups and spiro systems, each having from 5 to 10 members (unless a different number of members is specified) including at least one N and optionally 1, 2 or 3 additional heteroatoms selected from N, O and S, unless a different number of additional heteroatoms is specified.
  • additional heteroatoms is meant 1, 2 or 3 heteratoms in addition to the N already specified in the N-heterocycle ring.
  • the heterocycle includes 1 or more additional heteroatoms
  • the heteroatoms may be the same or different and are independently selected from N, O and S.
  • the compound of formula (I) includes two or more N-heterocyclic groups
  • the N-heterocyclic groups may be the same or different and are independently selected.
  • N-heerocycles may be bound through the N of the N-heterocyclic ring. Examples of N-heterocycles include piperidine, piperazine, pyrrolidine, morpholine and thiomorpholine.
  • heteroaryl refers to aromatic, monocyclic groups, aromatic fused bicyclic groups and fused bicyclic groups which have both aromatic and non-aromatic rings, each having from 5 to 10 members (unless a different number of members is specified) including 1, 2, 3, or 4 heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified.
  • the heteroaryl includes 2 or more heteroatoms
  • the heteroatoms may be the same or different and are independently selected from N, O and S.
  • the compound of formula (I) includes two or more heteroaryl groups
  • the heteroaryl groups may be the same or different and are independently selected.
  • heteroaryl groups include but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, tetrahydropyrimidine, triazine, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzothiophene, indole, indoline, indazole, benzodioxane, benzodioxin, benzodithiane, benzoxazine, benzopiperidine and benzopiperzine.
  • N-heteroaryl refers to aromatic, monocyclic groups, aromatic fused bicyclic groups and fused bicyclic groups which have both aromatic and non-aromatic rings, each having from 5 to 10 members (unless a different number of members is specified) including at least one N and optionally 1, 2 or 3 additional heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified.
  • additional heteroatoms is meant 1, 2 or 3 heteratoms in addition to the N already present in the N-heteroaryl.
  • the heteroaryl includes 1 or more additional heteroatoms, the heteroatoms may be the same or different and are independently selected from N, O and S.
  • the N-heteroaryl groups may be the same or different and are independently selected.
  • N-heteroaryls include pyrrole, imidazole, pyrazole, thiazole, isoxazole, pyridine, pyridazine, pyrazine, pyrimidine, triazine, quinoline, isoquinoline, indole, indoline, benzopiperidine and benzopiperzine.
  • the term “members” (and variants thereof e.g., “membered”) in the context of heterocyclic and heteroaryl groups refers to the total number of ring atoms, including carbon and heteroatoms N, O and/or S.
  • a 6-membered heterocyclic ring is piperidine and an example of a 6-membered heteroaryl ring is pyridine.
  • an N-heterocycle optionally including 1, 2 or 3 additional heteroatoms describes N-heterocycles including no additional heteroatoms as well as N-heterocycles including 1, 2 or 3 additional heteroatoms.
  • the present invention provides compounds of formula (I):
  • the compounds of the invention are defined wherein X 1 is halo. In one particular embodiment, Halo and X 1 are both F.
  • R 1 may be bound at any one of the 3-, 4- or 5-position of the phenyl ring as numbered below.
  • R 1 is bound at the 4-position of the phenyl ring.
  • R 1 is H or halo. In one particular embodiment, R 1 is H. In another particular embodiment, X 1 is halo and R 1 is H.
  • R 1 is bound at the 4-position of the phenyl ring and Halo, X 1 and R 1 are all F.
  • X 1 and R 1 are all F.
  • Halo and X 1 are both F and R 1 is H. This embodiment is depicted by the formula (I-a):
  • the compounds of the invention are defined wherein R 2 is H or O—C 1-3 alkyl (e.g., particularly O-methyl, O-ethyl, O-isopropyl and O-n-propyl).
  • R 2 is H.
  • R 2 is O-methyl.
  • R 2 is O-ethyl.
  • each R 3 is the same or different and is independently selected from H, halo, C 1-3 alkyl, haloC 1-3 alkyl and O—C 1-3 alkyl, or any subset thereof.
  • at least 1 R 3 is H and the other is selected from H, halo, C 1-3 alkyl, haloC 1-3 alkyl and O—C 1-3 alkyl, or any subset thereof.
  • at least 1 R 3 is H and the other is selected from H, F, Cl, methyl, CF 3 and O-methyl, or any subset thereof.
  • both R 3 are H.
  • 1 R 3 is H and the other is F.
  • R 4 and R 5 is selected from H, halo, alkyl and O-alkyl and the other of R 4 and R 5 is a moiety selected from:
  • one of R 4 and R 5 is selected from H, halo, alkyl and O-alkyl, and the other is a moiety (i).
  • R 4 is selected from H, halo, alkyl and O-alkyl, and R 5 is a moiety of formula (i). In one embodiment, R 4 is H and R 5 is a moiety (i).
  • the moiety (i) is defined wherein a is 2 or 3. In one particular embodiment, a is 2.
  • the moiety (i) is defined wherein each R 7 is the same or different and is independently H or OH. In one particular embodiment, each R 7 is H. A particular embodiment the moiety (i) is defined wherein a is 2 or 3 and each R 7 the same or different and is independently H or OH. A preferred embodiment of the invention is defined wherein R 5 is a moiety (i), a is 2 and each R 7 is H.
  • the moiety (i) is defined wherein R 8 is selected from N(alkyl) 2 and a group of formula (iv):
  • Ring D may be bound to the alkylene or substituted alkylene group through any available carbon or heteroatom of the ring.
  • the group of formula (iv) is defined wherein Ring D is selected from 5-6 membered monocyclic N-heterocycles optionally including 1 or 2 additional heteroatoms selected from N, O and S and R 14 is selected from H, halo, alkyl, OH, O-alkyl, oxo, SO 2 alkyl, alkylene-O-alkyl and alkylene-SO 2 alkyl.
  • Ring D may be bound to the alkylene or substituted alkylene group through any available carbon or heteroatom of the ring.
  • the moiety (i) is defined wherein R 8 is selected from N(C 1-3 alkyl) 2 and a group of formula (iv). In one preferred embodiment, R 8 is N(CH 3 ) 2 . In another preferred embodiment, R 8 is a group of formula (iv) wherein Ring D is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholine and thiomorpholine, or any subset thereof. In one embodiment, Ring D is selected from pyrrolidinyl, piperidinyl and piperazinyl, or any subset thereof.
  • R 14 may be bound to Ring D through any suitable carbon or heteroatom of the ring (to provide, for example, N-methyl or N-oxides).
  • R 14 is H, oxo (including N-oxide) or alkyl (including N-alkyl), or any subset thereof.
  • R 14 is H, oxo (including N-oxide) or methyl (including N-methyl).
  • the compounds of the invention are defined wherein one of R 4 and R 5 is selected from H, halo, alkyl and O-alkyl, and the other is a moiety of formula (ii):
  • R 5 is H and R 4 is a moiety of formula (ii).
  • a particular embodiment of the compounds of the invention is depicted in formula (I-a(ii)):
  • b is 0, 1 or 2 and each R 9 is H.
  • the moiety of formula (ii) is defined wherein b is 0. This embodiment is depicted as the moiety (ii-a):
  • Ring A is bound to the phenyl ring (when b is 0) or to the optional group (CHR 9 ) b through any available C or heteroatom of the ring (N or S).
  • the moiety (ii) is defined wherein Ring A is selected from 5-6 membered monocyclic heterocycles and heteroaryls including 1, 2 or 3 heteroatoms selected from N, O and S.
  • the moiety (ii) is defined wherein Ring A is selected from 5-6 membered monocyclic N-heterocycles and N-heteroaryls optionally including 1 or 2 additional heteroatoms selected from N, O and S.
  • the moiety (ii) is defined wherein Ring A is selected from 5-6 membered monocyclic N-heterocycles optionally including 1 additional heteroatom selected from N, O and S.
  • Ring A is selected from piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrazolyl, oxazolyl and oxadiazolyl, or any subset thereof.
  • Ring A is piperidinyl or piperazinyl, or any subset thereof.
  • Each R 10 may be bound to Ring A through any suitable carbon or heteroatom (to provide, for example, N-methyl or N-oxides).
  • the moiety (ii) is defined wherein n is 0 or 1. In one embodiment, n is 0.
  • R 10 is selected from halo, alkyl, haloalkyl, O-alkyl, oxo, NH 2 , N(H)alkyl, N(alkyl) 2 , SO 2 alkyl, alkylene-N(alkyl) 2 and alkylene-SO 2 alkyl, or any subset thereof.
  • R 10 is selected from alkyl, haloalkyl, N(alkyl) 2 , SO 2 alkyl and alkylene-SO 2 alkyl, or any subset thereof.
  • R 10 is SO 2 alkyl.
  • R 10 is alkylene-SO 2 alkyl.
  • groups defining R 10 include methyl, CF 3 , ethyl, CH 2 CH 2 F, isopropyl, n-propyl, OH, O-methyl, N(CH 3 ) 2 , CH 2 —N(CH 3 ) 2 and CH 2 CH 2 —SO 2 CH 3 , or any subset thereof.
  • the compounds of the invention are defined wherein one of R 4 and R 5 is selected from H, halo, alkyl and O-alkyl, and the other is a moiety (iii):
  • Ring B is referred to herein as “Ring B;”.
  • R 5 is H, F, Cl, methyl or ethyl, or any subset thereof, and R 4 is a moiety (iii).
  • R 5 is H, F, Cl, methyl or ethyl, or any subset thereof, and R 4 is a moiety (iii).
  • a particular embodiment of the compounds of the invention is depicted as formula (I-a(iii)):
  • q is 0.
  • R 11 is either not present (e.g., the valences of the ring atoms are all filled), or it is H (where the valences of the ring atoms are unfilled).
  • R 11 may be bound to Ring B through any suitable carbon or heteroatom (to provide, for example, N-methyl).
  • the moiety (iii) is defined wherein R 11 is halo, methyl or CF 3 , or any subset thereof.
  • the moiety (iii) is defined wherein c is 1 or 2 and each R 12 is H.
  • the moiety (iii) is defined wherein c is 0 or 1. In one preferred embodiment, q is 0, c is 1 and R 12 is H. Thus, in one particular embodiment, the moiety (iii) is a moiety (iii-a):
  • the compounds of the invention are defined wherein R 5 is H, F, Cl or methyl, or any subset thereof, and R 4 is a moiety (iii-a).
  • the moiety (iii) is defined wherein c is 0. In one particular embodiment, q is 0 and c is 0. Thus, in one particular embodiment, the moiety (iii) is a moiety (iii-b):
  • the compounds of the invention are defined wherein R 5 is H and R 4 is a moiety (iii-b).
  • R 5 is H and R 4 is a moiety (iii-b).
  • a particular embodiment of the compounds of the invention is depicted as formula (I-a(iii)b)):
  • Ring B is bound to the phenyl ring and to the optional group (CHR 12 ) c or to Ring C (when c is 0) through any available C or heteroatom (N or S).
  • the moiety (iii) is defined wherein Ring B is selected from 5-6 membered monocyclic heterocycles including 1, 2 or 3 heteroatoms selected from N, O and S and 5-6 membered monocyclic heteroaryls including 1, 2 or 3 heteroatoms selected from N, O and S.
  • Ring B is selected from 5-6 membered monocyclic N-heterocycles and
  • N-heteroaryls optionally including 1 or 2 additional heteroatoms selected from N, O and S.
  • groups defining Ring B include piperidinyl, piperazinyl and oxadiazolyl, or any subset thereof.
  • Ring B is bound to the phenyl or optional group (CHR 12 ) c or to Ring C (when c is 0), through the N of the N-heterocycle.
  • Ring C is bound to the optional group (CHR 12 ) c or to Ring B (when c is 0) through any available C or heteroatom (N or S).
  • the moiety (iii) is defined wherein Ring C is selected from 5-6 membered monocyclic and 9-10 membered fused bicyclic and spiro N-heterocycles optionally including 1 or 2 additional heteroatoms selected from N, O and S.
  • Ring C is a 5-6 membered monocyclic N-heterocycle optionally including 1 or 2 additional heteroatoms selected from N, O and S.
  • Specific examples of groups defining Ring C include:
  • Ring C is bound to the optional group (CHR 12 ) c or to Ring B, through the N of the N-heterocycle.
  • the moiety of formula (iii) is defined wherein p is 0 or 1. In one particular embodiment, the moiety of formula (iii) is defined wherein p is 0. In another particular embodiment, the moiety of formula (iii) is defined wherein p is 1.
  • R 13 may be bound to Ring C through any suitable carbon or heteroatom (to provide, for example, N-methyl or N-oxides).
  • each R 13 is the same or different and is independently selected from alkyl, haloalkyl, OH, O-alkyl, oxo, NH 2 , N(H)alkyl, N(alkyl) 2 , SO 2 alkyl, alkylene-NH 2 , alkylene-N(H)alkyl, alkylene-N(alkyl) 2 and alkylene-SO 2 alkyl, or any subset thereof.
  • p is 1 and R 13 is selected from alkyl, haloalkyl, OH, O-alkyl, N(alkyl) 2 , SO 2 alkyl and alkylene-SO 2 alkyl, or any subset thereof.
  • p is 1 and R 13 is haloalkyl.
  • p is 1 and R 13 is SO 2 alkyl.
  • p is 1 and R 13 is alkylene-SO 2 alkyl.
  • groups defining R 13 include F, methyl, CF 3 , CH 2 CH 2 F, OH, N(CH 3 ) 2 , SO 2 —CH 3 , and CH 2 CH 2 SO 2 CH 3 .
  • the compounds of the invention are defined wherein at least one R 6 is H.
  • one R 6 is H and the other R 6 is selected from H,
  • R 6 is H and the other R 6 is O-methyl. In another preferred embodiment, one R 6 is H and the other R 6 is O-ethyl. In another preferred embodiment, both R 6 are H.
  • Preferred compounds of the formula (I) include but are not limited to:
  • a particular preferred compound of formula (I) is N-(2,6-difluorophenyl)-3-[3-(2- ⁇ [4- ⁇ 4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl ⁇ -2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide
  • Another particular preferred compound of formula (I) is N-(2,6-difluorophenyl)-3-(3- ⁇ 2-[(2-(methyloxy)-4- ⁇ 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)benzamide
  • Another particular preferred compound of formula (I) is 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • Another particular preferred compound of formula (I) is N-(2,6-difluorophenyl)-5-(3- ⁇ 2-[(2-(ethyloxy)-5-methyl-4- ⁇ 4-[2-(methylsulfonyl)ethyl]-1-piperidinyl ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide
  • the compound is as the free base. In another particular embodiment, the compound is as the mono methanesulfonic acid salt
  • Another particular preferred compound of formula (I) is N-(2,6-difluorophenyl)-5-(3- ⁇ 2-[(5-ethyl-2-(methyloxy)-4- ⁇ 4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide
  • the compound is as the free base.
  • the compound is as the monocitric acid (citrate) salt.
  • the compounds of formula (I) may also be utilized in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable (i.e., non-toxic) inorganic or organic acids or bases as well as quaternary ammonium salts.
  • Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate (methanesulfonic acid), methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglu
  • the compound of formula (I) is in the form of the hydrochloride salt. In one embodiment, the compound of formula (I) is in the form of the methane sulfonic acid salt.
  • Compounds of the invention are believed to inhibit one or more kinases and in particular one or more IGF-1R family tyrosine kinases. Compounds of the invention may also inhibit one or more other kinases, and particularly other tyrosine kinases. Certain compounds of the invention inhibit IGF-1R (“IGF-1R inhibitor”) or inhibit IR (“IR inhibitor”), or inhibit both. For brevity herein, there term “IGF-1R/IR inhibitor” refers to inhibitors of either IGF-1R or IR or both. Certain compounds of the invention may inhibit both IGF-1R and IR and also one or more ErbB family kinases (“ErbB inhibitor”).
  • IGF-1R inhibitors e.g., EGFR and ErbB2 inhibitors
  • IR inhibitors e.g., EGFR and ErbB2 inhibitors
  • ErbB inhibitors e.g., EGFR and ErbB2 inhibitors
  • the anticancer and antitumor effects of these kinase inhibitors is currently believed to result from inhibition of IGF-1R and IR and/or ErbB family kinases, and the effect of such inhibition on cell lines whose growth and/or viability is dependent on the kinase activity of IGF-1R or IR and/or ErbB family kinases.
  • Compounds of the invention may be IGF-1R inhibitors, and/or IR inhibitors, and optionally also ErbB family kinases inhibitors. Certain compounds of the invention may inhibit both IGF-1R, IR and also one or more ErbB family kinases. In particular, certain compounds of the invention may inhibit one or both of IGF-1R and IR and one or both of EGFR and ErbB2.
  • Some compounds of the invention may be selective inhibitors of IGF-1R family tyrosine kinases, and particularly IGF-1R and IR, (“selective IGF-1R inhibitor”), meaning that preferential inhibition of IGF-1R family tyrosine kinases is significantly greater than that of any number of other kinases, for example by a factor of 5-fold or more.
  • Certain compounds of the invention may be selective inhibitors of ErbB family kinases (“selective ErbB inhibitor”), meaning that preferential inhibition of one or more ErbB family kinases is significantly greater than that of any number of other kinases, for example by a factor of 5-fold or more.
  • Still other compounds of the invention may selectively inhibit IGF-1R family tyrosine kinases and one or more ErbB family kinases over other kinases (“selective dual IGF-1R/ErbB inhibitor”), meaning that inhibition of IGF-1R family tyrosine kinases and one or more ErbB family kinases is significantly greater than that of any number of other kinases, for example by a factor of 5-fold or more.
  • the present invention is not limited to compounds which are selective inhibitors of IGF-1R family tyrosine kinases or both IGF-1R family tyrosine kinases and ErbB family kinases.
  • the present invention expressly contemplates that certain compounds of the invention may possess activity against multiple kinases, including kinases other than IGF-1R family tyrosine kinases and ErbB family kinases.
  • particular compounds of the invention may possess activity against multiple other kinases, including but not limited to Src, VEGFR, PDGFR, Met, c-Kit, Lyn, Lck, Aurora A and B, Syk, p38, BTK and BRK, as well.
  • Particular compounds of the invention may be deemed to be unselective, meaning that they are not considered by one skilled in the art to be selective for any particular kinase over others.
  • an IGF-1R/IR inhibitor is a compound that exhibits a pIC 50 of greater than about 6 against one or both of IGF-1R and IR in the IGF-1R enzyme inhibition (TR-FRET) assay described below and/or an IC 50 of at least about 1 ⁇ M potency against IGF-1R cellular autophosphorylation and/or in cell proliferation of a cell line that is dependent upon IGF signaling (e.g., Colo205, NCI-H929) in at least one of the assays described below.
  • TR-FRET IGF-1R enzyme inhibition
  • an IGF-1R/IR inhibitor refers to a compound of the invention that exhibits a pIC 50 of greater than about 7 against one or both of IGF-1R and IR in the IGF-1R enzyme inhibition assay described below and/or an IC 50 of at least about 500 nM potency against IGF-1R cellular autophosphorylation and/or in the cell proliferation of a cell line that is dependent upon IGF signaling (e.g., Colo205, NCI-H929) in at least one of the assays described below.
  • IGF signaling e.g., Colo205, NCI-H929
  • An ErbB inhibitor is a compound which exhibits a pIC 50 of greater than about 6 against at least one ErbB family kinase in the ErbB inhibition enzyme assay described below and/or an IC 50 of at least about 1 ⁇ M potency against at least one cell line (e.g., BT474 or HN5) that over expresses at least one ErbB family kinase in the cellular proliferation assay described below.
  • a cell line e.g., BT474 or HN5
  • a ErbB inhibitor refers to a compound of the invention which exhibits a pIC 50 of greater than about 7 against at least one ErbB family kinase in the ErbB inhibition enzyme assay described below and/or an IC 50 of at least about 500 nM potency against at least one cell line that over expresses at least one ErbB family kinase in the cellular proliferation assay described below.
  • the present invention provides compounds for use in medical therapy in a mammal in need thereof.
  • the present invention provides methods for the treatment of several conditions in a mammal in need thereof, all of which comprise the step of administering a therapeutically effective amount of a compound of the invention. All methods described herein are applicable to mammals, and particularly to humans.
  • the term “treatment” or “treating” in the context of therapeutic methods refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression invasion or metastatic spread of the condition and preventing or delaying the reoccurrence of the condition in a previously afflicted subject.
  • the present invention further provides use of a compounds of the invention for preparation of a medicament for the treatment of several conditions in a mammal (e.g., human) in need thereof.
  • the present invention provides compounds for use in the treatment of, a condition mediated by one or more IGF-1R family tyrosine kinases (e.g., IGF-1R and IR) in a mammal in need thereof.
  • the present invention further provides methods for the treatment of a condition mediated by one or more IGF-1R family tyrosine kinases (e.g., IGF-IR and IR) in a mammal in need thereof, which method comprises administering to the mammal a therapeutically effective amount of the compound of the invention.
  • the present invention provides compounds for use in regulating, modulating, binding, or inhibiting IGF-1R or IR in a mammal.
  • the invention also provides methods for regulating, modulating, binding, or inhibiting IGF-1R or IR in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the invention.
  • “Regulating, modulating, binding or inhibiting IGF-1R or IR” refers to regulating, modulating, binding or inhibiting the activity of IGF-1R or IR, as well as regulating, modulating, binding or inhibiting any overexpression of an upstream regulator of IGF-1R or IR in order to inhibit the cellular potency of its signaling ability.
  • the invention provides compounds for use in the treatment of a condition mediated by inappropriate activity of one or more IGF-1R family tyrosine kinases (particularly IGF-1R or IR), in a mammal in need thereof.
  • the present invention further provides methods for the treatment of condition mediated by inappropriate activity of one or more IGF-1R family tyrosine kinases (particularly IGF-1R or IR), in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition mediated by inappropriate activity of one or more IGF-1R family tyrosine kinases (particularly IGF-1R or IR), in a mammal.
  • a condition mediated by inappropriate activity of one or more IGF-1R family tyrosine kinases includes neoplasms.
  • inappropriate activity is meant kinase activity that deviates from the expected activity for that kinase (e.g., IGF-1R) or for an upstream regulator of that kinase (e.g., IGF-1R), in a particular mammal.
  • the inappropriate activity of an IGF-1R family tyrosine kinase may arise from one or more of IGF-1R, IR and IRR (particularly IGF-1R or IR), or an upstream regulator of an IGF-1R family tyrosine kinase (particularly IGF-1R or IR).
  • Inappropriate IGF-1R family tyrosine kinase activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and/or control of IGF-1R family tyrosine kinases.
  • Such inappropriate activity may result, for example, from overexpression or mutation of the protein kinase, upstream regulator, receptor or ligand and/or change in the expression patterns of IGF binding proteins leading to inappropriate or uncontrolled activation of the corresponding kinase or receptor.
  • the present invention provides compounds for use in the treatment of a condition which directly or indirectly results from altered signaling of one or more IGF-1R family tyrosine kinases (particularly IGF-1R and IR) in a mammal in need thereof.
  • the present invention provides methods for the treatment of a condition which directly or indirectly results from altered signaling of one or more IGF-1R family tyrosine kinases (particularly IGF-1R and IR) in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition which directly or indirectly results from altered signaling of one or more IGF-1R family tyrosine kinases (particularly IGF-1R and IR) in a mammal.
  • a condition which directly or indirectly results from altered signaling of IGF-1R family tyrosine kinases includes neoplasms.
  • IGF-1R family tyrosine kinase may reside in an abnormal source, such as a malignancy.
  • the level of IGF-1R family tyrosine kinase activity does not need to be abnormal to be considered inappropriate in the case where the activity derives from an abnormal source including, but not limited to, upstream activators or malignancy.
  • the present invention provides methods for the treatment of a condition which directly or indirectly results from mutation or overexpression of the receptor or the ligands or a change in the expression patterns of IGF binding proteins of IGF-1R or IR in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition which directly or indirectly results from mutation or overexpression of the receptor or the ligands or a change in the expression patterns of IGF binding proteins of IGF-1R or IR in a mammal.
  • a condition which directly or indirectly results from mutation or overexpression of the receptor or the ligands or a change in the expression patterns of IGF binding proteins of IGF-1R or IR includes neoplasms.
  • Compounds of the invention may be used in the treatment of conditions attenuated by inhibition of an IGF-1R family tyrosine kinase (particularly, IGF-1R or IR). Further provided are methods for treating a condition attenuated by inhibition of an IGF-1R family tyrosine kinase (particularly, IGF-1R or IR) in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • a compound of the invention for the preparation of a medicament for the treatment of a condition attenuated by inhibition of an IGF-1R family tyrosine kinase (particularly, IGF-1R or IR) in a mammal.
  • IGF-1R family tyrosine kinase particularly, IGF-1R or IR
  • Conditions attenuated by inhibition of IGF-1R family tyrosine kinases, and particularly IGF-1R and IR include but are not limited to neoplasms.
  • the present invention also provides compounds for use in the treatment of a condition mediated by an IGF-1R family tyrosine kinases (e.g., IGF-1R and IR) and at least one ErbB family kinase (e.g., EGFR and ErbB2) in a mammal in need thereof.
  • IGF-1R family tyrosine kinases e.g., IGF-1R and IR
  • ErbB family kinase e.g., EGFR and ErbB2
  • the present invention further provides methods for the treatment of a condition mediated by an IGF-1R family tyrosine kinase (e.g., IGF-IR and IR) and at least one ErbB family kinase (e.g., EGFR and ErbB2) in a mammal in need thereof, which method comprises administering to the mammal a therapeutically effective amount of the compound of the invention.
  • IGF-1R family tyrosine kinase e.g., IGF-IR and IR
  • ErbB family kinase e.g., EGFR and ErbB2
  • the present invention provides compounds for use in regulating, modulating, binding, or inhibiting IGF-1R or IR and at least one ErbB family kinase (e.g., EGFR and ErbB2) in a mammal.
  • the invention also provides methods for regulating, modulating, binding, or inhibiting IGF-1R or IR and at least one ErbB family kinase (e.g., EGFR and ErbB2) in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of the invention.
  • “Regulating, modulating, binding or inhibiting” in the context of IGF-1R family kinases is defined above.
  • “Regulating, modulating, binding or inhibiting at least one ErbB family kinase” refers to regulating, modulating, binding or inhibiting the activity of at least one ErbB family kinase, as well as regulating, modulating, binding or inhibiting any overexpression of at least one ErbB family kinase to inhibit the cellular potency of its signaling ability.
  • the invention provides compounds for use in the treatment of a condition mediated by inappropriate activity of one or more IGF-1R family tyrosine kinases (particularly IGF-1R or IR) and at least one ErbB family kinase (particularly EGFR and ErbB2), in a mammal in need thereof.
  • the present invention further provides methods for the treatment of a condition mediated by inappropriate activity of one or more IGF-1R family tyrosine kinases (particularly IGF-1R or IR) and at least one ErbB family kinase (particularly EGFR and ErbB2), in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition mediated by inappropriate activity of at least one IGF-1R family tyrosine kinase and at least one ErbB family kinase (particularly EGFR and ErbB2), in a mammal.
  • a condition mediated by inappropriate activity of one or more IGF-1R family tyrosine kinases and at least one ErbB family kinase includes neoplasms.
  • Inappropriate activity is defined above, as is a description of inappropriate activity of IGF-1R family tyrosine kinases.
  • the inappropriate activity of an ErbB family kinase may arise from one or more of EGFR, ErbB2 or ErbB4 (more particularly EGFR or ErbB2).
  • Inappropriate ErbB family kinase activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and/or control of ErbB family kinase activity or an upstream activator of ErbB family kinases.
  • Such inappropriate activity may result, for example, from overexpression or mutation of the protein kinase, upstream activator, receptor or ligand and/or change in the expression patterns of IGF binding proteins leading to inappropriate or uncontrolled activation of the corresponding kinase or receptor.
  • the present invention provides compounds for use in the treatment of a condition which directly or indirectly results from altered signaling of one or more IGF-1R family tyrosine kinases (particularly IGF-1R and IR) and overexpression of at least one ErbB family kinase (particularly EGFR and/or ErbB2) in a mammal in need thereof.
  • IGF-1R family tyrosine kinases particularly IGF-1R and IR
  • ErbB family kinase particularly EGFR and/or ErbB2
  • the present invention provides methods for the treatment of a condition which directly or indirectly results from altered signaling of one or more IGF-1R family tyrosine kinases (particularly IGF-1R and IR) and overexpression of at least one ErbB family kinase (particularly EGFR and/or ErbB2) in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • IGF-1R family tyrosine kinases particularly IGF-1R and IR
  • ErbB family kinase particularly EGFR and/or ErbB2
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition which directly or indirectly results from altered signaling of one or more IGF-1R family tyrosine kinases (particularly IGF-1R and IR) and overexpression of at least one ErbB family kinase (particularly EGFR and/or ErbB2) in a mammal.
  • a condition which directly or indirectly results from altered signaling of an IGF-1R family tyrosine kinase and overexpression of at least one ErbB family kinase includes neoplasms.
  • the unwanted ErbB family kinase activity may reside in an abnormal source, such as a malignancy.
  • an abnormal source such as a malignancy.
  • the level of ErbB family kinase activity does not need to be abnormal to be considered inappropriate in the case where the activity derives from an abnormal source including, but not limited to, upstream activators or malignancy.
  • the present invention provides methods for the treatment of a condition which directly or indirectly results from mutation or overexpression of the receptor or the ligands or a change in the expression patterns of IGF binding proteins of IGF-1R or IR and overexpression of at least one ErbB family kinase (particularly EGFR or ErbB2) in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition which directly or indirectly results from mutation or overexpression of the receptor or the ligands or a change in the expression patterns of IGF binding proteins of IGF-1R or IR and overexpression of at least one ErbB family kinase (particularly EGFR or ErbB2) in a mammal.
  • a condition which directly or indirectly results from mutation or overexpression of the receptor or the ligands or a change in the expression patterns of IGF binding proteins of IGF-1R or IR and overexpression of at least one ErbB family kinase (particularly EGFR or ErbB2) includes neoplasms.
  • Compounds of the invention may be used in the treatment of conditions attenuated by inhibition of one or more IGF-1R family tyrosine kinases (particularly, IGF-1R or IR) and at least one ErbB family kinase (particularly EGFR or ErbB2). Further provided are methods for treating a condition attenuated by inhibition of one or more IGF-1R family tyrosine kinase (particularly, IGF-1R or IR) and at least one ErbB family kinase (particularly EGFR or ErbB2) in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • a compound of the invention for the preparation of a medicament for the treatment of a condition attenuated by inhibition of one or more IGF-1R family tyrosine kinase (particularly, IGF-1R or IR) and at least one ErbB family kinase (particularly EGFR or ErbB2) in a mammal.
  • IGF-1R family tyrosine kinases particularly IGF-1R or IR
  • ErbB family kinase particularly EGFR or ErbB2
  • Conditions attenuated by inhibition of IGF-1R family tyrosine kinases, and particularly IGF-1R and IR, and at least one ErbB family kinase (particularly EGFR or ErbB2) include but are not limited to neoplasms.
  • Compounds of the invention may be used in the treatment of a neoplasm and particularly a susceptible neoplasm in a mammal (e.g., human) in need thereof.
  • the present invention further provides the use of a compound of the invention for the preparation of a medicament for the treatment of a neoplasm, and particularly a susceptible neoplasm, in a mammal (e.g., human) in need thereof.
  • the present invention also provides a method for treating a susceptible neoplasm (cancer or tumor) in a mammal in need thereof, which method comprises administering to the mammal a therapeutically effective amount of the compound of the invention.
  • “Susceptible neoplasm” as used herein refers to neoplasms which are susceptible to treatment by a kinase inhibitor and particularly neoplasms that are susceptible to treatment by an IGF-1R/IR inhibitor and neoplasms that are susceptible to treatment by an IGF-1R/IR inhibitor and an ErbB family kinase inhibitor.
  • Susceptible neoplasms include neoplasms which exhibit indicators of inappropriate activity of IGF-1R family tyrosine kinases and optionally also indicators of inappropriate activity of ErbB family kinases.
  • neoplasms which exhibit altered signaling or uncontrolled activation of IGF-1R or IR are “susceptible neoplasms” as that term is used herein.
  • neoplasms which exhibit overexpression of one or more ErbB family kinases are “susceptible neoplasms” as that term is used herein.
  • Neoplasms which exhibit indicators of inappropriate activity of IGF-1R family tyrosine kinases and are therefore susceptible to treatment with an IGF-1R inhibitor are known in the art, and include both primary and metastatic tumors and cancers.
  • Neoplasms which exhibit indicators of inappropriate activity of one or more ErbB family kinases and are therefore susceptible to treatment with an ErbB inhibitor are known in the art, and include both primary and metastatic tumors and cancers.
  • the susceptible neoplasm is breast cancer and the present invention provides a method for treating breast cancer in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the susceptible neoplasm is sarcoma and the invention provides a method for treating sarcoma in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the susceptible neoplasm is lung cancer (including non-small cell lung carcinomas (NSCLC) small cell lung carcinomas and mesotheliomas, and particularly NSCLC) and the present invention provides a method of treating lung cancer (e.g., NSCLC) in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • lung cancer e.g., NSCLC
  • the susceptible neoplasm is prostate cancer and the invention provides a method for treating prostate cancer in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the susceptible neoplasm is colorectal cancer and the present invention provides a method for treating colorectal cancer in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the susceptible neoplasm is pancreatic cancer and the invention provides a method for treating pancreatic cancer in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the susceptible neoplasm is a hematologic cancer and the invention provides a method for treating a hematologic cancer in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the hematologic cancer is multiple myeloma.
  • the susceptible neoplasm is head and neck cancer and the invention provides a method for treating head and neck cancer in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the susceptible neoplasm is ovarian cancer and the invention provides a method for treating ovarian cancer in a mammal in need thereof which comprises administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the compounds of the invention can be used alone in the treatment of each of the foregoing conditions or can be used to provide additive or potentially synergistic effects with certain existing chemotherapies, biological or immunotherapeutics (including monoclonal antibodies) and vaccines, and/or be used to restore effectiveness of certain existing chemotherapies and radiation. It is documented that IGF-1R family tyrosine kinase inhibitors may increase the sensitivity to other chemotherapies.
  • the term “therapeutically effective amount” means an amount of a compound of formula (I) which is sufficient, in the subject to which it is administered, to elicit the biological or medical response of a cell culture, tissue, system, mammal (including human) that is being sought, for instance, by a researcher or clinician.
  • the term also includes within its scope, amounts effective to enhance normal physiological function.
  • a therapeutically effective amount of a compound of the invention for the treatment of a condition mediated by IGF-1R family tyrosine kinase is an amount sufficient to treat the condition in the particular subject.
  • a therapeutically effective amount of a compound of the invention for the treatment of a susceptible neoplasm is an amount sufficient to treat the particular susceptible neoplasm in the subject.
  • a therapeutically effective amount of a compound of the invention is an amount sufficient to regulate, modulate, bind or inhibit at least one IGF-1R family tyrosine kinase.
  • a therapeutically effective amount of a compound of the invention is an amount sufficient to regulate, modulate, bind or inhibit at least one IGF-1R family tyrosine kinase and at least one ErbB family kinase.
  • the therapeutically effective amount of a compound of the invention is an amount sufficient to regulate, modulate, bind or inhibit IGF-1R, IR and one or both of EGFR and ErbB2 kinases.
  • the precise therapeutically effective amount of the compounds of the invention will depend on a number of factors including, but not limited to, the species, age and weight of the subject being treated, the precise condition requiring treatment and its severity, the bioavailability and other properties of the specific compound being administered, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • an estimated Human Equivalent Dosing (HED) range for humans may be calculated using the following formula.
  • HED Dose in animal (mg/kg)*(Wt animal/Wt humans) ⁇ 0.33
  • an estimated dose of a compound of the invention for treatment may be in the range of 0.2 to 136 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 100 mg/kg body weight per day.
  • Acceptable daily dosages may be from about 0.1 to about 10000 mg/day, and preferably from about 0.1 to about 1000 mg/day.
  • the actual amount per day may be from about 70 to about 7000 mg, more usually from about 70 to about 1000 mg, and particularly from about 70 to about 500 mg; and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the approximately the same.
  • a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) may be determined as a proportion of the therapeutically effective amount of the compound of formula (I) per se. It is envisaged that similar dosing would be appropriate for treatment of the susceptible neoplasms described above.
  • the invention further provides a pharmaceutical composition comprising a compound of the invention.
  • the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and/or excipients.
  • the carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the invention with one or more pharmaceutically acceptable carriers, diluents and/or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention (as a free-base, solvate (including hydrate) or salt, and in any form), depending on the condition being treated, the route of administration, the bioavailability of the specific compound, the species being treated, and the age, weight and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, a sub-dose, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate, delayed and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual), nasal, inhalation, topical (including transdermal), rectal, vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • oral including capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate, delayed and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual
  • nasal, inhalation including topical (including transdermal), rectal, vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s), excipient(s) or diluent.
  • the carrier, excipient or diluent employed in the pharmaceutical formulation is “non-toxic,” meaning that it/they is/are deemed safe for consumption in the amount delivered in the pharmaceutical composition, and “inert” meaning that it/they does/do not appreciably react with or result in an undesired effect on the therapeutic activity of the active ingredient.
  • compositions adapted for oral administration may be presented as discrete units such as liquid-filled or solid capsules; immediate, delayed or controlled release tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions, water-in-oil liquid emulsions or oral strips, such as impregnated gel strips.
  • the active ingredient can be combined with an oral pharmaceutically acceptable carrier such as ethanol, glycerol, water and the like.
  • an oral pharmaceutically acceptable carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a pharmaceutically acceptable alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a pharmaceutically acceptable vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research (1986) 3(6):318.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, metered dose inhalers, dry powder inhalers, nebulizers or insufflators.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation of pharmaceutically acceptable tonicity with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • a compound of the invention may be employed alone, in combination with one or more other compounds of the invention or in combination with other therapeutic methods or agents.
  • combination with other chemotherapeutic, biologic, hormonal, antibody and supportive care agents is envisaged as well as combination with surgical therapy and radiotherapy.
  • Supportive care agents include analgesics and anti-emetics.
  • Anti-emetics include but are not limited to 5HT 3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like; prochlorperazine, metaclopromide, diphenhydramine, promethazine; dexamethasone, lorazepam; haloperidol, dronabinol, olanzapine; and neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopitant administered alone or in various combinations.
  • chemotherapeutic refers to any chemical agent having a therapeutic effect on the subject to which it is administered.
  • “Chemotherapeutic” agents include but are not limited to anti-neoplastic agents.
  • anti-neoplastic agents include both cytotoxic and cytostatic agents including biological, immunological and vaccine therapies.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) and the use of at least one other treatment method.
  • combination therapies according to the present invention comprise the administration of at least one compound of the invention and surgical therapy.
  • combination therapies according to the present invention comprise the administration of at least one compound of the invention and radiotherapy.
  • combination therapies according to the present invention comprise the administration of at least one compound of the invention and at least one supportive care agent (e.g., at least one anti-emetic agent).
  • combination therapies according to the present invention comprise the administration of at least one compound of the invention and at least one other chemotherapeutic agent.
  • the present invention comprises the administration of at least one compound of the invention and at least one anti-neoplastic agent.
  • the present invention provides the methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one chemotherapeutic agent.
  • the chemotherapeutic agent is an anti-neoplastic agent.
  • the present invention provides a pharmaceutical composition as described above further comprising at least one other chemotherapeutic agent, more particularly, the chemotherapeutic agent is an anti-neoplastic agent.
  • the present invention also provides methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one supportive care agent (e.g., anti-emetic agent).
  • the compounds of the invention and at least one additional anti-neoplastic or supportive care therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination.
  • the administration of a compound of the invention with one or more other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both or all compounds or (2) separate pharmaceutical compositions each including one or more of the compounds.
  • the components of the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other(s) second or vice versa. Such sequential administration may be close in time or remote in time.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. The appropriate dose of the compound(s) of the invention and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.
  • any chemotherapeutic agent that has activity against a susceptible neoplasm being treated with a compound of the invention may be utilized in combination with the compounds the invention, provided that the particular agent is clinically compatible with therapy employing a compound of the invention.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to: alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents, topoisomerase I and II inhibitors, hormones and hormonal analogues; signal transduction pathway inhibitors including inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or other kinase inhibitors; cyclin dependent kinase inhibitors; antisense therapies and immunotherapeutic agents, including monoclonals, vaccines or other biological agents.
  • Alkylating agents are non-phase specific anti-neoplastic agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death. Alkylating agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • alkylating agents include but are not limited to: nitrogen mustards such as cyclophosphamides, temozolamide, melphalan, and chlorambucil; oxazaphosphorines; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; triazenes such as dacarbazine; and platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin.
  • nitrogen mustards such as cyclophosphamides, temozolamide, melphalan, and chlorambucil
  • oxazaphosphorines alkyl sulfonates
  • alkyl sulfonates such as busulfan
  • nitrosoureas such as carmustine
  • triazenes such as dacarbazine
  • platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. The end result of discontinuing S phase is cell death.
  • Antimetabolite neoplastic agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • antimetabolite anti-neoplastic agents include purine and pyrimidine analogues and anti-folate compounds, and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mercaptopurine and thioguanine.
  • purine and pyrimidine analogues and anti-folate compounds and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mercaptopurine and thioguanine.
  • Antitumor antibiotic agents are non-phase specific agents, which bind to or intercalate with DNA. Typically, such action disrupts ordinary function of the nucleic acids, leading to cell death. Antitumor antibiotics may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antitumor antibiotic agents include, but are not limited to, actinomycins such as dactinomycin; anthracyclines such as daunorubicin, doxorubicin, idarubicin, epirubicin and mitoxantrone; mitomycin C and bleomycins.
  • Antimicrotubule or antimitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • Antimitotic agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • antimitotic agents include, but are not limited to, diterpenoids, vinca alkaloids, polo-like kinase (PLK) inhibitors and CenpE inhibitors.
  • diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vindesine and vinorelbine.
  • PLK inhibitors are discussed further below.
  • Topoisomerase inhibitors include inhibitors of Topoisomerase II and inhibitors of Topoisomerase I.
  • Topoisomerase II inhibitors such as epipodophyllotoxins are anti-neoplastic agents derived from the mandrake plant, that typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, causing DNA strand breaks. The strand breaks accumulate and cell death follows.
  • Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Camptothecins, including camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors.
  • camptothecins include, but are not limited to amsacrine, irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin.
  • Topoisomerase inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • Antitumor hormones and hormonal analogues may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to antiestrogens, such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene and droloxifene; anti-androgens; such as flutamide, nilutamide, bicalutamide and cyproterone acetate; adrenocorticosteroids such as prednisone and prednisolone; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; progestrins such as megestrol acetate; 5 ⁇ -reductase inhibitors such as finasteride and dutasteride; and gonadotropin-releasing hormones (GnRH) and analogues thereof, such as Leutinizing Hormone-releasing Hor
  • Signal transduction pathway inhibitors are those inhibitors which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation or survival.
  • Signal transduction pathway inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases, myo-inositol signaling, and Ras oncogenes. Signal transduction pathway inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinase inhibitors which may be combined with the compounds of the invention include those involved in the regulation of cell growth, which receptor tyrosine kinases are sometimes referred to as “growth factor receptors.”
  • growth factor receptor inhibitors in addition to IGF-1R family tyrosine kinase inhibitors, include but are not limited to inhibitors of: epidermal growth factor family receptors (EGFR, ErbB2, and ErbB4); platelet derived growth factor receptors (PDGFRs), vascular endothelial growth factor receptors (VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), macrophage colony stimulating factor (c-fms), c-kit, c-met, fibroblast growth factor receptors (FGFRs), hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB, and TrkC), ephr
  • Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibody inhibitor of growth factor function.
  • An anti-erbB1 antibody inhibitor of growth factor function is cetuximab (ErbituxTM, C225).
  • Bevacizumab (Avastin®) is an example of a monoclonal antibody directed against VEGFR.
  • small molecule inhibitors of epidermal growth factor receptors include but are not limited to lapatinib (TykerbTM) and erlotinib (TARCEVA®).
  • Imatinib GLEEVEC®
  • VEGFR inhibitors include pazopanib, ZD6474, AZD2171, PTK787, sunitinib and sorafenib.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with an EGFR or ErbB2 inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with lapatinib.
  • the methods of the present invention comprise administering a compound of the invention in combination with trastuzumab.
  • the methods of the present invention comprise administering a compound of the invention in combination with erlotinib.
  • the methods of the present invention comprise administering a compound of the invention in combination with gefitinib.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a VEGFR inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with pazopanib.
  • Tyrosine kinases that are not transmembrane growth factor receptor kinases are termed non-receptor, or intracellular tyrosine kinases.
  • Inhibitors of non-receptor tyrosine kinases are sometimes referred to as “anti-metastatic agents” and are useful in the present invention.
  • Targets or potential targets of anti-metastatic agents include, but are not limited to, c-Src, Lck, Fyn, Yes, Jak, abl kinase (c-Abl and Bcr-Abl), FAK (focal adhesion kinase) and Bruton's tyrosine kinase (BTK).
  • Non-receptor kinases and agents, which inhibit non-receptor tyrosine kinase function are described in Sinha, S, and Corey, S. J., (1999) J. Hematother. Stem Cell Res. 8:465-80; and Bolen, J. B. and Brugge, J. S., (1997) Annu. Rev. of Immunol. 15:371-404.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, but not limited to, PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) and Ras-GAP.
  • Src inhibitors include but are not limited to dasatinib and BMS-354825 (J. Med. Chem. (2004) 47:6658-6661).
  • Inhibitors of serine/threonine kinases may also be used in combination with the compounds of the invention in any of the compositions and methods described above.
  • Examples of serine/threonine kinase inhibitors that may also be used in combination with a compound of the present invention include, but are not limited to polo-like kinase inhibitors (PIk family e.g., PIk1, PIk2, and PIk3), which play critical roles in regulating processes in the cell cycle including the entry into and the exit from mitosis; MAP kinase cascade blockers, which include Ras/Raf kinase inhibitors, mitogen or extracellular regulated kinases (MEKs), and extracellular regulated kinases (ERKs); Aurora kinase inhibitors (including inhibitors of Aurora A and Aurora B); protein kinase C (PKC) family member blockers, including inhibitors of PKC subtypes (alpha, beta, gamma, ep
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a PIk inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with 5- ⁇ 6-[(4-Methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl ⁇ -3- ⁇ (1R)-1-[2-(trifluoromethyl)phenyl]ethoxy ⁇ thiophene-2-carboxamide.
  • Urokinase also referred to as urokinase-type Plasminogen Activator (uPA) is a serine protease. Activation of the serine protease plasmin triggers a proteolysis cascade which is involved in thrombolysis or extracellular matrix degradation. Elevated expression of urokinase and several other components of the plasminogen activation system have been correlated with tumor malignancy including several aspects of cancer biology such as cell adhesion, migration and cellular mitotic pathways as well. Inhibitors of urokinase expression may be used in combination with the compounds of the invention in the compositions and methods described above.
  • Inhibitors of Ras oncogene may also be useful in combination with the compounds of the invention.
  • Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
  • Such inhibitors have been shown to block Ras activation in cells containing mutant Ras, thereby acting as antiproliferative agents.
  • inhibitors of kinases involved in the IGF-1R signaling axis may also be useful in combination with the compounds of the invention.
  • Such inhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K, AKT and MEK, and 14.3.3 signaling inhibitors.
  • AKT inhibitors are described in PCT Publication No. WO 2007/058850, published 24 May 2007 which corresponds to PCT Application No. PCT/US2006/043513, filed 9 Nov. 2006, to GlaxoSmithKline.
  • AKT inhibitor disclosed therein is 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7- ⁇ [(3S)-3-piperidinylmethyl]oxy ⁇ -1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol.
  • Cell cycle signaling inhibitors including inhibitors of cyclin dependent kinases (CDKs) are also useful in combination with the compounds of the invention in the compositions and methods described above.
  • CDKs cyclin dependent kinases
  • Examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania G. R., et al., Exp. Opin. Ther. Patents (2000) 10:215-230.
  • Receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related to VEGFR and TIE-2 are discussed above in regard to signal transduction inhibitors (both are receptor tyrosine kinases).
  • Other inhibitors may be used in combination with the compounds of the invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha beta 3 ) that inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the compounds of the invention.
  • One example of a anti-VEGF antibody is bevacizumab (AVASTIN®).
  • Inhibitors of phosphotidyl inositol-3-OH kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in combination with the present invention.
  • myo-inositol signaling inhibitors such as phospholipase C blockers and myoinositol analogues.
  • Antisense therapies may also be used in combination with the compounds of the invention.
  • antisense therapies include those directed towards the targets described above such as ISIS 2503 and gene therapy approaches such as those using thymidine kinase or cytosine deaminase.
  • Immunotherapeutic regimens include ex-vivo and in-vivo approaches to increasing immunogenicity of patient tumor cells such as transfection with cytokines (IL-2, IL-4, GMCFS and MCFS), approaches to increase T-cell activity, approaches with transfected immune cells and approaches with anti-idiotypic antibodies.
  • Another potentially useful immunotherapeutic regimen is monoclonal antibodies with wild-type Fc receptors that may illicit an immune response in the host (e.g., IGF-1R monoclonal antibodies).
  • Bcl-2 antisense oligonucleotides may also be used in combination with the compounds of the invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of Bcl-2 has therefore been linked to chemoresistance.
  • EGF epidermal growth factor
  • the process may further comprise the optional steps of:
  • compounds of formula (I) may be prepared by reacting a compound of formula (V) with an aniline of formula (VI) under acidic conditions with heating.
  • the reaction is typically carried out by mixing the compound of formula (V) with an aniline of formula (VI) in a suitable solvent in the presence of a suitable acid with heating.
  • suitable solvents include but are not limited to isopropyl alcohol, trifluoroethanol, dioxane, and N,N-dimethylformamide.
  • Suitable acids include but are not limited to hydrochloric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate.
  • the reaction is typically carried out at temperatures ranging from about 50° C. to about 120° C.
  • the reaction may optionally be performed under microwave conditions at temperatures typically ranging from about 120° C. to about 200° C.
  • Anilines of formula (VI) are either commercially available or can be prepared according to methods known to those skilled in the art.
  • Compounds of formula (V) may be prepared by reacting a compound of formula (III) with a brominating reagent followed by cyclization with an aminopyridine of formula (IV).
  • Suitable brominating reagents include but are not limited to N-bromosuccinimide (NBS), bromine, and tetrabutylammonium tribromide.
  • Suitable solvents for the bromination step include but are not limited to dichloromethane, chloroform, dioxane, tetrahydrofuran, and dichloroethane. The bromination step is typically carried out at ambient temperature.
  • Suitable solvents for cyclization with the aminopyridine of formula (IV) include but are not limited to dioxane, tetrahydrofuran, and N—N-dimethylformamide.
  • the cyclization step with aminopyridines of formula (IV) is typically carried out with a two to four fold excess of the aminopyridine, at temperatures ranging from 40° C. to 100° C.
  • Aminopyridines of formula (IV) are commercially available or can be prepared according to methods known to those skilled in the art.
  • Compounds of formula (III) may be prepared by reacting 2-chloro-4-methylpyrimidine with a suitable base and an aryl amide of formula (II).
  • the reaction can be carried out by reacting an aryl amide of formula (II) and 2-chloro-4-methylpyrimidine with a suitable base at temperatures typically ranging from about ⁇ 78° C. to ambient temperature.
  • suitable solvents include but are not limited to tetrahydrofuran, dioxane, and 1,2-dimethoxyethane.
  • Suitable bases include but are not limited to lithium bis(trimethylsilyl)amide, lithium diisopropylamide, and sodium bis(trimethylsilyl)amide.
  • aryl amides of formula (II) may be conveniently prepared according to the following Scheme.
  • the aryl amides of formula (II) may be prepared by an reacting acid chloride of formula (VIII) with an aniline of formula (IX) in the presence of a suitable base.
  • Suitable bases include but are not limited to trialkylamines and pyridines.
  • Suitable solvents for this reaction include but are not limited to dichloromethane, chloroform, dichloroethane, diethyl ether and tetrahydrofuran. The reaction is typically carried out at ambient temperature.
  • Anilines of formula (IX) are either commercially available or may be prepared according to methods known to those skilled in the art.
  • the acid chloride of formula (VIII) may be prepared by reacting a carboxylic acid of formula (VII) with a chlorinating reagent.
  • Suitable chlorinating reagents include but are not limited to oxalyl chloride with N,N-dimethylformamide, thionyl chloride and N-chlorosuccinimide.
  • Typical solvents for this reaction include but are not limited to dichloromethane, chloroform, benzene and toluene. The reaction is typically carried out at temperatures ranging from about 0° C. to about 110° C.
  • Carboxylic acids of formula (VII) wherein R 2 is H are commercially available or can be readily prepared by one skilled in the art.
  • Carboxylic acids of formula (VII) wherein R 2 is O-alkyl may be conveniently prepared according to the following Scheme.
  • the aryl ethers of formula (XI) may be prepared by reacting a phenol of formula (X) with a suitable alkylating agent in the presence of base.
  • suitable alkylating agents include but are not limited to alkyl halides, alkyl methanesulfonates, alkyl trifluoromethyl-sulfonates and alkyl benzenesulfonates.
  • Typical solvents include but are not limited to N,N-dimethylformamide, dimethylsulfoxide, acetone and 2-butanone.
  • the reaction is typically run at temperatures ranging from ambient temperature to about 120° C.
  • Phenols of formula (X) can be prepared using methods described in the literature (e.g., Hofslokken, N. U.; Skattebol, L. Acta Chemica Scandinavica 1999, 53, 258-262).
  • the process for preparing the compounds of formula (I) wherein R 2 is H according to this process comprises the steps of:
  • the process may further comprise the optional steps of:
  • compounds of formula (I) may be prepared by reacting a compound of formula (XV) with a suitable base and an aniline of formula (IX)
  • the reaction may be carried out in a suitable solvent.
  • suitable solvents include but are not limited to tetrahydrofuran, dioxane and 1,2-dimethoxyethane.
  • Suitable bases include but are not limited to lithium bis(trimethylsilyl)amide, lithium diisopropylamide and sodium bis(trimethylsilyl)amide.
  • Typical conditions involve the use of an excess of base (3 to 5 equivalents) and an excess of the aniline of formula (IX) (3 to 5 equivalents).
  • the reaction is typically run between 0° C. and ambient temperature.
  • Anilines of formula (IX) are either commercially available or can be prepared according to methods known to one skilled in the art.
  • Compounds of formula (XV) may be prepared by reacting compound of formula (XIV) with an aniline of formula (VI) under acidic conditions with heating.
  • the reaction may be carried out by mixing a compound of formula (XIV) with an aniline of formula (VI) in a suitable solvent in the presence of a suitable acid with heating.
  • suitable solvents include but are not limited to isopropyl alcohol, trifluoroethanol, dioxane and N,N-dimethylformamide.
  • Suitable acids include but are not limited to hydrochloric acid, p-toluenesulfonic acid and pyridinium p-toluenesulfonate.
  • the reaction is typically carried out at temperatures ranging from about 50° C. to about 120° C.
  • the reaction may optionally be performed under microwave conditions at temperatures typically ranging from about 120° C. to about 200° C.
  • Anilines of formula (VI) are either commercially available or can be prepared according to methods known to those skilled in the art.
  • Compounds of formula (XIV) may be prepared by reacting an ester of formula (XIII) with a brominating reagent followed by treatment with an aminopyridine of formula (IV).
  • This reaction may be carried out using the methods described above for the preparation of a compound of formula (V).
  • Esters of formula (XIII) may be prepared by reacting 2-chloro-4-methylpyrimidine with a suitable base and a diester of formula (XII), using the methods described above for the preparation of a compound of formula (III).
  • Diesters of formula (XII) are either commercially available or can be prepared according to methods known to those skilled in the art.
  • the process may further comprise the optional steps of:
  • compounds of formula (XV) may be prepared by hydrolyzing a compound of formula (XIX) with aqueous acid followed by esterification.
  • the basic hydrolysis reaction may be carried out in a mixture of a suitable solvent and water.
  • Suitable solvents include but are not limited to tetrahydrofuran, dioxane, methanol and ethanol.
  • Suitable bases include but are not limited to sodium hydroxide and potassium hydroxide.
  • the reaction is typically run between 25 and 100° C.
  • the esterification step may be carried out in a suitable solvent in the presence of acid.
  • Suitable solvents include but are not limited to methanol and ethanol.
  • Suitable acids include but are not limited to hydrochloric acid, p-toluenesulfonic acid and sulfuric acid.
  • Compounds of formula (XIX) may be prepared by reacting a compound of formula (XVIII) with an aniline of formula (VI) under acidic conditions with heating in the same manner as described above for the reaction of a compound of formula (XIV) with the aniline of formula (VI) to prepare a compound of formula (XV).
  • Compounds of formula (XVIII) may be prepared by reacting the compound of formula (XVII) with a brominating reagent followed by cyclization with an aminopyridine of formula (IV) in the same manner as described above for the reaction of a compound of formula (III) with the aminopyridine of formula (IV) to prepare a compound of formula (V).
  • Compounds of formula (XVII) may be prepared by reacting 2-chloro-4-methylpyrimidine with a suitable base and an ester of formula (XVI) in the same manner as described above for the reaction of an aryl amide of formula (II) with 2-chloro-4-methylpyrimidine.
  • reaction sequence employed to prepare a particular compound of formula (I) may depend upon the specific compound of formula (I) that is desired as well as the preference and availability of starting materials.
  • a compound of formula (I) may be converted to another compound of formula (I) using techniques well known in the art.
  • a compound of formula (I-B) may be converted to a compound of formula (I-C) by reacting with acetic anhydride in the presence of a base.
  • Suitable solvents for this reaction include but are not limited to dichloromethane, chloroform, tetrahydrofuran and toluene.
  • Suitable bases for this reaction include but are not limited to trialkylamines an pyridines.
  • a compound of formula I-D may be converted to a compound of formula I-E by reductive alkylation using techniques described herein below as well as those know in the art.
  • the present invention also provides radiolabeled analogs of compounds of formula (I) (i.e., a compound of formula (I) having a radiolabel bound thereto) and biotinylated analogs compounds of formula (I) (i.e., a compound of formula (I) having biotin bound thereto) and solid-support-bound versions thereof, i.e. a compound of formula (I) having a radiolabel or biotin bound thereto.
  • Radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) can be prepared using conventional techniques.
  • radiolabeled compounds of formula (I) can be prepared by reacting the compound of formula (I) with tritium gas in the presence of an appropriate catalyst to produce radiolabeled compounds of formula (I).
  • the compounds of formula (I) are tritiated.
  • the radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) are useful in assays for the identification of compounds which inhibit at least one IGF-1R family tyrosine kinase (particularly IGF-1R and/or IR) and/or at least one ErbB family kinase, for the identification of compounds for the treatment of a condition capable of being treated with an IGF-1R inhibitor, IR inhibitor or an ErbB inhibitor, e.g., for the treatment of neoplasms susceptible to treatment with an IGF-1R inhibitor, IR inhibitor or an ErbB inhibitor.
  • the present invention also provides an assay method for identifying such compounds, which method comprises the step of specifically binding a radiolabeled compound of the invention or a biotinylated compound of the invention to the target protein or cellular homogenate. More specifically, suitable assay methods will include competition binding assays.
  • the radiolabeled compounds of the invention and biotinylated compounds of the invention and solid-support-bound versions thereof, can also be employed in assays according to the methods conventional in the art.
  • Atm atm (atmosphere); g (grams); mg (milligrams); h (hour(s)); min (minutes); L (liters); mL (milliliters); ⁇ L (microliters); M (molar); mM (millimolar); H 2 (hydrogen); N 2 (nitrogen) Ac 2 O (acetic anhydride);
  • ATP adenosine triphosphate
  • BOC tert-butyloxycarbonyl
  • BOC-On (2-tert-butoxycarbony-loxyimino)-2-phenylacetonitrile
  • BSA bovine serum albumin
  • EDTA ethylenediaminetetraacetic acid
  • EtOH ethanol
  • EtOAc ethyl acetate
  • nm nanomolar
  • ⁇ m micromolar
  • mol molecular weight
  • mp melting point
  • psi pounds per square inch
  • rt room temperature
  • TLC thin layer chromatography
  • RP reverse phase
  • HCl hydrochloric acid
  • HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); hIGF1R or IGF-1R (human Insulin-like growth factor 1 receptor kinase); hIR (human insulin receptor kinase); HOAc (acetic acid); HNO 3 (nitric acid); HPLC (high pressure liquid chromatography); HRP (horseradish peroxidase); iPrOH (isopropanol); K 2 CO 3 (potassium carbonate); KHSO 4 (potassium hydrogensulfate); KOH (potassuim hydroxide); LAH (lithium aluminum hydride) LCMS (liquid chromatography mass spectrometry); LiHMDS (lithium hexamethyldisilazide); LiOH (lithium hydroxide); Me (methyl; —CH 3 ) MeOH (methanol); MgCl 2 (magnesium chloride); MgCO
  • NaCl sodium chloride
  • Na 2 CO 3 sodium carbonate
  • NaHCO 3 sodium bicarbonate
  • NaH sodium hydride
  • NaHMDS sodium hexamethyldisilazide
  • Na 2 SO 4 sodium sulfate
  • NBS N-bromosuccinimide
  • PdCl 2 (dppf)*DCM Dichloro[1,1′-bis-(diphenylphosphino)ferrocene]pa Iladium (II) dichloromethane adduct); PhMe (toluene); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran) and Tris-HCl (Tris(hydroxymethyl)amino-methane hydrochloride).
  • Step A methyl 3- ⁇ [(2,6-difluorophenyl)amino]carbonyl ⁇ benzoate
  • Step B 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-fluorophenyl)benzamide and 3-[(E)-2-(2-chloro-4-pyritnidinyl)-1-hydroxyethenyl]-N-(2,6-difluorophenyl)benzamide
  • the reaction was quenched with 10% aqueous ammonium chloride solution.
  • the mixture was poured into water and EtOAc, and the layers were separated.
  • the organic layer was washed with brine, and the combined aqueous layers were extracted with EtOAc.
  • the combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.
  • the resultant solid was triturated with 50% EtOAc/hexanes and filtered.
  • the solid was washed with 50% diethyl ether/hexanes.
  • the solid was air dried and collected to afford 3.60 g (52%) of the desired product.
  • the filtrate was concentrated and purified by flash chromatography.
  • Step C 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide
  • Methyl 4-hydroxybenzoate (3.00 g, 19.7 mmol) and magnesium chloride (2.81 g, 29.5 mmol) were stirred in 100 mL of acetonitrile.
  • TEA (10.3 mL, 73.9 mmol) was added via syringe.
  • Paraformaldehyde (12.0 g, 133 mmol) was added in a single portion and the reaction was heated to reflux. The reaction was stirred at reflux for 24 hours and cooled to rt. The reaction was quenched by the addition of approximately 100 mL of 1N HCl and poured into EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc.
  • Step B methyl 3-formyl-4-(methyloxy)benzoate
  • Methyl 3-formyl-4-hydroxybenzoate (2.06 g, 11.4 mmol) and K 2 CO 3 (2.36 g, 17.1 mmol) were stirred in 50 mL of DMF.
  • Methyl iodide (1.42 mL, 22.8 mmol) was added via syringe, and the reaction was stirred for 6 hours at rt.
  • the reaction was poured into H 2 O and diethyl ether, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with diethyl ether. The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo to afford 2.24 g of crude desired product.
  • the solid was transferred to an Erlenmeyer flask with the aid of 30-40 mL of DCM. Approximately 50 mL of hexanes was added. Air was blown over the solution to allow most of the DCM to evaporate. Diethyl ether was added (20-30 mL), and the suspension was filtered. The solid was washed with hexanes, collected, and dried to afford 1.96 g (82% over 2 steps) of the desired compound.
  • Step D methyl 3- ⁇ [(2,6-difluorophenyl)amino]carbonyl ⁇ -4-(methyloxy)benzoate
  • Step E 5-[(2-Chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide and 5-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide
  • Step F 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide
  • Step A methyl 3-[(2-chloro-4-pyrimidinyl)acetyl]benzoate and methyl 3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]benzoate
  • Step B methyl 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate
  • Step A 5-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)benzonitrile and 5-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]-2-(methyloxy)benzonitrile
  • Step B 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-2-(methyloxy)-benzonitrile
  • Step A 3-[(2-chloro-4-pyrimidinyl)acetyl]benzonitrile and 3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]benzonitrile
  • Lithium bis(trimethylsilyl)amide (1M in THF, 36.0 mL, 36.0 mmol) was added to 100 mL of THF and cooled to ⁇ 78° C.
  • 2-Chloro-4-methylpyrimidine (3.07 g, 23.9 mmol) in 20 mL of THF was added dropwise over 10 minutes.
  • the addition funnel was rinsed with 10 mL of THF.
  • 3-cyano-N-methyl-N-(methyloxy)benzamide see Organic Lett. 2006, 8, 4843-4846) (5.00 g, 26.3 mmol) in 25 mL of THF was added dropwise over 10 minutes.
  • the addition funnel was rinsed with 10 mL of THF.
  • the reaction was stirred for one hour and allowed to warm to 0° C.
  • the reaction was quenched with saturated ammonium chloride solution and poured into H 2 O and EtOAc.
  • the layers were separated, and the organic layer was washed with brine.
  • the combined aqueous layers were extracted with EtOAc.
  • the combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.
  • the residue was purified by flash chromatography to afford the product contaminated with 3-cyano-N-methyl-N-(methyloxy)benzamide.
  • the mixture was triturated with 30% EtOAc in hexanes, filtered, and the solid washed with 30% EtOAc in hexanes followed by hexanes.
  • Step B 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzonitrile
  • the reaction was stirred overnight and cooled to rt.
  • the reaction was poured into H 2 O and EtOAc.
  • the layers were separated, and the organic layer was washed with brine.
  • the combined aqueous layers were extracted with DCM (2 ⁇ ) and EtOAc.
  • the combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.
  • the residue was purified by flash chromatography, and fractions containing product were concentrated in vacuo.
  • the residue was triturated with diethyl ether and hexanes ( ⁇ 1:1), filtered, and the solid was washed with diethyl ether and hexanes ( ⁇ 1:1).
  • the solid was collected to provide 1.50 g (75%) of the title compound.
  • Step B 5-(3- ⁇ 2-[(3- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo-[1,2-a]pyridin-2-yl)-2-(methyloxy)benzonitrile
  • Step C methyl 5-(3- ⁇ 2-[(3- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl)amino]-4-pyrimidinyl ⁇ -imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzoate
  • Step D N-(2,6-difluorophenyl)-5-(3- ⁇ 2-[(3- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide
  • Step A phenylmethyl 4-[(3-methyl-4-nitrophenyl)oxy]-1-piperidinecarboxylate
  • Step B phenylmethyl 4-[(4-amino-3-methylphenyl)oxy]-1-piperidinecarboxylate
  • Phenylmethyl 4-[(3-methyl-4-nitrophenyl)oxy]-1-piperidinecarboxylate (0.798 g, 2.15 mmol) was dissolved in 20 mL of MeOH with stirring.
  • Nickel(II) chloride hexahydrate (0.256 g, 1.08 mmol) was added and the mixture was cooled to 0° C.
  • Sodium borohydride (0.163 g, 4.31 mmol) was added, and the mixture was stirred for 20 min. Additional sodium borohydride ( ⁇ 20 to 30 mg) was added, and the mixture was stirred for 10 min more. The reaction was quenched by the addition of approximately 15 mL of 2N sodium hydroxide solution.
  • Step C phenylmethyl 4-([4-( ⁇ 4-[2-(3-cyanophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinyl ⁇ amino)-3-methylphenyl]oxy ⁇ -1-piperidinecarboxylate
  • Step D methyl 3-[3-(2- ⁇ [2-methyl-4-(4-piperidinyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate
  • Phenylmethyl 4- ⁇ [4-( ⁇ 4-[2-(3-cyanophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinyl ⁇ amino)-3-methylphenyl]oxy ⁇ -1-piperidinecarboxylate (0.699 g, 1.10 mmol) was dissolved in 20 mL of EtOH with stirring. To the solution was added 20 mL of 2N NaOH solution. The reaction was placed in a 60° C. oil bath, and 20 mL of THF was added. The reaction was stirred at 60° C. overnight. Solid NaOH (1.6 g, 40 mmol) was added and the heat was increased to 80° C.
  • Step E N-(2,6-difluorophenyl)-3-[3-(2- ⁇ [2-methyl-4-(4-piperidinyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide
  • Step A methyl 3-(3- ⁇ 2-[(3- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl)amino]-4-pyrimidinyl ⁇ -imidazo[1,2-a]pyridin-2-yl)benzoate
  • Step B N-(5-chloro-2-fluorophenyl)-3-(3- ⁇ 2-[(3- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl)-amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)benzamide
  • 3-Bromoaniline (0.50 mL, 4.6 mmol) was dissolved in 30 mL of PhMe with stirring, and 15 mL of EtOH was added.
  • Na 2 CO 3 (3.06 g, 28.9 mmol) in 15 mL of H 2 O was added followed by 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-1H-pyrazole (0.955 g, 4.59 mmol).
  • Pd(PPh 3 ) 4 (0.265 g, 0.229 mmol) was added, and the mixture was heated to reflux with stirring overnight. The mixture was cooled to rt and poured into EtOAc and H 2 O.
  • Step B N-(2,6-difluorophenyl)-3-[3-(2- ⁇ [3-(1-methyl-1H-pyrazol-4-yl)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide
  • Step A Dimethyl ⁇ 2 -[(2-methyl-3-nitrophenyl)oxy]ethyl ⁇ amine
  • Step B 2-[(3-Amino-2-methylphenyl)oxy]ethyl ⁇ dimethylamine
  • Step C methyl 3-(3- ⁇ 2-[(3- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ -2-methylphenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)benzoate
  • Step D N-(2,6-difluorophenyl)-3-(3- ⁇ 2-[(3- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ -2-methylphenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)benzamide
  • Step A 5-fluoro-2-nitrophenyl methyl ether
  • Step B 1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine
  • Step D 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • step B The title compound of step B was prepared from 1-methyl-4-[(2-methyl-3-nitrophenyl)methyl]-piperazine in an analogous manner as that described for the synthesis of 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C).
  • Step C N-(2,6-difluorophenyl)-3-(3- ⁇ 2-[(5- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ -2-methylphenyl)amino]-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl)benzamide
  • Step B N′-(chloroacetyl)-3-(methyloxy)-4-nitrobenzohydrazide
  • Step D 4- ⁇ 5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl ⁇ -2-(methyloxy)aniline
  • step D The reaction was filtered through Celite® and concentrated to provide the title compound of step D (0.326 g, 1.32 mmol, 89% over two steps).
  • Step E N-(2,6-difluorophenyl)-5-[3-(2- ⁇ [4- ⁇ 5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl ⁇ -2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-2-(methyloxy)benzamide
  • Step A 2-[3-(methyloxy)-4-nitrophenyl]-5-(1-pyrrolidinylmethyl)-1,3,4-oxadiazole
  • step C To 2-(chloromethyl)-5-[3-(methyloxy)-4-nitrophenyl]-1,3,4-oxadiazole (Example 26, step C) (1.01 g, 3.75 mmol) in dioxane (10 mL) was added pyrrolidine (0.800 mL, 9.58 mmol). The reaction was stirred at rt overnight. Upon completion by TLC, the reaction mixture was treated with BOC-anhydride (0.371 g, 1.69 mmol) and cooled to 0° C. The mixture was treated with TEA (0.279 mL, 2.00 mmol). Purification by flash chromatography provided the title compound of step A (1.13 g, 3.70 mmol, 99%).
  • Step B 2-(methyloxy)-4-[5-(1-pyrrolidinylmethyl)-1,3,4-oxadiazol-2-yl]aniline
  • Step C N-(2,6-difluorophenyl)-2-(methyloxy)-5- ⁇ 3-[2-( ⁇ 2-(methyloxy)-4-[5-(1-pyrrolidinylmethyl)-1,3,4-oxadiazol-2-yl]phenyl]amino)-4-pyrimidinyl ⁇ imidazo[1,2-a]pyridin-2-yl ⁇ benzamide
  • Step B 3-[3-(2- ⁇ [5-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • Step A 5-[3-(2- ⁇ [5-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide
  • the title compound (0.079 g, 0.10 mmol, 43%) was prepared in an analogous manner to that described for the preparation of Example 23 with the following notable exception: 5-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline was used instead of 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline.
  • Step A 1′- ⁇ 3[(2-methylpropyl)oxy]-4-nitrophenyl ⁇ -1,4′-bipiperidine
  • step A The title compound of step A (4 g, 11 mmol, 68%) was prepared in an analogous manner to that described for Example 22, steps A-B, with the following notable exception: isobutyl bromide was used instead of iodomethane in the step described in Example 22, Step A.
  • Step B 4-(1,4′-bipiperidin-1′-yl)-2-[(2-methylpropyl)oxy]aniline
  • Step C Step B: 3- ⁇ 3-[2-( ⁇ 4-(1,4′-bipiperidin-1′-yl)-2-[(2-methylpropyl)oxy]phenyl ⁇ amino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl ⁇ -N-(2,6-difluorophenyl)benzamide
  • Step A 4-(1,4′-bipiperidin-1′-yl)-2-(propyloxy)aniline
  • step A The title compound of step A (3.1 g, 9.8 mmol, 96% in final step) was prepared in a manner analogous to that described for the synthesis of Example 32, step A-B) with the following notable exception: n-propyl bromide was used instead of isobutyl bromide in Example 32, step A. MS (M+H) 318.
  • Step B 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-2-(propyloxy)phenyl]amino ⁇ -4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • Step A 4-(1,4′-bipiperidin-1′-yl)-2-(ethyloxy)aniline
  • step A The title compound of step A (3.2 g, 10.6 mmol, 92% in final step) was prepared in a manner analogous to that described for the synthesis of 4-(1,4′-bipiperidin-1′-yl)-2-[(2-methylpropyl)oxy]aniline (Example 32, steps A-B) with the following notable exception:
  • Step B 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-2-(ethyloxy)phenyl]amino ⁇ -4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • Step A 4-(1,4′-bipiperidin-1′-yl)-2-[(1-methylethyl)oxy]aniline
  • step A The title compound of step A (1.8 g, 5.7 mmol, 56% in final step) was prepared in a manner analogous to that described for the synthesis of Example 32, steps A-B with the following notable exception: isopropyl bromide was used instead of isobutyl bromide in Example 32, step A. MS (M+H) 318.
  • Step B 3- ⁇ 3-[2-( ⁇ 4-(1,4′-bipiperidin-1′-yl)-2-[(1-methylethyl)oxy]phenyl ⁇ amino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl ⁇ -N-(2,6-difluorophenyl)benzamide
  • Step B 1,1-dimethylethyl4-(1-piperidinylmethyl)-1-piperidinecarboxylate
  • Step D 2-(methyloxy)-4-[4-(1-piperidinylmethyl)-1-piperidinyl]aniline
  • Step E N-(2,6-difluorophenyl)-3- ⁇ 3-[2-( ⁇ 2-(methyloxy)-4-[4-(1-piperidinylmethyl)-1-piperidinyl]phenyl ⁇ amino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl ⁇ benzamide
  • Step B N-(2,6-difluorophenyl)-3- ⁇ 3-[2-( ⁇ 2-(methyloxy)-4-[4-(4-morpholinyl)-1-piperidinyl]phenyl ⁇ amino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl ⁇ benzamide
  • Step C 1′-(3-ethyl-4-nitrophenyl)-1,4′-bipiperidine
  • step C The title compound of step C (2.4 g, 7.56 mmol, 100%) was prepared in an analogous manner to that of Example 22, step B, with the following notable exceptions:
  • Step D 4-(1,4′-bipiperidin-1′-yl)-2-ethylaniline
  • step D The title compound of step D (2.1 g, 7.3 mmol, 100%) was prepared from 1′-(3-ethyl-4-nitrophenyl)-1,4′-bipiperidine in an analogous manner to that described for Example 32, step B. MS (M+H) 288.
  • Step E 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-2-ethylphenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • Step B 4-fluoro-1-nitro-2-(2-propen-1-yl)benzene
  • step B (11.0 g, 60.7 mmol, 42%).
  • Step E 1′-(4-nitro-3-propylphenyl)-1,4′-bipiperidine
  • step E The title compound of step E (4.20 g, 12.7 mmol, 84%) was prepared in an analogous manner to that of Example 22, step B with the following notable exceptions:
  • Step F 4-(1,4′-bipiperidin-1′-yl)-2-propylaniline
  • step F The title compound of step F (3.10 g, 10.3 mmol, 82%) was prepared from 1′-(4-nitro-3-propylphenyl)-1,4′-bipiperidine in an analogous manner to that described for Example 32, step B. MS (M+H) 302.
  • Step G 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-2-propylphenyl]amino ⁇ -4-pyrimidinyl)imidazo-[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • Step A 1,1-dimethylethyl4-methyl-1,4′-bipiperidine-1′-carboxylate
  • Step B 4-methyl-1,4′-bipiperidine dihydrochloride
  • 1,1-Dimethylethyl4-methyl-1,4′-bipiperidine-1′-carboxylate (33.0 g, 117 mmol) in HCl (60.0 mL, 4M in MeOH, 240 mmol) was refluxed at 60° C. for 1 h. The reaction was concentrated and the residue was taken up in MeOH (100 mL), filtered and concentrated to provide the title compound of step B (10.8 g, 42.5 mmol, 36%).
  • Step C 4-methyl-1′(3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine
  • step C The title compound of step C (6.02 g, 18.1 mmol, 77%) was prepared in an analogous manner to that of Example 22, step B, with the following notable exceptions:
  • Step D 4-(4-methyl-1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline
  • step D The title compound of step D (1.55 g, 5.1 mmol, 28%) was prepared from 4-methyl-1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine in an analogous manner to that described for Example 32, step B. MS (M+H) 304.
  • Step E N-(2,6-difluorophenyl)-3-[3-(2- ⁇ [4-(4-methyl-1,4′-bipiperidin-1′-yl)-2-(methyloxy)-phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide
  • step A The title compound of step A (2.5 g, 9.1 mmol, 59%) was prepared in a manner analogous to that described for Example 32, steps A-B, with the following notable exception: 5-fluoro-2-nitrotoluene was used instead of 5-fluoro-2-nitrophenyl2-methylpropyl ether in Example 32, step A. MS (M+H) 274.
  • Step B 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-2-methylphenyl]amino ⁇ -4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide
  • Step A 1′-(3-chloro-2-methyl-4-nitrophenyl)-1,4′-bipiperidine
  • step A The title compound of step A (0.86 g, 5.50 mmol, 91%) was prepared in an analogous manner to that described for Example 22, step B with the following notable exceptions:
  • Step B 1′-[2-methyl-3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine
  • Step C 4-(1,4′-bipiperidin-1′-yl)-3-methyl-2-(methyloxy)aniline
  • step C The title compound of step C (1.87 g, 6.16 mmol, 64%) was prepared from 1′-[2-methyl-3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine in a manner analogous to that described for Example 32, step B. MS (M+H) 304.
  • Step D 3-[3-(2- ⁇ [4-(1,4′-bipiperidin-1′-yl)-3-methyl-2-(methyloxy)phenyl]amino ⁇ -4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide

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