WO2003035615A2 - Tyrosine kinase inhibitors - Google Patents

Tyrosine kinase inhibitors Download PDF

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Publication number
WO2003035615A2
WO2003035615A2 PCT/US2002/033920 US0233920W WO03035615A2 WO 2003035615 A2 WO2003035615 A2 WO 2003035615A2 US 0233920 W US0233920 W US 0233920W WO 03035615 A2 WO03035615 A2 WO 03035615A2
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Prior art keywords
methyl
ethyl
tert
amino
butyl
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PCT/US2002/033920
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French (fr)
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WO2003035615A3 (en
Inventor
B. Wesley Trotter
Ian M. Bell
C. Blair Zartman
Craig Lindsley
Zhijian Zhao
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Merck & Co., Inc.
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Priority to AU2002348394A priority Critical patent/AU2002348394A1/en
Publication of WO2003035615A2 publication Critical patent/WO2003035615A2/en
Publication of WO2003035615A3 publication Critical patent/WO2003035615A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins.
  • the consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation; i.e., virtually all aspects of cell life, in one way or another depend on PK activity.
  • abnormal PK activity has been related to a host of disorders, ranging from relatively non life-threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
  • PKs can be broken into two classes, the protein tyrosine kinases (PTKs) and the serine- threonine kinases (STKs).
  • RTKs receptor tyrosine kinases
  • IGF-1R insulin-like growth factor I receptor
  • IRR insulin receptor related receptor
  • IGF-1R Insulin-like Growth Factor- 1 Receptor
  • IGF-1 and IGF-2 are abnormally expressed in numerous tumors, including, but not limited to, breast, prostate, thyroid, lung, hepatoma, colon, brain, neuroendocrine, and others.
  • CTK non-receptor tyrosine kinases
  • cellular tyrosine kinases a family of entirely intracellular PTKs. This latter designation, abbreviated “CTK”, will be used herein. CTKs do not contain extracellular and transmembrane domains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified.
  • the Src subfamily appears so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • Src Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including significantly, cancer.
  • Other pathogenic conditions which have been associated with PTKs include, without limitation, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, autoimmune diseases and a variety of renal disorders.
  • the present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases.
  • the compounds of the instant invention possess a core structure that comprises a 2-carboxy pyrrole.
  • the present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.
  • the compounds of this invention are useful in the inhibition of kinases and are illustrated by a compound of Formula I:
  • V is selected from
  • Ra is independently selected from
  • Rb is independently selected from
  • Rl is independently selected from 1) H,
  • R3 is selected from
  • R5 is independently selected from
  • R6 is independently selected from 1) H,
  • R7 is independently selected from 1) H, 2) unsubsti tuted or substituted Ci-C 10 alkyl,
  • n is 0 to 6
  • p is 0 to 6
  • q is 0 to 5
  • r is 0 to 6;
  • a second embodiment of the instant invention is a compound of Formula I, as described above, wherein:
  • R4 is selected from
  • a further embodiment is a compound as described in the second embodiment above, wherein:
  • Rl is independently selected from
  • n 0 to 2
  • p 0 to 4
  • q 0 to 3
  • r 0 to 4
  • Examples of compounds of the instant invention include 2-tert-butyl 4-ethyl 3-benzyl-5- ⁇ [(4-chlorophenyl)amino]methyl ⁇ -lH-pyrrole-2,4- dicarboxylate;
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
  • the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • any variable e.g. aryl, heterocycle, Rl, Ra etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms or heteroatoms.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
  • alkyl is intended to include both branched, straight- chain, and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C ⁇ -C ⁇ o as in “C ⁇ -C ⁇ o alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement.
  • C ⁇ -C ⁇ o alkyl specifically includes methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, adamantyl, and so on.
  • Cycloalkyl as used herein is intended to include non-aromatic cyclic hydrocarbon groups, having the specified number of carbon atoms, which may or may not be bridged or structurally constrained.
  • Examples of such cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl, tetrahydro-naphthalene, methylenecylohexyl, and the like.
  • examples of "C3 - C ⁇ o cycloalkyl” may include, but are not limited to:
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. If no number of carbon atoms is specified, the term “alkenyl” refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C2-C6 alkenyl” means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl As desc ⁇ bed above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon t ⁇ ple bond. Up to 3 carbon-carbon t ⁇ ple bonds may be present.
  • C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms
  • Alkynyl groups include ethynyl, propynyl and butynyl As desc ⁇ bed above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain t ⁇ ple bonds and may be substituted if a substituted alkynyl group is indicated
  • aryl is intended to mean any stable monocyclic or bicychc carbon ⁇ ng of up to 7 atoms in each ⁇ ng, wherein at least one ⁇ ng is aromatic
  • aryl elements include phenyl, naphthyl, tetrahydro- naphthyl, indanyl, indanonyl, biphenyl, tetralinyl, tetralonyl, fluorenonyl, phenanthryl, anthryl, acenaphthyl, tetrahydronaphthyl, and the like.
  • halo or halogen as used herein is intended to include chloro, fluoro, bromo and lodo.
  • heteroaryl represents a stable monocyclic or bicychc ⁇ ng of up to 7 atoms in each ⁇ ng, wherein at least one ⁇ ng is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: ac ⁇ dinyl, carbazolyl, cinnol yl, quinoxalmyl, pyrrazolyl, indolyl, benzodioxolyl, benzot ⁇ azolyl, benzothiofuranyl, benzothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, benzoquinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrahydronaphthyl, tetrahydroquinoline, and the like.
  • heterocycle or heterocyclic or heterocyclyl represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • Heterocycle or “heterocyclyl” therefore includes the above mentioned heteroaryls, as well as dihydro and tetrathydro analogs thereof.
  • Further examples of “heterocyclyl” include, but are not limited to the following: benzodioxolyl, benzodioxinyl, benzofuranyl, benzofurazanyl, benzoimidazolyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzothiofuranyl, benzothiophenyl, benzothiopyranyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, diazapinonyl, dihydrobenzofuranyl, dihydrobenzofuryl, dihydrobenzoimidazolyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenz
  • heterocycle is selected from oxoazepinyl, benzimidazolyl, diazapinonyl, imidazolyl, oxoimidazolidinyl, indolyl, isoquinolinyl, mo ⁇ holinyl, piperidyl, piperazinyl, pyridyl, py ⁇ olidinyl, oxopiperidinyl, oxopyrimidinyl, o opyrrolidinyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.
  • aralkyl is intended to mean an aryl moiety, as defined above, attached through a C ⁇ -C ⁇ o alkyl linker, where alkyl is defined above.
  • alkyl is defined above.
  • examples of aralkyls include, but are not limited to, benzyl, naphthylmethyl and phenylpropyl.
  • heterocyclylalkyl is intended to mean a heterocyclic moiety, as defined below, attached through a C ⁇ -C ⁇ o alkyl linker, where alkyl is defined above.
  • heterocyclylalkyls include, but are not limited to, pyridylmethyl, imidazolylethyl, pyrrolidinylmethyl, mo ⁇ holinylethyl, quinolinylmethyl, imidazolylpropyl and the like.
  • substituted C ⁇ -C ⁇ o alkyl and "substituted
  • C ⁇ -C6 alkoxy are intended to include the branch or straight-chain alkyl group of the specified number of carbon atoms, wherein the carbon atoms may be substituted with one to three substituents selected from the group which includes, but is not limited to, halo, C ⁇ -C20 alkyl, CF3, NH2, N(C ⁇ -C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(C ⁇ -C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Co-C ⁇ alkyl) S(O) ⁇ -2-, (C 0 -C 6 alkyl)S(O) 0 -2(C ⁇ -C 6 alkyl)-, (C 0 -C 6 alkyl)C(O)NH-, H 2 N-C(NH)-, -O(C ⁇ -C6 alkyl)CF 3 , (C 0
  • substituted C3-C10 cycloalkyl As used herein, the terms “substituted C3-C10 cycloalkyl”, “substituted aryl”, “substituted heterocycle”, “substituted aralkyl” and “substituted heterocyclylalkyl” are intended to include the cyclic group containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
  • the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, CF3, NH2, N(C ⁇ -C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(C ⁇ -C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Co-Cg alkyl) S(O)0-2-, (C ⁇ -C 6 alkyl)S(O) 0 -2(C ⁇ -C 6 alkyl)-, (C 0 -C 6 alkyl)C(O)NH-, H2N-C(NH)-, -O(C ⁇ -C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (C 0 -C6alkyl)O(C ⁇ -C6 alkyl)O(
  • R is selected from H, unsubstituted or substituted C1-C10 alkyl, halo, OR7, N(R7)2, C(O)OR7, and -S(O)2N(R5) .
  • R is selected from -C(O)OR7, -C(0)N(R7) 2 , -C(O)NHR7OR7, -C(O)NH(CRb2) q R7, -C(O)NHR7NHC(O)R7, -C(0)NHR7 S(O)2OR7, and -C(O)NH(CRb2) q C(O)N(R7) 2 . More preferably, R is selected from -C(O)OR7, -C(0)N(R7) 2 , -C(O)NHR7OR7, -C(O)NH(CRb 2 ) q R7.
  • R3 is unsubstituted or substituted C ⁇ -C ⁇ o alkyl and unsubstituted or substitited aralkyl.
  • n, p and q are independently 0, 1, 2 or 3. More preferably, n is 1.
  • any substituent or variable e.g., Rl, R a , n, etc.
  • -N(R7) 2 represents -NHH, -NHCH3, -NHC 2 H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
  • salts of the compounds of Formula I will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly prefened are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N, Nl-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, mo ⁇ holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Particularly prefened are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • the free form of compounds of Formula I is the free form of compounds of Formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some of the specific compounds exemplified herein are the protonated salts of amine compounds.
  • the term "free form” refers to the amine compounds in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of Formula I.
  • the free form of the specific salt compounds described may be isolated using techniques known in the art.
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for pu ⁇ oses of the invention.
  • the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • DMAP 4-Dimethylaminopyridine
  • DME 1,2-Dimethoxyethane
  • HEPES 4-(2-Hydroxyethyl)-l-piperazineethanesulfonic acid; HOAc Acetic acid; HOBT 1-Hydroxybenzotriazole hydrate;
  • this present invention relates to a method of modulating the catalytic activity of PKs (protein kinases) in a mammal in need thereof comprising contacting the PK with a compound of Formula I.
  • PKs protein kinases
  • modulation refers to the alteration of the catalytic activity of receptor tyrosine kinases (RTKs), cellular tyrosine kinases (CTKs)and serine-threonine kinases (STKs).
  • modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTKs, CTKs or STKs is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
  • catalytic activity refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
  • contacting refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly; i.e., by interacting with the kinase itself, or indirectly; i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent.
  • Such "contacting” can be accomplished “in vitro,” i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment.
  • the ability of a particular compound to affect a PK related disorder i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted.
  • IC50 of the compound defined below
  • cells outside the organism multiple methods exist, and are well known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
  • the above-referenced PK is selected from the group comprising an RTK, a CTK or an STK in another aspect of this invention.
  • the PK is an RTK.
  • the receptor tyrosine kinase (RTK) whose catalytic activity is modulated by a compound of this invention is selected from the group comprising EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR ⁇ , PDGFR ⁇ , TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-IR, Flk4, KDR/Flk- 1 , Fit- 1 , FGFR- IR, FGFR- IR, FGFR-3R and FGFR-4R.
  • RTK receptor tyrosine kinase
  • the RTK is preferably, the receptor protein kinase is selected from IR, IGF-1R, or IRR.
  • the cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf.
  • this invention relates to a method for treating or preventing a PK-related disorder in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of one or more of the compounds described above.
  • PK-related disorder As used herein, "PK-related disorder,” “PK driven disorder,” and “abnormal PK activity” all refer to a condition characterized by inappropriate (i.e., diminished or, more commonly, exessive) PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
  • Excessive-activity of a PK refers to either amplification of the gene encoding a particular PK or its ligand, or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases).
  • "Treat,” “treating” or “treatment” with regard to a PK-related disorder refers to alleviating or abrogating the cause and/or the effects of a PK-related disorder.
  • the terms “prevent”, “preventing” and “prevention” refer to a method for barring a mammal from acquiring a PK-related disorder in the first place.
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concu ⁇ ent and sequential introduction of the compound or prodrug thereof and other agents.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • the protein kinase-related disorder may be selected from the group comprising an RTK, a CTK or an STK-related disorder in a further aspect of this invention.
  • the protein kinase-related disorder is an RTK-related disorder.
  • the above referenced PK-related disorder may be selected from the group consisting of an EGFR-related disorder, a PDGFR-related disorder, an IGFR-related disorder and a flk-related disorder.
  • the above referenced PK-related disorder may be a cancer selected from, but not limited to, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, chrondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thyoma, thyroid cancer, testicular cancer and osteosarcoma in a further aspect of this invention. More preferably, the PK-related disorder is a cancer selected from brain cancer, breast
  • a pharmaceutical composition which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier.
  • the present invention also encompasses a method of treating or preventing cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of Formula I.
  • Types of cancers which may be treated using compounds of Formula I include, but are not limited to, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, chrondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyona, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thymona, thyroid cancer, testicular cancer and osteosarcoma in a further aspect of this invention. More preferably, the cancer being treated is selected from breast cancer, prostate cancer, colorectal cancer
  • the above-referenced PK-related disorder may be an IGFR-related disorder selected from diabetes, an autoimmune disorder, Alzheimer's and other cognitive disorders, a hype ⁇ roliferation disorder, aging, cancer, acromegaly, Crohn's disease, endometriosis, diabetic retinopathy, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
  • an IGFR-related disorder selected from diabetes, an autoimmune disorder, Alzheimer's and other cognitive disorders, a hype ⁇ roliferation disorder, aging, cancer, acromegaly, Crohn's disease, endometriosis, diabetic retinopathy, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
  • a method of treating or preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of Formula I is also encompassed by the present invention.
  • Methods of treating or preventing ocular diseases such as diabetic retinopathy and age-related macular degeneration, are also part of the invention.
  • Also included within the scope of the present invention is a method of treating or preventing inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions, as well as treatment or prevention of bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets.
  • Other disorders which might be treated with compounds of this invention include, without limitation, immunological and cardiovascular disorders such as atherosclerosis.
  • the invention also contemplates the use of the instantly claimed compounds in combination with a second compound selected from the group consisting of:
  • retinoid receptor modulator 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent,
  • a preferred angiogenesis inhibitor is selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF.
  • a tyrosine kinase inhibitor an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polys
  • Preferred estrogen receptor modulators are tamoxifen and raloxifene. Also included in the scope of the claims is a method of treating cancer, which comprises administering a therapeutically effective amount of a compound of Formula I in combination with a compound selected from the group consisting of:
  • PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs).
  • RTKs receptor tyrosine kinases
  • CTKs cellular tyrosine kinases
  • STKs serine-threonine kinases
  • RTK-mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization (or conformational changes in the case of IR, IGF-1R or IRR), transient stimulation of the intrinsic protein tyrosine kinase activity, autophosphorylation and subsequent phosphorylation of other substrate proteins. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects on the extracellular microenvironment, etc.). See Schlessinger and Ullrich, 1992, Neuron 9:303-391.
  • PK signal transduction results in, among other responses, cell proliferation, differentiation, growth, metabolism, and cellular mobility.
  • Abnormal cell proliferation may result in a wide anay of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and/or vasculogenesis.
  • PKs typically possess a bi-lobate structure wherein ATP appears to bind in the cleft between the two lobes in a region where the amino acids are conserved among PKs.
  • Inhibitors of PKs are believed to bind by non-covalent interactions such as hydrogen bonding, van der Waals forces and ionic interactions in the same general region where the aforesaid ATP binds to the PKs.
  • the compounds disclosed herein may have utility as in vitro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins.
  • the protein kinase (PK), the catalytic activity of which is modulated by contact with a compound of this invention is a protein tyrosine kinase (PTK), more particularly, a receptor protein tyrosine kinase (RTK).
  • PTK protein tyrosine kinase
  • RTK receptor protein tyrosine kinase
  • RTKs whose catalytic activity can be modulated with a compound of this invention, or salt thereof, are, without limitation, EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR ⁇ , PDGFR ⁇ , TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-IR, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R. Most preferably, the RTK is selected from IGF-1R.
  • the protein tyrosine kinase whose catalytic activity is modulated by contact with a compound of this invention, or a salt or a prodrug thereof, can also be a non-receptor or cellular protein tyrosine kinase (CTK).
  • CTKs such as, without limitation, Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, may be modulated by contact with a compound or salt of this invention.
  • Still another group of PKs which may have their catalytic activity modulated by contact with a compound of this invention are the serine-threonine protein kinases such as, without limitation, CDK2 and Raf.
  • This invention is also directed to compounds that modulate PK signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins.
  • the present invention is directed to compounds which modulate RTK, CTK and/or STK mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including, but not limited to, carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melonoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention.
  • Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreatic cancers, colon cancers, blood cancers, breast cancers, prostrate cancers, renal cell carcinomas, lung cancer and bone cancers.
  • disorders related to inappropriate PK activity are cell proliferative disorders, fibrotic disorders and metabolic disorders.
  • IGF-IR Insulin-like Growth Factor-1 Receptor
  • IGF-IR belongs to the family of transmembrane tyrosine kinase receptors such as platelet-derived growth factor receptor, the epidermal growth factor receptor, and the insulin receptor.
  • IGF-1 and IGF-2 two known ligands for the IGF-IR receptor.
  • IGF refers to both IGF-1 and IGF-2.
  • the insulin-like growth factor family of ligands, receptors and binding proteins is reviewed in Krywicki and Yee, Breast Cancer Research and Treatment, 22:7-19, 1992. IGF/IGF-1R driven disorders are characterized by inappropriate or over-activity of IGF/IGF-1R.
  • Inappropriate IGF activity refers to either: (1) IGF or IGF-IR expression in cells which normally do not express IGF or IGF-IR; (2) increased IGF or IGF-IR expression leading to unwanted cell proliferation such as cancer; (3) increased IGF or IGF-IR activity leading to unwanted cell proliferation, such as cancer; and/or over-activity of IGF or IGF-IR.
  • Over-activity of IGF or IGF- IR refers to either an amplification of the gene encoding IGF-1, IGF-2, IGF-IR or the production of a level of IGF activity which can be conelated with a cell proliferative disorder (i.e., as the level of IGF increases the severity of one or more of the symptoms of the cell proliferative disorder increases) the bioavailability of IGF-1 and IGF-2 can also be affected by the presence or absence of a set of IGF binding presence or absence of a set of IGF binding proteins (IGF BPs) of which there are six know.
  • IGF BPs IGF binding proteins
  • IGF/IGF-1R Over activity of IGF/IGF-1R can also result from a down regulation of IGF-2 which contains an IGF-2 binding domain, but no intracellular kinase domain.
  • IGF/IGF-1R driven disorders include the various IGF/IGF-1R related human malignancies reviewed in Cullen, et al, Cancer Investigation, 9(4):443-454, 1991, inco ⁇ orated herein by reference in its entirety, including any drawings.
  • IGF/IGF- IRs clinical importance and role in regulating osteoblast function is reviewed in Schmid, ournal of Internal Medicine, 234:535-542, 1993.
  • IGF-IR activities include: (1) phosphorylation of IGF-IR protein; (2) phosphorylation of an IGF-IR protein substrate; (3) interaction with an IGF adapter protein; (4) IGF-IR protein surface expression. Additional IGF-IR protein activities can be identified using standard techniques. IGF-IR activity can be assayed by measuring one or more of the following activities: (1) phosphorylation of IGF-IR; (2) phosphorylation of an IGF-IR substrate; (3) activation of an IGF-IR adapter molecule; and (4) activation of downstream signaling molecules, and/or (5) increased cell division. These activities can be measured using techniques described below and known in the arts.
  • IGF-IR has been implicated as an absolute requirement for the establishment and maintenance of the transformed phenotype both in vitro and in vivo in several cell types (R. Baserga, Cancer Research 55:249-252, 1995).
  • Herbimycin A has been said to inhibit the IGF-IR protein tyrosine kinase and cellular proliferation in human breast cancer cells (Sepp-Lorenzino, et al., 1994, J. Cell Biochem. Suppl. 18b: 246).
  • Antisense strategies, dominant negative mutants, and antibodies to the IGF-IR have led to the suggestion that IGR-1R may be a prefened target for therapeutic interventions.
  • IGF-IR in addition to being implicated in nutritional support and in type- ⁇ diabetes, has also been associated with several types of cancers.
  • IGF-1 has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteago et al., J. Clin. Invest., 1989, 84:1418-1423) and small lung tumor cells (Macauley et al., Cancer Res., 1989, 50:2511-2517).
  • IGF-1 while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas.
  • IGF-2's protential involvement in colorectal cancer may be found in the up-regulation of IGF-2 mRNA in colon tumors relative to normal color tissue.
  • IGF-2 may also play a role in hypoxia induced neovascularization of tumors.
  • IGF-2 may also play a role in tumorigenesis through activation of an insulin receptor isoform-A.
  • IGF-2 activation of insulin receptor isoform-A activates cell survival signaling pathways in cells but its relative contribution to tumor cell growth and survival is unknown at this time.
  • Insulin receptor isoform-A's kinase domain is identical to the standard insulin receptor's. Scalia et al., 2001, J. Cell Biochem. 82:610-618.
  • IGF-IR insulin growth factor-1
  • fibroblasts epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)
  • IGF-1 the ligands in cell types in culture
  • Goldring and Goldring Eukaryotic Gene Expression, 1991, 1:301-326.
  • Baserga and others suggests that IGF-IR plays a central role in the mechanism of transformation and, as such, could be a prefened target for therapeutic interventions for a broad spectrum of human malignancies.
  • the predominant cancers that may be treated using a compound of the instant invention include, but are not limited to breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma, or endometrial carcinoma.
  • IGF-1 has also been associated with retinal neovascularization.
  • Compounds of the instant invention may also be useful as anti-aging agents. It has been observed that there is a link between IGF signalling and aging. Experiments have shown that calorie-restricted mammals have low levels of insulin and IGF-1 and have a longer life span. Similar observations have been made for insects as well. (See C. Kenyon, Cell, 2001, 105:165-168; E. Strauss, Science, 2001, 292:41-43; K.D. Kimura et al., Science 1997, 277:942-946; M. Tatar et al., Science, 2001, 292:107-110). STKs have been implicated in many types of cancer including, notably, breast cancer (Cance et al., Int. J. Cancer, 1993, 54:571-77).
  • RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, epidermal hype ⁇ roliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas.
  • diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, epidermal hype ⁇ roliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas.
  • EGFR has been indicated in comeal and dermal wound healing.
  • Defects in Insulin-R and IGF-IR are indicated in type-II diabetes mellitus.
  • a more complete conelation between specific RTKs and their therapeutic indications is set forth in Plowman et al., DN&P, 1994, 7:334-339.
  • CTKs including, but not limited to, src, abl, fps, yes, fyn, lyn, lck, Zap70, blk, hck, fgr and yrk (reviewed by Bolen et al., FASEB J., 1993, 6:3403-3409) are involved in the proliferative and metabolic signal transduction pathway and thus could be expected, and have been shown, to be involved in may PTK-mediated disorders to which the present invention is directed.
  • mutated src v-src
  • mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders.
  • Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders.
  • STKs have been associated with inflammation, autoimmune disease, immunoresponses, and hype ⁇ roliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.
  • the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents.
  • a method for identifying a chemical compound that modulates the catalytic activity of one or more of the above discussed protein kinases is another aspect of this invention.
  • the method involved contacting cells expressing the desired protein kinase with a compound of this invention (or its salt or prodrug) and monitoring the cells for any effect that the compound has on them.
  • the effect may be any observable, either to the naked eye or through the use of instrumentation, change or absence of change in a cell phenotype.
  • the change or absence of change in the cell phenotype monitored may be, for example, without limitation, a change or absence of change in the catalytic activity of the protein kinase in the cells or a change or absence of change in the interaction of the protein kinase with a natural binding partner.
  • compositions of the above compounds are a further aspect of this invention.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents.
  • suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's bloodstream by local bolus injection.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pynolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
  • the compounds of the instant invention may also be co-administered with other well-known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • combinations that would be useful include those with antireso ⁇ tive bisphosphonates, such as alendronate and risedronate; integrin blockers (defined further below), such as ⁇ v ⁇ 3 antagonists; conjugated estrogens used in hormone replacement therapy, such as PREMPRO®, PREMARIN® and ENDOMETRION®; selective estrogen receptor modulators (SERMs), such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene; cathespin K inhibitors; and ATP proton pump inhibitors.
  • SERMs selective estrogen receptor modulators
  • the instant compounds are also useful in combination with known anti-cancer agents.
  • known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG- CoA reductase inhibitors, HTV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • the instant compounds are particularly useful when coadminsitered with radiation therapy. The synergistic effects of inhibiting VEGF in combination with radiation therapy have been described in the art. (see WO 00/61186.)
  • Estrogen receptor modulators refers to compounds, which interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l- oxopropoxy-4-methyl-2-[4-[2-(l-piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]- phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl- hydrazone, and SH646.
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds, which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N-(4'- hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Cytotoxic agents refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, doxorubicin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl- pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis- mu-(hexane
  • microtubulin inhibitors include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L- valyl-L-prolyl-L-proline-t-butylamide, TDX258, and BMS 188797.
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene- chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-lH,12H- benzo[de]pyrano[3 ' ,4' :b,7]indolizino[ 1 ,2b]quinoline- 10, 13(9H, 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, e
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'- deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)ure
  • Antiproliferative agents also includes monoclonal antibodies to growth factors, other than those listed under “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Patent No. 6,069,134, for example).
  • angiogenesis inhibitors such as trastuzumab
  • tumor suppressor genes such as p53
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • Compounds which have inhibitory activity for HMG- CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
  • the terms "HMG-CoA reductase inhibitor” and “inhibitor of HMG-CoA reductase” have the same meaning when used herein.
  • Examples of HMG-CoA reductase inhibitors that may be used include, but are not limited to, lovastatin (MEVACOR®, see U.S. Patent Nos. 4,231,938,
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • An illustration of the lactone portion and its conesponding open-acid form is shown below as structures I and ⁇ .
  • HMG-CoA reductase inhibitors where an open-acid form can exist
  • salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein.
  • the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin.
  • the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non- toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-py ⁇ olidine-l '-yl-methylbenz- imidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
  • a suitable organic or inorganic base particularly those
  • salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, 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, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamao
  • Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-IJ (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-IJ
  • prenyl-protein transferase inhibiting compounds examples include (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl) methyl]-4-(3- chlorophenyl)- 1 -methyl-2( lH)-quinolinone, (-)-6- [amino(4-chlorophenyl)( 1 -methyl - l ⁇ -imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(lH)-quinolinone, (+)-6- [amino(4-chlorophenyl)(l-methyl-l ⁇ -imidazol-5-yl) methyl]-4-(3-chlorophenyl)-l- methyl-2(lH)-quinolinone, 5(S)-n-butyl-l-(2,3-dimethylphenyl)-4-[l-(4- cyanobenzyl)
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent No. 5,420,245, U.S. Patent No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S. Patent No. 5,589,485, U.S. Patent No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ.
  • FflN protease inhibitors examples include amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632.
  • Examples of reverse transcriptase inhibitors include delaviridine, efavirenz, GS-840, ⁇ B Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR20), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- ⁇ , interleukin- 12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti- inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy- genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol.
  • NSAIDs nonsteroidal anti- inflammatories
  • NSAID's which are potent COX-2 inhibiting agents.
  • an NSAID is potent if it possess an IC50 for the inhibition of COX-2 of l ⁇ M or less as measured by the cell or microsomal assay disclosed herein.
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by the cell or microsomal assay disclosed hereinunder.
  • Such compounds include, but are not limited to those disclosed in U.S. 5,474,995, issued December 12, 1995, U.S. 5,861,419, issued January 19, 1999, U.S. 6,001,843, issued December 14, 1999, U.S. 6,020,343, issued February 1, 2000, U.S.
  • Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and
  • Patent No. 5,550,142 issued August 27, 1996 U.S. Patent No. 5,604,260 issued February 18, 1997
  • U.S. Patent No. 5,698,584 issued December 16, 1997 U.S. Patent No. 5,710,140 issued January 20,1998.
  • angiogenesis inhibitors include, but are not limited to, endostation, ukrain, ranpirnase, EM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2- butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-lH-l,2,3-triazole-4- carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pynolocarbonyl- imino[N-methyl-4,2-pynole]-carbonylimino]-
  • integrated circuit Mockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ v ⁇ 3 integrin and the 0C ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ v ⁇ , ⁇ v ⁇ s, cq ⁇ i, ct2 ⁇ l, ocs ⁇ l, ⁇ i and 0C6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3, ⁇ v ⁇ 5, ⁇ v ⁇ , ocv ⁇ s, cq ⁇ i, 0C2 ⁇ l, ⁇ 5 ⁇ l, oc ⁇ l and c ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N- (trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpynol-5- yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3- chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-mo ⁇ holinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro- 10-(hydroxymethyl)- 10-hydroxy-9-methyl-9, 12-epoxy- 1 H- diindolo[l,2,3-fg:3',2',l'-kl]pynol
  • the instant compounds are also useful, alone or in combination with platelet fibrinogen receptor (GP Ilb/lTia) antagonists, such as tirofiban, to inhibit metastasis of cancerous cells.
  • Tumor cells can activate platelets largely via thrombin generation. This activation is associated with the release of VEGF.
  • the release of VEGF enhances metastasis by increasing extravasation at points of adhesion to vascular endothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, the present compounds can serve to inhibit metastasis, alone or in combination with GP Ilb/lTia) antagonists.
  • fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and/or topical routes of administration. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pynolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula I may also be administered in the form of a suppositories for rectal administration of the drug.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical application shall include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the compounds of the instant invention may be administered to a mammal in need thereof using a gel extrusion mechanism (GEM) device, such as that described in U.S. Patent No. 4,976,697, filed on December 11, 1990, which is hereby inco ⁇ orated by reference.
  • GEM gel extrusion mechanism
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. These schemes, therefore, are not limited by the compounds listed nor by any particular substituents employed for illustrative pu ⁇ oses. Substituent numbering, as shown in the schemes, does not necessarily conelate to that used in the claims.
  • Scheme 1 details the synthesis of pynole 1
  • the illustrated synthesis of the required beta-ketoester intermediate utilizes the method of Yonemitsu, et al. (JOC (1978) Vol. 43, 2087-2088)
  • R v represents ⁇ , as described in Formula I; andRz represents OR7, N(R7) 2 , N ⁇ R70R7, NH(CRb 2 ) q R7, NHR7NHC(O)R7, N ⁇ R7S(0) 2 0R7, or NH(CRb 2 ) q C(O)N(R7) 2 as described in Formula I.
  • Step B tert-butyl 3-oxo-4-phenylbutanoate
  • Step C 2-tert-butyl 4-ethyl 3-benzyl-5-methyl-lH-pynole-2,4-dicarboxylate
  • Step E 2-tert-butyl 4-ethyl 3-benzyl-5- ⁇ [(4-chlorophenyl)amino]methyl ⁇ -lH- pynole-2,4-dicarboxylate
  • Step A 5-( 1 -hydroxypropylidene)-2.2-dimethyl- 1 ,3-dioxane-4,6-dione
  • Step B tert-butyl 3-oxopentanoate
  • Step C 2-tert-butyl 4-ethyl 3-ethyl-5-methyl-lH-pynole-2,4-dicarboxylate
  • Step D 2-tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate
  • Step E [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-py ⁇ ol-2-yl]-
  • Step A 5-(l-hvdroxypropylidene)-2.2-dimethyl- 3-dioxane-4,6-dione
  • Step C 2-tert-butyl 4-methyl 3-ethyl-5-methyl-lH-pynole-2.4-dicarboxylate
  • Step D 2-tert-butyl 4-methyl 3-ethyl-5-formyl- lH-pynole-2,4-dicarboxylate
  • Step E 2-tert-butyl 4-methyl 3-ethyl-5- ⁇ [(4-methoxyphenyl)amino]methyl ⁇ - lH-pynole-2,4-dicarboxylate
  • 2-tert-butyl 4-methyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-methoxyaniline in place of 4-chloroaniline, the titled compound was obtained.
  • Step A diethyl 5-methyl-3-phenyl-lH-pynole-2,4-dicarboxylate
  • Step B diethyl 5-formyl-3-methyl-lH-pynole-2,4-dicarboxylate
  • Step C diethyl 5- ⁇ [(4-chlorophenyl)amino]methyl ⁇ -3-methyl-lH-pynole-2,4- dicarboxylate
  • Step A diethyl 3-isopropyl-5-methyl-lH-pynole-2.4-dicarboxylate Following the procedures described in Example 1, Step C, but using ethyl 4-methyl-3-oxopentanoate in place of tert-butyl 3-oxo-4-phenylbutanoate, the titled compound was obtained.
  • Step B diethyl 5-formyl-3-isopropyl-lH-pynole-2,4-dicarboxylate Following the procedures described in Example 1, Step D, but using diethyl 3-isopropyl-5-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-methyl-lH-pynole-2,4-dicarboxylate, the titled compound was obtained.
  • Step C [3,5-bis(ethoxycarbonyl)-4-isopropyl-lH-py ⁇ ol-2-yl]-N-(pyridin-2- ylmethyDmethanaminium chloride
  • Step A 5-(l-hydroxypropylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione
  • Step B tert-butyl 3-oxopentanoate
  • Step C 4-benzyl 2-tert-butyl 3-ethyl-5-methyl- lH-pynole-2.4-dicarboxylate
  • Step D 4-benzyl 2-tert-butyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxyIate
  • Step E N- ⁇ [3-[(benzyloxy)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH- py ⁇ ol-2-yl]methyl ⁇ -4-methoxybenzenaminium trifluoroacetate
  • Step E N- ⁇ [3-[(benzyloxy)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH- py ⁇ ol-2-yl]methyl ⁇ -4-methoxybenzenaminium trifluoroacetate

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Abstract

The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises a 2-carboxy pyrrole. The present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.

Description

TITLE OF THE INVENTION TYROSINE KINASE INHIBITORS
BACKGROUND OF THE INVENTION Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation; i.e., virtually all aspects of cell life, in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non life-threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer). PKs can be broken into two classes, the protein tyrosine kinases (PTKs) and the serine- threonine kinases (STKs).
Certain growth factor receptors exhibiting PK activity are known as receptor tyrosine kinases (RTKs). They comprise a large family of transmembrane receptors with diverse biological activity. As present, at least nineteen (19) distinct subfamilies of RTKs have been identified. One RTK subfamily contains the insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor related receptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-IJ to activate a hetero-tetramer composed of two entirely extracellular glycosylated α subunits and two β subunits which cross the cell membrane and which contain the tyrosine kinase domain. The Insulin-like Growth Factor- 1 Receptor (IGF-1R), and its ligands, IGF-1 and IGF-2, are abnormally expressed in numerous tumors, including, but not limited to, breast, prostate, thyroid, lung, hepatoma, colon, brain, neuroendocrine, and others.
A more complete listing of the known RTK subfamilies is described in Plowman et al., KN&P, 1994, 7(6) :334-339 which is incoφorated by reference, including any drawings, as if fully set forth herein.
In addition to the RTKs, there also exists a family of entirely intracellular PTKs called "non-receptor tyrosine kinases" or "cellular tyrosine kinases." This latter designation, abbreviated "CTK", will be used herein. CTKs do not contain extracellular and transmembrane domains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified. The Src subfamily appears so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. For a more detailed discussion of CTKs, see Bolen, Oncogene, 1993, 8:2025-2031, which is incorporated by reference, including any drawings, as if fully set forth herein.
RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including significantly, cancer. Other pathogenic conditions which have been associated with PTKs include, without limitation, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, autoimmune diseases and a variety of renal disorders.
SUMMARY OF THE INVENTION
The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises a 2-carboxy pyrrole. The present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition of kinases and are illustrated by a compound of Formula I:
Figure imgf000003_0001
wherein
V is selected from
1) Ci-Cio alkyl,
2) aryl,
3) heterocycle,
4) C3-C10 cycloalkyl, and
5) -C(O);
Ra is independently selected from
1) H,
2) OR7,
3) unsubstituted or substituted C1-C10 alkyl
4) unsubstituted or substituted aryl, and 5) unsubstituted or substituted heterocycle;
Rb is independently selected from
1) H,
2) ORV, 3) unsubstituted or substituted C1-C10 alkyl,
4) unsubstituted or substituted aryl, and
5) unsubstituted or substituted heterocycle;
Rl is independently selected from 1) H,
2) unsubstituted or substituted C i-C 10 alkyl,
3) unsubstituted or substituted C3-C10 cycloalkyl,
4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle, 6) OR7,
7) C(O)R7,
8) C(O)OR7,
Figure imgf000005_0001
11) halo, and
12) -S(0)2N(R5)2;
is selected from
1) unsubstituted or substituted Ci-Cio alkyl,
2) -C(O)OR7,
3) unsubstituted or substituted aryl,
4) -(CRb2)nN(R7)2,
Figure imgf000005_0002
6) -C(O)NHR7OR7,
7) -C(O)NH(CRb2)qR7,
8) -C(O)NHR7NHC(O)R7,
9) -C(0)NHR7S(0)20R7,
Figure imgf000005_0003
11) -C(O)NH(CRb2)qC(O)N(R7)2;
R3 is selected from
1) H,
2) unsubstituted or substituted Ci-Cio alkyl,
3) unsubstituted or substituted aralkyl
4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle, and
6) unsubstituted or substituted heterocyclylalkyl;
- A - R4 is selected from
1 ) unsubstituted or substituted C i -C i o alkyl ,
2) unsubstituted or substituted aryl, 3) unsubstituted or substituted aralkyl, and
4) unsubstituted or substituted heterocycle;
R5 is independently selected from
1) H, 2) unsubstituted or substituted C i -C i o alkyl ,
3) unsubstituted or substituted aryl, and
4) unsubstituted or substituted heterocycle;
R6 is independently selected from 1) H,
2) unsubstituted or substituted Ci-Cio alkyl,
3) unsubstituted or substituted aryl,
4) unsubstituted or substituted heterocycle,
5) OR7, 6) unsubstituted or substituted aralkyl, and
7) unsubstituted or substituted heterocyclylalkyl;
R7 is independently selected from 1) H, 2) unsubsti tuted or substituted Ci-C 10 alkyl,
3) unsubstituted or substituted aralkyl,
4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle, and
6) unsubstituted or substituted heterocyclylalkyl; n is 0 to 6, p is 0 to 6, q is 0 to 5, and r is 0 to 6;
or a pharmaceutically acceptable salt or stereoisomer thereof.
A second embodiment of the instant invention is a compound of Formula I, as described above, wherein:
R4 is selected from
1 ) unsubstituted or substituted C i -C l o alkyl , and
2) unsubstituted or substituted aryl;
or a pharmaceutically acceptable salt or stereoisomer thereof.
A further embodiment is a compound as described in the second embodiment above, wherein:
Rl is independently selected from
1) H,
2) unsubstituted or substituted Ci-Cio alkyl,
3) unsubstituted or substituted C3-C10 cycloalkyl, 4) OR7,
5) C(O)R7,
6) C(O)OR7,
7) C(O)N(R7)2,
Figure imgf000007_0001
9) halo, and
10) -S(0) N(R5)2;
n is 0 to 2, p is 0 to 4, q is 0 to 3, and r is 0 to 4,
or a pharmaceutically acceptable salt or stereoisomer thereof.
Examples of compounds of the instant invention include 2-tert-butyl 4-ethyl 3-benzyl-5-{ [(4-chlorophenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(5- oxopyrrolidin-2-yl)methyl]methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-(lH-indol-2- ylmethyl)methanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3,4- dichlorobenzenaminium trifluoroacetate;
N-{[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- methylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- hydroxybenzenaminium trifluoroacetate; N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyrrol-2-yl] methyl } -4- methoxybenzenaminium trifluoroacetate;
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyrrol-2-yl]methyl } -4- chloro-N-methylbenzenaminium trifluoroacetate;
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)methyl]-6-methylpyridinium bis(trifluoroacetate);
3-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)methyl]-5-cyclopropyl-lH-pyrazol-l-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(3,5- dimethyl- lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(5-phenyl- l,3,4-oxadiazol-2-yl)methyl]methanaminium trifluoroacetate;
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)methyl]-lH-imidazol-l-ium bis(trifluoroacetate);
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)methyl]-3-methyl-4H-l,2,4-triazole-l,4-diium tris(trifluoroacetate);
6-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)methyl]-2-methylimidazo[2,l-b][l,3]thiazol-7-ium bis(trifluoroacetate);
2-[( { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyrrol-2-yl]methyl } ammonio)methyl]-4-methyl-lH-imidazol-3-ium bis(trifluoroacetate); 2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)methyl]-l-methyl-lH-imidazol-3-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(5-oxo-4,5- dihydro-lH-l,2,4-triazol-3-yl)methyl]methanaminium trifluoroacetate;
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)methyl]-lH-l,2,4-triazol-l-ium bis(trifluoroacetate);
6-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)methyl]imidazo[2,l-b][l,3]thiazol-4-ium bis(trifluoroacetate);
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)methyl]-5-chloro-3H-benzimidazol-l-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(4-oxo-3,4- dihydrophthalazin-l-yl)methyl]methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-(lH-indol-6- ylmethyl)methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(4-methyl- 1 ,3-thiazol-2-yl)methyl]methanaminium trifluoroacetate;
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)methyl]-8-methylimidazo[l,2-a]pyridin-4-ium bis(trifluoroacetate);
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} arnmonio)methyl]-3H-benzimidazol-l-ium bis(trifluoroacetate); N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3- methylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- isopropylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- ethylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl }-3,5- dimethylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3,4- dimethoxybenzenaminium trifluoroacetate;
2-[2-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)ethyl]pyridinium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(l-methyl- lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- ethoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl }-3,4- dimethylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-l,3- benzodioxol-5-aminium trifluoroacetate; N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyrrol-2-yl]methyl } -4- isopropoxybenzenaminium trifluoroacetate;
4-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)methyl]-l,3-thiazol-3-ium bis(trifluoroacetate);
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)methyl]-l ,3-thiazol-3-ium bis(trifluoroacetate);
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)methyl]-l,3-thiazol-3-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-(isoxazol-5- ylmethyl)methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-[(l,5- dimethyl-lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- tert-butylbenzenaminium trifluoroacetate;
2-tert-butyl 4-ethyl 5-({ [4-(dimethylamino)phenyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate bis(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl }-2- methylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-2- methoxybenzenaminium trifluoroacetate; N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- propylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-2,5- dimethoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- butylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl }-3- hydroxy-4-methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-lH- indol-4-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-lH- indol-6-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3- methoxypropan-1-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ethanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} butan-1-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3- methoxybenzenaminium trifluoroacetate; N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3- carboxypropan-1-aminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N- methylmethanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-2- methylpropan- 1 -aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } pentan-1 -aminium trifluoroacetate;
2-(aminosulfonyl)-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH- pyrrol-2-yl]methyl Jethanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-(lH-pyrrol-2- ylmethyl)methanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-4- chlorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3- chlorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl }-2- chlorobenzenaminium chloride;
3-bromo-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl] methyl Jbenzenaminium chloride; 2-bromo-N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyrrol-2-yl] methyl }benzenaminium chloride;
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyrrol-2-yl] methyl } -4- fluorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}-3- fluorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl }-2- fluorobenzenaminium chloride;
3-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl} ammonio)pyridinium dichloride;
2-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } ammonio)-5-chloropyridinium dichloride;
4-bromo-N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyrrol-2-yl] methyl Jbenzenaminium chloride;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
N-{[5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pyrrol-2-yl]methyl}-4- pentylbenzenaminium trifluoroacetate;
N- { [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)- lH-pyrrol-2-yl]methyl } - 1 , 1 -biphenyl-4-aminium trifluoroacetate; N-{[5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pyrrol-2-yl]methyl}- 3 ,4,5-trimethoxybenzenaminium trifluoroacetate;
3-[4-({ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pyrrol-2-yl]methyl} ammonio)phenyl]-5-methyl-4H-l,2,4-triazol-4-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-{ [(2R)-5- oxopyιτolidin-2-yl]methyl } methanaminium trifluoroacetate;
diethyl 5-{ [(4-chlorophenyl)amino]methyl}-3-methyl-lH-pyrrole-2,4-dicarboxylate;
N-benzyl[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pyrrol-2-yl]methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pyrrol-2-yl]-N-(pyridin-2-ylmethyl) methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pyrrol-2-yl]-N-(2-chlorobenzyl) methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pyrrol-2-yl]-N-(3-chlorobenzyl) methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-isopropyl-lH-pyrrol-2-yl]-N-(pyridin-2-ylmethyl) methanaminium chloride;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]-N-(pyridin-2- ylmethyl)methanaminium chloride;
N-{ [3-[(benzyloxy)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl] methyl } -4-methoxybenzenaminium trifluoroacetate; N-{ [5-(tert-butoxycarbonyl)-3-carboxy-4-ethyl-lH-pyrrol-2-yl]methyl}-4- methoxybenzenaminium trifluoroacetate;
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(2-hydroxyethyl)amino]carbonyl }-lH-pyrrol- 2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
N-({5-(tert-butoxycarbonyl)-4-ethyl-3-[(ethylamino)carbonyl]-lH-pyrrol-2-yl} methyl)-4-methoxybenzenaminium trifluoroacetate;
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyrrol-3-yl)carbonyl]amino }methyl)pyridinium bis(trifluoroacetate);
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyrrol-3-yl)carbonyl]amino}methyl)pyridinium bis(trifluoroacetate);
N-({5-(tert-butoxycarbonyl)-4-ethyl-3-[(propylamino)carbonyl]-lH-pyrrol-2-yl} methyl)-4-methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl]amino}carbonyl)-lH-pyrrol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
2-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}ethyl)pyridinium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}methyl)-lH-imidazol-l-ium bis(trifluoroacetate); N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-oxopyrrolidin-2-yl)methyl]amino} carbonyl)-lH-pyrrol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyrrol-3-yl)carbonyl]amino } methyl )pyridinium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyrrol-3-yl)carbonyl]amino}methyl)-3H-benzimidazol-l-ium bis(trifluoroacetate);
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(isoxazol-3-ylmethyl)amino]carbonyl}-lH- pyrrol-2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
N-{ [3-({ [2-(acetylamino)ethyl]amino}carbonyl)-5-(tert-butoxycarbonyl)-4-ethyl-lH- pyrrol-2-yl]methyl }-4-methoxybenzenaminium trifluoroacetatetate;
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-methyl-l,3,4-oxadiazol-2-yl)methyl] amino}carbonyl)-lH-pyrrol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(2-sulfoethyl)amino]carbonyl}-lH-pyrrol-2- yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
N-{ [3-[(benzylamino)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl] methyl } -4-methoxybenzenaminium trifluoroacetate;
3-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}ethyl)-5-methyl-4H-l,2,4-triazol-4-ium bi s(trifluoroacetate) ;
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl J-1H- pyrrol-3-yl)carbonyl]amino}methyl)-2-methyl-l,3-thiazol-3-ium bis(trifluoroacetate); 4-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- 1 H-pyrrol-3-yl)carbonyl] amino } ethyl)- lH-pyrazol- 1 -ium bis(trifluoroacetate) ;
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(lH-indol-6-ylmethyl)amino]carbonyl}-lH- pyrrol-2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
6-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyrrol-3-yl)carbonyl]amino}methyl)-2-methylimidazo[2,l-b][l,3]thiazol-7-ium bis(trifluoroacetate);
5-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}methyl)-3-methyl-4H-l,2,4-triazole-l,4-diium tri s (trifluoroacetate) ;
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl}-lH- pyrrol-3-yl)carbonyl]amino}methyl)-l-methyl-lH-pyrazol-2-ium bis(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(l-methyl-5-oxopyrrolidin-2-yl)methyl] amino }carbonyl)-lH-pyrrol-2-yl]methyl } -4-methoxybenzenaminium trifluoroacetate;
2-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}ethyl)-5-methoxy-3H-benzimidazol-l-ium bis(trifluoroacetate);
5-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}ethyl)-lH-l,2,4-triazol-l-ium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{[(4-methoxyphenyl)ammonio] methyl }-lH-pyπOl-3-yl)carbonyl]amino}methyl)-l-methyl-lH-imidazol- 3-ium bis(trifluoroacetate); 6-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}methyl)-2,3-dihydroimidazo[2,l-b][l,3]thiazol- 4-ium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pyrrol-3-yl)carbonyl]amino}methyl)-4-methyl-lH-imidazol- 3-ium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyπOl-3-yl)carbonyl]amino}methyl)-8-methylimidazo[l,2-a]pyridin-4-ium bis(trifluoroacetate);
3-(l-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pyrrol-3-yl)carbonyl]amino}ethyl)-5-methyl-4H-l,2,4-triazol- 4-ium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}methyl)quinolinium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino } methyl)-6-methylpyridinium bis(trifluoroacetate);
N- { [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(4-methyl- 1 ,3-thiazol-2-yl)methyl]amino } carbonyl)-lH-pyrrol-2-yl]methyl }-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyιrol-3-yl)carbonyl]amino}methyl)-6,7-dihydro-5H-cyclopenta[b]pyridinium bi s (trifluoroacetate) ; 3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl J-1H- pyrrol-3-yl)carbonyl]amino}methyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinium bis(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [2-(4-methyl-l,3-thiazol-5-yl)ethyl] amino}carbonyl)-lH-pyrrol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyrrol-3-yl)carbonyl]amino}methyl)-l-methylpiperidinium bis(trifluoroacetate);
4-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl } - lH-pyrrol-3-yl)carbonyl]amino } - l-pyridinium-4-ylethyl)morpholin- 4-ium tris(trifluoroacetate);
4-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pyrrol-3-yl)carbonyl]amino}-l-pyridinium-3-ylethyl)moφholin- 4-ium tris(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-yl) methyl]amino}carbonyl)-lH-pyrrol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyrrol-3-yl)carbonyl]amino}methyl)-5-cyclopropyl-lH-pyrazol-l-ium bis(trifluoroacetate);
2-{ [{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl } (hydroxy)ammonio]methyl Jpyridinium bis(trifluoroacetate); 2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyrrol-3-yl)carbonyl]oxy } methyl)pyridinium bis(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-(2-phenylethyl)-lH-pyrrol-2-yl] methyl }-4-chlorobenzenaminium trifluoroacetate;
2-amino-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2- yl]methyl } glycinamide trifluoroacetate;
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3- glycinamide -lH-pyrrol-2-yl)methyl]-4- methoxybenzenaminium trifluoroacetate;
or a stereoisomer thereof.
Further examples of compounds of the instant invention include:
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(5-oxopyrrolidin-2-yl)methyl]amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-indol-2-ylmethyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,4-dichlorophenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-methylphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-hydroxyphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-chlorophenyl)(methyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate; 2-tert-butyl 4-ethyl 3-ethyl-5-({ [(6-methylpyridin-2-yl)methyl]amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(5-cyclopropyl-lH-pyrazol-3-yl)methyl]amino}methyl)-3-ethyl- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(3,5-dimethyl-lH-pyrazol-4-yl)methyl]amino}methyl)-3-ethyl- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-indol-2-ylmethyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-imidazol-2-ylmethyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(5-methyl-4H-l,2,4-triazol-3-yl)methyl]amino}methyl)- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(2-methylimidazo[2,l-b][l,3]thiazol-6-yl)methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(4-methyl-lH-imidazol-2-yl)methyl]amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(l-methyl-lH-imidazol-2-yl)methyl]amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-l,2,4-triazol-5-ylmethyl)amino]methyl}-lH-pyrrole-
2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(imidazo[2,l-b][l,3]thiazol-6-ylmethyl)amino]methyl}- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(6-chloro-lH-benzimidazol-2-yl)methyl]amino}methyl)-3-ethyl- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(4-oxo-3,4-dihydrophthalazin-l-yl)methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-indol-6-ylmethyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate; 2-tert-butyl 4-ethyl 3-ethyl-5-({ [(4-methyl- l,3-thiazol-2-yl)methyl]amino} methyl)- 1H- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(8-methylimidazo[l,2-a]pyridin-2-yl)methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(lH-benzimidazol-2-ylmethyl)amino]methyl }-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-methylphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-isopropylphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-ethylphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,5-dimethylphenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,4-dimethoxyphenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-pyridin-2-ylethyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(l-methyl-lH-pyrazol-4-yl)methyl]amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-ethoxyphenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,4-dimethylphenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-[(l,3-benzodioxol-5-ylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-isopropoxyphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(l,3-thiazol-4-ylmethyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate; 2-tert-butyl 4-ethyl 3-ethyl-5-{ [(l,3-thiazol-5-ylmethyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(l,3-thiazol-2-ylmethyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(isoxazol-5-ylmethyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(l,5-dimethyl-lH-pyrazol-4-yl)methyl]amino}methyl)-3-ethyl- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-tert-butylphenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [4-(dimethylamino)phenyl]amino}methyl)-3-ethyl-lH-pyrrole-
2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-methylphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-methoxyphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-propylphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(2,5-dimethoxyphenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-butylphenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-hydroxy-4-methoxyphenyl)amino]methyl }-lH-pyrrole-
2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(lH-indol-4-ylamino)methyl]-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(lH-indol-6-ylamino)methyl]-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-methoxypropyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate; 2-tert-butyl 4-ethyl 3-ethyl-5-[(ethylamino)methyl]-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-[(butylamino)methyl]-3-ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-methoxyphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
4-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl]methyl}amino) butanoic acid;
2-tert-butyl 4-ethyl 3-ethyl-5-[(methylamino)methyl]-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(isobutylamino)methyl]-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(pentylamino)methyl]-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [2-(aminosulfonyl)ethyl]amino}methyl)-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-pyrrol-2-ylmethyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-chlorophenyl)amino]methyl }-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3-chlorophenyl)amino]methyl }-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(2-chlorophenyl)amino]methyl }-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3-bromophenyl)amino]methyl }-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(2-bromophenyl)amino]methyl }-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-fluorophenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-fluorophenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-fluorophenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(pyridin-3-ylamino)methyl]-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-ethyl 5-{ [(5-chloropyridin-2-yl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-bromophenyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-pentylphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[(l,l -biphenyl-4-ylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(3,4,5-trimethoxyphenyl)amino]methyl}-lH-pyrrole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[({ [(2R)-5-oxopyrrolidin-2-yl]methyl }amino)methyl]-lH- pyrrole-2,4-dicarboxylate; diethyl 5-[(benzylamino)methyl]-3-methyl-lH-pyrrole-2,4-dicarboxylate; diethyl 3-methyl-5-{ [(pyridin-2-ylmethyl)amino]methyl }-lH-pyrrole-2,4-dicarboxylate; diethyl 5-{ [(2-chlorobenzyl)amino]methyl}-3-methyl-lH-pyrrole-2,4-dicarboxylate; diethyl 5-{ [(3-chlorobenzyl)amino]methyl }-3-methyl-lH-pyrrole-2,4-dicarboxylate; diethyl 3-isopropyl-5-{ [(pyridin-2-ylmethyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(pyridin-2-ylmethyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate;
4-benzyl 2-tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
5-(tert-butoxycarbonyl)-4-ethyl-2- { [(4-methoxyphenyl)amino]methyl } - lH-pyrrole-3- carboxylic acid; tert-butyl 3-ethyl-4-{ [(2-hydroxyethyl)amino]carbonyl }-5-{ [(4-methoxyphenyl)amino] methyl } -lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-4-[(ethylamino)carbonyl]-5-{ [(4-methoxyphenyl)amino] methyl }-lH- pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(pyridin-2-ylmethyl)amino] carbonyl }-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-{ [(pyridin-4-ylmethyl)amino] carbonyl }-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-[(propylamino)carbonyl]-lH- pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(5-oxo-4,5-dihydro-lH- l,2,4-triazol-3-yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(2-pyridin-2-ylethyl)amino] carbonyl }- lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-4-{ [(lH-imidazol-2-ylmethyl)amino]carbonyl } -5- { [(4-methoxyphenyl) amino]methyl}-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(5-oxopyrrolidin-2-yl) methyl] amino } carbonyl)- 1 H-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-{ [(pyridin-3-ylmethyl)amino] carbonyl }-lH-pyrrole-2-carboxylate; tert-butyl 4-{ [(lH-benzimidazol-2-ylmethyl)amino]carbonyl }-3-ethyl-5-{ [(4- methoxyphenyl)amino]methyl}-lH-pyrrole-2-carboxylate tert-butyl 3-ethyl-4-{ [(isoxazol-3-ylmethyl)amino]carbonyl}-5-{ [(4-methoxyphenyl) amino]methyl}-lH-pyrrole-2-carboxylate; tert-butyl 4-({ [2-(acetylamino)ethyl]amino}carbonyl)-3-ethyl-5-{ [(4-methoxyphenyl) amino] methyl } - 1 H-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(5-methyl-l ,3,4-oxadiazol-
2-yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate;
2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)amino]methyl }-lH-pyrrol-3- yl)carbonyl]amino Jethanesulfonic acid; tert-butyl 4-[(benzylamino)carbonyl]-3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-lH- pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({[2-(5-methyl-4H-l,2,4- triazol-3-yl)ethyl]amino Jcarbonyl)- lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(2-methyl-l,3-thiazol-4- yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [2-(lH-pyrazol-4- yl)ethyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-4-{ [(lH-indol-6-ylmethyl)amino]carbonyl}-5-{ [(4-methoxyphenyl) amino]methyl } - lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(2-methylimidazo[2,l- b][l,3]thiazol-6-yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{[(4-methoxyphenyl)amino]methyl}-4-({ [(5-methy]-4H-l,2,4-triazol-
3-yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [( 1 -methyl- lH-pyrazol -4- yl)methyl] amino } carbonyl)- lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(l-methyl-5-oxopyrrolidin-
2-yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-4-({ [2-(6-methoxy-lH-benzimidazol-2-yl)ethyl]amino}carbonyl)-5-
{ [(4-methoxyphenyl)amino]methyl }-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [2-(lH-l,2,4-triazol-5- yl)ethyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(l-methyl-lH-imidazol-2- yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 4-{ [(2,3-dihydroimidazo[2,l-b][l,3]thiazol-6-ylmethyl)amino]carbonyl }-3- ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(4-methyl-lH-imidazol-2- yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(8-methylimidazo[l,2- a]pyridin-2-yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [l-(5-methyl-4H- 1,2,4- triazol-3-yl)ethyl]amino}carbonyl)-lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(quinolin-2-ylmethyl) amino]carbonyl } - lH-pyrrole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(6-methylpyridin-2- yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(4-methyl- l,3-thiazol-2- yl)methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate;
Tert-butyl 4-{ [(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylmethyl)amino]carbonyl }-3- ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pyrrole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-3-ylmethyl)amino]carbonyl}-lH-pyrrole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [2-(4-methyl-l,3-thiazol-5- yl)ethyl]amino}carbonyl)-lH-pyrrole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(l-methylpiperidin-3-yl) methyl]amino}carbonyl)-lH-pyrrole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino] methyl }-4-{ [(2-moφholin-4-yl-2- pyridin-4-ylethyl)amino]carbonyl}-lH-pyrrole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-{ [(2-moφholin-4-yl-2- pyridin-3-ylethyl)amino]carbonyl}-lH-pyrrole-2-carboxylate;
Tert-butyl 3-ethyl-4-({ [(5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-yl)methyl]amino} carbonyl)-5-{ [(4-methoxyphenyl)amino]methyl }-lH-pyrrole-2-carboxylate;
Tert-butyl 4-({ [(5-cyclopropyl-lH-pyrazol-3-yl)methyl]amino}carbonyl)-3-ethyl-5-{ [(4- methoxyphenyl)amino]methyl}-lH-pyrrole-2-carboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [hydroxy(pyridin-2-ylmethyl)amino]methyl }-lH-pyrrole-
2,4-dicarboxylate;
2-tert-butyl 4-(pyridin-2-ylmethyl) 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-chlorophenyl)amino]methyl}-3-(2-phenylethyl)-lH-pyrrole-
2,4-dicarboxylate;
2-amino-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyrrol-2-yl] methyl } glycinamide;
4-(Carbamoylmethyl-carbamoyl)-3-ethyl-5-[(4-methoxy-phenylamino)-methyl]-lH- pyrrole-2-carboxylic acid tert-butyl ester; or a pharmaceutically acceptable salt or stereoisomer thereof.
Also included in the instant invention is a TFA salt of a compound selected from: 2-tert-Butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl J-1H- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-methyl-l,3-benzothiazol-6-yl)amino]methyl J-1Η- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(lH-pyrazol-l-yl)phenyl]amino} methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(2-oxoimidazolidin-l-yl)phenyl]amino}methyl)- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(3-methyl-2-oxoimidazolidin-l-yl)phenyl] amino}methyl)-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl }-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(cyclopropylmethyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-phenoxyphenyl)amino]methyl }-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-({ [4-(aminocarbonyl) phenyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
4-({ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pyrrol-2-yl]methyl} amino)-2-hydroxybenzoic acid; 2-tert-butyl 4-methyl 5-[(cyclopropylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(6-chloro-l,3-benzothiazol-2-yl)amino] methyl }-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2-chloropyrimidin-4-yl)amino]methyl}-3-ethyl-lH-pyrrole- 2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(2-chloro-6,7-dimethoxyquinazolin-4-yl)amino]methyl}-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromopyridin-2-yl)amino]methyl }-3-ethyl-lH-pyrrole-
2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-[(pyrimidin-2-ylamino)methyl]-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[(l ,3-benzoxazol-2-ylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromopyrimidin-2-yl)amino]methyl}-3-ethyl-lH-pyrrole- 2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [5-chloro-2-(4H-l,2,4-triazol-4-yl)benzyl] amino }methyl)-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-[({ [3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4- yl]methyl}amino)methyl]-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}methyl)-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [2-(aminocarbonyl) cyclohexyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromo-2-fluorobenzyl)amino]methyl}-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [2-(3,4-dichlorophenyl) ethyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(lH-l,2,4-triazol-l-yl)ethyl] amino}methyl)-lH- pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [4-(4-tert-butoxyphenyl)butyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [l-(lH-benzimidazol-2-yl)ethyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({[2-(lH-l,2,4-triazol-3-yl)ethyl] amino}methyl)-lH- pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({[2-(4-methyl-l,3-thiazol-5-yl)ethyl] amino }methyl)- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcyclopentyl)methyl] amino } methyl)- lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-piperidin-l-yl-2-pyridin-3-ylethyl) amino]methyl}-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(3-phenylisoxazol-5-yl)methyl]amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-2-ylethyl) amino] methyl } - 1 H-pyrrole-2,4-dicarboxyl ate ;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcycloheptyl)methyl] amino} methyl)- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2,2,2-trifluoro-l-pyridin-3-ylethyl) amino]methyl}- lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2-thien-2-yl-l,3-thiazol-4-yl)methyl] amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(5-phenyl-lH-l,2,4-triazol-3-yl) ethyl] amino }methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(6-methoxy-lH-benzimidazol-2-yl)methyl] amino}methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2,3-dihydro-l,4-benzodioxin-2-ylmethyl) amino]methyl}-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({methyl[(5-phenylisoxazol-3-yl) methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-[(quinoxalin-2-ylamino)methyl]-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(l,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate; 2-tert-butyl 4-methyl 5-[({2-[4-(aminosulfonyl) phenyl]ethyl } amino) methyl]-3-ethyl- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(3,4-dihydroxybenzyl) amino]methyl}-3-ethyl-lH-pyrrole-
2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(l-benzylpiperidin-4-yl)amino]methyl }-3-ethyl-lH-pyrrole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [4-(aminosulfonyl) benzyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-3-ylethyl) amino] methyl }-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[({ [l-(tert-butoxycarbonyl)-lH-indol-3-yl]methyl } amino) methyl]-3-ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [(4-benzylmoφholin-3-yl)methyl]amino}methyl)-3-ethyl- lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(4-phenylmoφholin-3-yl) methyl]amino}methyl)-
1 H-pyrrole-2 ,4-dicarboxyl ate ;
2-tert-butyl 4-methyl 3-ethyl-5-({ methyl [(5-methyl-lH-indol-3-yl) methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[(l,3-benzothiazol-2-ylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(l-phenyl-lH-tetrazol-5-yl)amino] methyl }-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl] [(2S)-2-(3- fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(4-fluorophenyl)-2-hydroxyethyl] amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({bis[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]amino}methyl)- 3-ethyl-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [l-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)- lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({bis[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino}methyl)- 3-ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluoroρhenyl)-2-hydroxyethyl][l-(4- fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
or a stereoisomer thereof.
Additional examples of compounds of the instant invention include:
2-tert-Butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl }-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-methyl-l,3-benzothiazol-6-yl)amino]methyl}-lΗ- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(lH-pyrazol-l-yl)phenyl]amino} methyl)-lH- pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(2-oxoimidazolidin-l-yl)phenyl]amino}methyl)- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(3-methyl-2-oxoimidazolidin-l-yl)phenyl] amino } methyl )- 1 H-pyrrole-2 ,4-dicarboxyl ate ;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl}-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(cyclopropylmethyl)amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-phenoxyphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate; 2-tert-butyl 4-methyl 5-({ [4-(aminocarbonyl) phenyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
4-({ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pyrrol-2-yl]methyl} amino)-2-hydroxybenzoic acid; 2-tert-butyl 4-methyl 5-[(cyclopropylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(6-chloro-l,3-benzothiazol-2-yl)amino] methyl }-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2-chloropyrimidin-4-yl)amino]methyl }-3-ethyl-lH-pyrrole- 2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2-chloro-6,7-dimethoxyquinazolin-4-yl)amino]methyl}-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromopyridin-2-yl)amino]methyl}-3-ethyl-lH-pyrrole-
2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-[(pyrimidin-2-ylamino)methyl]-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[(l,3-benzoxazol-2-ylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromopyrimidin-2-yl)amino]methyl }-3-ethyl-lH-pyrrole- 2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [5-chloro-2-(4H-l,2,4-triazol-4-yl)benzyl] amino }methyl)-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-[({ [3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4- yl]methyl}amino)methyl]-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}methyl)-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [2-(aminocarbonyl) cyclohexyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromo-2-fluorobenzyl)amino]methyl}-3-ethyl-lH- pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({[2-(3,4-dichlorophenyl) ethyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(lH-l,2,4-triazol-l-yl)ethyl] amino}methyl)-lH- pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [4-(4-tert-butoxyphenyl)butyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [l-(lH-benzimidazol-2-yl)ethyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(lH-l,2,4-triazol-3-yl)ethyl] amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(4-methyl-l,3-thiazol-5-yl)ethyl] amino Jmethyl)- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcyclopentyl)methyl] amino}methyl)-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-piperidin-l-yl-2-pyridin-3-ylethyl) amino]methyl}-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(3-phenylisoxazol-5-yl)methyl]amino}methyl)-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-2-ylethyl) amino] methyl }-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcycloheptyl)methyl] amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2,2,2-trifluoro-l-pyridin-3-ylethyl) amino]methyl}- lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2-thien-2-yl-l,3-thiazol-4-yl)methyl] amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(5-phenyl-lH-l,2,4-triazol-3-yl) ethyl] amino}methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(6-methoxy-lH-benzimidazol-2-yl)methyl] amino }methyl)-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(2,3-dihydro-l,4-benzodioxin-2-ylmethyl) amino]methyl}-3- ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({methyl[(5-phenylisoxazol-3-yl) methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-[(quinoxalin-2-ylamino)methyl]-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(l,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pyrrole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[({2-[4-(aminosulfonyl) phenyl]ethyl } amino) methyl]-3-ethyl- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(3,4-dihydroxybenzyl) amino]methyl}-3-ethyl-lH-pyrrole-
2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(l-benzylpiperidin-4-yl)amino]methyl}-3-ethyl-lH-pyrrole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [4-(aminosulfonyl) benzyl]amino}methyl)-3-ethyl-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-3-ylethyl) amino] methyl }-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[({[l-(tert-butoxycarbonyl)-lH-indol-3-yl]methyl} amino) methyl]-3-ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [(4-benzylmoφholin-3-yl)methyl]amino}methyl)-3-ethyl- lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(4-phenylmoφholin-3-yl) methyl ] amino Jmethyl)- lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({methyl[(5-methyl-lH-indol-3-yl) methyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[(l,3-benzothiazol-2-ylamino)methyl]-3-ethyl-lH-pyrrole-2,4- dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(1 -phenyl- lH-tetrazol-5-yl)amino] methyl }-lH- pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl][(2S)-2-(3- fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-( { bi s [(2R)-2-(4-fluorophenyl)-2-hydroxyethyl] amino } methyl)- 3-ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [l-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)-
1 H-pyrrole-2 ,4-dicarboxyl ate ; 2-tert-butyl 4-methyl 5-({ bis[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino }methyl)-
3-ethyl-lH-pyrrole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluoroρhenyl)-2-hydroxyethyl][l-(4- fluorophenyl)-2-hydroxyethyl] amino} methyl)-lH-pyrrole-2,4-dicarboxylate;
or a pharmaceutically acceptable salt or stereoisomer thereof.
Specific examples of compounds of the instant invention include
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate
Figure imgf000040_0001
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(pyridin-2-ylmethyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate
Figure imgf000040_0002
2-tert-butyl 4-ethyl 3-ethyl-5-[({ [(2R)-5-oxopyrrolidin-2-yl]methyl }amino)methyl]- lH-pyrrole-2,4-dicarboxylate
Figure imgf000040_0003
tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(pyridin-2- ylmethyl)amino]carbonyl } - lH-pyrrole-2-carboxylate
Figure imgf000041_0001
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-pentylphenyl)amino]methyl}-lH-pyrrole-2,4- dicarboxylate
Figure imgf000041_0002
or the pharmaceutically acceptable salt or stereoisomer thereof.
The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
When any variable (e.g. aryl, heterocycle, Rl, Ra etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms or heteroatoms.
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
As used herein, "alkyl" is intended to include both branched, straight- chain, and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, Cι-Cχo, as in "Cχ-Cιo alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement. For example, "Cι-Cχo alkyl" specifically includes methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, adamantyl, and so on.
"Cycloalkyl" as used herein is intended to include non-aromatic cyclic hydrocarbon groups, having the specified number of carbon atoms, which may or may not be bridged or structurally constrained. Examples of such cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl, tetrahydro-naphthalene, methylenecylohexyl, and the like. As used herein, examples of "C3 - Cχo cycloalkyl" may include, but are not limited to:
Figure imgf000042_0001
As used herein, the term "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. If no number of carbon atoms is specified, the term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C2-C6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl As descπbed above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon tπple bond. Up to 3 carbon-carbon tπple bonds may be present. Thus, "C2-C6 alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms Alkynyl groups include ethynyl, propynyl and butynyl As descπbed above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain tπple bonds and may be substituted if a substituted alkynyl group is indicated
As used herein, "aryl" is intended to mean any stable monocyclic or bicychc carbon πng of up to 7 atoms in each πng, wherein at least one πng is aromatic Examples of such aryl elements include phenyl, naphthyl, tetrahydro- naphthyl, indanyl, indanonyl, biphenyl, tetralinyl, tetralonyl, fluorenonyl, phenanthryl, anthryl, acenaphthyl, tetrahydronaphthyl, and the like.
As appreciated by those of skill in the art, "halo" or "halogen" as used herein is intended to include chloro, fluoro, bromo and lodo.
The term heteroaryl, as used herein, represents a stable monocyclic or bicychc πng of up to 7 atoms in each πng, wherein at least one πng is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: acπdinyl, carbazolyl, cinnol yl, quinoxalmyl, pyrrazolyl, indolyl, benzodioxolyl, benzotπazolyl, benzothiofuranyl, benzothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, benzoquinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrahydronaphthyl, tetrahydroquinoline, and the like.
The term heterocycle or heterocyclic or heterocyclyl, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. "Heterocycle" or "heterocyclyl" therefore includes the above mentioned heteroaryls, as well as dihydro and tetrathydro analogs thereof. Further examples of "heterocyclyl" include, but are not limited to the following: benzodioxolyl, benzodioxinyl, benzofuranyl, benzofurazanyl, benzoimidazolyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzothiofuranyl, benzothiophenyl, benzothiopyranyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, diazapinonyl, dihydrobenzofuranyl, dihydrobenzofuryl, dihydrobenzoimidazolyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrocyclopentapyridinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyπolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, furyl, furanyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazothiazolyl, imidazopyridinyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoquinolinone, isoquinolyl, isothiazolyl, isothiazolidinyl, isoxazolinyl, isoxazolyl, methylenedioxybenzoyl, moφholinyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxetanyl, oxoazepinyl, oxadiazolyl, oxodihydrophthalazinyl, oxodihydroindolyl, oxoimidazolidinyl, oxopiperazinyl, oxopiperdinyl, oxopyπolidinyl, oxopyrimidinyl, oxopyrrolyl, oxotriazolyl, piperidyl, piperidinyl, piperazinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyπolyl, pyrrolidinyl, quinazolinyl, quinolinyl, quinolyl, quinolinonyl, quinoxalinyl, tetrahydrocycloheptapyridinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiazolinyl, thienofuryl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, and the like. Preferably, heterocycle is selected from oxoazepinyl, benzimidazolyl, diazapinonyl, imidazolyl, oxoimidazolidinyl, indolyl, isoquinolinyl, moφholinyl, piperidyl, piperazinyl, pyridyl, pyπolidinyl, oxopiperidinyl, oxopyrimidinyl, o opyrrolidinyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.
As used herein, "aralkyl" is intended to mean an aryl moiety, as defined above, attached through a Cχ-Cιo alkyl linker, where alkyl is defined above. Examples of aralkyls include, but are not limited to, benzyl, naphthylmethyl and phenylpropyl. As used herein, "heterocyclylalkyl" is intended to mean a heterocyclic moiety, as defined below, attached through a Cχ-Cιo alkyl linker, where alkyl is defined above. Examples of heterocyclylalkyls include, but are not limited to, pyridylmethyl, imidazolylethyl, pyrrolidinylmethyl, moφholinylethyl, quinolinylmethyl, imidazolylpropyl and the like. As used herein, the terms "substituted Cχ-Cχo alkyl" and "substituted
Cχ-C6 alkoxy" are intended to include the branch or straight-chain alkyl group of the specified number of carbon atoms, wherein the carbon atoms may be substituted with one to three substituents selected from the group which includes, but is not limited to, halo, Cχ-C20 alkyl, CF3, NH2, N(Cχ-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(Cχ-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Co-Cβ alkyl) S(O)θ-2-, (C0-C6 alkyl)S(O)0-2(Cθ-C6 alkyl)-, (C0-C6 alkyl)C(O)NH-, H2N-C(NH)-, -O(Cχ-C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (C0-C6 alkyl)O (Cχ-C6 alkyl)-, (C0-C6 alkyl)C(O)ι.2(Co-C6 alkyl)-, (C0-C6 alkyl)OC(O)NH-, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano- heterocyclylalkyl.
As used herein, the terms "substituted C3-C10 cycloalkyl", "substituted aryl", "substituted heterocycle", "substituted aralkyl" and "substituted heterocyclylalkyl" are intended to include the cyclic group containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Preferably, the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, CF3, NH2, N(Cχ-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(Cχ-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Co-Cg alkyl) S(O)0-2-, (Cθ-C6 alkyl)S(O)0-2(Cθ-C6 alkyl)-, (C0-C6 alkyl)C(O)NH-, H2N-C(NH)-, -O(Cχ-C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (C0-C6alkyl)O(Cχ-C6 alkyl)-, (Co-C6 alkyl)C(O)i-2(Co-C6 alkyl)-, (C0-C6 alkyl )OC(O)NH-, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo- heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl .
Preferably, R is selected from H, unsubstituted or substituted C1-C10 alkyl, halo, OR7, N(R7)2, C(O)OR7, and -S(O)2N(R5) .
Preferably, R is selected from -C(O)OR7, -C(0)N(R7)2, -C(O)NHR7OR7, -C(O)NH(CRb2)qR7, -C(O)NHR7NHC(O)R7, -C(0)NHR7 S(O)2OR7, and -C(O)NH(CRb2)qC(O)N(R7)2. More preferably, R is selected from -C(O)OR7, -C(0)N(R7)2, -C(O)NHR7OR7, -C(O)NH(CRb2)qR7.
Preferably, R3 is unsubstituted or substituted Cχ-Cιo alkyl and unsubstituted or substitited aralkyl. Preferably, n, p and q are independently 0, 1, 2 or 3. More preferably, n is 1.
It is intended that the definition of any substituent or variable (e.g., Rl, Ra, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R7)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
For use in medicine, the salts of the compounds of Formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly prefened are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N, Nl-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmoφholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, moφholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly prefened are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19.
Included in the instant invention is the free form of compounds of Formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof. Some of the specific compounds exemplified herein are the protonated salts of amine compounds. The term "free form" refers to the amine compounds in non-salt form. The encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of Formula I. The free form of the specific salt compounds described may be isolated using techniques known in the art. For example, the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for puφoses of the invention.
It will also be noted that the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
Abbreviations which may be used in the description of the chemistry and in the Examples that follow include:
Ac2O Acetic anhydride; AcOH Acetic acid;
AIBN 2,2'-Azobisisobutyronitrile;
BINAP 2,2'-Bis(diphenylphosphino)-l,l' binaphthyl;
Bn Benzyl; BOC/Boc tert-Butoxycarbonyl;
BSA Bovine Serum Albumin;
CAN Ceric Ammonia Nitrate;
CBz Carbobenzyloxy;
CI Chemical Ionization; DBAD Di-tert-butyl azodicarboxylate;
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene;
DCE 1,2-Dichloroethane;
DJJEA N,N-Diisopropylethylamine;
DMAP 4-Dimethylaminopyridine; DME 1,2-Dimethoxyethane;
DMF NN-Dimethylformamide;
DMSO Methyl sulfoxide;
DPPA Diphenylphosphoryl azide;
DTT Dithiothreitol; EDC l-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide-hydrochloride;
EDTA Ethylenediaminetetraacetic acid;
ES Electrospray;
ESI Electrospray ionization;
Et2O Diethyl ether; Et3Ν Triethylamine;
EtOAc Ethyl acetate;
EtOH Ethanol;
FAB Fast atom bombardment;
HEPES 4-(2-Hydroxyethyl)-l-piperazineethanesulfonic acid; HOAc Acetic acid; HOBT 1-Hydroxybenzotriazole hydrate;
HOOBT 3-Hydroxy-l ,2,2-benzotriazin-4(3H)-one;
ΗPLC High-performance liquid chromatography;
HRMS High Resolution Mass Spectroscopy; KOtBu Potassium tert-butoxide;
LAH Lithium aluminum hydride;
LCMS Liquid Chromatography Mass Spectroscopy;
MCPBA m-Chloroperoxybenzoic acid;
Me Methyl; MeOH Methanol;
Ms Methanesulfonyl;
MS Mass Spectroscopy;
MsCl Methanesulfonyl chloride; n-Bu n-butyl; n-Bu3P Tri-π-butylphosphine;
NaHMDS Sodium bis(trimethylsilyl)amide;
NBS N-Bromosuccinimide;
Pd(PPh3)4 Palladium tetrakis(triphenylphosphine);
Pd2(dba) 2 Tris(dibenzylideneacetone)dipalladium (0) Ph phenyl;
PMSF α-Toluenesulfonyl fluoride;
Py or pyr Pyridine;
PYBOP Benzotriazol-1-yloxytripyrrolidinophosphonium
(or PyBOP) hexafluorophosphate; RPLC Reverse Phase Liquid Chromatography;
RT Room Temperature; t-Bu tert-Butyl;
TBAF Tetrabutylammonium fluoride;
TBSC1 tert-Butyldimethylsilyl chloride; TFA Trifluoroacetic acid; THF Tetrahydrofuran;
TIPS Triisopropylsilyl;
TMS Tetramethylsilane; and
Tr Trityl.
UTILITY
In another aspect, this present invention relates to a method of modulating the catalytic activity of PKs (protein kinases) in a mammal in need thereof comprising contacting the PK with a compound of Formula I.
As used herein, the term "modulation" or "modulating" refers to the alteration of the catalytic activity of receptor tyrosine kinases (RTKs), cellular tyrosine kinases (CTKs)and serine-threonine kinases (STKs). In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTKs, CTKs or STKs is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
The term "catalytic activity" as used herein refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
The term "contacting" as used herein refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly; i.e., by interacting with the kinase itself, or indirectly; i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such "contacting" can be accomplished "in vitro," i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder; i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
The above-referenced PK is selected from the group comprising an RTK, a CTK or an STK in another aspect of this invention. Preferably, the PK is an RTK.
Furthermore, it is an aspect of this invention that the receptor tyrosine kinase (RTK) whose catalytic activity is modulated by a compound of this invention is selected from the group comprising EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRα, PDGFRβ, TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-IR, Flk4, KDR/Flk- 1 , Fit- 1 , FGFR- IR, FGFR- IR, FGFR-3R and FGFR-4R. Preferably, the RTK is preferably, the receptor protein kinase is selected from IR, IGF-1R, or IRR. In addition, it is an aspect of this invention that the cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
Another aspect of this invention is that the serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf.
In another aspect, this invention relates to a method for treating or preventing a PK-related disorder in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of one or more of the compounds described above.
As used herein, "PK-related disorder," "PK driven disorder," and "abnormal PK activity" all refer to a condition characterized by inappropriate (i.e., diminished or, more commonly, exessive) PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Excessive-activity of a PK refers to either amplification of the gene encoding a particular PK or its ligand, or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases). "Treat," "treating" or "treatment" with regard to a PK-related disorder refers to alleviating or abrogating the cause and/or the effects of a PK-related disorder.
As used herein, the terms "prevent", "preventing" and "prevention" refer to a method for barring a mammal from acquiring a PK-related disorder in the first place.
The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and its variants are each understood to include concuπent and sequential introduction of the compound or prodrug thereof and other agents.
The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
The term "treating cancer" or "treatment of cancer" refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer. The protein kinase-related disorder may be selected from the group comprising an RTK, a CTK or an STK-related disorder in a further aspect of this invention. Preferably, the protein kinase-related disorder is an RTK-related disorder. In yet another aspect of this invention, the above referenced PK-related disorder may be selected from the group consisting of an EGFR-related disorder, a PDGFR-related disorder, an IGFR-related disorder and a flk-related disorder.
The above referenced PK-related disorder may be a cancer selected from, but not limited to, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, chrondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thyoma, thyroid cancer, testicular cancer and osteosarcoma in a further aspect of this invention. More preferably, the PK-related disorder is a cancer selected from brain cancer, breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma or endometrial carcinoma.
Included within the scope of the present invention is a pharmaceutical composition, which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier. The present invention also encompasses a method of treating or preventing cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of Formula I. Types of cancers which may be treated using compounds of Formula I include, but are not limited to, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, chrondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyona, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thymona, thyroid cancer, testicular cancer and osteosarcoma in a further aspect of this invention. More preferably, the cancer being treated is selected from breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non- small cell lung cancer, renal cell carcinoma, or endometrial carcinoma.
The above-referenced PK-related disorder may be an IGFR-related disorder selected from diabetes, an autoimmune disorder, Alzheimer's and other cognitive disorders, a hypeφroliferation disorder, aging, cancer, acromegaly, Crohn's disease, endometriosis, diabetic retinopathy, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
A method of treating or preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of Formula I is also encompassed by the present invention. Methods of treating or preventing ocular diseases, such as diabetic retinopathy and age-related macular degeneration, are also part of the invention. Also included within the scope of the present invention is a method of treating or preventing inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions, as well as treatment or prevention of bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets. Other disorders which might be treated with compounds of this invention include, without limitation, immunological and cardiovascular disorders such as atherosclerosis.
The invention also contemplates the use of the instantly claimed compounds in combination with a second compound selected from the group consisting of:
1) an estrogen receptor modulator,
2) an androgen receptor modulator,
3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent,
6) a prenyl-protein transferase inhibitor,
7) an HMG-CoA reductase inhibitor,
8) an HJN protease inhibitor, 9) a reverse transcriptase inhibitor, and
10) angiogenesis inhibitor.
A preferred angiogenesis inhibitor is selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF. Preferred estrogen receptor modulators are tamoxifen and raloxifene. Also included in the scope of the claims is a method of treating cancer, which comprises administering a therapeutically effective amount of a compound of Formula I in combination with a compound selected from the group consisting of:
1) an estrogen receptor modulator,
2) an androgen receptor modulator, 3) retinoid receptor modulator,
4) a cytotoxic agent,
5) an antiproliferative agent,
6) a prenyl-protein transferase inhibitor,
7) an HMG-CoA reductase inhibitor, 8) an HTV protease inhibitor,
9) a reverse transcriptase inhibitor, and
10) angiogenesis inhibitor.
And yet another embodiment is the method of treating cancer using the combination discussed above, in combination with radiation therapy. And yet another embodiment of the invention is a method of treating cancer which comprises administering a therapeutically effective amount of a compound of Formula I in combination with paclitaxel or trastuzumab. The PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs). RTK-mediated signal transduction, is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization (or conformational changes in the case of IR, IGF-1R or IRR), transient stimulation of the intrinsic protein tyrosine kinase activity, autophosphorylation and subsequent phosphorylation of other substrate proteins. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects on the extracellular microenvironment, etc.). See Schlessinger and Ullrich, 1992, Neuron 9:303-391.
It has been shown that tyrosine phosphorylation sites, on growth factor receptors, function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Fantl et al., 1992, Cell 69:413-423; Songyang et al., 1994, Mol., Cell. Biol. 14:2777-2785); Songyang et al., 1993, Cell 72:767-778; and Koch et al., 1991, Science 252:668-678. Another signaling molecule domain, which interacts with phosphorylated tyrosines, is termed a PTB domain. Blaikie et al., 1994, J. Biol. Chem. 269:32031-32034; Gustafson et al., 1995, Mol. Cell Biol., 15:2500-25008; Kavanaugh and Williams, 1994, Science 266:1862-1865. Several intracellular substrate proteins that associate with RTKs have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain, but which serve as adapters and associate with catalytically active molecules. Songyang et al., 1993, Cell 72:767-778. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 or PTB domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. Songyang et al., 1993, Cell 72:767-778. These observations suggest that the function of each RTK is determined not only by its pattern of expression and ligand availability, but also by the anay of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step, which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors. STKs, being primarily cytosolic, affect the internal biochemistry of the cell, often as a down-stream response to a PTK event. STKs have been implicated in the signaling process which initiates DNA synthesis and subsequent mitosis leading to cell proliferation.
Thus, PK signal transduction results in, among other responses, cell proliferation, differentiation, growth, metabolism, and cellular mobility. Abnormal cell proliferation may result in a wide anay of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and/or vasculogenesis.
A precise understanding of the mechanism by which the compounds of this invention inhibit PKs is not required in order to practice the present invention. However, while not hereby being bound to any particular mechanism or theory, it is believed that the compounds interact with the amino acids in the catalytic region of PKs. PKs typically possess a bi-lobate structure wherein ATP appears to bind in the cleft between the two lobes in a region where the amino acids are conserved among PKs. Inhibitors of PKs are believed to bind by non-covalent interactions such as hydrogen bonding, van der Waals forces and ionic interactions in the same general region where the aforesaid ATP binds to the PKs. The compounds disclosed herein may have utility as in vitro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins.
In another aspect, the protein kinase (PK), the catalytic activity of which is modulated by contact with a compound of this invention, is a protein tyrosine kinase (PTK), more particularly, a receptor protein tyrosine kinase (RTK). Among the RTKs whose catalytic activity can be modulated with a compound of this invention, or salt thereof, are, without limitation, EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRα, PDGFRβ, TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-IR, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R. Most preferably, the RTK is selected from IGF-1R.
The protein tyrosine kinase whose catalytic activity is modulated by contact with a compound of this invention, or a salt or a prodrug thereof, can also be a non-receptor or cellular protein tyrosine kinase (CTK). Thus, the catalytic activity of CTKs such as, without limitation, Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, may be modulated by contact with a compound or salt of this invention.
Still another group of PKs which may have their catalytic activity modulated by contact with a compound of this invention are the serine-threonine protein kinases such as, without limitation, CDK2 and Raf. This invention is also directed to compounds that modulate PK signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds which modulate RTK, CTK and/or STK mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including, but not limited to, carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melonoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreatic cancers, colon cancers, blood cancers, breast cancers, prostrate cancers, renal cell carcinomas, lung cancer and bone cancers.
Further examples, without limitation, of the types of disorders related to inappropriate PK activity that the compounds described herein may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders and metabolic disorders.
As previously mentioned, the Insulin-like Growth Factor-1 Receptor (IGF-IR) belongs to the family of transmembrane tyrosine kinase receptors such as platelet-derived growth factor receptor, the epidermal growth factor receptor, and the insulin receptor. There are two known ligands for the IGF-IR receptor. They are IGF-1 and IGF-2. As used herein, the term "IGF" refers to both IGF-1 and IGF-2. The insulin-like growth factor family of ligands, receptors and binding proteins is reviewed in Krywicki and Yee, Breast Cancer Research and Treatment, 22:7-19, 1992. IGF/IGF-1R driven disorders are characterized by inappropriate or over-activity of IGF/IGF-1R. Inappropriate IGF activity refers to either: (1) IGF or IGF-IR expression in cells which normally do not express IGF or IGF-IR; (2) increased IGF or IGF-IR expression leading to unwanted cell proliferation such as cancer; (3) increased IGF or IGF-IR activity leading to unwanted cell proliferation, such as cancer; and/or over-activity of IGF or IGF-IR. Over-activity of IGF or IGF- IR refers to either an amplification of the gene encoding IGF-1, IGF-2, IGF-IR or the production of a level of IGF activity which can be conelated with a cell proliferative disorder (i.e., as the level of IGF increases the severity of one or more of the symptoms of the cell proliferative disorder increases) the bioavailability of IGF-1 and IGF-2 can also be affected by the presence or absence of a set of IGF binding presence or absence of a set of IGF binding proteins (IGF BPs) of which there are six know. Over activity of IGF/IGF-1R can also result from a down regulation of IGF-2 which contains an IGF-2 binding domain, but no intracellular kinase domain. Examples of IGF/IGF-1R driven disorders include the various IGF/IGF-1R related human malignancies reviewed in Cullen, et al, Cancer Investigation, 9(4):443-454, 1991, incoφorated herein by reference in its entirety, including any drawings. IGF/IGF- IRs clinical importance and role in regulating osteoblast function is reviewed in Schmid, ournal of Internal Medicine, 234:535-542, 1993.
Thus, IGF-IR activities include: (1) phosphorylation of IGF-IR protein; (2) phosphorylation of an IGF-IR protein substrate; (3) interaction with an IGF adapter protein; (4) IGF-IR protein surface expression. Additional IGF-IR protein activities can be identified using standard techniques. IGF-IR activity can be assayed by measuring one or more of the following activities: (1) phosphorylation of IGF-IR; (2) phosphorylation of an IGF-IR substrate; (3) activation of an IGF-IR adapter molecule; and (4) activation of downstream signaling molecules, and/or (5) increased cell division. These activities can be measured using techniques described below and known in the arts.
IGF-IR has been implicated as an absolute requirement for the establishment and maintenance of the transformed phenotype both in vitro and in vivo in several cell types (R. Baserga, Cancer Research 55:249-252, 1995). Herbimycin A has been said to inhibit the IGF-IR protein tyrosine kinase and cellular proliferation in human breast cancer cells (Sepp-Lorenzino, et al., 1994, J. Cell Biochem. Suppl. 18b: 246). Experiments studying the role of IGF-IR in transformation have used antisense strategies, dominant negative mutants, and antibodies to the IGF-IR and have led to the suggestion that IGR-1R may be a prefened target for therapeutic interventions.
IGF-IR, in addition to being implicated in nutritional support and in type-π diabetes, has also been associated with several types of cancers. For example, IGF-1 has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteago et al., J. Clin. Invest., 1989, 84:1418-1423) and small lung tumor cells (Macauley et al., Cancer Res., 1989, 50:2511-2517). In addition, IGF-1, while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg-Nordqvist et al., Cancer Res., 1993, 53:2475-2478. An example of IGF-2' s protential involvement in colorectal cancer may be found in the up-regulation of IGF-2 mRNA in colon tumors relative to normal color tissue. (Zhang et al., Science (1997) 276:1268-1272.) IGF-2 may also play a role in hypoxia induced neovascularization of tumors. (Minet et al., Int. J. Mol. Med. (2000) 5:253-259.) IGF-2 may also play a role in tumorigenesis through activation of an insulin receptor isoform-A. IGF-2 activation of insulin receptor isoform-A activates cell survival signaling pathways in cells but its relative contribution to tumor cell growth and survival is unknown at this time. Insulin receptor isoform-A's kinase domain is identical to the standard insulin receptor's. Scalia et al., 2001, J. Cell Biochem. 82:610-618.
The importance of IGF-IR and its ligands in cell types in culture (fibroblasts, epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)) is illustrated by the ability of IGF-1 to stimulate cell growth and proliferation. Goldring and Goldring, Eukaryotic Gene Expression, 1991, 1:301-326. In a series of recent publications, Baserga and others suggests that IGF-IR plays a central role in the mechanism of transformation and, as such, could be a prefened target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, Cancer Res., 1995, 55:249- 252; Baserga, Cell, 1994, 79:927-930; Coppola et al., Mol. Cell. Biol., 1994, 14:4588-4595; Baserga, Trends in Biotechnology, 1996, 14: 150-152; H.M.
Khandwala et al., Endocrine Reviews, 21 :215-244, 2000. The predominant cancers that may be treated using a compound of the instant invention include, but are not limited to breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma, or endometrial carcinoma. IGF-1 has also been associated with retinal neovascularization.
Proliferative diabetes retinopathy has been seen in some patients having high levels of IGF-1. (L.E. Smith et al., Nature Medicine, 1999, 5:1390-1395.)
Compounds of the instant invention may also be useful as anti-aging agents. It has been observed that there is a link between IGF signalling and aging. Experiments have shown that calorie-restricted mammals have low levels of insulin and IGF-1 and have a longer life span. Similar observations have been made for insects as well. (See C. Kenyon, Cell, 2001, 105:165-168; E. Strauss, Science, 2001, 292:41-43; K.D. Kimura et al., Science 1997, 277:942-946; M. Tatar et al., Science, 2001, 292:107-110). STKs have been implicated in many types of cancer including, notably, breast cancer (Cance et al., Int. J. Cancer, 1993, 54:571-77).
The association between abnormal PK activity and disease is not restricted to cancer. For example, RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, epidermal hypeφroliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas. For example, EGFR has been indicated in comeal and dermal wound healing. Defects in Insulin-R and IGF-IR are indicated in type-II diabetes mellitus. A more complete conelation between specific RTKs and their therapeutic indications is set forth in Plowman et al., DN&P, 1994, 7:334-339.
As noted previously, not only RTKs but CTKs including, but not limited to, src, abl, fps, yes, fyn, lyn, lck, Zap70, blk, hck, fgr and yrk (reviewed by Bolen et al., FASEB J., 1993, 6:3403-3409) are involved in the proliferative and metabolic signal transduction pathway and thus could be expected, and have been shown, to be involved in may PTK-mediated disorders to which the present invention is directed. For example, mutated src (v-src) has been shown to be an oncoprotein (pp60v"src) in chicken. Moreover, its cellular homolog, the protooncogene ρp60c-src transmits oncogenic signals of many receptors. Over-expression of EGFR or HER2/neu in tumors leads to the constitutive activation of pp60c-src, which is characteristic of malignant cells, but absent in normal cells. On the other hand, mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders.
Similarly, Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders. STKs have been associated with inflammation, autoimmune disease, immunoresponses, and hypeφroliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.
PKs have also been implicated in embryo implantation. Thus, the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents.
Finally, both RTKs and CTKs are cunently suspected as being involved in hyperimmune disorders.
These and other aspects of the invention will be apparent from the teachings contained herein.
A method for identifying a chemical compound that modulates the catalytic activity of one or more of the above discussed protein kinases is another aspect of this invention. The method involved contacting cells expressing the desired protein kinase with a compound of this invention (or its salt or prodrug) and monitoring the cells for any effect that the compound has on them. The effect may be any observable, either to the naked eye or through the use of instrumentation, change or absence of change in a cell phenotype. The change or absence of change in the cell phenotype monitored may be, for example, without limitation, a change or absence of change in the catalytic activity of the protein kinase in the cells or a change or absence of change in the interaction of the protein kinase with a natural binding partner.
COMPOSITION
Pharmaceutical compositions of the above compounds are a further aspect of this invention. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's bloodstream by local bolus injection.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pynolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absoφtion in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
The compounds of the instant invention may also be co-administered with other well-known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, in the case of bone-related disorders, combinations that would be useful include those with antiresoφtive bisphosphonates, such as alendronate and risedronate; integrin blockers (defined further below), such as αvβ3 antagonists; conjugated estrogens used in hormone replacement therapy, such as PREMPRO®, PREMARIN® and ENDOMETRION®; selective estrogen receptor modulators (SERMs), such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene; cathespin K inhibitors; and ATP proton pump inhibitors.
The instant compounds are also useful in combination with known anti-cancer agents. Such known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG- CoA reductase inhibitors, HTV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors. The instant compounds are particularly useful when coadminsitered with radiation therapy. The synergistic effects of inhibiting VEGF in combination with radiation therapy have been described in the art. (see WO 00/61186.)
"Estrogen receptor modulators" refers to compounds, which interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l- oxopropoxy-4-methyl-2-[4-[2-(l-piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]- phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl- hydrazone, and SH646.
"Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
"Retinoid receptor modulators" refers to compounds, which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N-(4'- hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
"Cytotoxic agents" refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
Examples of cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, doxorubicin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl- pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis- mu-(hexane-l,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro) platinum (II)]tetrachloride, diarizidinylspermine, arsenic trioxide, l-(ll-dodecylamino-10- hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3 ' -deamino-3 ' -moφholino- 13-deoxo- 10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, and 4-demethoxy-3-deamino-3-aziridinyl-4- methylsulphonyl-daunorubicin (see WO 00/50032).
Examples of microtubulin inhibitors include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L- valyl-L-prolyl-L-proline-t-butylamide, TDX258, and BMS 188797.
Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene- chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-lH,12H- benzo[de]pyrano[3 ' ,4' :b,7]indolizino[ 1 ,2b]quinoline- 10, 13(9H, 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'- dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy- 5,6-dimethyl-6H-pyrido[4,3-b]carbazole-l-carboxamide, asulacrine, (5a, 5aB,
8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5- dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3',4':6,7)naphtho(2,3-d)-l,3-dioxol- 6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]- phenanthridinium, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione, 5- (3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H- pyrazolo[4,5,l-de]acridin-6-one, N-[l-[2(diethylamino)ethylamino]-7-methoxy-9- oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4- carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,l-c] quinolin-7-one, and dimesna. "Antiproliferative agents" includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'- deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno- heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo- 4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][l,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L- glutamic acid, aminopterin, 5-flurouracil, alanosine, ll-acetyl-8-
(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-l,ll-diazatetracyclo(7.4.1.0.0)- tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-l-B-D-arabino furanosyl cytosine, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. "Antiproliferative agents" also includes monoclonal antibodies to growth factors, other than those listed under "angiogenesis inhibitors", such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Patent No. 6,069,134, for example).
"HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase. Compounds which have inhibitory activity for HMG- CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. The terms "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" have the same meaning when used herein. Examples of HMG-CoA reductase inhibitors that may be used include, but are not limited to, lovastatin (MEVACOR®, see U.S. Patent Nos. 4,231,938,
4,294,926 and 4,319,039); simvastatin (ZOCOR®, see U.S. Patent Nos. 4,444,784,
4,820,850 and 4,916,239); pravastatin (PRAVACHOL®, see U.S. Patent Nos.
4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589); fluvastatin (LESCOL®, see U.S. Patent Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853,
5,290,946 and 5,356,896); atorvastatin (LIPITOR®, see U.S. Patent Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952); and cerivastatin (also known as rivastatin and
BAYCHOL®, see US Patent No. 5,177,080). The structural formulae of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention. An illustration of the lactone portion and its conesponding open-acid form is shown below as structures I and π.
Figure imgf000070_0001
Lactone Open-Acid
I II
In HMG-CoA reductase inhibitors where an open-acid form can exist, salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein. Preferably, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin. Herein, the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non- toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyπolidine-l '-yl-methylbenz- imidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane. Further examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, 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, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.
Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
"Prenyl-protein transferase inhibitor" refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-IJ (GGPTase-II, also called Rab GGPTase). Examples of prenyl-protein transferase inhibiting compounds include (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl) methyl]-4-(3- chlorophenyl)- 1 -methyl-2( lH)-quinolinone, (-)-6- [amino(4-chlorophenyl)( 1 -methyl - lΗ-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(lH)-quinolinone, (+)-6- [amino(4-chlorophenyl)(l-methyl-lΗ-imidazol-5-yl) methyl]-4-(3-chlorophenyl)-l- methyl-2(lH)-quinolinone, 5(S)-n-butyl-l-(2,3-dimethylphenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, (S)-l-
(3-chlorophenyl) -4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl) methyl)-2-piperazinone, 5(S)-n-Butyl-l-(2-methylphenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl]-2-piperazinone, l-(3-chlorophenyl) -4-[l-(4-cyanobenzyl)-2- methyl-5-imidazolylmethyl]-2-piperazinone, l-(2,2-diphenylethyl)-3-[N-(l-(4- cyanobenzyl)-lΗ-imidazol-5-ylethyl)carbamoyl]piperidine, 4-{5-[4-hydroxymethyl-4- (4-chloropyridin-2-ylmethyl)-piperidine- 1 -ylmethyl] -2-methylimidazol- 1 -ylmethyl } benzonitrile, 4-{5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-l-ylmethyl]-2- meth ylimidazol-1 -ylmethyl} benzonitrile, 4-{3-[4-(2-oxo-2H-pyridin-l-yl)benzyl]-3H- imidazol-4-ylmethyl}benzonitrile, 4-{3-[4-(5-chloro-2-oxo-2H-[l,2']bipyridin-5'- ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile, 4-{3-[4-(2-oxo-2H-[l,2']bipyridin- 5'-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile, 4-[3-(2-oxo-l-phenyl-l,2- dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl}benzonitrile, 18,19-dihydro-19- oxo-5H,17H-6,10:12,16-dimetheno-lH-imidazo[4,3-c][l,ll,4]dioxaazacyclo - nonadecine-9-carbonitrile, (±)-19,20-dihydro-19-oxo-5H-18,21-ethano-12,14-etheno- 6,10-metheno-22H-benzo[-i]imidazo[4,3- :][l,6,9,12]oxatriaza-cyclooctadecine-9- carbonitrile, 19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6,10:12,16-dimetheno- 22H-imidazo[3,4- ι][l,8,l l,14]oxatriazacycloeicosine-9-carbonitrile, and (±)-19,20- dihydro-3-methyl- 19-oxo-5H- 18,21 -ethano- 12,14-etheno-6, 10-metheno-22H-benzo [d]imidazo[4,3-fc][l,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.
Other examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent No. 5,420,245, U.S. Patent No. 5,523,430, U.S. Patent No. 5,532,359, U.S. Patent No. 5,510,510, U.S. Patent No. 5,589,485, U.S. Patent No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Patent No. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535,
WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Patent No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S. Patent No. 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No. 9, pp.1394-1401 (1999).
Examples of FflN protease inhibitors include amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632. Examples of reverse transcriptase inhibitors include delaviridine, efavirenz, GS-840, ΗB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl. "Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR20), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-α, interleukin- 12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti- inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy- genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p.573 (1990); Anat. Rec, Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)- fumagillol, thalidomide, angiostatin, troponin-1, angiotensin π antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF. (see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186). As described above, the combinations with NSAID's are directed to the use of NSAID's which are potent COX-2 inhibiting agents. For puφoses of this specification an NSAID is potent if it possess an IC50 for the inhibition of COX-2 of lμM or less as measured by the cell or microsomal assay disclosed herein.
The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For puφoses of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by the cell or microsomal assay disclosed hereinunder. Such compounds include, but are not limited to those disclosed in U.S. 5,474,995, issued December 12, 1995, U.S. 5,861,419, issued January 19, 1999, U.S. 6,001,843, issued December 14, 1999, U.S. 6,020,343, issued February 1, 2000, U.S. 5,409,944, issued April 25, 1995, U.S. 5,436,265, issued July 25, 1995, U.S. 5,536,752, issued July 16, 1996, U.S. 5,550,142, issued August 27, 1996, U.S. 5,604,260, issued February 18, 1997, U.S. 5,698,584, issued December 16, 1997, U.S. 5,710,140, issued January 20,1998, WO 94/15932, published July 21, 1994, U.S. 5,344,991, issued June 6, 1994, U.S. 5,134,142, issued July 28, 1992, U.S. 5,380,738, issued January 10, 1995, U.S. 5,393,790, issued February 20, 1995, U.S. 5,466,823, issued November 14, 1995, U.S. 5,633,272, issued May 27, 1997, and U.S. 5,932,598, issued August 3, 1999, all of which are hereby incoφorated by reference.
Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and
Figure imgf000074_0001
5-chloro-3-(4-methylsulfony])phenyl-2-(2-methyl-5-pyridinyl)pyridine;
Figure imgf000074_0002
or a pharmaceutically acceptable salt thereof.
General and specific synthetic procedures for the preparation of the COX-2 inhibitor compounds described above are found in U.S. Patent No. 5,474,995, issued December 12, 1995, U.S. Patent No. 5,861,419, issued January 19, 1999, and U.S. Patent No. 6,001,843, issued December 14, 1999, all of which are herein incoφorated by reference.
Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to, the following:
Figure imgf000075_0001
or a pharmaceutically acceptable salt thereof. Compounds, which are described as specific inhibitors of COX-2 and are therefore useful in the present invention, and methods of synthesis thereof, can be found in the following patents, pending applications and publications, which are herein incoφorated by reference: WO 94/15932, published July 21, 1994, U.S. Patent No. 5,344,991, issued June 6, 1994, U.S. Patent No. 5,134,142, issued July 28, 1992, U.S. Patent No. 5,380,738, issued January 10, 1995, U.S. Patent No. 5,393,790, issued February 20, 1995, U.S. Patent No. 5,466,823, issued November 14, 1995, U.S. Patent No. 5,633,272, issued May 27, 1997, and U.S. Patent No. 5,932,598, issued August 3, 1999. Compounds which are specific inhibitors of COX-2 and are therefore useful in the present invention, and methods of synthesis thereof, can be found in the following patents, pending applications and publications, which are herein incoφorated by reference: U.S. Patent No. 5,474,995 issued December 12, 1995, U.S. Patent No. 5,861,419 issued January 19, 1999, U.S. Patent No. 6,001,843 issued December 14, 1999, U.S. Patent No. 6,020,343 issued February 1, 2000, U.S. Patent No. 5,409,944 issued April 25, 1995, U.S. Patent No. 5,436,265 issued July 25, 1995, U.S. Patent No. 5,536,752 issued July 16, 1996, U.S. Patent No. 5,550,142 issued August 27, 1996, U.S. Patent No. 5,604,260 issued February 18, 1997, U.S. Patent No. 5,698,584 issued December 16, 1997, and U.S. Patent No. 5,710,140 issued January 20,1998.
Other examples of angiogenesis inhibitors include, but are not limited to, endostation, ukrain, ranpirnase, EM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2- butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-lH-l,2,3-triazole-4- carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pynolocarbonyl- imino[N-methyl-4,2-pynole]-carbonylimino]-bis-(l,3-naphthalene disulfonate), and 3-[(2,4-dimethylpynol-5-yl)methylene]-2-indolinone (SU5416).
As used above, "integrin Mockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the αvβ3 integrin and the 0Cγβ5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the αvββ, αvβs, cqβi, ct2βl, ocsβl, αββi and 0C6β4 integrins. The term also refers to antagonists of any combination of αvβ3, αvβ5, αvβό, ocvβs, cqβi, 0C2βl, α5βl, oc^βl and c<6β4 integrins.
Some specific examples of tyrosine kinase inhibitors include N- (trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpynol-5- yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3- chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-moφholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro- 10-(hydroxymethyl)- 10-hydroxy-9-methyl-9, 12-epoxy- 1 H- diindolo[l,2,3-fg:3',2',l'-kl]pynolo[3,4-i][l,6]benzodiazocin-l-one, SH268, genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyπolo[2,3- d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7- dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-l-phthalazinamine, and EMD121974.
The instant compounds are also useful, alone or in combination with platelet fibrinogen receptor (GP Ilb/lTia) antagonists, such as tirofiban, to inhibit metastasis of cancerous cells. Tumor cells can activate platelets largely via thrombin generation. This activation is associated with the release of VEGF. The release of VEGF enhances metastasis by increasing extravasation at points of adhesion to vascular endothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, the present compounds can serve to inhibit metastasis, alone or in combination with GP Ilb/lTia) antagonists. Examples of other fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352. FORMULATIONS
The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and/or topical routes of administration. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
For oral use of a compound according to this invention, particularly for chemotherapy ,the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pynolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant. The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
The injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this puφose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Compounds of Formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For puφoses of this application, topical application shall include mouth washes and gargles.)
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. Additionally, the compounds of the instant invention may be administered to a mammal in need thereof using a gel extrusion mechanism (GEM) device, such as that described in U.S. Patent No. 4,976,697, filed on December 11, 1990, which is hereby incoφorated by reference. When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
The compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. These schemes, therefore, are not limited by the compounds listed nor by any particular substituents employed for illustrative puφoses. Substituent numbering, as shown in the schemes, does not necessarily conelate to that used in the claims. Scheme 1 details the synthesis of pynole 1 The illustrated synthesis of the required beta-ketoester intermediate utilizes the method of Yonemitsu, et al. (JOC (1978) Vol. 43, 2087-2088)
Scheme 2 illustrates the synthesis of pynoles 4 and 5 using the intermediate pynole 3. In the schemes below:
— \— (CH2)p — v — (R1) Rv represents ^ , as described in Formula I; andRz represents OR7, N(R7)2, NΗR70R7, NH(CRb2)qR7, NHR7NHC(O)R7, NΗR7S(0)20R7, or NH(CRb2)qC(O)N(R7)2 as described in Formula I. SCHEME 1
Figure imgf000083_0001
Figure imgf000083_0002
SCHEME 2
Figure imgf000084_0001
EXAMPLES
Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limiting of the reasonable scope thereof.
EXAMPLE 1
2-tert-butyl 4-ethyl 3-benzyl-5-{ [(4-chlorophenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate Step A: 5-(l-hvdroxy-2-phenylethylidene)-2.2-dimethyl-L3-dioxane-4.6-dione
A solution of Meldrum's acid (10 g, 69.4 mmol) in CH2CI2 (170 mL) was cooled to 0°C. Pyridine (11.2 ml, 138.8 mmmol) and phenylacetyl chloride (10.1 mL, 76.3 mmol) were added via syringe. The resulting solution was stined at 0°C for 1 hour, then warmed to room temperature and stined for 1 hour. The reaction was diluted with CH2CI2 and washed with aq HCl (15 mL cone HCl in 200 mL water, 1 x) and water (1 x). The organic solution was dried over Na2SO4 and concentrated to give a dark red solid.
Step B: tert-butyl 3-oxo-4-phenylbutanoate
A solution of 5-(l-hydroxy-2-phenylethylidene)-2,2-dimethyl-l,3- dioxane-4,6-dione (18.2 g, 69.4 mmol), t-BuOH (19.9 ml, 208 mmol) and benzene (400 ml) was heated at reflux for 6 hours. Concentration in vacuo gave a red liquid.
Step C: 2-tert-butyl 4-ethyl 3-benzyl-5-methyl-lH-pynole-2,4-dicarboxylate
To a 14°C solution of tert-butyl 3-oxo-4-phenylbutanoate (69.4 mmol) in AcOH (44 mL) was added NaNO2 (4.55 g, 65.9 mmol) in 12 mL H2O via cannula. The rate of addition was controlled such that the temperature was maintained below 0°C. The resulting orange brown solution was stined at room temperature overnight, then added via cannula to a mixture of ethyl 3-oxobutanoate (9.7 ml, 76.3 mmol), NH4OAC (13.4 g, 173.5 mmol), and Zn (14.1 g, 215.1 mmol) in 26 mL of AcOH. The rate of addition was controlled such that the temperature was maintained between 55 and 70°C. The resulting suspension was stined overnight. 150 mL of ice water was added, and the suspension was filtered. The solids were rinsed thoroughly with CH2CI2, then the aqueous solution was separated and washed once with CH2C12- The combined organic solutions were washed with saturated aqueous sodium bicarbonate (2 x), then dried over Na2SO4 and concentrated. Purification by flash chromatography gave a white solid. Step D: 2-tert-butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate
To a solution of 2-tert-butyl 4-ethyl 3-benzyl-5-methyl-lH-pynole-2,4- dicarboxylate (2.75 mmol) in THF (32 mL), AcOH (40 mL), and H2O (32 mL) was added CAN in one portion. The reaction was stined at room temperature for 4 hours, then poured into water (500 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic solutions were washed with saturated aqueous sodium bicarbonate (1 x 200 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography gave a white solid.
Step E: 2-tert-butyl 4-ethyl 3-benzyl-5-{ [(4-chlorophenyl)amino]methyl}-lH- pynole-2,4-dicarboxylate
To a solution of 2-tert-butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4- dicarboxylate (0.23 mmol) and 4-chloroaniline in dichloroethane (2 mL) was added Na(OAc)3BH (68 mg, 0.32 mmol). The reaction was stined overnight, then 1 ml of MeOH was added, and the mixture was concentrated in vacuo. The residue was taken up in acetonitrile, filtered, and purified by reverse phase HPLC to give a pale yellow solid. HRMS (ES) exact mass calcd for C26H29CIN2O4 (M+H* : 469.1889. Found 469.1859.
EXAMPLE 2
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-py oxopynolidin-2-yl)methyl1methanaminium trifluoroacetate
Step A: 5-( 1 -hydroxypropylidene)-2.2-dimethyl- 1 ,3-dioxane-4,6-dione
Following the procedures described in Example 1, Step A, but using propanoyl chloride in place of phenylacetyl chloride, the titled compound was obtained. Step B: tert-butyl 3-oxopentanoate
Following the procedures described in Example 1, Step B, but using 5- (l-hydroxypropylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione in place of 5-(l-hydroxy- 2-phenylethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione, the titled compound was obtained.
Step C: 2-tert-butyl 4-ethyl 3-ethyl-5-methyl-lH-pynole-2,4-dicarboxylate
Following the procedures described in Example 1, Step C, but using tert-butyl 3-oxopentanoate in place of tert-butyl 3-oxo-4-phenylbutanoate, the titled compound was obtained.
Step D: 2-tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate
Following the procedures described in Example 1, Step D, but using 2- tert-butyl 4-ethyl 3-ethyl-5-methyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-methyl-lH-pyπole-2,4-dicarboxylate, the titled compound was obtained.
Step E: [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyπol-2-yl]-
N-[(5-oxopynolidin-2-yl)methyl]methanaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 5-(aminomethyl) pynolidin-2-one in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C20H31N3O5 (M+H*): 394.2355. Found 394.2355.
EXAMPLE 3
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(lH-indol-2- ylmethvPmethanaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2-tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and l-(lH-indol-2-yl) methanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H3χN3θ4 (M+Ff): 426.2308. Found 426.2388.
EXAMPLE 4
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyπ dichlorobenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using
2-tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3,4-dichloroaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C21H26CI2 2O4 (M+HT): 441.1343. Found 441.1344.
EXAMPLE 5
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-py methylbenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and 4-methylphenyl- amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H30N2O4 (M+H+): 387.2279. Found 387.2274.
EXAMPLE 6
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- hydroxybenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2-tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-aminophenol in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C21H28N2O5 (M+H+): 389.2071. Found 389.2070.
EXAMPLE 7
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- methoxybenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-methoxyaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H30N2O6 (M+H+): 403.2228. Found 403.2221.
EXAMPLE 8
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- chloro-N-methylbenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-chloro-N- methylaniline in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C22H29CIN2O4 (M+H* : 421.1889. Found 421.1895.
EXAMPLE 9
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-6-methylρyridinium bis(trifluoroacetate) Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (6-methylpyridin- 2-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C22H31N3O4 (M+H ): 402.2388. Found 402.2386.
EXAMPLE 10
3-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ammonio)methvn-5-cyclopropyl-lH-pyrazol-l-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-foπnyl-lH-pyπole-2,4-dicarboxylate and (5-cyclopropyl-lH- pyrazol-3-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H32N4O4 (M+H+): 417.2497. Found 417.2481.
EXAMPLE 11
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(3,5- dimethyl-lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (3,5-dimethyl-lH- pyrazol-4-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C21H32N4O4 (M+H+): 405.2497. Found 405.2517. EXAMPLE 12
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(5-phenyl-
1 ,3.4-oxadiazol-2-yl)methyl]methanaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and (5-phenyl-l,3,4- oxadiazol-2-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H30N4O5 (M+H*): 455.2289. Found 455.2293.
EXAMPLE 13
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyll-lH-imidazol-l-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-(lH-imidazol-2- yl)methanamine in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C 9H28N4O4 (M+H+): 377.2184. Found 377.2170.
EXAMPLE 14
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl1-3-methyl-4H-1.2,4-triazole- 4-diium tris(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (5-methyl-4H- l,2,4-triazol-3-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C19H29N5O4 (M+H+): 392.2293. Found 392.2292.
EXAMPLE 15
6-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl1-2-methylimidazo[2.1-b1[ 31thiazol-7-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (2-methylimidazo [2,l-b][l,3]thiazol-6-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H3θN4θ4S (M+H*): 447.2061. Found 447.2058.
EXAMPLE 16
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-4-methyl-lH-imidazol-3-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (4-methyl- 1H- imidazol-2-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2oH3θN4θ4 (M+lT): 391.2340. Found 391.2332.
EXAMPLE 17
2-[({[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl1-l-methyl-lH-imidazol-3-ium bis(trifluoroacetate) Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (1-methyl-lH- imidazol-2-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2oH3θN4θ4 (M+H+): 391.2340. Found 391.2329.
EXAMPLE 18
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(5-oxo-4,5- dihydro-lH-l,2,4-triazol-3-yl)methyl1methanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 5-(aminomethyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for CιsH27N5θ5 (M+BT): 394.2085. Found 394.2074.
EXAMPLE 19
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl1-lH- 2,4-triazol-l-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 1-(1H-1,2,4- triazol-5-yl)methanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C18HZ7N5O4 (M-rirT): 378.2136. Found 378.2132. EXAMPLE 20
6-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl1imidazo[2,l-biri.31thiazol-4-ium bis(trifluoroacetate) Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 6-(aminomethyl) imidazo[2,l-b][l,3]thiazol-4-ium in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2 H28N4θ4S (M+H+): 433.1904. Found 433.1879.
EXAMPLE 21
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-5-chloro-3H-benzimidazol-l-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and (6-chloro-lH- benzimidazol-2-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H29ClN4θ4 (M+H*): 461.1950. Found 461.1945.
EXAMPLE 22
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(4-oxo-3,4- dihvdrophthalazin-l-yl)methvHmethanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-(aminomethyl) phthalazin-l(2H)-one in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for 4H30N4O5 (M+H+): 455.2289. Found 455.2286.
EXAMPLE 23
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(lH-indol-6- ylmethyQmethanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-(lH-indol-ό-yl) methanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H31N3O4 (M+H -): 426.2388. Found 426.2365.
EXAMPLE 24
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(4-methyl-
1.S-thiazol-Σ-vDmethyllmethanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (4-methyl- 1,3- thiazol-2-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2oH29N3θ4S (M+H+): 408.1952. Found 408.1968.
EXAMPLE 25
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methvn-8-methylimidazorL2-a1pyridin-4-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (8-methylimidazo [l,2-a]pyridin-2-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H32N4O4 (M+H+): 441.2497. Found 441.2466.
EXAMPLE 26
2-[({[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl 1 -3H-benzimidazol- 1 -ium bis(trifluoroacetate) Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 1-(1H- benzimidazol-2-yl)methanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for Q3H30N4O4 (M+H+): 427.2340. Found 427.2332.
EXAMPLE 27
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- methylbenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3-methylphenyl- amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H3oN2O4 (M+H+): 387.2279. Found 387.2275.
EXAMPLE 28
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-4- isopropylbenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-isopropylaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C 4H34N2O4 (M+i ): 415.2592. Found 415.2589.
EXAMPLE 29
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- ethylbenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and 4-ethylaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H32N2O4 (M+lT): 401.2435. Found 401.2479.
EXAMPLE 30
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3,5- dimethylbenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3,5-dimethylaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for 3H32N2O4 (M+H*): 401.2435. Found 401.2444.
EXAMPLE 31
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3,4- dimethoxybenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3,4- dimethoxyaniline in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C23H32N2O6 (M+Ff): 433.2333. Found 433.2335.
EXAMPLE 32
2-[2-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ammonio)ethvHpyridinium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 2-pyridin-2- ylethanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H31N3O4 (M+H+): 402.2388. Found 402.2412.
EXAMPLE 33
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(l-methyl- lH-pyrazol-4-yl)methyl]methan aminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (1-methyl-lH- pyrazol-4-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C20H30N4O4 (M+H+): 391.2340. Found 391.2353. EXAMPLE 34
N-{[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- ethoxybenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-ethoxyaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H32N2O5 (M+H+): 417.2384. Found 417.2385.
EXAMPLE 35
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3,4- dimethylbenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and 3,4-dimethylaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H32N2O4 (M+lT): 401.2435. Found 401.2431.
EXAMPLE 36
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-l,3- benzodioxol-5-aminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l,3-benzodioxol-5- amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2 H28N2θ6 (M+H+): 417.2020. Found 417.2022. EXAMPLE 37
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } -4- isopropoxybenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-isopro- poxyaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H34N2O5 (M+H+): 431.2541. Found 431.2549.
EXAMPLE 38
4-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-l ,3-thiazol-3-ium bis(trifluoroacetate) Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and l,3-thiazol-4- ylmethylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for CX9H27N3O4S (M+ϊ ): 394.1795. Found 394.1803.
EXAMPLE 39
5-[({[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl1-L3-thiazol-3-ium bis(trifluoroacetate) Following the procedures described in Example 1 , Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l,3-thiazol-5- ylmethylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for CX9H27N3O4S (M+H*): 394.1795. Found 394.1803. EXAMPLE 40
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-l ,3-thiazol-3-ium bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l,3-thiazol-2- ylmethylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C19H27N3O4S (M+H+): 394.1795. Found 394.1803.
EXAMPLE 41
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(isoxazol-5- ylmethvDmethanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-isoxazol-5- ylmethanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for CX9H27N3O5 (M+H+): 378.2024. Found 378.2019.
EXAMPLE 42
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(l,5- dimethyl- lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (1,5-dimethyl-lH- pyrazol-4-yl)methylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C21H32N4O4 (M+H+): 405.2497. Found 405.2487.
EXAMPLE 43
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- tert-butylbenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-tert-butylaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H36N2O4 (M+H+): 429.2748. Found 429.2749.
EXAMPLE 44
2-tert-butyl 4-ethyl 5-({ [4-(dimethylamino)phenyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate bis(trifluoroacetate)
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and N,N- dimethylbenzene-l,4-diamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H33N3O4 (M+H+): 416.2544. Found 416.2553.
EXAMPLE 45
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } -2- methylbenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2;4-dicarboxylate and 2- methylphenylamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H3θN2θ4 (M+H*): 387.2279. Found 387.2282.
EXAMPLE 46
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-2- methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 2-methoxyaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H3oN2O5 (M+H*): 403.2228. Found 403.2226.
EXAMPLE 47
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-4- propylbenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-propylaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C 4H34N2O4 (M+H4): 415.2592. Found 415.2600. EXAMPLE 48
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyπol-2-yl]methyl } -2,5- dimethoxybenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and 2,5-dimethoxy- aniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H32N2O6 (M+H4): 433.2333. Found 433.2346.
EXAMPLE 49
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pyπol-2-yl]m butylbenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and 4-butylaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H36N2O4 (M+H+): 429.2748. Found 429.2725.
EXAMPLE 50
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- hydroxy-4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 5-amino-2- methoxyphenol in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C22H30N2O6 (M+H1-): 419.2177. Found 419.2183. EXAMPLE 51
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyπol-2-yl]methyl } - 1H- indol-4-aminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and lH-indol-4-amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H29N3O4 (M+H+): 412.2231. Found 412.2233.
EXAMPLE 52
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } - 1H- indol-6-aminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and lH-indol-6-amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H29N3O4 (M+H4): 412.2231. Found 412.2219.
EXAMPLE 53
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- methoxypropan-1 -aminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3-methoxypropan- 1-amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C 9H32N2O5 (M+H4): 369.2384. Found 369.2367. EXAMPLE 54
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } ethanaminium trifluoroacetatetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and ethanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for Cχ7H28N2θ4 (M+H4): 325.2122. Found 325.2098.
EXAMPLE 55
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} butan-1 -aminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and butan-1 -amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C19H32N2O4 (M+H4): 353.2435. Found 353.2416.
EXAMPLE 56
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- methoxybenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3-methoxyaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H30N2O5 (M+H4): 403.2228. Found 403.2265. EXAMPLE 57
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- carboxypropan-1 -aminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-aminobutanoic acid in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for CX9H30N2O6 (M+H4): 383.2177. Found 383.2181.
EXAMPLE 58
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N- methylmethanaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and methanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C 6H26 2O4 (M+H4): 311.1966. Found 311.1964.
EXAMPLE 59
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethy methylpropan-1 -aminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 2-methylpropan-l- amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C19H32N2O4 (M+H4): 353.2435. Found 353.2452. EXAMPLE 60
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } pentan-1 -aminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and pentan-1 -amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2θH34N2θ4 (M+H4): 367.2592. Found 367.2579.
EXAMPLE 61
2-(aminosulfonyl)-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethy pynol-2-yllmethyl }ethanaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and pentan-1 -amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for Cχ7H 9N3θ6S (M+H4): 404.1850. Found 404.1841.
EXAMPLE 62
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(lH-pynol-2- ylmethyPmethanaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-(lH-pynol-2- yl)methanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C oH29N3θ4 (M+H4): 376.2231. Found 376.2234. EXAMPLE 63
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- chlorobenzenaminium chloride
Following the procedures described in Example 1 , Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate, the titled compound was obtained. HRMS (ES) exact mass calcd for C2lH 7ClN2O4 (M+H4): 407.1732. Found 407.1729.
EXAMPLE 64
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- chlorobenzenaminium chloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3-chloroaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C χH27ClN2θ4 (M+H4): 407.1732. Found 407.1729.
EXAMPLE 65
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-2- chlorobenzenaminium chloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 2-chloroaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C χH27ClN2θ4 (M+H4): 407.1732. Found 407.1731. EXAMPLE 66
3-bromo-N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl] methyl Ibenzenaminium chloride
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3-bromoaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2lH27BrN2θ4 (M+H4): 451.1227. Found 451.1233.
EXAMPLE 67
2-bromo-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl] methyl }benzenamini urn chloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 2-bromoaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2lH27BrN2θ4 (M+H4): 451.1227. Found 451.1232.
EXAMPLE 68
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- fluorobenzenaminium chloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-fluoroaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C21H27FN2O4 (M+H4): 391.2028. Found 391.2024. EXAMPLE 69
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- fluorobenzenaminium chloride
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 3-fluoroaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C21H27FN2O4 (M+H4): 391.2028. Found 391.2031.
EXAMPLE 70
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-2- fluorobenzenaminium chloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 2-fluoroaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C21H27FN2O4 (M+H ): 391.2028. Found 391.2028.
EXAMPLE 71
3-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)pyridinium dichloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and pyridin-3 -amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C20H27N3O4 (M+H4): 374.2074. Found 374.2063. EXAMPLE 72
2-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)-5-chloropyridinium dichloride
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 5-chloropyridin-2- amine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C20H26CIN3O4 (M+H4): 408.1685. Found 408.1680.
EXAMPLE 73
4-bromo-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl] methyl Ibenzenaminium chloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-bromoaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C2lH27BrN2θ4 (M+H4): 451.1227. Found 451.1230.
EXAMPLE 74
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pynole-2,4- dicarboxylate
Step A: 5-(l-hvdroxypropylidene)-2.2-dimethyl- 3-dioxane-4,6-dione
Following the procedures described in Example 1, Step A, but using propanoyl chloride in place of phenylacetyl chloride, the titled compound was obtained.
Il l Step B: tert-butyl 3-oxopentanoate
Following the procedures described in Example 1, Step B, but using 5- (l-hydroxypropylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione in place of 5-(l-hydroxy- 2-phenylethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione, the titled compound was obtained.
Step C: 2-tert-butyl 4-methyl 3-ethyl-5-methyl-lH-pynole-2.4-dicarboxylate
Following the procedures described in Example 1, Step C, but using tert-butyl 3-oxopentanoate in place of tert-butyl 3-oxo-4-phenylbutanoate and methyl 3-oxobutanoate in place of ethyl 3-oxobutanoate, the titled compound was obtained.
Step D: 2-tert-butyl 4-methyl 3-ethyl-5-formyl- lH-pynole-2,4-dicarboxylate
Following the procedures described in Example 1, Step D, but 2-tert- butyl 4-methyl 3-ethyl-5-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4-ethyl 3-benzyl-5-methyl-lH-pyπole-2,4-dicarboxylate, the titled compound was obtained.
Step E: 2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }- lH-pynole-2,4-dicarboxylate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-methyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-methoxyaniline in place of 4-chloroaniline, the titled compound was obtained. 1H NMR (500 MHz, CDC13) δ 9.38 (br s, IH); 6.76 (d, J = 8.8 Hz, 2H); 6.56 (d, J = 8.8 Hz, 2H); 4.57 (s, 2H); 4.00 (br s, IH); 3.84 (s, 3H); 3.74 (s, 3H); 3.06 (q, J = 7.4 Hz, 2H); 1.54 (s, 9H); 1.17 (t, J = 7.3 Hz, 3H). HRMS (ES) exact mass calcd for C21H28N2O5 (M+H4): 389.2071. Found 389.2065. EXAMPLE 75
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl}-4- pentylbenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-methyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-pentylaniline in place of 4-chloroaniline, the titled compound was obtained. 1H NMR (500 MHz, CD3OD) 67.30 (d, J = 8.3 Hz, 2H); 7.17 (d, J = 8.5 Hz, 2H); 4.67 (s, 2H); 3.91 (s, 3H); 3.07 (q, J = 7.3 Hz, 2H); 2.63 (t, J = 7.7 Hz, 2H); 1.61 (m, 2H); 1.57 (s, 9H); 1.33 (m, 4H); 1.14 (t, J = 7.5 Hz, 3H); 0.90 (t, J = 7.2 Hz, 3H). HRMS (ES) exact mass calcd for C25H36N2O4 (M+H4): 429.2748. Found 429.277.
EXAMPLE 76
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl}-
1 , 1 '-biphenyl-4-aminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-methyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 1,1 -biphenyl-4- amine in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C26H30N2O4 (M+H4): 435.2279. Found 435.2274.
EXAMPLE 77
N-{[5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl}-
3.4.5-trimethoxybenzenaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-methyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-foπnyl-lH-pynole-2,4-dicarboxylate and 3,4,5- trimethoxyaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H32N2O7 (M+H4): 449.2283. Found 449.2291.
EXAMPLE 78
3-[4-({ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl} ammonio)phenyl]-5-methyl-4H-1.2.4-triazol-4-ium bis(trifluoroacetate) Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-methyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-(5-methyl-4H- l,2,4-triazol-3-yl)aniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C23H29N5O4 (M+H4): 440.2293. Found 440.2313.
EXAMPLE 79
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-{[(2R)-5- oxopynolidin-2-vHmethyl } methanaminium trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pyπole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and (5R)-5- (aminomethyl) pynolidin-2-one in place of 4-chloroaniline, the titled compound was obtained. 1H NMR (500 MHz, CD3OD) δ 4.48 (d, J = 13 Hz, 1 H); 4.41 (d, J = 13
Hz, 1 H); 4.41 (q, J = 7 Hz, 2 H); 4.07-4.04 (m, 1 H); 3.21 (m, 2 H); 3.08 (q, J = 7 Hz, 2 H); 2.45-2.34 (m, 3 H); 1.93-1.88 (m, IH); 1.59 (s, 9 H); 1.41 (t, J = 7 Hz, 3 H); 1.16 (t, J = 7 Hz, 3 H). HRMS (ES) exact mass calcd for C20H31N3O5 (M+H4): 394.2336. Found 394.2355. EXAMPLE 80
diethyl 5-{ [(4-chlorophenyl)amino1methyl }-3-methyl-lH-pynole-2,4-dicarboxylate
Step A: diethyl 5-methyl-3-phenyl-lH-pynole-2,4-dicarboxylate
Following the procedures described in Example 1, Step C, but ethyl 3- oxobutanoate in place of tert-butyl 3-oxo-4-phenylbutanoate, the titled compound was obtained.
Step B: diethyl 5-formyl-3-methyl-lH-pynole-2,4-dicarboxylate
Following the procedures described in Example 1, Step D, but diethyl 5-methyl-3-phenyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4-ethyl 3- benzyl-5-methyl-lH-pynole-2,4-dicarboxylate, the titled compound was obtained.
Step C: diethyl 5-{ [(4-chlorophenyl)amino]methyl}-3-methyl-lH-pynole-2,4- dicarboxylate
Following the procedures described in Example 1, Step E, but using diethyl 5-formyl-3-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate, the titled compound was obtained.
Elemental analysis calculated for C 8H21CIN2O4 :
C: 58.6; H: 5.78; N: 7.57 Found: C: 58.54; H: 5.42; N: 7.45
EXAMPLE 81
N-benzyl[3.5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]methanaminium chloride
Following the procedures described in Example 1, Step E, but using diethyl 5-formyl-3-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 1-phenylmethanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C19H24N2O4 (M+H4): 345.1809. Found 345.1802.
EXAMPLE 82
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]-N-(pyridin-2-ylmethyl) methanaminium chloride
Following the procedures described in Example 1, Step E, but using diethyl 5-formyl-3-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-pyridin-2- ylmethanamine in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for CX8H24CIN3O4 (M+H4): 346.1762. Found 346.1772.
EXAMPLE 83
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]-N-(2-chlorobenzyl) methanaminium chloride
Following the procedures described in Example 1, Step E, but using diethyl 5-formyl-3-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-(2-chlorophenyl) methanamine in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for C 9H23CIN2O4 (M+H4): 379.1419. Found 379.1448.
EXAMPLE 84
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]-N-(3-chlorobenzyl) methanaminium chloride
Following the procedures described in Example 1, Step E, but using diethyl 5-formyl-3-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-(3-chlorophenyl) methanamine in place of 4-chloroaniline, the titled compound was obtained.HRMS (ES) exact mass calcd for Cχ9H23ClN2θ4 (M+H4): 379.1419. Found 379.1444.
EXAMPLE 85
[3,5-bis(ethoxycarbonyl)-4-isopropyl-lH-pynol-2-yl]-N-(pyridin-2-ylmethyl) methanaminium chloride
Step A: diethyl 3-isopropyl-5-methyl-lH-pynole-2.4-dicarboxylate Following the procedures described in Example 1, Step C, but using ethyl 4-methyl-3-oxopentanoate in place of tert-butyl 3-oxo-4-phenylbutanoate, the titled compound was obtained.
Step B: diethyl 5-formyl-3-isopropyl-lH-pynole-2,4-dicarboxylate Following the procedures described in Example 1, Step D, but using diethyl 3-isopropyl-5-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-methyl-lH-pynole-2,4-dicarboxylate, the titled compound was obtained.
Step C: [3,5-bis(ethoxycarbonyl)-4-isopropyl-lH-pyπol-2-yl]-N-(pyridin-2- ylmethyDmethanaminium chloride
Following the procedures described in Example 1, Step E, but using diethyl 5-formyl-3-isopropyl-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4- ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and l-pyridin-2- ylmethanamine in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C20H27N3O4 (M+H4): 374.2075. Found 374.2088. EXAMPLE 86
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(pyridin-2- ylmethvDmethanaminium chloride Following the procedures described in Example 1, Step E, but using 2- tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pyπole-2,4-dicarboxylate and l-pyridin-2- ylmethanamine in place of 4-chloroaniline, the titled compound was obtained. 1H NMR (500 MHz, CD3OD) δ 8.71 (br d, J = 4 Hz, 1 H); 8.07 (dt, J = 8, 2 Hz, 1 H); 7.67 (d, J = 8 Hz, 1 H); 7.60 (dd, J = 7, 5 Hz, 1 H); 4.57 (s, 2H); 4.50 (s, 2H); 4.38 (q, J = 7 Hz, 2H); 3.06 (q, J = 7 Hz, 2 H); 1.59 (s, 9H); 1.40 (t, J = 7 Hz, 3H); 1.13 (t, J = 7 Hz, 3 H). HRMS (ES) exact mass calcd for C21H29N3O4 (M+H4): 388.2231. Found 388.2247.
EXAMPLE 87
N-{ [3-[(benzyloxy)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH-pynol-2-yl] methyl )-4-methoxybenzenaminium trifluoroacetate
Step A: 5-(l-hydroxypropylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione
Following the procedures described in Example 1, Step A, but using propanoyl chloride in place of phenylacetyl chloride, the titled compound was obtained.
Step B: tert-butyl 3-oxopentanoate
Following the procedures described in Example 1, Step B, but using 5- (l-hydroxypropylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione in place of 5-(l-hydroxy- 2-phenylethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione, the titled compound was obtained . Step C: 4-benzyl 2-tert-butyl 3-ethyl-5-methyl- lH-pynole-2.4-dicarboxylate
Following the procedures described in Example 1, Step C, but using tert-butyl 3-oxopentanoate in place of tert-butyl 3-oxo-4-phenylbutanoate and benzyl 3-oxobutanoate in place of ethyl 3-oxobutanoate, the titled compound was obtained.
Step D: 4-benzyl 2-tert-butyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxyIate
Following the procedures described in Example 1, Step D, but 4- benzyl 2-tert-butyl 3-ethyl-5-methyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-methyl-lH-pynole-2,4-dicarboxylate, the titled compound was obtained.
Step E: N-{ [3-[(benzyloxy)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH- pyπol-2-yl]methyl }-4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 4- benzyl-2-tert-butyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl-3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and 4-methoxyaniline in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H32N2O5 (M+H4): 465.2384. Found 465.2385.
EXAMPLE 88
N-{[5-(tert-butoxycarbonyl)-3-carboxy-4-ethyl-lH-pyπol-2-yl]methyl}-4- methoxybenzenaminium trifluoroacetate
A suspension of N-{ [3-[(benzyloxy)carbonyl]-5-(tert-butoxycarbonyl)- 4-ethyl- lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate (1.04 mmol) and 10% Pd-C (1 lmg, 0.10 mmol) in EtOH (3ml) was placed under a H2 balloon. The reaction was stined at room temperature for 2 hours. The balloon was then removed and the reaction mixture was purged with argon. The mixture was filtered through celite and rinsed thoroughly with EtOH. 30mg of the crude reaction product was purified by reverse phase HPLC to give a white solid. HRMS (ES) exact mass calcd for C20H26 2O5 (M+H4): 375.1915. Found 375.1918.
EXAMPLE 89
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(2-hydroxyethyl)am
2-yl)methyn-4-methoxybenzenaminium trifluoroacetate
A solution of N-{ [5-(tert-butoxycarbonyl)-3-carboxy-4-ethyl-lH- pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate (0.12 mmol) in 1ml of DMF was treated with 2-aminoethanol (10 ml, 0.14 mmol), DIEA (0.100 ml, 0.59 mmol), and HOBT (31.9 mg, 0.24 mmol). EDC (24.9 mg, 0.13 mmol) was then added and the reaction mixture stined at room temperature overnight. The reaction was purified by reverse phase HPLC to give a white powder. HRMS (ES) exact mass calcd for C22H31N3O5 (M+H4): 418.2336. Found 418.2337.
EXAMPLE 90
N-({ 5-(tert-butoxycarbonyl)-4-ethyl-3-[(ethylamino)carbonyl]- lH-pynol-2-yl } methyl)-4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 120, but using ethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H31N3O4 (M+H4): 402.2387. Found 402.2382.
EXAMPLE 91
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl1amino}methyl)pyridinium bis(trifluoroacetate)
Following the procedures described in Example 120, but using l-pyridin-2-ylmethanamine in place of 2-aminoethanol, the titled compound was obtained. 1H NMR (500 MHz, CD3OD) δ 8.60 (br d, J = 5 Hz, 1 H); 8.06 (t, J = 9 Hz, 1 H); 7.66 (d, J = 6 Hz, 1 H); 7.53 (m, 1 H); 7.23 (d, J - 9 Hz, 2 H); 7.00 (d, J = 9 Hz, 2 H); 4.82 (s, 2 H); 4.58 (s, 2 H); 3.81 (s, 3 H); 3.10 (q, J = 7 Hz, 2 H); 1.57 (s, 9 H); 1.20 (t, J = 7 Hz, 3 H). HRMS (ES) exact mass calcd for C26H32N4O4 (M+H4): 465.2496. Found 465.2497.
EXAMPLE 92
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino ImethvDpyridinium bis(trifluoroacetate) Following the procedures described in Example 120, but using 1- pyridin-4-ylmethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C26H32N4O4 (M+H4): 465.2496. Found 465.2494.
EXAMPLE 93
N-({5-(tert-butoxycarbonyl)-4-ethyl-3-[(propylamino)carbonyl]-lH-pynol-2-yl} methyl)-4-methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 120, but using propan- 1-amine in place of 2-aminoethanol, the titled compound was obtained.
HRMS (ES) exact mass calcd for C23H33N3O4 (M+H4): 416.2544. Found 416.2550.
EXAMPLE 94
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl]amino}carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate
A solution of N-{ [5-(tert-butoxycarbonyl)-3-carboxy-4-ethyl-lH- pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate (0.107 mmol) in 1ml of DMF was treated with 5-(aminomethyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (31.8 mg, 0.32 mmol), DIEA (0.09 ml, 0.54 mmol), and HOAT (29.1 mg, 0.21 mmol). EDC (22.6 mg, 0.12 mmol) was then added and the reaction mixture stined at room temperature overnight. The reaction was purified by reverse phase HPLC to give a white solid. HRMS (ES) exact mass calcd for C23H30N6O5 (M+H4): 471.2350. Found 471.2337.
EXAMPLE 95
2-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl1amino)ethyl)pyridinium bis(trifluoroacetate)
Following the procedures described in Example 94, but using 2-pyridin-2-ylethanamine in place of 5-(aminomethyl)-2,4-dihydro-3H-l,2,4-triazol- 3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H34N4O4 (M+H4): 479.2653. Found 479.2672.
EXAMPLE 96
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)arrιmonio]methyl }- lH-pynol-3-yl)carbonyl1amino)methyl)-lH-imidazol-l-ium bis(trifluoroacetate) Following the procedures described in Example 94, but using l-(lH-imidazol-2-yl)methanamine in place of 5-(aminomethyl)-2,4-dihydro-3H- 1,2,4- triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H3XN5O4 (M+H4): 454.2449. Found 454.2405.
EXAMPLE 97
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-oxopynolidin-2-yl)methyl]amino} carbonyl)-lH-pynol-2-yl1methyl}-4-methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 94, but using 5-(aminomethyl)pynolidin-2-one in place of 5-(aminomethyl)-2,4-dihydro-3H-l,2,4- triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H34N4O5 (M+H4): 471.2592. Found 471.2602.
EXAMPLE 98
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl}-lH- pynol-3-yl)carbonvnamino)methyl)pyridinium bis(trifluoroacetate)
Following the procedures described in Example 94, but using l-pyridin-3-ylmethanamine in place of 5-(aminomethyl)-2,4-dihydro-3H- 1,2,4- triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C26H32N4O4 (M+H4): 465.2487. Found 465.2497.
EXAMPLE 99
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl}-lH- pynol-3-yl)carbonyl1amino}methyl)-3H-benzimidazol-l-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using l-(lH-benzimidazol-2-yl)methanamine in place of 5-(aminomethyl)-2,4-dihydro-3H- l,2,4-triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C28H33N5O4 (M+H4): 504.2606. Found 504.2600.
EXAMPLE 100
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(isoxazol-3-ylmethyl)amino]carbonyl}-lH- pynol-2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 94, but using l-isoxazol-3-ylmethanamine in place of 5-(aminomethyl)-2,4-dihydro-3H- 1,2,4- triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for
C24H30N4O5 (M+H4): 455.2289. Found 455.2281. EXAMPLE 101
N-{ [3-({ [2-(acetylamino)ethyl]amino}carbonyl)-5-(tert-butoxycarbonyl)-4-ethyl-lH- pynol-2-yllmethyl }-4-methoxybenzenaminium trifluoroacetatetate Following the procedures described in Example 94, but using N-(2- aminoethyl)acetamide in place of 5-(aminomethyl)-2,4-dihydro-3H-l,2,4-triazol-3- one, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H34N4O5 (M+H4): 459.2602. Found 459.2590.
EXAMPLE 102
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({[(5-methyl-l,3,4-oxadiazol-2-yl)methyl] amino)carbonyl)-lH-pynol-2-yl]methyl|-4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 94, but using (5- methyl-l,3,4-oxadiazol-2-yl)methylamine in place of 5-(aminomethyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H3XN5O5 (M+H4): 470.2398. Found 470.2381.
EXAMPLE 103
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(2-sulfoethyl)amino]carbonyl}-lH-pynol-2- yl)methvn-4-methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 94, but using 2-aminoethanesulfonic acid in place of 5-(aminomethyl)-2,4-dihydro-3H-l,2,4- triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H31N3O7S (M+H4): 482.1956. Found 482.1956. EXAMPLE 104
N-{ [3-[(benzylamino)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH-pynol-2-yl] methyl ) -4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 120, but using
1-phenylmethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H33N3O4 (M+H4): 464.2544. Found 464.2545.
EXAMPLE 105
3-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}ethyl)-5-methyl-4H-l,2,4-triazol-4-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using 2-(5-methyl-4H-l,2,4-triazol-3-yl)ethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H34N6O4 (M+H4): 483.2715. Found 483.2687.
EXAMPLE 106
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonvnamino)methyl)-2-methyl-1.3-thiazol-3-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using (2-methyl-l,3-thiazol-4-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H32N4O4S (M+H4): 485.2217. Found 485.2201. EXAMPLE 107
4-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)an monio]methyl }- lH-pynol-3-yl)carbonyl1amino)ethyl)-lH-pyrazol-l-ium bis(trifluoroacetate) Following the procedures described in Example 94, but using
2-(lH-pyrazol-4-yl)ethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H33N5O4 (M+H4): 468.2606. Found 468.2610.
EXAMPLE 108
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(lH-indol-6-ylmethyl)amino]carbonyl}-lH- pynol-2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 94, but using l-(lH-indol-6-yl)methanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C29H34N4O4 (M+H4): 503.2653. Found 503.2653.
EXAMPLE 109
6-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl}-lH- pynol-3-yl)carbonyl]amino}methyl)-2-methylimidazo[2,l-b][l,3]thiazol-7-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using (2-methylimidazo[2,l-b][l,3]thiazol-6-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H33N5O4S (M+H4): 524.2326. Found 524.2300. EXAMPLE 110
5-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino }methyl)-3-methyl-4H-l ,2,4-triazole- 1 ,4-diium tris(trifluoroacetate)
Following the procedures described in Example 94, but using (5-methyl-4H-l,2,4-triazol-3-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H32N6O4 (M+H4): 469.2558. Found 469.2511.
EXAMPLE 111
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl1amino}methyl)-l-methyl-lH-pyrazol-2-ium bis(trifluoroacetate) Following the procedures described in Example 94, but using
(l-methyl-lH-pyrazol-4-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H33N5O4 (M+H4): 468.2606. Found 468.2598.
EXAMPLE 112
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(l-methyl-5-oxopynolidin-2-yl)methyl] amino}carbonyl)-lH-pynol-2-yllmethyl)-4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 94, but using 5-(aminomethyl)-l-methylpynolidin-2-one in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C26H36N4O5 (M+H4): 485.2759. Found 485.2752 EXAMPLE 113
2-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}ethyl)-5-methoxy-3H-benzimidazol-l-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using 2-(6-methoxy-lH-benzimidazol-2-yl)ethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C30H37N5O5 (M+H4): 548.2868. Found 548.2868.
EXAMPLE 114
5-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyπol-3-yl)carbonyl^amino}ethyl)-lH-l,2,4-triazol-l-ium bis(trifluoro^ Following the procedures described in Example 94, but using
2-(lH-l,2,4-triazol-5-yl)ethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C24H32N6O4 (M+H4): 469.2558. Found 469.2542.
EXAMPLE 115
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl}-lH-pynol-3-yl)carbonyl]amino}methyl)-l-methyl-lH-imidazol-
3-ium bis(trifluoroacetate) Following the procedures described in Example 94, but using
(l-methyl-lH-imidazol-2-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H33N5O4 (M+H4): 468.2606. Found 468.2610. EXAMPLE 116
6-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pyπol-3-yl)carbonyl]amino}methyl)-2,3-dihydroimidazo[2,l-b][l,3]thiazol-
4-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using (l-methyl-lH-imidazol-2-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C26H33N5O4S (M+H4): 512.2326. Found 512.2278.
EXAMPLE 117
2-( { [(5-(tert-butoxycarbonyl)-4-ethyl-2- { [(4-methoxyphenyl)ammonio] methyl }-lH-pyπol-3-yl)carbonyl]amino}methyl)-4-methyl-lH-imidazol- 3-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using (4-methyl- lH-imidazol-2-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H33N5O4 (M+H4): 468.2606. Found 468.2589.
EXAMPLE 118
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-8-methylimidazo[l,2-a]pyridin-4-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using (8-methylimidazo[l,2-a]pyridin-2-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C29H35N5O4 (M+H4): 518.2762. Found 518.2747. EXAMPLE 119
3-(l-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyρhenyl)ammonio] methyl }-lH-pynol-3-yl)carbonyl]amino}ethyl)-5-methyl-4H-l,2,4-triazol-
4-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using l-(5-methyl-4H-l,2,4-triazol-3-yl)ethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H34N6O4 (M+H4): 483.2715. Found 483.2720.
EXAMPLE 120
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino } methvDquinolinium bis(trifluoroacetate) Following the procedures described in Example 94, but using l-quinolin-2-ylmethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C30H34N4O4 (M+H4): 515.2653. Found 515.2617.
EXAMPLE 121
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino)methyl)-6-methylpyridinium bis(trifluoroacetate) Following the procedures described in Example 94, but using (6-methylpyridin-2-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H34N4O4 (M+H4): 479.2553. Found 479.2627. EXAMPLE 122
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(4-methyl-l,3-thiazol-2-yl)methyl]amino} carbonyl)-lH-pynol-2-yl]methyl)-4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 94, but using
(4-methyl- l,3-thiazol-2-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C25H32N4O4S (M+H4): 485.2217. Found 485.2215.
EXAMPLE 123
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-6,7-dihydro-5H-cyclopenta[b]pyridinium bi s (trifluoroacetate) Following the procedures described in Example 94, but using l-(6,7- dihydro-5H-cyclopenta[b]pyridin-3-yl)methanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C29H36N4O4 (M+H4): 505.2810. Found 505.2807.
EXAMPLE 124
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino}methyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinium bis(trifluoroacetate) Following the procedures described in Example 94, but using l-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl)methanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C3XH40N4O4 (M+H4): 533.3123. Found: 533.3108. EXAMPLE 125
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [2-(4-methyl-l,3-thiazol-5-yl)ethyl] amino}carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate Following the procedures described in Example 94, but using
2-(4-methyl-l,3-thiazol-5-yl)ethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C26H34N4O4S (M+H4): 499.2374. Found 499.2408.
EXAMPLE 126
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl1amino}methyl)-l-methylpiperidinium bis(trifluoroacetate)
Following the procedures described in Example 94, but using (l-methylpiperidin-3-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H40N4O4 (M+H4): 485.3123. Found 485.3099.
EXAMPLE 127
4-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pynol-3-yl)carbonyl]amino}-l-pyridinium-4-ylethyl)moφholin-
4-ium tris(trifluoroacetate)
Following the procedures described in Example 94, but using 2-moφholin-4-yl-2-pyridin-4-ylethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C3χH_4 N5θ5 (M+H4): 564.3181. Found 564.3199. EXAMPLE 128
4-(2-{[(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pynol-3-yl)carbonyl]amino}-l-pyridinium-3-ylethyl)moφholin-
4-ium tris(trifluoroacetate)
Following the procedures described in Example 94, but using 2-moφholin-4-yl-2-pyridin-3-ylethanamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C3 H4 N5O5 (M+H4): 564.3181. Found 564.3167.
EXAMPLE 129
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-yl) methyl]amino}carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 94, but using 3-(aminomethyl)-5-fluoro-l,3-dihydro-2H-indol-2-one in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C29H33FN4O5 (M+H ): 537.2508. Found 537.2512.
EXAMPLE 130
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-5-cyclopropyl-lH-pyrazol-l-ium bis(trifluoroacetate)
Following the procedures described in Example 94, but using (5-cyclopropyl-lH-pyrazol-3-yl)methylamine in place of 2-aminoethanol, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H35N5O4 (M+H4): 494.2762. Found 494.2757. EXAMPLE 131
2-{ [{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }
(hydroxy)ammonio]methyl Ipyridinium bis(trifluoroacetate) To a solution of 2-tert-butyl 4-ethyl 3-ethyl-5-{ [(E)-oxido(pyridin-2- ylmethylene)amino]methyl}-lH-pynole-2,4-dicarboxylate in 5 ml MeOH was added solid NaBF j. (170 mg, 4.48 mmol). The reaction stined at room temperature for 30 minutes and was then quenched by adding IN HCl. The mixture was poured into a separatory funnel containing saturated NaHCO3 and extracted with EtOAc (3x). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The reaction was purified by normal phase chromatography using 0-4% MeOH in CH2CI2 to give a white solid. HRMS (ES) exact mass calcd for C21H29N3O5 (M+H4): 404.2180. Found 404.2174.
EXAMPLE 132
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonvnoxy}methyl)pyridinium bis(trifluoroacetate)
A solution of N-{ [5-(tert-butoxycarbonyl)-3-carboxy-4-ethyl-lH- pynol-2-yl]methyl} -4-methoxyaniline (0.53 mmol) was dissolved in dry THF (800 ul). Pyridin-2-ylmethanol (lOul, 0.05mmol) and triphenylphosphine (21.7 mg, 0.08 mmol) were added to the solution, followed by DEAD (lOul, 0.05 mmol). The reaction stined at room temperature for 1.5 hours and then concentrated in vacuo. The residue was dissolved in acetonitrile and purified by reverse phase chroma- tography to give a white solid. HRMS (ES) exact mass calcd for C26H31N3O5 (M+H4): 466.2337. Found 466.2346. EXAMPLE 133
N-{[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-(2-phenylethyl)-lH-pynol-2-yl] methyl I -4-chlorobenzenaminium trifluoroacetate
Step A: 5-(l-hydroxy-3-phenylpropylidene)-2,2-dimethyl-l,3-dioxane-4,6- dione
Following the procedures described in Example 1, Step A, but using 3- phenylpropanoyl chloride in place of phenyl acetyl chloride, the titled compound was obtained.
Step B: tert-butyl 3-oxo-5-phenylpentanoate
Following the procedures described in Example 1, Step B, but using 5-(l-hydroxy-3-phenylpropylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione in place of 5-(l-hydroxy-2-phenylethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione, the titled compound was obtained.
Step C: 2-tert-butyl 4-ethyl 5-methyl-3-(2-phenylethyl)-lH-pynole-2,4-
Dicarboxylate Following the procedures described in Example 1, Step C, but using tert-butyl 3-oxo-5-phenylpentanoate in place of tert-butyl 3-oxo-4-phenylbutanoate, the titled compound was obtained.
Step D: 2-tert-butyl 4-ethyl 5-formyl-3-(2-phenylethyl)-lH-pyπole-2,4- Dicarboxylate
Following the procedures described in Example 1, Step D, but using
2-tert-butyl 4-ethyl 5-methyl-3-(2-phenylethyl)-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4-ethyl 3-benzyl-5-methyl-lH-pyπole-2,4-dicarboxylate, the titled compound was obtained. Step E: N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-(2-phenylethyl)- lH-pynol-2-yllmethyl }-4-chlorobenzenaminium trifluoroacetate Following the procedures described in Example 1, Step E, but using 2-tert-butyl 4-ethyl 5-formyl-3-(2-phenylethyl)-lH-pynole-2,4-dicarboxylate in place of 2-tert-butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate, the titled compound was obtained. HRMS (ES) exact mass calcd for C27H31CIN2O4 (M+H4): 483.2045. Found 483.2064.
EXAMPLE 134
2-amino-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2- yllmethyl } glycinamide trifluoroacetate
Following the procedures described in Example 1, Step E, but using 2-tert-butyl 4-ethyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate in place of 2-tert- butyl 4-ethyl 3-benzyl-5-formyl-lH-pynole-2,4-dicarboxylate and glycinamide in place of 4-chloroaniline, the titled compound was obtained. HRMS (ES) exact mass calcd for CX7H27N3O5 (M+H4): 354.2024. Found 354.2040.
EXAMPLE 135
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3- glycinamide -lH-pynol-2-yl)methyl]-4- methoxybenzenaminium trifluoroacetate
Following the procedures described in Example 97, but using glycinamide in place of 5-(aminomethyl)-2,4-dihydro-3H-l,2,4-triazol-3-one, the titled compound was obtained. HRMS (ES) exact mass calcd for C22H30N4O5 (M+H4): 431.2289. Found 431.2282. EXAMPLE 136
The salt compounds prepared above may be neutralized using techniques know in the art. For example, the salt may be treated with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate to produce the free form, or non-salt form, of the compound. Listed below is the free form name for conesponding salt compound described in the example recited:
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0002
EXAMPLE 137
Figure imgf000147_0001
2-tert-Butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl}-lH- pynole-2,4-dicarboxylate
2-tert-butyl 4-methyl 3-ethyl-5-formyl-lH-pynole-2,4-dicarboxylate (28 mg, 0.1 mmol) and 3-fluoro-4-methoxyaniline (16 mg, 0.11 mmol.) were dissolved in ΗOAc-DCE (10/90, 1.5 mL). MP-cyanoborohydride (110 mg, 3.7mmol/g, 0.4 mmol) was added to the mixture solution. The reaction was shaken overnight at rt. After this period, the resin was filtered and washed with MeOH (1 mL). The collected solution was concentrated to afford the crude product. The crude material was then purified on an Agilent 1100 series Mass Guided HPLC purification system to afford the TFA salt of the product as a yellow solid.
Analytical LCMS: single peak (214 nm) at 3.537 min (CH3CN/H2O/l%TFA, 4 min gradient), M+l peak m/e 407.2.
1H NMR (300 MHz, free base in CDC13): δ 9.36 (s, IH), 6.81 (t, 7=9.0 Hz, IH), 6.39
(dd, 7=13.0, 2.8 Hz, IH), 6.27-6.32 (m, IH), 4.56 (s, 2H), 4.08(s, IH), 3.85 (s, 3H),
3.81 (s, 3H), 3.05 (q, 7=7.3 Hz, 2H), 1.54 (s, 9H), 1.17 (t, J=7.3 Hz, 2H). HRMS: calc'd for C21H28FN2O5 (M+H), 407.1982; found
The compounds shown in the table below were also made as salts using the above-described techniques and are named in their free form.
Chemical Name Structure MS
2-tert-butyl 4-methyl 430.2
3-ethyl-5-{ [(2- methyl-1,3- benzothiazol-6-
Figure imgf000148_0001
yl)amino]methyl}- lH-pynole-2,4- dicarboxylate
2-tert-butyl 4-methyl 425.2
3-ethyl-5-({[4-(lH- pyrazol-1- yl)phenyl]amino} methyl)- lH-pyπole-
Figure imgf000148_0002
2,4-dicarboxylate
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
ASSAYS
The compounds of the instant invention described in the Examples above were tested by the assays described below and were found to have kinase inhibitory activity. In particular, the compounds of the instant invention inhibited IGF-IR or insulin receptor kinase activity with an IC50 of less than or equal to about
100 μM. Other assays are known in the literature and could be readily performed by those with skill in the art (see for example, Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem. 274:9116-9121; Sheu et al, Anticancer Res. 18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl Cancer Inst. 52:413- 427; Nicosia et al, In Vitro 18:538-549).
IGF-IR KINASE ASSAY
IGF-IR receptor kinase activity is measured by incoφoration of phosphate into a peptide substrate containing a tyrosine residue. Phosphorylation of the peptide substrate is quantitated using anti -IGF-IR and anti-phosphotyrosine antibodies in an HTRF (Homogeneous Time Resolved Fluorescence) detection system. (Park, Y-W., et al. Anal. Biochem., (1999) 269, 94-104) Materials
IGF-IR Receptor Kinase Domain
The intracellular kinase domain of human IGF-IR was cloned as a glutathione S-transferase fusion protein. IGF-IR β-subunit amino acid residues 930 to 1337 (numbering system as per Ullrich et al., EMBO J. (1986) 5, 2503-2512) were cloned into the baculovirus transfer vector pAcGHLT-A (BD-Pharmingen) such that the N-terminus of the IGF-IR residues are fused to the C-terminus of the GST domain encoded in the transfer vector pAcGHLT-A. Recombinant virus was generated and the fusion protein expressed in SF-9 insect cells (BD-Pharmingen). Enzyme was purified by means of a glutathione sepharose column.
Insulin Receptor Kinase Domain
The intracellular kinase domain of human insulin receptor was cloned as a glutathione S-transferase fusion protein. Insulin receptor β-subunit amino acid residues 941 tol343 (numbering system as per Ullrich et al., Nature, (1985) 313, 756- 761) were cloned into the baculovirus transfer vector pAcGHLT-A (BD-Pharmingen) such that the N-terminus of the IGF-IR residues are fused to the C-terminus of the GST domain encoded in the transfer vector pAcGHLT-A. Recombinant virus was generated and the fusion protein expressed in SF-9 insect cells (BD-Pharmingen) Enzyme was purified by means of a glutathione sepharose column.
Insect Cell Lysis Buffer lOmM Tris pH 7.5; 130mM NaCl; 2mM DTT; 1% Triton X-100; lOmM NaF; lOmM NaPi; lOmM NaPPi; IX protease inhibitor cocktail (Pharmingen).
Wash Buffer
Phosphate Buffered Saline (PBS): 137Mm NaCl, 2.6mM KC1, lOmM Na2HPO4, 1.8mM KH2PO4, pH 7.4; lmM DTT; IX protease inhibitor cocktail Dialysis Buffer
20mM Tris pH 7.5; ImM DTT; 200mM NaCl; 0.05% Triton X-100 and 50% glycerol
Enzyme Dilution Buffer 50mM Tris pH 7.5; ImM DTT; lOOmM NaCl; 10% glycerol; lmg/ml BSA
Enzyme Reaction Buffer
20mM Tris pH 7.4; lOOmM NaCl; lmg/ml BSA; 5mM MgCl2; 2mM DTT
Quench Buffer
125mM Tris pH 7.8; 75mM EDTA; 500mM KF; 0.125% Triton X-100; 1.25% BSA; 60 nM SA-XL665 (Packard); 300 pM europium cryptate labeled anti-phosphotyrosine antibody (Eu-PY20)
Peptide Substrate
Sequence LCB-EQEDEPEGDYFEWLE-NH2; stock solution is ImM disolved in DMSO; diluted to luM in IX enzyme reaction buffer for 10X working stock. (LCB = aminohexanoylbiotin)
ATP
Stock solution is 0.5 M ATP (Boehringer) pH 7.4; stock solution is diluted to 40mM ATP in enzyme reaction buffer to give 20X working stock solution
HEK-21 Cell Line Human embryonic kidney cells (HEK-293) (ATCC) were transfected with an expression plasmid containing the entire IGF-IR coding sequence. After antibiotic selection, colonies were screened for IGF-IR overexpression by western blot analysis.
One clone, designated HEK-21 was selected for cell based IGF-IR autophosphorylation assays. HEK Cell Growth Media
Dulbecco's Modified Eagle's Media (DMEM), 10% Fetal Calf Serum, IX Penn/
Strep, IX Glutamine, IX Non-essential amino acids (all from Life Technologies)
Cell Lysis Buffer
50mM Tris-HCl pH 7.4; 150mM NaCl; 1% Triton X-100 (Sigma); IX Mammalian protease inhibitors (Sigma); lOmM NaF; ImM NaVanadate
Western Blocking Buffer 20mM Tris-HCl pH 8.0; 150mM NaCl; 5% BSA (Sigma); 0.1% Tween 20 (Biorad)
Methods
A. Protein Purifications Spodoptera frugiperda SF9 cells were transfected with recombinant virus encoding either the GST-IGF-1R β-subunit or GST-InsR fusion protein at an MOI of 4 virus particles/cell. Cells are grown for 48 hours at 27°C, harvested by centrifugation and washed once with PBS. The cell pellet is frozen at -70°C after the final centrifugation. All subsequent purification steps are performed at 4°C. 10 grams of frozen cell paste is thawed in a 90ml volume of insect cell lysis buffer (BD- Pharmingen) and held on ice with occasional agitation for 20 minutes. The lysate is centrifuged at 12000g to remove cellular debris. Lysis supernatant was mixed with 45ml of glutathione agarose beads (BD-Pharmingen) and agitated slowly at 4°C for one hour after which the beads were centrifuged and washed 3X with wash buffer. The beads are resuspended in 45 ml of wash buffer and poured as a sluny into a chromatography column. The column is washed with 5 volumes of wash buffer and the GST-IGF-1R is eluted from the column with 5mM Glutathione in wash buffer. Pooled fractions are dialyzed vs. dialysis buffer and stored at -20°C. B. IGF-IR Kinase Assay
The IGF-IR enzyme reaction is run in a 96 well plate format. The enzyme reaction consists of enzyme reaction buffer plus O.lnM GST-IGF-1R, 100 nM peptide substrate and 2mM ATP in a final volume of 60 microliters. Inhibitor, in DMSO, is added in a volume 1 microliter and preincubated for 10 minutes at 22°C. Final inhibitor concentration can range from lOOuM to InM. The kinase reaction is initiated with 3 microliters of 40mM ATP. After 20 minutes at 22°C, the reaction is stopped with 40 microliters of quench buffer and allowed to equilibrate for 2 hours at 22°C. Relative fluorescent units are read on a Discovery plate reader (Packard). IC50s for compounds are determined by 4 point sigmoidal curve fit.
C. Insulin Receptor Kinase Assay
The kinase reaction for insulin receptor is identical to that used to assay IGF-IR (above), except that GST-InsR is substituted at a final concentration of O.lnM.
D. Cell Based IGF-IR Autophosphorylation Assay
IGF-IR inhibitor compounds are tested for their ability to block IGF-I induced IGF-IR autophosphorylation in a IGF-IR transfected human embryonic kidney cell line (HEK-21). HEK-21 cells over-expressing the human IGF-IR receptor are cultured in 6-well plates (37°C in a 5% CO2 atmosphere) in HEK cell growth media to 80% of confluence. Cells are serum starved for four hours in HEK growth media with 0.5% fetal calf serum. A 10X concentration of inhibitor in growth media is added to the cells in one-tenth the final media volume and allowed to preincubate for one hour at 37°C. Inhibitor concentration can range from lOnM to lOOuM. IGF-I (Sigma) is added to the serum starved cells to a final concentration of 30ng/ml. After a 10 minute incubation in the presence of IGF-I at 37°C, the media is removed, the cells washed once with PBS and 0.5mls of cold cell lysis buffer added. After 5 minutes incubation on ice, cells are scraped from the wells and lysis buffer plus cells are transfened to a 1.5ml microfuge tube. The total lysate is held at 4°C for twenty minutes and then centrifuged at top speed in a microfuge. The supernatant is removed and saved for analysis. Phosphorylation status of the receptor is assessed by Western blot. Lysates are electrophoresed on 8% denaturing Tris-Glycine polyacrylamide gels and the proteins transfened to nitrocellulose filters by electro- blotting. The blots are blocked with blocking reagent for 10 minutes after which anti- phosphotyrosine antibody (4G10, Upstate Biotechnology) is added to a final dilution of 1:1500. Blots and primary antibody are incubated at 4°C overnight. After washing with PBS plus 0.2% Tween 20 (Biorad), an HRP conjugated anti-mouse secondary antibody (Jackson Labs) is added at a dilution of 1:15000 and incubated at 4°C for 2 hours. Blots are then washed with PBS-Tween and developed using ECL (Amersham) luminescent reagent. Phosphorylated IGF-IR on the blots is visualized by autoradiography or imaging using a Kodak Image Station 440. IC50s are determined through densitometric scanning or quantitation using the Kodak Digital Science software.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I
)r
Figure imgf000169_0001
wherein
V is selected from
1) Cχ-Cιo alkyl,
2) aryl,
3) heterocycle, 4) C3-C10 cycloalkyl, and
5) -C(O);
Ra is independently selected from
1) H, 2) OR7,
3) unsubstituted or substituted Cχ-Cχo alkyl
4) unsubstituted or substituted aryl, and
5) unsubstituted or substituted heterocycle;
Rb is independently selected from
1) H,
2) OR7,
3) unsubstituted or substituted Cχ-Cχo alkyl,
4) unsubstituted or substituted aryl, and 5) unsubstituted or substituted heterocycle; Rl is independently selected from
1) H,
2) unsubstituted or substituted C -Cχo alkyl,
3) unsubstituted or substituted C3-C10 cycloalkyl,
4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle,
6) OR7,
7) C(O)R7,
8) C(O)OR7,
Figure imgf000170_0001
11) halo, and
12) -S(O)2N(R5)2;
R2 is selected from
1) unsubstituted or substituted Cχ-Cιo alkyl,
2) -C(O)OR7,
3) unsubstituted or substituted aryl,
4) -(CRb2)nN(R7)2,
Figure imgf000170_0002
6) -C(O)NHR7OR7,
7) -C(O)NH(CRb2)qR7,
8) -C(O)NHR7NHC(O)R7,
Figure imgf000170_0003
10) (CRb2)nOR7, and
11) -C(O)NH(CRb2)qC(O)N(R7)2; R3 is selected from
1) H,
2) unsubstituted or substituted Cχ-Cχo alkyl,
3) unsubstituted or substituted aralkyl 4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle, and
6) unsubstituted or substituted heterocyclylalkyl;
R4 is selected from 1) unsubstituted or substituted Cχ-Cχo alkyl,
2) unsubstituted or substituted aryl,
3) unsubstituted or substituted aralkyl, and
4) unsubstituted or substituted heterocycle;
R is independently selected from
1) H,
2) unsubstituted or substituted C x -C o alkyl ,
3) unsubstituted or substituted aryl, and
4) unsubstituted or substituted heterocycle;
R6 is independently selected from
1) H,
2) unsubstituted or substituted Cχ-Cχo alkyl,
3) unsubstituted or substituted aryl, 4) unsubstituted or substituted heterocycle,
5) OR7,
6) unsubstituted or substituted aralkyl, and
7) unsubstituted or substituted heterocyclylalkyl; R7 is independently selected from
1) H,
2) unsubstituted or substituted C -C i o alkyl ,
3) unsubstituted or substituted aralkyl, 4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle, and
6) unsubstituted or substituted heterocyclylalkyl;
n is 0 to 6, p is 0 to 6, q is 0 to 5, and r is 0 to 6;
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of Claim 1 wherein:
R4 is selected from
1) unsubstituted or substituted Cχ-Cχo alkyl, and 2) unsubstituted or substituted aryl;
or a pharmaceutically acceptable salt or stereoisomer thereof.
3. The compound of Claim 2 wherein:
Rl is independently selected from
1) H,
2) unsubstituted or substituted Cχ-Cιo alkyl,
3) unsubstituted or substituted C3-C o cycloalkyl, 4) OR7, 5) C(O)R7,
6) C(O)OR7,
7) C(O)N(R7)2,
Figure imgf000173_0001
9) halo, and
10) -S(O) N(R5)2;
n is 0 to 2, p is 0 to 4, q is 0 to 3, and r is 0 to 4,
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound of Claim 1 selected from:
2-tert-butyl 4-ethyl 3-benzyl-5-{ [(4-chlorophenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(5- oxopynolidin-2-yl)methyl]methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(lH-indol-2- ylmethyl)methanaminium trifluoroacetate;
N-{[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3,4- dichlorobenzenaminium trifluoroacetate;
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } -4- methylbenzenaminium trifluoroacetate; N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- hydroxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- chloro-N-methylbenzenaminium trifluoroacetate;
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ammonio)methyl]-6-methylpyridinium bis(trifluoroacetate);
3-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-5-cyclopropyl-lH-pyrazol-l-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(3,5- dimethyl-lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(5-phenyl- l,3,4-oxadiazol-2-yl)methyl]methanaminium trifluoroacetate;
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-lH-imidazol-l-ium bis(trifluoroacetate);
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ammonio)methyl]-3-methyl-4H-l,2,4-triazole-l,4-diium tris(trifluoroacetate);
6-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-2-methylimidazo[2,l-b][l,3]thiazol-7-ium bis(trifluoroacetate); 2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-4-methyl-lH-imidazol-3-ium bis(trifluoroacetate);
2-[({[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-l-methyl-lH-imidazol-3-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(5-oxo-4,5- dihydro-lH-l,2,4-triazol-3-yl)methyl]methanaminium trifluoroacetate;
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ammonio)methyl]-lH-l ,2,4-triazol-l-ium bis(trifluoroacetate);
6-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]imidazo[2,l-b][l,3]thiazol-4-ium bis(trifluoroacetate);
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-5-chloro-3H-benzimidazol-l-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(4-oxo-3,4- dihydrophthalazin-l-yl)methyl]methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(lH-indol-6- ylmethyl)methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(4-methyl- 1 ,3-thiazol-2-yl)methyl]methanaminium trifluoroacetate;
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} arnmonio)methyl]-8-methylimidazo[l,2-a]pyridin-4-ium bis(trifluoroacetate); 2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-3H-benzimidazol-l-ium bis(trifluoroacetate);
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } -3- methylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- isopropylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-4- ethylbenzenaminium trifluoroacetate;
N-{[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3,5- dimethylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3,4- dimethoxybenzenaminium trifluoroacetate;
2-[2-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)ethyl]pyridinium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(l-methyl- lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-4- ethoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3,4- dimethylbenzenaminium trifluoroacetate; N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } - 1 ,3- benzodioxol-5-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- isopropoxybenzenaminium trifluoroacetate;
4-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-l,3-thiazol-3-ium bis(trifluoroacetate);
5-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ammonio)methyl]-l,3-thiazol-3-ium bis(trifluoroacetate);
2-[({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)methyl]-l,3-thiazol-3-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(isoxazol-5- ylmethyl)methanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-[(l,5- dimethyl-lH-pyrazol-4-yl)methyl]methanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- tert-butylbenzenaminium trifluoroacetate;
2-tert-butyl 4-ethyl 5-({ [4-(dimethylamino)phenyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate bis(trifluoroacetate);
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } -2- methylbenzenaminium trifluoroacetate; N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl]methyl } -2- methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- propylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-2,5- dimethoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-4- butylbenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- hydroxy-4-methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-lH- indol-4-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-lH- indol-6-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- methoxypropan-1 -aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ethanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} butan-1 -aminium trifluoroacetate; N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-3- carboxypropan-1 -aminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N- methylmethanaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-2- methylpropan- 1 -aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} pentan-1 -aminium trifluoroacetate;
2-(aminosulfonyl)-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH- pynol-2-yl]methyl }ethanaminium trifluoroacetate;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(lH-pynol-2- ylmethyl)methanaminium trifluoroacetate;
N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pyπol-2-yl]methyl } -4- chlorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-3- chlorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-2- chlorobenzenaminium chloride; 3-bromo-N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl] methyl }benzenaminium chloride;
2-bromo-N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl] methyl }benzenaminium chloride;
N-{[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-4- fluorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl }-3- fluorobenzenaminium chloride;
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}-2- fluorobenzenaminium chloride;
3-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } ammonio)pyridinium dichloride;
2-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl} ammonio)-5-chloropyridinium dichloride;
4-bromo-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl] methyl }benzenaminium chloride;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl}-4- pentylbenzenaminium trifluoroacetate; N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl}- 1 , 1 -biphenyl -4-aminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl}- 3,4,5-trimethoxybenzenaminium trifluoroacetate;
3-[4-({ [5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl} ammonio)phenyl]-5-methyl-4H-l,2,4-triazol-4-ium bis(trifluoroacetate);
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-{ [(2R)-5- oxopynolidin-2-yl]methyl } methanaminium trifluoroacetate;
diethyl 5-{ [(4-chlorophenyl)amino]methyl }-3-methyl-lH-pynole-2,4-dicarboxylate;
N-benzyl[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]-N-(pyridin-2-ylmethyl) methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]-N-(2-chlorobenzyl) methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-methyl-lH-pynol-2-yl]-N-(3-chlorobenzyl) methanaminium chloride;
[3,5-bis(ethoxycarbonyl)-4-isopropyl-lH-pynol-2-yl]-N-(pyridin-2-ylmethyl) methanaminium chloride;
[5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]-N-(pyridin-2- ylmethyl)methanaminium chloride; N-{ [3-[(benzyloxy)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH-pynol-2-yl] methyl }-4-methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-3-carboxy-4-ethyl-lH-pyπol-2-yl]methyl }-4- methoxybenzenaminium trifluoroacetate;
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(2-hydroxyethyl)amino]carbonyl}-lH-pynol- 2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
N-({5-(tert-butoxycarbonyl)-4-ethyl-3-[(ethylamino)carbonyl]-lH-pynol-2-yl} methyl)-4-methoxybenzenaminium trifluoroacetate;
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino}methyl)pyridinium bis(trifluoroacetate);
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl}-lH- pynol-3-yl)carbonyl]amino}methyl)pyridinium bis(trifluoroacetate);
N-({ 5-(tert-butoxycarbonyl)-4-ethyl-3-[(propylamino)carbonyl]-lH-pynol-2-yl } methyl)-4-methoxybenzenaminium trifluoroacetate;
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl) methyl]amino}carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
2-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}ethyl)pyridinium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-lH-imidazol-l-ium bis(trifluoroacetate);
N- { [5-(tert-butoxycarbonyl)-4-ethyl-3-( { [(5-oxopynolidin-2-yl)methyl]amino } carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pyπol-3-yl)carbonyl]amino }methyl)pyridinium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino}methyl)-3H-benzimidazol-l-ium bis(trifluoroacetate);
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(isoxazol-3-ylmethyl)amino]carbonyl}-lH- pynol-2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
N-{ [3-({ [2-(acetylamino)ethyl]amino }carbonyl)-5-(tert-butoxycarbonyl)-4-ethyl-lH- pynol-2-yl] methyl }-4-methoxybenzenaminium trifluoroacetatetate;
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-methyl-l,3,4-oxadiazol-2-yl)methyl] amino}carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(2-sulfoethyl)amino]carbonyl}-lH-pynol-2- yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
N-{ [3-[(benzylamino)carbonyl]-5-(tert-butoxycarbonyl)-4-ethyl-lH-pynol-2-yl] methyl } -4-methoxybenzenaminium trifluoroacetate;
3-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl )ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}ethyl)-5-methyl-4H-l,2,4-triazol-4-ium bis(trifluoroacetate); 4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino}methyl)-2-methyl-l,3-thiazol-3-ium bis(trifluoroacetate);
4-(2- { [(5-(tert-butoxycarbonyl)-4-ethyl-2- { [(4-methoxyphenyl)ammonio]methyl } - lH-pynol-3-yl)carbonyl]amino}ethyl)-lH-pyrazol-l-ium bis(trifluoroacetate);
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3-{ [(lH-indol-6-ylmethyl)amino]carbonyl}-lH- pynol-2-yl)methyl]-4-methoxybenzenaminium trifluoroacetate;
6-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino}methyl)-2-methylimidazo[2,l-b][l,3]thiazol-7-ium bi s (trifluoroacetate) ;
5-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-3-methyl-4H-l,2,4-triazole-l,4-diium tris(trifluoroacetate);
4-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino}methyl)-l-methyl-lH-pyrazol-2-ium bis(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(l-methyl-5-oxopynolidin-2-yl)methyl] amino}carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
2-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}ethyl)-5-methoxy-3H-benzimidazol-l-ium bis(trifluoroacetate);
5-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}ethyl)-lH-l,2,4-triazol-l-ium bis(trifluoroacetate); 2-( { [(5-(tert-butoxycarbonyl)-4-ethyl-2- { [(4-methoxyphenyl)ammonio] methyl}-lH-pynol-3-yl)carbonyl]amino}methyl)-l-methyl-lH-imidazol- 3-ium bis(trifluoroacetate);
6-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-2,3-dihydroimidazo[2,l-b][l,3]thiazol- 4-ium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pynol-3-yl)carbonyl]amino}methyl)-4-methyl-lH-imidazol- 3-ium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-8-methylimidazo[l,2-a]pyridin-4-ium bis(trifluoroacetate);
3-( 1 - { [(5-(tert-butoxycarbonyl)-4-ethyl-2- { [(4-methoxyphenyl)ammonio] methyl }-lH-pyπol-3-yl)carbonyl]amino}ethyl)-5-methyl-4H-l,2,4-triazol- 4-ium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)quinolinium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-6-methylpyridinium bis(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(4-methyl- l,3-thiazol-2-yl)methyl]amino} carbonyl)- lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-6,7-dihydro-5H-cyclopenta[b]pyridinium bis(trifluoroacetate);
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl}-lH- pynol-3-yl)carbonyl]amino}methyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinium bi s(tri fl uoroacetate) ;
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [2-(4-methyl-l,3-thiazol-5-yl)ethyl] amino }carbonyl)-lH-pynol-2-yl]methyl }-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]amino}methyl)-l-methylpiperidinium bis(trifluoroacetate);
4-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pynol-3-yl)carbonyl]amino}-l-pyridinium-4-ylethyl)moφholin- 4-ium tris(trifluoroacetate);
4-(2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio] methyl }-lH-pynol-3-yl)carbonyl]amino}-l-pyridinium-3-ylethyl)moφholin- 4-ium tris(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-4-ethyl-3-({ [(5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-yl) methyl]amino}carbonyl)-lH-pynol-2-yl]methyl}-4-methoxybenzenaminium trifluoroacetate;
3-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }- lH-pynol-3-yl)carbonyl]amino}methyl)-5-cyclopropyl-lH-pyrazol-l-ium bi s (trifluoroacetate) ; 2-{ [{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl } (hydroxy)ammonio]methyl }pyridinium bis(trifluoroacetate);
2-({ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)ammonio]methyl }-lH- pynol-3-yl)carbonyl]oxy}methyl)pyridinium bis(trifluoroacetate);
N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-(2-phenylethyl)-lH-pynol-2-yl] methyl }-4-chlorobenzenaminium trifluoroacetate;
2-amino-N-{ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2- yl]methyl } glycinamide trifluoroacetate;
N-[(5-(tert-butoxycarbonyl)-4-ethyl-3- glycinamide -lH-pynol-2-yl)methyl]-4- methoxybenzenaminium trifluoroacetate;
or a stereoisomer thereof.
5. A compound selected from: 2-tert-butyl 4-ethyl 3-ethyl-5-({ [(5-oxopyπolidin-2-yl)methyl]amino}methyl)-lH- pyπole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-indol-2-ylmethyl)amino]methyl }-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,4-dichlorophenyl)amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-methylphenyl)amino]methyl }-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-hydroxyphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate; 2-tert-butyl 4-ethyl 5-{ [(4-chlorophenyl)(methyl)amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(6-methylpyridin-2-yl)methyl]amino}methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(5-cyclopropyl-lH-pyrazol-3-yl)methyl]amino}methyl)-3-ethyl- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(3,5-dimethyl-lH-pyrazol-4-yl)methyl]amino}methyl)-3-ethyl- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-indol-2-ylmethyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-imidazol-2-ylmethyl)amino]methyl}-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(5-methyl-4H-l,2,4-triazol-3-yl)methyl]amino}methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(2-methylimidazo[2,l-b][l,3]thiazol-6-yl)methyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(4-methyl-lH-imidazol-2-yl)methyl]amino}methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(l-methyl-lH-imidazol-2-yl)methyl]amino}methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-l,2,4-triazol-5-ylmethyl)amino]methyl }-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(imidazo[2,l-b][l,3]thiazol-6-ylmethyl)amino]methyl}- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(6-chloro-lH-benzimidazol-2-yl)methyl]amino}methyl)-3-ethyl- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(4-oxo-3,4-dihydrophthalazin-l-yl)methyl]amino} methyl)-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-indol-6-ylmethyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(4-methyl-l,3-thiazol-2-yl)methyl]amino}methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(8-methylimidazo[l,2-a]pyridin-2-yl)methyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(lH-benzimidazol-2-ylmethyl)amino]methyl}-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-methylphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-isopropylphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-ethylphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,5-dimethylphenyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,4-dimethoxyphenyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-pyridin-2-ylethyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-({ [(l-methyl-lH-pyrazol-4-yl)methyl]amino}methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-ethoxyphenyl)amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3,4-dimethylphenyl)amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-[(l,3-benzodioxol-5-ylamino)methyl]-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-isopropoxyphenyl)amino]methyl}-lH-pynole-2,4- dicarboxylate; 2-tert-butyl 4-ethyl 3-ethyl-5-{ [(l,3-thiazol-4-ylmethyl)amino]methyl }-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(l,3-thiazol-5-ylmethyl)amino]methyl }-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(l,3-thiazol-2-ylmethyl)amino]methyl }-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(isoxazol-5-ylmethyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [(l,5-dimethyl-lH-pyrazol-4-yl)methyl]amino}methyl)-3-ethyl- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-tert-butylphenyl)amino]methyl }-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [4-(dimethylamino)phenyl]amino}methyl)-3-ethyl-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-methylphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-methoxyphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-propylphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(2,5-dimethoxyphenyl)amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-butylphenyl)amino]methyl }-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-hydroxy-4-methoxyphenyl)amino]methyl }-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(lH-indol-4-ylamino)methyl]-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(lH-indol-6-ylamino)methyl]-lH-pynole-2,4- dicarboxylate; 2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-methoxypropyl)amino]methyl}-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(ethylamino)methyl]-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-[(butylamino)methyl]-3-ethyl-lH-pyπole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(3-methoxyphenyl)amino]methyl }-lH-pynole-2,4- dicarboxylate;
4-({ [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl-lH-pynol-2-yl]methyl}amino) butanoic acid;
2-tert-butyl 4-ethyl 3-ethyl-5-[(methylamino)methyl]-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(isobutylamino)methyl]-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(pentylamino)methyl]-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-({ [2-(aminosulfonyl)ethyl]amino}methyl)-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(lH-pyπol-2-ylmethyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-chlorophenyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3-chlorophenyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(2-chlorophenyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(3-bromophenyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(2-bromophenyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(4-fluorophenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{[(3-fluorophenyl)amino]methyl}-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(2-fluorophenyl)amino]methyl}-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[(pyridin-3-ylamino)methyl]-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(5-chloropyridin-2-yl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-bromophenyl)amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-pentylphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[(l,l'-biphenyl-4-ylamino)methyl]-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(3,4,5-trimethoxyphenyl)amino]methyl}-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-[({ [(2R)-5-oxopynolidin-2-yl]methyl}amino)methyl]-lH- pynole-2,4-dicarboxylate; diethyl 5-[(benzylamino)methyl]-3-methyl-lH-pynole-2,4-dicarboxylate; diethyl 3-methyl-5-{ [(pyridin-2-ylmethyl)amino]methyl }-lH-pynole-2,4-dicarboxylate; diethyl 5-{ [(2-chlorobenzyl)amino]methyl}-3-methyl-lH-pynole-2,4-dicarboxylate; diethyl 5-{ [(3-chlorobenzyl)amino]methyl }-3-methyl-lH-pynole-2,4-dicarboxylate; diethyl 3-isopropyl-5-{ [(pyridin-2-ylmethyl)amino]methyl }-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(pyridin-2-ylmethyl)amino]methyl }-lH-pyπole-2,4- dicarboxylate;
4-benzyl 2-tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pynole-2,4- dicarboxylate;
5-(tert-butoxycarbonyl)-4-ethyl-2- { [(4-methoxyphenyl)amino]methyl } - lH-pynole-3- carboxylic acid; tert-butyl 3-ethyl-4-{ [(2-hydroxyethyl)amino]carbonyl }-5-{ [(4-methoxyphenyl)amino] methyl }- lH-pynole-2-carboxylate; tert-butyl 3-ethyl-4-[(ethylamino)carbonyl]-5-{ [(4-methoxyphenyl)amino]methyl}-lH- pynole-2-carboxyl ate ; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-{ [(pyridin-2-ylmethyl)amino] carbonyl }-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(pyridin-4-ylmethyl)amino] carbonyl }-lH-pyπole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-[(propylamino)carbonyl]-lH- pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(5-oxo-4,5-dihydro-lH- l,2,4-triazol-3-yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(2-pyridin-2-ylethyl)amino] carbonyl }-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-4-{ [(lH-imidazol-2-ylmethyl)amino]carbonyl }-5-{ [(4-methoxyphenyl) amino]methyl}-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(5-oxopynolidin-2-yl) methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(pyridin-3-ylmethyl)amino] carbonyl }-lH-pynole-2-carboxylate; tert-butyl 4-{ [(lH-benzimidazol-2-ylmethyl)amino]carbonyl }-3-ethyl-5-{ [(4- methoxyphenyl)amino]methyl } - lH-pynole-2-carboxylate tert-butyl 3-ethyl-4-{ [(isoxazol-3-ylmethyl)amino]carbonyl}-5-{ [(4-methoxyphenyl) amino]methyl}-lH-pynole-2-carboxylate; tert-butyl 4-({ [2-(acetylamino)ethyl]amino}carbonyl)-3-ethyl-5-{ [(4-methoxyphenyl) amino]methyl}-lH-pyπole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(5-methyl-l,3,4-oxadiazol-
2-yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate;
2-{ [(5-(tert-butoxycarbonyl)-4-ethyl-2-{ [(4-methoxyphenyl)amino]methyl }-lH-pynol-3- yl)carbonyl] amino }ethanesulfonic acid; tert-butyl 4-[(benzylamino)carbonyl]-3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-lH- pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [2-(5-methyl-4H- 1,2,4- triazol-3-yl)ethyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(2-methyl-l,3-thiazol-4- yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [2-(lH-pyrazol-4- yl)ethyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-4-{ [(lH-indol-6-ylmethyl)amino]carbonyl }-5-{ [(4-methoxyphenyl) amino]methyl}-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(2-methylimidazo[2,l- b][l,3]thiazol-6-yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [(5-methyl-4H-l,2,4-triazol-
3-yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(1 -methyl- lH-pyrazol-4- yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(l-methyl-5-oxopynolidin-
2-yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-4-({[2-(6-methoxy-lH-benzimidazol-2-yl)ethyl]amino}carbonyl)-5-
{ [(4-methoxyphenyl)amino]methyl}-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [2-(lH-l,2,4-triazol-5- yl)ethyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(l-methyl-lH-imidazol-2- yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 4-{ [(2,3-dihydroimidazo[2,l-b][l,3]thiazol-6-ylmethyl)amino]carbonyl}-3- ethyl-5-{[(4-methoxyphenyl)amino]methyl}-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(4-methyl- lH-imidazol-2- yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(8-methylimidazo[l,2- a]pyridin-2-yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [l-(5-methyl-4H- 1,2,4- triazol-3-yl)ethyl]amino}carbonyl)-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(quinolin-2-ylmethyl) amino]carbonyl}-lH-pynole-2-carboxylate; tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(6-methylpyridin-2- yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(4-methyl- l,3-thiazol-2- yl)methyl]amino}carbonyl)-lH-pynole-2-carboxylate;
Tert-butyl 4-{ [(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylmethyl)amino]carbonyl }-3- ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH-pynole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-{ [(6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-3-ylmethyl)amino]carbonyl}-lH-pynole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-4-({ [2-(4-methyl-l ,3-thiazol-5- yl)ethyl]amino}carbonyl)-lH-pynole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-({ [(l-methylpiperidin-3-yl) methyl] amino } carbonyl)- lH-pynole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(2-moφholin-4-yl-2- pyridin-4-ylethyl)amino]carbonyl}-lH-pynole-2-carboxylate;
Tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(2-moφholin-4-yl-2- pyridin-3-ylethyl)amino]carbonyl}-lH-pynole-2-carboxylate;
Tert-butyl 3-ethyl-4-({ [(5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-yl)methyl]amino} carbonyl)-5-{[(4-methoxyphenyl)amino]methyl}-lH-pynole-2-carboxylate;
Tert-butyl 4-({ [(5-cyclopropyl-lH-pyrazol-3-yl)methyl]amino}carbonyl)-3-ethyl-5-{ [(4- methoxyphenyl)amino]methyl}-lH-pynole-2-carboxylate;
2-tert-butyl 4-ethyl 3-ethyl-5-{ [hydroxy(pyridin-2-ylmethyl)amino]methyl }-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-(pyridin-2-ylmethyl) 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-ethyl 5-{ [(4-chlorophenyl)amino]methyl}-3-(2-phenylethyl)-lH-pynole-
2,4-dicarboxylate;
2-amino-N- { [5-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)-4-ethyl- lH-pynol-2-yl] methyl } glycinamide; 4-(Carbamoylmethyl-carbamoyl)-3-ethyl-5-[(4-methoxy-phenylamino)-methyl]-lH- pyπole-2-carboxylic acid tert-butyl ester; or the pharmaceutically acceptable salt or stereoisomer thereof.
6. A TFA salt of the compound of Claim 1 selected from:
2-tert-Butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl }-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-methyl-l,3-benzothiazol-6-yl)amino]methyl}-lΗ- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(lH-pyrazol-l-yl)phenyl]amino} methyl)-lH- pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(2-oxoimidazolidin-l-yl)phenyl]amino}methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(3-methyl-2-oxoimidazolidin-l-yl)phenyl] amino}methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl}-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(cyclopropylmethyl)amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-phenoxyphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate; 2-tert-butyl 4-methyl 5-({ [4-(aminocarbonyl) phenyl]amino}methyl)-3-ethyl-lH- pynole-2 ,4-dicarboxyl ate ;
4-({[5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl} amino)-2-hydroxybenzoic acid;
2-tert-butyl 4-methyl 5-[(cyclopropylamino)methyl]-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(6-chloro-l,3-benzothiazol-2-yl)amino] methyl }-3-ethyl-lH- pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(2-chloropyrimidin-4-yl)amino]methyl }-3-ethyl-lH-pyπole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2-chloro-6,7-dimethoxyquinazolin-4-yl)amino]methyl }-3- ethyl-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(5-bromopyridin-2-yl)amino]methyl}-3-ethyl-lH-pyπole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-[(pyrimidin-2-ylamino)methyl]-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[(l ,3-benzoxazol-2-ylamino)methyl]-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromopyrimidin-2-yl)amino]methyl}-3-ethyl-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [5-chloro-2-(4H-l,2,4-triazol-4-yl)benzyl] amino }methyl)-3- ethyl-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-[({ [3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4- yl]methyl}amino)methyl]-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}methyl)-3- ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [2-(aminocarbonyl) cyclohexyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromo-2-fluorobenzyl)amino]methyl}-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [2-(3,4-dichlorophenyl) ethyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(lH-l,2,4-triazol-l-yl)ethyl] amino } methyl)- 1H- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [4-(4-tert-butoxyphenyl)butyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [l-(lH-benzimidazol-2-yl)ethyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(lH-l,2,4-triazol-3-yl)ethyl] amino } methyl)- 1H- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(4-methyl-l,3-thiazol-5-yl)ethyl] amino Jmethyl)-
1 H-pynole-2 ,4-dicarboxyl ate ; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcyclopentyl)methyl] amino}methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-piperidin-l-yl-2-pyridin-3-ylethyl) amino]methyl}-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(3-phenylisoxazol-5-yl)methyl]amino}methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-2-ylethyl) amino] methyl }-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcycloheptyl)methyl] amino} methyl)-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(2,2,2-trifluoro-l-pyridin-3-ylethyl) amino]methyl}- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2-thien-2-yl-l,3-thiazol-4-yl)methyl] amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(5-phenyl-lH-l,2,4-triazol-3-yl) ethyl] amino} methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(6-methoxy-lH-benzimidazol-2-yl)methyl] amino}methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2,3-dihydro-l,4-benzodioxin-2-ylmethyl) amino]methyl}-3- ethyl-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({methyl[(5-phenylisoxazol-3-yl) methyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-[(quinoxalin-2-ylamino)methyl]-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(l,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(2,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[({2-[4-(aminosulfonyl) phenyl]ethyl } amino) methyl]-3-ethyl- lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(3,4-dihydroxybenzyl) amino]methyl}-3-ethyl-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(l-benzylpiperidin-4-yl)amino]methyl}-3-ethyl-lH-pynole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [4-(aminosulfonyl) benzyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-3-ylethyl) amino] methyl }-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[({ [l-(tert-butoxycarbonyl)-lH-indol-3-yl]methyl} amino) methyl]-3-ethyl-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [(4-benzylmoφholin-3-yl)methyl]amino }methyl)-3-ethyl- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({[(4-phenylmoφholin-3-yl) methyl]amino}methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({methyl[(5-methyl-lH-indol-3-yl) methyljamino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[(l,3-benzothiazol-2-ylamino)methyl]-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{[(l-phenyl-lH-tetrazol-5-yl)amino] methyl }-lH- pynole-2 ,4-dicarboxyl ate ; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]amino } methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl][(2S)-2-(3- fluorophenyl)-2-hydroxyethyl] amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(4-fluorophenyl)-2-hydroxyethyl] amino} methyl)- lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({bis[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]amino}methyl)- 3-ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [l-(4-fluorophenyl)-2-hydroxyethyl] amino} methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({bis[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino}methyl)- 3-ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluorophenyl)-2-hydroxyethyl][l-(4- fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
or a stereoisomer thereof.
7. A compound selected from 2-tert-Butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl}-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-methyl-l,3-benzothiazol-6-yl)amino]methyl}-lΗ- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(lH-pyrazol-l-yl)phenyl]amino} methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(2-oxoimidazolidin-l-yl)phenyl]amino}methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [4-(3-methyl-2-oxoimidazolidin-l-yl)phenyl] amino} methyl)- lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(3-fluoro-4-methoxyphenyl)amino]methyl }-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(cyclopropylmethyl)amino]methyl }-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-phenoxyphenyl)amino]methyl}-lH-pynole-2,4- dicarboxylate; 2-tert-butyl 4-methyl 5-({ [4-(aminocarbonyl) phenyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
4-({[5-(tert-butoxycarbonyl)-4-ethyl-3-(methoxycarbonyl)-lH-pynol-2-yl]methyl} amino)-2-hydroxybenzoic acid; 2-tert-butyl 4-methyl 5-[(cyclopropylamino)methyl]-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(6-chloro-l,3-benzothiazol-2-yl)amino] methyl }-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2-chloropyrimidin-4-yl)amino]methyl}-3-ethyl-lH-pyπole- 2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2-chloro-6,7-dimethoxyquinazolin-4-yl)amino]methyl}-3- ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromopyridin-2-yl)amino]methyl}-3-ethyl-lH-pynole-
2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-[(pyrimidin-2-ylamino)methyl]-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[(l ,3-benzoxazol-2-ylamino)methyl]-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromopyrimidin-2-yl)amino]methyl}-3-ethyl-lH-pyπole- 2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [5-chloro-2-(4H-l,2,4-triazol-4-yl)benzyl] amino }methyl)-3- ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-[({ [3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4- yljmethyl } amino)methyl]- lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}methyl)-3- ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [2-(aminocarbonyl) cyclohexyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(5-bromo-2-fluorobenzyl)amino]methyl}-3-ethyl-lH- pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [2-(3,4-dichlorophenyl) ethyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(lH-l,2,4-triazol-l-yl)ethyl] amino}methyl)-lH- pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({ [4-(4-tert-butoxyphenyl)butyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [l-(lH-benzimidazol-2-yl)ethyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(lH-l,2,4-triazol-3-yl)ethyl] amino} methyl)- 1H- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(4-methyl-l,3-thiazol-5-yl)ethyl] amino }methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcyclopentyl)methyl] amino }methyl)-lH-pyπole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-piperidin-l-yl-2-pyridin-3-ylethyl) amino]methyl}-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(3-phenylisoxazol-5-yl)methyl]amino}methyl)-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-2-ylethyl) amino] methyl }-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(l-moφholin-4-ylcycloheptyl)methyl] amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2,2,2-trifluoro-l-pyridin-3-ylethyl) amino]methyl}- lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2-thien-2-yl-l,3-thiazol-4-yl)methyl] amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [2-(5-phenyl-lH-l,2,4-triazol-3-yl) ethyl] amino}methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(6-methoxy-lH-benzimidazol-2-yl)methyl] amino}methyl)-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(2,3-dihydro-l,4-benzodioxin-2-ylmethyl) amino]methyl}-3- ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({methyl[(5-phenylisoxazol-3-yl) methyl]amino} methyl)-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-[(quinoxalin-2-ylamino)methyl]-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(l,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pyπole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-{ [(2,2-diphenylethyl) amino]methyl}-3-ethyl-lH-pynole-2,4- dicarboxylate;
2-tert-butyl 4-methyl 5-[({2-[4-(aminosulfonyl) phenyl]ethyl } amino) methyl]-3-ethyl- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5- { [(3,4-dihydroxybenzyl) amino]methyl}-3-ethyl-lH-pynole-
2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-{ [(l-benzylpiperidin-4-yl)amino]methyl }-3-ethyl-lH-pyπole-
2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [4-(aminosulfonyl) benzyl]amino}methyl)-3-ethyl-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-{ [(2-moφholin-4-yl-2-pyridin-3-ylethyl) amino] methyl }-lH-pyπole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[({ [l-(tert-butoxycarbonyl)-lH-indol-3-yl]methyl} amino) methyl]-3-ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({ [(4-benzylmoφholin-3-yl)methyl]amino}methyl)-3-ethyl-
1 H-pynole-2 ,4-dicarboxylate ; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(4-phenylmoφholin-3-yl) methyl] amino }methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({methyl[(5-methyl-lH-indol-3-yl) methyljamino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-[(l,3-benzothiazol-2-ylamino)methyl]-3-ethyl-lH-pyπole-2,4- dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-{ [(l-phenyl-lH-tetrazol-5-yl)amino] methyl }-lH- pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pynole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(3-fluorophenyl)-2-hydroxyethyl][(2S)-2-(3- fluorophenyl)-2-hydroxyethyl]amino} methyl)- lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 5-({bis[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]amino}methyl)- 3-ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({[l-(4-fluorophenyl)-2-hydroxyethyl]amino} methyl)- lH-pyπole-2,4-dicarboxylate; 2-tert-butyl 4-methyl 5-({bis[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]amino}methyl)-
3-ethyl-lH-pynole-2,4-dicarboxylate;
2-tert-butyl 4-methyl 3-ethyl-5-({ [(2S)-2-(4-fluorophenyl)-2-hydroxyethyl][l-(4- fluorophenyl)-2-hydroxyethyl]amino} methyl)-lH-pynole-2,4-dicarboxylate;
or a pharmaceutically acceptable salt or stereoisomer thereof.
8. A compound selected from: 2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl }-lH-pyπole-2,4- dicarboxylate
Figure imgf000205_0001
2-tert-butyl 4-ethyl 3-ethyl-5-{ [(pyridin-2-ylmethyl)amino]methyl }-lH-pynole-2,4- dicarboxylate
Figure imgf000205_0002
2-tert-butyl 4-ethyl 3-ethyl-5-[({ [(2R)-5-oxopynolidin-2-yl]methyl}amino)methyl]- lH-pynole-2,4-dicarboxylate
Figure imgf000205_0003
tert-butyl 3-ethyl-5-{ [(4-methoxyphenyl)amino]methyl}-4-{ [(pyridin-2-ylmethyl) amino]carbonyl } - 1 H-pynole-2-carboxylate
Figure imgf000206_0001
2-tert-butyl 4-methyl 3-ethyl-5-{ [(4-pentylphenyl)amino]methyl}-lH-pyπole-2,4- dicarboxylate
Figure imgf000206_0002
or the pharmaceutically acceptable salt or stereoisomer thereof.
9. A pharmaceutical composition which is comprised of a compound in accordance with Claim 1 and a pharmaceutically acceptable carrier.
10. A method of modulating the catalytic activity of protein kinases in a mammal in need thereof comprising contacting the protein kinase with a compound of Claim 1.
11. The method of Claim 10 wherein the protein kinase is an RTK.
12. The method of Claim 11, wherein the RTK is selected from IR, IGF-IR and ERR.
13. A method of treating or preventing a PK-related disorder in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of Claim 1.
14. A method of Claim 13, wherein the PK-related disorder is an
IGF-lR-related disorder selected from: a) cancer, b) diabetes, c) an autoimmune disorder, d) a hypeφroliferation disorder, e) aging, f) acromegaly, and g) Crohn's disease.
15. A method of treating cancer in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of Claim 1.
16. A method of treating retinal vascularization comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compoung of Claim 1.
17. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of Claim 1 in combination with a second compound selected from:
1) an estrogen receptor modulator,
2) an androgen receptor modulator,
3) retinoid receptor modulator,
4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor,
7) an HMG-CoA reductase inhibitor,
8) an H1N protease inhibitor,
9) a reverse transcriptase inhibitor, and 10) an angiogenesis inhibitor.
18. The method of Claim 17, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.
19. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of Claim 1 in combination with radiation therapy.
20. The method of Claim 17 wherein radiation therapy is also administered.
21. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of Claim 1 and paclitaxel or trastuzumab.
22. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of Claim 1 and a GPIIb/πia antagonist.
23. The method of Claim 22 wherein the GPJJb/JRa antagonist is tirofiban.
24. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of Claim 1 in combination with a COX-2 inhibitor.
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