WO2014164708A1 - Histone dementhylase inhibitors - Google Patents

Histone dementhylase inhibitors Download PDF

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Publication number
WO2014164708A1
WO2014164708A1 PCT/US2014/023273 US2014023273W WO2014164708A1 WO 2014164708 A1 WO2014164708 A1 WO 2014164708A1 US 2014023273 W US2014023273 W US 2014023273W WO 2014164708 A1 WO2014164708 A1 WO 2014164708A1
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Prior art keywords
compound
formula
embodiment provides
another embodiment
pyridine
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PCT/US2014/023273
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French (fr)
Inventor
Young K. Chen
Michael Brennan Wallace
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Celgene Quanticel Research Inc
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Quanticel Pharmaceuticals Inc
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Priority to US14/774,329 priority Critical patent/US9738637B2/en
Priority to CA2903473A priority patent/CA2903473A1/en
Priority to JP2016501190A priority patent/JP6320506B2/en
Priority to EP14778281.7A priority patent/EP2968282B1/en
Priority to AU2014249050A priority patent/AU2014249050B2/en
Publication of WO2014164708A1 publication Critical patent/WO2014164708A1/en
Anticipated expiration legal-status Critical
Priority to US15/652,174 priority patent/US9873697B2/en
Priority to US15/842,700 priority patent/US10174026B2/en
Priority to US16/202,072 priority patent/US10494369B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • substituted pyrrolopyridine derivative compounds and pharmaceutical compositions comprising said compounds.
  • the subject compounds and compositions are useful for inhibition histone demethylase.
  • the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.
  • the substituted pyrrolopyridine derivative compounds described herein are based upon a disubstituted pyrrolo[3,2-b]pyridine ring system bearing at the 7-position a carboxylic acid or bioisostere thereof, and a second substituent at the 2-position.
  • the 2-position substituent in various embodiments, is selected from a wide variety of groups, such as, but not limited to, alkyl, aryl, carbocyclyl, and the like.
  • One embodiment provides a compound having the structure of Formula (I),
  • Y is -CO 2 R 1 , -C(0)N(H)CN, -C(0)N(H)OH or tetrazolyl;
  • R 1 is hydrogen or alkyl
  • G is X-R 2 or X 1 -alkyl, wherein
  • X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S0 2 -;
  • R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl
  • X I is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S0 2 -;
  • R is hydrogen, halogen or alkyl.
  • R 1 is hydrogen or alkyl
  • G is X-R 2 or X 1 -alkyl, wherein
  • X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S0 2 -;
  • R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl
  • X I is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S0 2 -;
  • R is hydrogen, halogen or alkyl.
  • One embodiment provides a pharmaceutical composition comprising a
  • One embodiment provides a method for treating cancer in subject comprising administering a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • Amino refers to the -NH 2 radical.
  • Cyano refers to the -CN radical.
  • Niro refers to the -N0 2 radical.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., C ⁇ -C % alkyl).
  • an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl).
  • an alkyl comprises one to four carbon atoms (e.g., C 1 -C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl).
  • an alkyl comprises two to five carbon atoms (e.g., C 2 - C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (n- propyl), 1 -methyl ethyl (z ' so-propyl), 1 -butyl (n-butyl), 1-methylpropyl (sec-butyl), 2- methylpropyl (z ' so-butyl), 1 , 1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -OC(O)- N(R a ) 2 , -N(R a )C(0)R a , -N(R a )S(0),R a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),R a (where t is 1 or 2) and -S
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O- alkyl, where alkyl is an alkyl chain as defined above.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l ,4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-l-enyl i.e., allyl
  • but-l-enyl pent-l-enyl, penta-l ,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -OC(O)- N(R a ) 2 , -N(R a )C(0)R a , -N(R a )S(0),R a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),R a (where t is 1 or 2) and -
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl has two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -OC(O)- N(R a ) 2 , -N(R a )C(0)R a , -N(R a )S(0),R a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),R a (where t is 1 or 2) and
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -OC(O)- N(R a ) 2 , -N(R a )C(0)R a , -N(R a )S(0),R a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),OR a (where t is 1 or 2), -S(0),R a (where t is 1 or 2) and -S
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R b -OC(0)-N(R a ) 2 ,
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain,
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Alkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • “Aralkoxy” refers to a radical bonded through an oxygen atom of the formula - 0-R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms.
  • a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond.
  • Carbocyclyl may be saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.)
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as
  • cycloalkenyl examples include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R b -OC(0)-N(R a ) 2
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl
  • each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain
  • R c is a straight or branched alkylene or alkenylene chain
  • Carbocyclylalkyl refers to a radical of the formula -R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula -0-R c -carbocyclyl where R c is an alkylene chain as defined above.
  • R c is an alkylene chain as defined above.
  • the alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Halo or "halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxoxo
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R b -OC(0)-N(R a ) 2
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl
  • each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain
  • R c is a straight or branched alkylene or alkenylene chain
  • N-heterocyclyl or "N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the
  • heterocyclyl radical An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals.
  • Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
  • Heterocyclylalkyl refers to a radical of the formula -R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing
  • heterocyclyl the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula -0-R°-heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl
  • each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain
  • R c is a straight or branched alkyl ene or alkenylene chain
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula -0-R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkyl ene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the
  • heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
  • Examples of carboxylic acid bioisosteres include, but are not limited to,
  • the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds presented herein may, in certain embodiments, exist as tautomers. In circumstances where
  • tautomeric equilibrium a chemical equilibrium of the tautomers will exist.
  • the exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the substituted pyrrolopyridine derivative compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine,
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Prodrug is meant to indicate a compound that may be converted under
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism ⁇ see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are provided in Higuchi, T., et al, "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
  • Substituted pyrrolopyridine derivative compounds are described herein that inhibit a histone demethylase enzyme. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and neoplastic disease. The compounds described herein may, therefore, be useful for treating prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.
  • One embodiment provides a com ound having the structure of Formula (I),
  • Y is -CO 2 R 1 , -C(0)N(H)CN, -C(0)N(H)OH or tetrazolyl;
  • R 1 is hydrogen or alkyl
  • G is X-R 2 or X 1 -alkyl, wherein
  • X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -
  • R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl
  • X 1 is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S0 2 -;
  • R is hydrogen, halogen or alkyl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein Y is -CO 2 R 1 and R 1 is hydrogen. Another embodiment provides the compound having the structure of Formula (I), wherein Y is -CO 2 R 1 and R 1 is alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein Y is - C(0)N(H)CN. Another embodiment provides the compound having the structure of Formula (I), wherein Y is -C(0)N(H)OH. Another embodiment provides the compound having the structure of Formula (I), wherein Y is tetrazolyl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein R is hydrogen.
  • Another embodiment provides the compound having the structure of Formula (I), wherein G is X-R . Another embodiment provides the compound having the structure of Formula (I), wherein X is a bond and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
  • Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is CI- C3 alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene and R is heteroaryl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
  • Another embodiment provides the compound having the structure of Formula (I), wherein X is CI- C3 alkylene and R is heteroaryl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene and R is heterocyclyl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
  • Another embodiment provides the compound having the structure of Formula (I), wherein X is C1-C3 alkylene and R is heterocyclyl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is - C(0)-NH- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(0)-NH- and R is heteroaryl. Another embodiment provides
  • Another embodiment provides the compound having the structure of Formula (I), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH-C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH-C(O)- and R is heteroaryl. Another embodiment provides the compound having the compound having the
  • Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -O- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S0 2 - and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S0 2 - and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S0 2 - and R is carbocyclyl. Another 2 embodiment provides the compound having the structure of Formula (I), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S0 2 - and R is heterocyclyl.
  • Another embodiment provides the compound having the structure of Formula (I), wherein G is X ⁇ alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is a bond. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a 1-hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C2-C4 1-hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is -C(O)-.
  • Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is - C(0)-NH-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is -NH-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is - NH-C(O)-.
  • Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is -0-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is -S-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is -S0 2 -. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X 1 is -S0 2 -. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alky
  • R 1 is hydrogen or alkyl
  • G is X-R 2 or X 1 -alkyl, wherein
  • X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S0 2 -;
  • R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl
  • X I is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S0 2 -;
  • R is hydrogen, halogen or alkyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein R 1 is hydrogen. Another embodiment provides the compound having the structure of Formula (II), wherein R 1 is alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein G is X-R . Another embodiment provides the compound having the structure of Formula (II), wherein X is a bond and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
  • embodiments provide the compound having the structure of Formula (II), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is C1-C3 alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is C1-C3 alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (II), wherein X is C1-C3 alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(O)- and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is - C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is heterocyclyl. Another embodiment
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH-C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH-C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH-C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is carbocyclyl. Another embodiment provides the compound having the structure
  • Formula (II), wherein R is C3-C7 carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is heterocyclyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is -S0 2 - and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is -S0 2 - and R is heteroaryl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X is -S0 2 - and R is carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl.
  • Another embodiment provides the compound having the structure having the structure of Formula (II), wherein R is C3-C7 carbocyclyl.
  • Another embodiment provides the compound having the structure having the structure of Formula (II), wherein R is C3-C7 carb
  • Another embodiment provides the compound having the structure of Formula (II), wherein G is X ⁇ alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is a bond. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a 1-hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C2-C4 1-hydroxyalkyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is -C(O)-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is - C(0)-NH-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is -NH-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is - NH-C(O)-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is -0-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is -S-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein X 1 is -SO 2 -. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein the alkylene is a C1-C3 alkylene. [0065] One embodiment provides a compound having the structure of Formula (la),
  • Y is -CO 2 R 1 , -C(0)NH-(C1-C3)alkyl, -C(0)N(H)CN, -C(0)N(H)OH or tetrazolyl;
  • R 1 is hydrogen, alkyl, heterocyclylalkyl, or carbocyclylalkyl
  • G is X-R 2 or X 1 -alkyl, wherein
  • X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S0 2 -;
  • R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl
  • X I is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S0 2 -;
  • R is hydrogen, halogen or alkyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein Y is -CO 2 R 1 and R 1 is hydrogen. Another embodiment provides the compound having the structure of Formula (la), wherein Y is -CO 2 R 1 and R 1 is alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein Y is - CO 2 R 1 and R 1 is heterocyclylalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein Y is -CO 2 R 1 and R 1 is carbocyclylalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein Y is - C(0)NH-(C1-C3)alkyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein Y is -C(0)N(H)CN. Another embodiment provides the compound having the structure of Formula (la), wherein Y is -C(0)N(H)OH. Another embodiment provides the compound having the structure of Formula (la), wherein Y is tetrazolyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein R is hydrogen.
  • Another embodiment provides the compound having the structure of Formula (la), wherein G is X-R . Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is a C1-C3 alkylene and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein the carbocyclyl is a 1 -hydroxy carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is CI- C3 alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is C1-C3 alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (la), wherein X is C1-C3 alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH- and R is heterocyclyl. Another
  • embodiment provides the compound having the structure of Formula (la), wherein X is - NH-C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH-C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH-C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH-C(O)- and R is heterocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is aryl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is -SO 2 - and R is heterocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein G is X ⁇ alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is a bond. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a 1- hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C2-C4 1 -hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is -C(O)-.
  • Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is -C(0)-NH-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is -NH-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is -NH-C(O)-.
  • Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is -O- . Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is -S-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X 1 is - SO 2 -.
  • Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-, and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein 2
  • X is alkylene- ⁇ -, and R is heteroaryl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-, and R is carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein R is C3- C7 carbocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-, and R is heterocyclyl.
  • Another embodiment provides the compound having the structure of Formula (la), wherein the alkylene is a Cl- C3 alkylene.
  • the compound of Formula (I), (la), or (II) as disclosed herein has the structure provided in Table 1.
  • the compound of Formula (I), (la), or (II) is selected from a compound provided in Table 2, or alkyl ester derivative thereof.
  • compound A and terminal alkyne compound B are combined and treated under a variety of palladium-mediated Sonogashira cross-coupling conditions to form compound C.
  • the mixture of compound A and an alkyne B can be subjected to conditions similar to procedures described in literature (Tetrahedron Lett. 1975, 4467-4470; Org. Lett. 2006, 3307-3310) using various catalyst, co-catalyst, ligand, base, and solvent, at temperatures ranging from 40 °C to 100 °C.
  • the azaindole compound D can be prepared by cycloisomerization of compound C using a base, such as KOtBu at 0 °C, or catalyzed by Cul at temperature ranging from 100 °C to 140 °C.
  • Acid compound E can be prepared by hydrolysis of ester compound D using base, such as NaOH, or by other conditions known in the art for ester hydrolysis.
  • compound A and a ketone compound F are mixed and treated to palladium-mediated direct annulation conditions to form compound D.
  • the mixture of compound A and an ketone B can be subjected to conditions similar to procedures described in literature (Angew. Chem. Int. Ed. 2004, 4526-4528) using a Pd catalyst, ligand, acid, base, and solvent, at temperatures range up to 140 °C.
  • the various substituents may be selected from among the various substituents otherwise taught herein.
  • a substituted pyrrolopyridine derivative compound as described herein is administered as a pure chemical. In other embodiments, the substituted pyrrolopyridine derivative compound as described herein is combined with a
  • pharmaceutically suitable or acceptable carrier also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier
  • a pharmaceutically suitable (or acceptable) excipient selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in
  • a pharmaceutical composition comprising at least one substituted pyrrolopyridine derivative compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient ⁇ i.e., the subject) of the composition.
  • One embodiment provides a pharmaceutical composition comprising a
  • One embodiment provides a pharmaceutical composition comprising a
  • One embodiment provides a pharmaceutical composition comprising a
  • the substituted pyrrolopyridine derivative compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • Suitable nontoxic solid carriers can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,
  • the dose of the composition comprising at least one substituted pyrrolopyridine derivative compound as described herein may differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.
  • compositions may be administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts.
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the patient.
  • Oral doses can typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • Chromatin is the complex of DNA and protein that makes up chromosomes.
  • Histones are the major protein component of chromatin, acting as spools around which DNA winds. Changes in chromatin structure are affected by covalent modifications of histone proteins and by non-histone binding proteins. Several classes of enzymes are known which can covalently modify histones at various sites.
  • Proteins can be post-translationally modified by methylation on amino groups of lysines and guanidino groups of arginines or carboxymethylated on aspartate, glutamate, or on the C-terminus of the protein.
  • Post-translational protein methylation has been implicated in a variety of cellular processes such as RNA processing, receptor mediated signaling, and cellular differentiation.
  • Post-translational protein methylation is widely known to occur on histones, such reactions known to be catalyzed by histone methyltransferases, which transfer methyl groups from S-adenyosyl methionine (SAM) to histones.
  • SAM S-adenyosyl methionine
  • Histone methylation is known to participate in a diverse range of biological processes including heterochromatin formation, X-chromosome inactivation, and transcriptional regulation (Lachner et al, (2003) J. Cell Sci. 116:2117-2124; Margueron et al, (2005) Curr. Opin. Genet. Dev. 15: 163-176).
  • H3K9, H3K27 and H4K20 are linked to gene silencing, while methylation on H3K4, H3K36, and H3K79 is generally associated with active gene expression.
  • tri- and di- methylation of H3K4 generally marks the transcriptional start sites of actively transcribed genes, whereas mono-methylation of H3K4 is associated with enhancer sequences.
  • demethylase may demethylate one or more of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4 demethylase may demethylate histone H4K20.
  • Demethylases are known which can demethylate either a mono-, di- and/or a tri-methylated substrate. Further, histone demethylases can act on a methylated core histone substrate, a
  • a mononucleosome substrate a dinucleosome substrate and/or an oligonucleosome substrate, peptide substrate and/or chromatin (e.g., in a cell-based assay).
  • JmjC domain containing histone demthylases were predicted, and confirmed when a H3K36 demethylase was found using a formaldehyde release assay, which was named JmjC domain containing histone
  • JHDM1/KDM2A JHDM1/KDM2A
  • JmjC domain-containing proteins were subsequently identified and they can be phylogenetically clustered into seven subfamilies: JHDM1, JHDM2, JHDM3, JMJD2, J ARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.
  • JMJD2 Family [0095] The JMJD2 family of proteins are a family of histone-demethylases known to demethylate tri- and di-methylated H3-K9, and were the first identified histone tri-methyl demethylases. In particular, ectopic expression of JMJD2 family members was found to dramatically decrease levels of tri-and di-methylated H3-K9, while increasing levels of mono-methylated H3- K9, which delocalized Heterochromatin Protein 1 (HP1) and reduced overall levels of heterochromatin in vivo.
  • Members of the JMJD2 subfamily of jumonji proteins include JMJD2C and its homologues JMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found in the JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD and Tdr sequences.
  • JMJD2C also known as GASC1 and KDM4C, is known to demethylate tri- methylated H3K9 and H3K36. Histone demethylation by JMJD2C occurs via a
  • JMJD2C hydroxylation reaction dependent on iron and a-ketoglutarate.
  • oxidative decarboxylation of a-ketoglutarate by JMJD2C produces carbon dioxide, succinate, and ferryl and ferryl subsequently hydroxylates a methyl group of lysine H3K9, releasing formaldehyde.
  • JMJD2C is known to modulate regulation of adipogenesis by the nuclear receptor PPARy and is known to be involved in regulation of self-renewal in embryonic stem cells.
  • JARID protein includes proteins in the JARIDl subfamily (e.g., JARIDIA, JARID IB, JARID 1C and JARID ID proteins) and the JARID2 subfamily, as well as homologues thereof.
  • JARIDl subfamily e.g., JARIDIA, JARID IB, JARID 1C and JARID ID proteins
  • JARID2 subfamily as well as homologues thereof.
  • JARIDIA also called KDM5A or RBP2
  • KDM5A retinoblastoma
  • RBP2 retinoblastoma
  • JARIDIA was initially found as a binding partner of retinoblastoma (Rb) protein.
  • JARIDIA was subsequently found to function as a demethylase of tri- and di-methylated H3K4 , and has been found to promote cell growth, while inhibiting senescence and differentiation. For instance, abrogation of JARIDIA from mouse cells inhibits cell growth, induces senescence and differentiation, and causes loss of pluripotency of embryonic stem cells in vitro. JARIDIA has been found to be
  • RBP2 retinoblastome binding protein 2
  • JARIDIB also referred to as KDM5B and PLU1
  • JARIDIB was originally found in experiments to discover genes regulated by the HER2 tyrosine kinase.
  • JARIDIB has consistently been found to be expressed in breast cancer cell lines, although restriction of JARIDIB has been found in normal adult tissues, with the exception of the testis.
  • 90% of invasive ductal carcinomas have been found to express JARIDIB.
  • JARIDIB has been found to be up-regulated in prostate cancers, while having more limited expression in benign prostate, and has also been found to be up-regulated in bladder cancer and lung cancer (both SCLC and NSCLC).
  • JARIDIB has also been found to repress tumor suppressor genes such as BRCA1, CAV1 and 14-3-3 ⁇ , and knockdown of JARIDIB was found to increase the levels of tri-methylated H3K4 at these genes.
  • a method for inhibiting a histone- demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting a histone- demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (la), or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting a histone- demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • the method for inhibiting a histone- demethylase enzyme comprises a JmjC domain.
  • the method for inhibiting a histone-demethylase enzyme is selected from JARIDIA, JARIDIB, JMJD2C, or JMJD2A.
  • Demethylation can be modulated to control a variety of cellular functions, including without limitation: differentiation; proliferation; apoptosis; tumorigenesis, leukemogenesis or other oncogenic transformation events; hair loss; or sexual differentiation.
  • the invention provides a method of treating a disease regulated by histone methylation and/or demethylation in a subject in need thereof by modulating the activity of a demethylase comprising a JmjC domain (e.g., a histone demethylase such as a JHDM protein(s)).
  • composition comprising a compound of Formula (I), (la), or (II), or a pharmaceutically acceptable salt thereof.
  • cancer is selected from prostate cancer, breast cancer, bladder cancer, lung cancer or melanoma.
  • a method for inhibiting the growth of a tumor comprising administering a composition comprising a compound of Formula (I), (la), or (II), or a pharmaceutically acceptable salt thereof, wherein the tumor is characterized by a loss of retinoblastoma gene (RBI) function.
  • a composition comprising a compound of Formula (I), (la), or (II), or a pharmaceutically acceptable salt thereof, wherein the tumor is characterized by a loss of retinoblastoma gene (RBI) function.
  • a method for inhibiting the growth of a tumor comprising administering a composition comprising a compound of Formula (I), (la), or (II), or a pharmaceutically acceptable salt thereof, wherein the tumor is characterized by a loss of multiple endocrine neoplasia type 1 gene (Menl) function.
  • Example 102 methyl 2-[l-(4-fluorophenyl)-l-hydroxyethyl]-lH-pyrrolo[3,2-3 ⁇ 4]pyridine-7- carboxylate
  • Example 111 methyl-2-(3-chloro-4-fluorobenzyl)- lH-pyrrolo[3,2-3 ⁇ 4]pyridine-7- carboxylate
  • Example 120 2-[(3-phen lpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid
  • Example 121 methyl 2-(2-l,2,3,4-tetrahydroisoquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7- carboxylate
  • Example 135 methyl 2-[4-chloro-3-(trifluoromethyl)benzyl]-lH-pyrrolo[3,2-3 ⁇ 4]pyridine-7- carboxylate
  • Example 141 methyl-2-[4-chloro-3-(trifluoromethoxy)benzyl]-lH-pyrrolo[3,2-3 ⁇ 4]pyridine- 7-carboxylate
  • Example 142 2-[4-chloro-3-(trifluoromethoxy)benzyl]-lH-pyrrolo[3,2-3 ⁇ 4]pyridine-7- carboxylic acid
  • This assay determines the ability of a test compound to inhibit JaridlA, JaridlB, JMJD2C, and JMJD2A demethylase activity.
  • Baculovirus expressed JaridlA GenBank Accession #NM_001042603, AAl-1090 was purchased from BPS Bioscience
  • Baculovirus expressed JaridlB (GenBank Accession #NM_006618, AA 2- 751) was purchased from BPS Bioscience (Cat # 50121) or custom made by
  • Baculovirus expressed JMJD2C (GenBank Accession #BC143571, AA 2-372) was purchased from BPS Bioscience (Cat#50105).
  • Baculovirus expressed JMJD2A (GenBank Accession #NM_014663, AA 1-350) was purchased from BPS Bioscience (Cat#50123).
  • the enzymatic assay of JaridlA activity is based upon Time Resolved- Fluorescence Resonance Energy Transfer (TR-FRET) detection.
  • TR-FRET Time Resolved- Fluorescence Resonance Energy Transfer
  • the ability of test compounds to inhibit the activity of JaridlA was determined in 384-well plate format under the following reaction conditions: 1 nM JaridlA, 300 nM H3K4me3-biotin labeled peptide (Anaspec cat # 64357), 2 ⁇ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij ' 35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 ⁇ sodium L-ascorbate, and 2 ⁇ ammonium iron(II) sulfate.
  • Reaction product was determined quantitatively by TR- FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-mono-or di-methylated histone H3 lysine 4 (H3K4mel-2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 25 nM and 1 nM, respectively.
  • the assay reaction was initiated by the following: 2 ⁇ of the mixture of 900 nM H3K4me3-biotin labeled peptide and 6 ⁇ alpha-ketoglutaric acid with 2 ⁇ of 11 -point serial diluted inhibitor in 3%> DMSO was added to each well of plate, followed by the addition of 2 ⁇ of 3 nM JaridlA to initiate the reaction. The reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 ⁇ of 5 mM EDTA in LANCE detection buffer containing 50 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K4mel-2 antibody.
  • test compounds to inhibit the activity of JaridlB was determined in 384-well plate format under the following reaction conditions: 0.8 nM JaridlB, 300 nM H3K4me3-biotin labeled peptide (Anaspec cat # 64357), 2 ⁇ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 ⁇ sodium L-ascorbate, and 2 ⁇ ammonium iron(II) sulfate.
  • Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-mono-or di-methylated histone H3 lysine 4 (H3K4mel-2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 25 nM and 1 nM, respectively.
  • detection Phycolink Streptavidin-allophycocyanin Prozyme
  • H3K4mel-2 Europium-anti-mono-or di-methylated histone H3 lysine 4
  • the assay reaction was initiated by the following: 2 ⁇ of the mixture of 900 nM H3K4me3-biotin labeled peptide and 6 ⁇ alpha-ketoglutaric acid with 2 ⁇ of 11 -point serial diluted inhibitor in 3% DMSO was added to each well of the plate, followed by the addition of 2 ⁇ of 2.4 nM JaridlB to initiate the reaction.
  • the reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 ⁇ of 5 mM EDTA in LANCE detection buffer containing 50 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K4mel-2 antibody.
  • test compounds to inhibit the activity of JMJD2C was determined in 384-well plate format under the following reaction conditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide (Anaspec cat # 64360), 2 ⁇ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 ⁇ sodium L-ascorbate, and 2 ⁇ ammonium iron(II) sulfate.
  • Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.
  • the assay reaction was initiated by the following: 2 ⁇ of the mixture of 900 nM H3K9me3-biotin labeled peptide and 6 ⁇ alpha-ketoglutaric acid with 2 ⁇ of 11 -point serial diluted inhibitor in 3% DMSO were added to each well of the plate, followed by the addition of 2 ⁇ of 0.9 nM JMJD2C to initiate the reaction.
  • the reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 ⁇ of 5 mM EDTA in LANCE detection buffer containing 100 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.
  • test compounds to inhibit the activity of JMJD2A was determined in 384-well plate format under the following reaction conditions: 2 nM JMJD2A, 300 nM H3K9me3-biotin labeled peptide (Anaspec cat # 64360), 2 ⁇ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 ⁇ sodium L-ascorbate, and 2 ⁇ ammonium iron(II) sulfate.
  • Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.
  • the assay reaction was initiated by the following: 2 ⁇ of the mixture of 900 nM H3K9me3-biotin labeled peptide and 6 ⁇ alpha-ketoglutaric acid with 2 ⁇ of 11 -point serial diluted inhibitor in 3% DMSO were added to each well of plate, followed by the addition of 2 ⁇ of 6 nM JMJD2A to initiate the reaction.
  • the reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 ⁇ of 5 mM EDTA in LANCE detection buffer containing 100 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.
  • Biochemical assay IC 50 data are designated within the following ranges:
  • Example 2a In Vitro Cell-based Assay - ZR-75-1 cell line
  • This assay is a fluorometric immunoassay for the quantification of tri-methyl H3K4 extracted from cells treated with test compound and is used as a measure of the cellular inhibition of KDM5A/B.
  • ZR-75-1 PTEN null, ER+ breast cancer cells numbering 50,000 (ATCC) were seeded into each well of a 96-well tissue culture treated plate and then exposed to an 1 1 point dilution of test compound with final concentration ranges of test compound ranging from 1250 ⁇ to 10 nM. Cells were left in the presence of test compound for 72 hours. Extracts were prepared containing all of the cellular histone material using detergent based lysis and sonication methods. These lysates were subsequently normalized for total protein content using a colorimetric bicinchonic acid assay ⁇ MicroBCA Pierce/Thermo Scientific).
  • Example 2b In Vitro Cell-based Assay - KYSE-150 cell line
  • the primary cellular assay for JMJD2C inhibition is an assay which measures cellular proliferation via Bromodeoxyuridine (BrdU) incorporation after 168 hours of compound incubation.
  • This assay is a quantitative ELISA assay measuring DNA
  • the KYSE-150 cell line is a JMJD2C gene amplified cell line.
  • Cells treated for 168 hours with test compounds are assayed for their ability to go through S-phase as a measure of their proliferative potential.
  • the human KYSE-150 (SMAD4 mut, TP53 mut) esophageal carcinoma cell line was seeded at 2,000 cells/well on a 96-well tissue culture treated plate. After an overnight incubation, cells were treated with a test compound in an 11 point dilution series with final concentrations ranging from 100 ⁇ to 2 nM. Cells were then incubated in the presence of compound for 168 hours. After compound incubation, the cells were assayed using a BrdU Cell Proliferation ELISA (Roche). The cells were first incubated with BrdU labeling reagent for 2 hours.
  • Table 4 provides the cellular IC 5 o values of various compounds disclosed herein.
  • Time release pellets containing 0.72 mg 17- ⁇ Estradiol are subcutaneously implanted into nu/nu mice.
  • MCF-7 cells are grown in RPMI containing 10% FBS at 5% CO2, 37 °C. Cells are spun down and re-suspended in 50% RPMI (serum free) and 50%> Matrigel at 1X10 7 cells/mL.
  • MCF-7 cells are subcutaneously injected on the right flank 2-3 days post pellet implantation and tumor volume (length x width I ) is monitored bi-weekly. When tumors reach an average volume of -200 mm animals are randomized and treatment is started. Animals are treated with vehicle or compound daily for 4 weeks. Tumor volume and body weight are monitored bi-weekly throughout the study. At the conclusion of the treatment period, plasma and tumor samples are taken for
  • a tablet is prepared by mixing 48% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of low-substituted hydroxypropyl cellulose, and 2%> by weight of magnesium stearate. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 250-500 mg.

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Abstract

The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyrrolopyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

Description

HISTONE DEMETHYLASE INHIBITORS
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application 61/778,193, filed March 12, 2013, the content of which is hereby incorporated by reference in its entirety.
BACKGROUND
[0002] A need exists in the art for an effective treatment of cancer and neoplastic disease.
BRIEF SUMMARY OF THE INVENTION
[0003] Provided herein are substituted pyrrolopyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like. The substituted pyrrolopyridine derivative compounds described herein are based upon a disubstituted pyrrolo[3,2-b]pyridine ring system bearing at the 7-position a carboxylic acid or bioisostere thereof, and a second substituent at the 2-position. The 2-position substituent, in various embodiments, is selected from a wide variety of groups, such as, but not limited to, alkyl, aryl, carbocyclyl, and the like.
[0004] One embodiment provides a compound having the structure of Formula (I),
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof,
wherein,
Y is -CO2R1, -C(0)N(H)CN, -C(0)N(H)OH or tetrazolyl;
R1 is hydrogen or alkyl;
G is X-R 2 or X 1 -alkyl, wherein
X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S02-;
R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl;
XI is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S02-; and
R is hydrogen, halogen or alkyl. [0005] Another embodiment provides the compound of Formula (I) represented by the structure of Formula (II),
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof,
wherein,
R1 is hydrogen or alkyl;
G is X-R 2 or X 1 -alkyl, wherein
X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S02-;
R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl;
XI is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S02-; and
R is hydrogen, halogen or alkyl.
[0006] One embodiment provides a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[0007] One embodiment provides a method for treating cancer in subject comprising administering a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
INCORPORATION BY REFERENCE
[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
[0009] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term
"comprising" (and related terms such as "comprise" or "comprises" or "having" or
"including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of the described features.
Definitions
[0010] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0011] "Amino" refers to the -NH2 radical.
[0012] "Cyano" refers to the -CN radical.
[0013] "Nitro" refers to the -N02 radical.
[0014] "Oxa" refers to the -O- radical.
[0015] "Oxo" refers to the =0 radical.
[0016] "Thioxo" refers to the =S radical.
[0017] "Imino" refers to the =N-H radical.
[0018] "Oximo" refers to the =N-OH radical.
[0019] "Hydrazino" refers to the =N-NH2 radical.
[0020] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C\-C% alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2- C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n- propyl), 1 -methyl ethyl (z'so-propyl), 1 -butyl (n-butyl), 1-methylpropyl (sec-butyl), 2- methylpropyl (z'so-butyl), 1 , 1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0),Ra (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0),Ra (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0021] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O- alkyl, where alkyl is an alkyl chain as defined above.
[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l ,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0),Ra (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0),Ra (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0),Ra (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0),Ra (where t is 1 or 2) and -S(0),N(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or
heteroarylalkyl.
[0024] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0),Ra (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0),Ra (where t is 1 or 2) and -S(0),N(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or
heteroarylalkyl.
[0025] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2,
-Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0),N(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0026] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
[0027] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
[0028] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain. [0029] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula - 0-Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
[0030] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl may be saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as
"cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa,
-Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra,
-Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0031] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
[0032] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -0-Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
[0033] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.
[0034] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
[0035] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa,
-Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0),N(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0036] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the
heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
[0037] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
[0038] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing
heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
[0039] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -0-R°-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
[0040] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,
benzo[£][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5, 6-dihydrobenzo[h] cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9, 10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1 ,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,
5,6,6a,7,8,9, 10,1 Oa-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5.6.7.8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa,
-Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra,
-Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkyl ene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0041] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0042] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0043] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
[0044] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -0-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkyl ene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the
heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
[0045] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,
Figure imgf000013_0001
[0046] The compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are
contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers {e.g., cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers {e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
[0047] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein may, in certain embodiments, exist as tautomers. In circumstances where
tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000014_0001
[0048] "Optional" or "optionally" means that a subsequently described event or
circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
[0049] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the substituted pyrrolopyridine derivative compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
[0050] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
[0051] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al, supra.
[0052] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
[0053] "Prodrug" is meant to indicate a compound that may be converted under
physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism {see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
[0054] A discussion of prodrugs is provided in Higuchi, T., et al, "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
[0055] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
Substituted Pyrrolopyridine Derivative Compounds
[0056] Substituted pyrrolopyridine derivative compounds are described herein that inhibit a histone demethylase enzyme. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and neoplastic disease. The compounds described herein may, therefore, be useful for treating prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.
[0057] One embodiment provides a com ound having the structure of Formula (I),
Figure imgf000017_0001
Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein,
Y is -CO2R1, -C(0)N(H)CN, -C(0)N(H)OH or tetrazolyl;
R1 is hydrogen or alkyl;
G is X-R 2 or X 1 -alkyl, wherein
X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -
SO2-;
2
R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl;
X1 is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S02-; and
R is hydrogen, halogen or alkyl.
[0058] Another embodiment provides the compound having the structure of Formula (I), wherein Y is -CO2R1 and R1 is hydrogen. Another embodiment provides the compound having the structure of Formula (I), wherein Y is -CO2R1 and R1 is alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein Y is - C(0)N(H)CN. Another embodiment provides the compound having the structure of Formula (I), wherein Y is -C(0)N(H)OH. Another embodiment provides the compound having the structure of Formula (I), wherein Y is tetrazolyl.
[0059] Another embodiment provides the compound having the structure of Formula (I), wherein R is hydrogen.
[0060] Another embodiment provides the compound having the structure of Formula (I), wherein G is X-R . Another embodiment provides the compound having the structure of Formula (I), wherein X is a bond and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene and R is aryl.
Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another
embodiment provides the compound having the structure of Formula (I), wherein X is a CI- C3 alkylene and R is aryl. Another embodiment provides the compound having the 2
structure of Formula (I), wherein X is a bond and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein the carbocyclyl is a 1 -hydroxy carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is a bond and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is a bond and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is CI- C3 alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (I), wherein X is CI- C3 alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (I), wherein X is C1-C3 alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is - C(0)-NH- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(0)-NH- and R is heteroaryl. Another embodiment provides
2 the compound having the structure of Formula (I), wherein X is -C(0)-NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -C(0)-NH- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH-C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH-C(O)- and R is heteroaryl. Another embodiment provides the compound having the
2
structure of Formula (I), wherein X is -NH-C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -NH-C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -O- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -O- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -O- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -O- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S02- and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S02- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S02- and R is carbocyclyl. Another 2 embodiment provides the compound having the structure of Formula (I), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein X is -S02- and R is heterocyclyl.
[0061] Another embodiment provides the compound having the structure of Formula (I), wherein G is X^alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is a bond. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a 1-hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C2-C4 1-hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is -C(O)-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is - C(0)-NH-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is -NH-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is - NH-C(O)-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is -0-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is -S-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (I), wherein X1 is -S02-. Another embodiment provides the compound having the structure of Formula (I), wherein the alkyl is a C1-C4 alkyl. Another
embodiment provides the compound having the structure of Formula (I), wherein X is alkylene-O-. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene-O-, and R is aryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene-O-, and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (I), wherein X is alkylene-O-, and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (I), wherein R is C3-C7 carbocyclyl. Another embodiment provides 2 the compound having the structure of Formula (I), wherein X is alkylene-O-, and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula
(I) , wherein the alkylene is a C1-C3 alkylene.
[0062] Another embodiment provides the compound of Formula (I) represented by the structure of Formula (II),
Figure imgf000021_0001
Formula (II)
or a pharmaceutically acceptable salt thereof,
wherein,
R1 is hydrogen or alkyl;
G is X-R 2 or X 1 -alkyl, wherein
X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S02-;
R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl;
XI is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S02-; and
R is hydrogen, halogen or alkyl.
[0063] Another embodiment provides the compound having the structure of Formula (II), wherein R1 is hydrogen. Another embodiment provides the compound having the structure of Formula (II), wherein R1 is alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein G is X-R . Another embodiment provides the compound having the structure of Formula (II), wherein X is a bond and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or
dialkylamino. Another embodiment provides the compound having the structure of Formula
(II) , wherein X is a C1-C3 alkylene and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is a bond and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein the carbocyclyl is a 1 -hydroxy carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is a bond and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is a bond and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another
embodiment provides the compound having the structure of Formula (II), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is C1-C3 alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (II), wherein X is C1-C3 alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (II), wherein X is C1-C3 alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is - C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -C(0)-NH- and R is heterocyclyl. Another embodiment
2 provides the compound having the structure of Formula (II), wherein X is -NH- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH-C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH-C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH-C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -NH-C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -O- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is carbocyclyl. Another embodiment provides the compound having the structure of
2
Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S02- and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S02- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is -S02- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure
2
of Formula (II), wherein X is -S02- and R is heterocyclyl. [0064] Another embodiment provides the compound having the structure of Formula (II), wherein G is X^alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is a bond. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a 1-hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C2-C4 1-hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is -C(O)-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is - C(0)-NH-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is -NH-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is - NH-C(O)-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is -0-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is -S-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X1 is -SO2-. Another embodiment provides the compound having the structure of Formula (II), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is aryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein X is alkylene-O-, and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (II), wherein the alkylene is a C1-C3 alkylene. [0065] One embodiment provides a compound having the structure of Formula (la),
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof,
wherein,
Y is -CO2R1, -C(0)NH-(C1-C3)alkyl, -C(0)N(H)CN, -C(0)N(H)OH or tetrazolyl;
R1 is hydrogen, alkyl, heterocyclylalkyl, or carbocyclylalkyl;
G is X-R 2 or X 1 -alkyl, wherein
X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S02-;
R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl;
XI is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S02-; and
R is hydrogen, halogen or alkyl.
[0066] Another embodiment provides the compound having the structure of Formula (la), wherein Y is -CO2R1 and R1 is hydrogen. Another embodiment provides the compound having the structure of Formula (la), wherein Y is -CO2R1 and R1 is alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein Y is - CO2R1 and R1 is heterocyclylalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein Y is -CO2R1 and R1 is carbocyclylalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein Y is - C(0)NH-(C1-C3)alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein Y is -C(0)N(H)CN. Another embodiment provides the compound having the structure of Formula (la), wherein Y is -C(0)N(H)OH. Another embodiment provides the compound having the structure of Formula (la), wherein Y is tetrazolyl.
[0067] Another embodiment provides the compound having the structure of Formula (la), wherein R is hydrogen.
[0068] Another embodiment provides the compound having the structure of Formula (la), wherein G is X-R . Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is aryl.
Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (la), wherein X is a C1-C3 alkylene and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein the carbocyclyl is a 1 -hydroxy carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is a bond and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is CI- C3 alkylene and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
Another embodiment provides the compound having the structure of Formula (la), wherein X is C1-C3 alkylene and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino. Another embodiment provides the compound having the structure of Formula (la), wherein X is C1-C3 alkylene and R is heterocyclyl. Another embodiment provides the compound having the structure of
2
Formula (la), wherein X is -C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -C(0)-NH- and R is aryl. Another embodiment provides the compound 2
having the structure of Formula (la), wherein X is -C(0)-NH- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is - C(0)-NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -C(0)-NH- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH- and R is heterocyclyl. Another
embodiment provides the compound having the structure of Formula (la), wherein X is - NH-C(O)- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH-C(O)- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH-C(O)- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -NH-C(O)- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -O- and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -S- and R is heterocyclyl. Another embodiment provides the compound
2
having the structure of Formula (la), wherein X is -S02- and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is - SO2- and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is -SO2- and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3-C7 carbocyclyl.
Another embodiment provides the compound having the structure of Formula (la), wherein X is -SO2- and R is heterocyclyl.
[0069] Another embodiment provides the compound having the structure of Formula (la), wherein G is X^alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is a bond. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a 1- hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C2-C4 1 -hydroxyalkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is -C(O)-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is -C(0)-NH-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is -NH-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is -NH-C(O)-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is -O- . Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is -S-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X1 is - SO2-. Another embodiment provides the compound having the structure of Formula (la), wherein the alkyl is a C1-C4 alkyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-, and R is aryl. Another embodiment provides the compound having the structure of Formula (la), wherein 2
X is alkylene-Ο-, and R is heteroaryl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-, and R is carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein R is C3- C7 carbocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein X is alkylene-O-, and R is heterocyclyl. Another embodiment provides the compound having the structure of Formula (la), wherein the alkylene is a Cl- C3 alkylene.
[0070] In some embodiments, the compound of Formula (I), (la), or (II) as disclosed herein has the structure provided in Table 1.
Figure imgf000029_0001
Figure imgf000030_0001
carboxylic acid
Figure imgf000031_0001
carboxylate
Figure imgf000032_0001
carboxylate
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
carboxylic acid
Figure imgf000037_0001
carboxylate
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
N Cr acid
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
[0071] In additional embodiments, the compound of Formula (I), (la), or (II) is selected from a compound provided in Table 2, or alkyl ester derivative thereof.
TABLE 2
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000050_0001
,2-
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Preparation of the Substituted Pyrrolopyridine Derivative Compounds
[0072] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals
(Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).
[0073] Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al, "Organic Functional Group
Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,
"Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March,
"Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed.,
Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0- 19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1 ; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0- 471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527- 29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[0074] Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the substituted pyrrolopyridine derivative compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. [0075] The substituted pyrrolopyridine derivative compounds are prepared by the general synthetic routes described below in Schemes 1 and 2.
Scheme 1
Figure imgf000057_0001
[0076] Referring to Scheme 1, compound A and terminal alkyne compound B are combined and treated under a variety of palladium-mediated Sonogashira cross-coupling conditions to form compound C. For example, the mixture of compound A and an alkyne B can be subjected to conditions similar to procedures described in literature (Tetrahedron Lett. 1975, 4467-4470; Org. Lett. 2006, 3307-3310) using various catalyst, co-catalyst, ligand, base, and solvent, at temperatures ranging from 40 °C to 100 °C. The azaindole compound D can be prepared by cycloisomerization of compound C using a base, such as KOtBu at 0 °C, or catalyzed by Cul at temperature ranging from 100 °C to 140 °C. Acid compound E can be prepared by hydrolysis of ester compound D using base, such as NaOH, or by other conditions known in the art for ester hydrolysis.
Scheme 2
Figure imgf000057_0002
[0077] Referring to Scheme 2, compound A and a ketone compound F are mixed and treated to palladium-mediated direct annulation conditions to form compound D. For example, the mixture of compound A and an ketone B can be subjected to conditions similar to procedures described in literature (Angew. Chem. Int. Ed. 2004, 4526-4528) using a Pd catalyst, ligand, acid, base, and solvent, at temperatures range up to 140 °C. [0078] In each of the above reaction procedures or schemes, the various substituents may be selected from among the various substituents otherwise taught herein.
Pharmaceutical Compositions
[0079] In certain embodiments, a substituted pyrrolopyridine derivative compound as described herein is administered as a pure chemical. In other embodiments, the substituted pyrrolopyridine derivative compound as described herein is combined with a
pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in
Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference, in its entirety.
[0080] Accordingly, provided herein is a pharmaceutical composition comprising at least one substituted pyrrolopyridine derivative compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient {i.e., the subject) of the composition.
[0081] One embodiment provides a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0082] One embodiment provides a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of Formula (la), or a pharmaceutically acceptable salt thereof.
[0083] One embodiment provides a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
[0084] In certain embodiments, the substituted pyrrolopyridine derivative compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method. [0085] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Suitable nontoxic solid carriers can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,
Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
[0086] The dose of the composition comprising at least one substituted pyrrolopyridine derivative compound as described herein may differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.
[0087] Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the patient.
[0088] Oral doses can typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
Histone Demethylase
[0089] Chromatin is the complex of DNA and protein that makes up chromosomes.
Histones are the major protein component of chromatin, acting as spools around which DNA winds. Changes in chromatin structure are affected by covalent modifications of histone proteins and by non-histone binding proteins. Several classes of enzymes are known which can covalently modify histones at various sites.
[0090] Proteins can be post-translationally modified by methylation on amino groups of lysines and guanidino groups of arginines or carboxymethylated on aspartate, glutamate, or on the C-terminus of the protein. Post-translational protein methylation has been implicated in a variety of cellular processes such as RNA processing, receptor mediated signaling, and cellular differentiation. Post-translational protein methylation is widely known to occur on histones, such reactions known to be catalyzed by histone methyltransferases, which transfer methyl groups from S-adenyosyl methionine (SAM) to histones. Histone methylation is known to participate in a diverse range of biological processes including heterochromatin formation, X-chromosome inactivation, and transcriptional regulation (Lachner et al, (2003) J. Cell Sci. 116:2117-2124; Margueron et al, (2005) Curr. Opin. Genet. Dev. 15: 163-176).
[0091] Unlike acetylation, which generally correlates with transcriptional activation, whether histone methylation leads to transcription activation or repression depends on the particular site of methylation and the degree of methylation (e.g., whether a particular histone lysine residue is mono-, di-, or tri-methylated). However, generally, methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, while methylation on H3K4, H3K36, and H3K79 is generally associated with active gene expression. In addition, tri- and di- methylation of H3K4 generally marks the transcriptional start sites of actively transcribed genes, whereas mono-methylation of H3K4 is associated with enhancer sequences.
[0092] A "demethylase" or "protein demethylase," as referred to herein, refers to an enzyme that removes at least one methyl group from an amino acid side chain. Some demethylases act on histones, e.g., act as a histone H3 or H4 demethylase. For example, an H3
demethylase may demethylate one or more of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4 demethylase may demethylate histone H4K20. Demethylases are known which can demethylate either a mono-, di- and/or a tri-methylated substrate. Further, histone demethylases can act on a methylated core histone substrate, a
mononucleosome substrate, a dinucleosome substrate and/or an oligonucleosome substrate, peptide substrate and/or chromatin (e.g., in a cell-based assay).
[0093] The first lysine demethylase discovered was lysine specific demethylase 1
(LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 or H3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC) domain containing histone demthylases were predicted, and confirmed when a H3K36 demethylase was found using a formaldehyde release assay, which was named JmjC domain containing histone
demethylase 1 (JHDM1/KDM2A).
[0094] More JmjC domain-containing proteins were subsequently identified and they can be phylogenetically clustered into seven subfamilies: JHDM1, JHDM2, JHDM3, JMJD2, J ARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.
JMJD2 Family [0095] The JMJD2 family of proteins are a family of histone-demethylases known to demethylate tri- and di-methylated H3-K9, and were the first identified histone tri-methyl demethylases. In particular, ectopic expression of JMJD2 family members was found to dramatically decrease levels of tri-and di-methylated H3-K9, while increasing levels of mono-methylated H3- K9, which delocalized Heterochromatin Protein 1 (HP1) and reduced overall levels of heterochromatin in vivo. Members of the JMJD2 subfamily of jumonji proteins include JMJD2C and its homologues JMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found in the JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD and Tdr sequences.
[0096] JMJD2C, also known as GASC1 and KDM4C, is known to demethylate tri- methylated H3K9 and H3K36. Histone demethylation by JMJD2C occurs via a
hydroxylation reaction dependent on iron and a-ketoglutarate., wherein oxidative decarboxylation of a-ketoglutarate by JMJD2C produces carbon dioxide, succinate, and ferryl and ferryl subsequently hydroxylates a methyl group of lysine H3K9, releasing formaldehyde. JMJD2C is known to modulate regulation of adipogenesis by the nuclear receptor PPARy and is known to be involved in regulation of self-renewal in embryonic stem cells.
JARID Family
[0097] As used herein, a "JARID protein" includes proteins in the JARIDl subfamily (e.g., JARIDIA, JARID IB, JARID 1C and JARID ID proteins) and the JARID2 subfamily, as well as homologues thereof. A further description and listing of JARID proteins can be found in Klose et al. (2006) Nature Reviews/Genetics 7:715-727. The JARIDl family contains several conserved domains: JmjN, ARID, JmjC, PHD and a C5HC2 zing finger.
[0098] JARIDIA, also called KDM5A or RBP2, was initially found as a binding partner of retinoblastoma (Rb) protein. JARIDIA was subsequently found to function as a demethylase of tri- and di-methylated H3K4 , and has been found to promote cell growth, while inhibiting senescence and differentiation. For instance, abrogation of JARIDIA from mouse cells inhibits cell growth, induces senescence and differentiation, and causes loss of pluripotency of embryonic stem cells in vitro. JARIDIA has been found to be
overexpressed in gastric cancer and the loss of JARIDIA has been found to reduce tumorigenesis in a mouse cancer model. Additionally, studies have demonstrated that loss of the retinoblastome binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rbl or Menl (Lin etal. Proc. Natl. Acad. Sci. USA, August 16, 2011, 108(33), 13379-86; doi: 10.1073/pnas. l 110104108) and lead to the conclusion that RBP2-inhibitory drugs would have anti-cancer activity.
[0099] JARIDIB, also referred to as KDM5B and PLU1, was originally found in experiments to discover genes regulated by the HER2 tyrosine kinase. JARIDIB has consistently been found to be expressed in breast cancer cell lines, although restriction of JARIDIB has been found in normal adult tissues, with the exception of the testis. In addition, 90% of invasive ductal carcinomas have been found to express JARIDIB. In addition, JARIDIB has been found to be up-regulated in prostate cancers, while having more limited expression in benign prostate, and has also been found to be up-regulated in bladder cancer and lung cancer (both SCLC and NSCLC). JARIDIB has also been found to repress tumor suppressor genes such as BRCA1, CAV1 and 14-3-3σ, and knockdown of JARIDIB was found to increase the levels of tri-methylated H3K4 at these genes.
[00100] In an additional embodiment is a method for inhibiting a histone- demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[00101] In an additional embodiment is a method for inhibiting a histone- demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (la), or a pharmaceutically acceptable salt thereof.
[00102] In an additional embodiment is a method for inhibiting a histone- demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
[00103] In an additional embodiment is the method for inhibiting a histone- demethylase enzyme, wherein the histone-demethylase enzyme comprises a JmjC domain. In an additional embodiment is the method for inhibiting a histone-demethylase enzyme, wherein the histone-demethylase enzyme is selected from JARIDIA, JARIDIB, JMJD2C, or JMJD2A.
Methods of Treatment
[00104] Disclosed herein are methods of modulating demethylation in a cell or in a subject, either generally or with respect to one or more specific target genes. Demethylation can be modulated to control a variety of cellular functions, including without limitation: differentiation; proliferation; apoptosis; tumorigenesis, leukemogenesis or other oncogenic transformation events; hair loss; or sexual differentiation. For example, in particular embodiments, the invention provides a method of treating a disease regulated by histone methylation and/or demethylation in a subject in need thereof by modulating the activity of a demethylase comprising a JmjC domain (e.g., a histone demethylase such as a JHDM protein(s)).
[00105] In an additional embodiment is a method for treating cancer in subject comprising administering a composition comprising a compound of Formula (I), (la), or (II), or a pharmaceutically acceptable salt thereof.
[00106] In a further embodiment is the method for treating cancer in a subject wherein the cancer is selected from prostate cancer, breast cancer, bladder cancer, lung cancer or melanoma.
[00107] In an additional embodiment is a method for inhibiting the growth of a tumor comprising administering a composition comprising a compound of Formula (I), (la), or (II), or a pharmaceutically acceptable salt thereof, wherein the tumor is characterized by a loss of retinoblastoma gene (RBI) function.
[00108] In an additional embodiment is a method for inhibiting the growth of a tumor comprising administering a composition comprising a compound of Formula (I), (la), or (II), or a pharmaceutically acceptable salt thereof, wherein the tumor is characterized by a loss of multiple endocrine neoplasia type 1 gene (Menl) function.
[00109] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.
EXAMPLES
I. Chemical Synthesis
[00110] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants, J are reported in Hertz. For proton spectra the solvent peak was used as the reference peak. Example 1: 3-chloro-lH-pyrrolo[3 -b]pyridine-7-carboxylic acid
Figure imgf000064_0001
[00111] To a vial charged with lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid (130 mg,
0.8 mmol) in acetonitrile (2 mL) was added NCS (133.5 mg, 1.0 mmol). The reaction was allowed to stir at 70 °C for 2 h. The reaction was quenched with water and pH adjusted to ~3 with HC1 (I N). The precipitate was filtered and washed successively with water, ethanol, and dried in vacuo to afford the title compound (79 mg, 40%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (d, J=4.80 Hz, 1 H), 7.82 (d, J=3.03 Hz, 1 H), 8.56 (d, J=4.80 Hz, 1 H), 11.54 - 11.87 (m, 1 H), 13.90 (br. s., 1 H). [M+H] calc'd for
C8H5N202C1, 197; found 197.
Example 2: 2-phenyl-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000064_0002
[00112] Methyl 3-amino-2-chloroisonicotinate (187 mg, 1.0 mmol), Pd(PPh3)2Cl2 (35 mg, 0.05 mmol), Cul (38 mg, 0.20 mmol), TEA (278 μΕ,2.0 mmol) and phenylacetylene (130 mg, 1.2 mmol) were suspended in DMF (2mL). N2 was bubbled into the reaction for 2 min and it was allowed to stir at 100 °C for 16 hrs. The reaction was concentrated in vacuo and purified by column chromatography (0-50% gradient of EtO Ac/Hex) to afford methyl 3-amino-2-(phenylethynyl)pyridine-4-carboxylate (195 mg, 77%) as a brown foam. [M+H] calc'd for C14H10N2O2, 239; found 239.
[00113] Methyl 3-amino-2-(phenylethynyl)pyridine-4-carboxylate (50 mg, 0.2 mmol) in NMP (1 mL) was added KO-t-Bu (67.5 mg, 0.6 mmol) and allowed to stir for 2 h. Water was added and the pH was adjusted to ~3 with HC1 (IN). The precipitate was filtered and the filter cake was successively washed with water followed by ethanol to afford the title compound as a white solid (34 mg, 74%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.18 (s, 1 H), 7.38 - 7.63 (m, 5 H), 8.02 (d, J=7.33 Hz, 2 H), 8.36 - 8.62 (m, 1 H). [M+H] calc'd for C14H10N2O2, 239; found 239. Example 3: 2-(2-methylphenyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000065_0001
[00114] The title compound was prepared in 64% yield using 2-ethynyltoluene according to the procedure for the preparation of Example 2. 1H NMR (400 MHz, DMSO- d6): δ ppm 2.43 (s, 3 H), 6.80 (s, 1 H), 7.30 - 7.42 (m, 3 H), 7.45 - 7.66 (m, 2 H), 8.49 (d, J=4.80 Hz, 1 H), 11.21 (br. s., 1 H), 13.66 (br. s., 1 H). [M+H] calc'd for Ci5H12N202, 253; found 253.
Example 4: methyl 2-(2-hydrox ropan-2-yl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000065_0002
[00115] Methyl 3-amino-2-chloroisonicotinate (186mg, lmmol), PdCl2(CH3CN)2
(5.2 mg, 0.02 mmol), X-Phos (19 mg, 0.04 mmol), K2C03(278 mg, 2.0 mmol), and 2- methyl-3-butyn-2-ol(130 mg, 1.2 mmol) in CH3CN (2 mL) was purged with N2 for 2 min. The reaction was allowed to stir at 80 °C for 16 hrs. The reaction was concentrated in vacuo and purified by column chromatography (0-50% gradient of EtO Ac/Hex) to afford methyl 3 -amino-2-(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)pyridine-4-carboxylate (191 mg, 81%).
[M+H] calc'd for Ci2Hi4N203, 235; found 235.
[00116] Methyl 3 -amino-2-(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)pyridine-4-carboxylate
(191 mg,0.82 mmol) and Cul (47.5 mg, 0.25 mmol) in DMF (2 mL) was purged with N2 for 2 min, and the reaction was allowed to stir at 110 °C for 2 hrs. The reaction mixture was concentrated and purified by column chromatography (0-50% gradient of EtO Ac/Hex) to afford the title compound as an amorphous solid (172 mg, 74%).1H NMR (400 MHz, DMSO-de): δ ppm 2.43 (s, 3 H), 6.80 (s, 1 H), 7.30 - 7.42 (m, 3 H), 7.45 - 7.66 (m, 2 H), 8.49 (d, J=4.80 Hz, 1 H), 11.21 (br. s., 1 H), 13.66 (br. s., 1 H). [M+H] calc'd for
Ci2H14N203, 235; found 235. Example 5: 2-(2-hydroxypropan-2-yl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000066_0001
[00117] To methyl 2-(2-hydroxypropan-2-yl)-lH-pyrrolo[3,2-b]pyridine-7- carboxylate (100 mg, 0.45 mmol) in MeOH (lmL) was added NaOH (75 μΐ., IN), and the reaction stirred at 60 °C for 30 min. HC1 (Ί5μΙ^, IN) was added at ambient temperature to give a suspension. The solid was filtered and washed successively with water followed by ethanol and dried in vacuo to afford the title compound (68 mg, 69%) as an off-white solid, 1H NMR (400 MHz, DMSO-d6): δ ppm 1.50 (s, 6 H), 5.56 (br. s., 1 H), 6.40 (s, 1 H), 7.41 (d, J=5.05 Hz, 1 H), 8.33 (d, J=4.80 Hz, 1 H), 10.30 (br. s., 1 H). [M+H] calc'd for C11H12N2O3, 221; found 221.
Example 6: methyl 2-benzyl-l -pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000066_0002
[00118] The title compound was prepared in 60% yield using 3-phenyl-propyne according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDCI3): δ ppm 3.98 (s, 3 H), 4.22 (s, 2 H), 6.59 - 6.63 (m, 1 H), 7.27 - 7.42 (m, 5 H), 7.55 (d, J=4.80 Hz, 1 H), 8.50 (d, J=5.05 Hz, 1 H), 9.26 (br. s., 1 H). [M+H] calc'd for C16H14N2O2, 267; found 267.
Example 7: 2-benzyl-lH-pyrro -b]pyridine-7-carboxylic acid, sodium salt
Figure imgf000066_0003
[00119] The title compound was prepared in 94% yield with methyl 2-benzyl-lH- pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. The title compound (67 mg, 0.27 mmol) was taken up in CH3CN/water (1 : 1) and NaOH (293 μΕ, IN) and lyophilized for 16 hrs to afford the sodium salt. 1H NMR (400 MHz, DMSO-de): δ ppm 4.11 (s, 2 H), 6.12 (d, J=2.02 Hz, 1 H), 7.17 (d, J=4.80 Hz, 2 H), 7.21 - 7.31 (m, 4 H), 8.08 (d, J=4.80 Hz, 1 H), 10.66 (br. s., 1 H). [M+H] calc'd for Ci5H12N202, 253; found 253.
Example 8: 2-propyl-lH-pyrrol -b]pyridine-7-carboxylic acid
Figure imgf000067_0001
[00120] The title compound was prepared in 28% yield using 1-pentyne according to the procedures for the preparation of Examples 4 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.84 - 0.97 (m, 3H), 1.67 (m, 2H), 6.52 (s, 1 H), 7.57 - 7.70 (m, 1 H), 8.42 - 8.59 (m, 1 H), 11.79 (br. s., 1 H). [M+H] calc'd for CnH12N202, 205; found 205.
Example 9: methyl-2-(hydroxymeth l)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000067_0002
[00121] Methyl 3-amino-2-chloroisonicotinate (1.04 g, 5.64 mmol), propargyl alcohol (393 μΕ, 6.76 mmol), Pd(PPh3)2Cl2 (198 mg, 0.28 mmol), Cul (28 mg, 0.14 mmol), and TEA (2.84 g, 28.18 mmol) were combined in acetonitrile (20 mL). The reaction was purged with nitrogen for 2 min and then was stirred at 40 °C for 16 hrs. The reaction was concentrated in vacuo and the residue suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (PE/EA = 3/1 ~ 1/1) to afford methyl 3-amino-2-(3-hydroxyprop-l-yn-l-yl)pyridine-4- carboxylate (200 mg, 18%). 1H NMR (300 MHz, DMSO-d6): δ 3.86 (3H, s), 4.39 (2H, d, J = 8.0 Hz), 5.42 (1H, t, J= 8.0 Hz), 6.24 (2H, s), 7.55 (1H, d, J= 6.4 Hz), 7.81 (1H, d, J = 5.6 Hz). [M+H] Calc'd for Ci0Hi0N2O3, 207; Found, 207.
[00122] Methyl 3-amino-2-(3-hydroxyprop-l-yn-l-yl)pyridine-4-carboxylate (476 mg, 2.31 mmol), CaC03 (427 mg, 4.27 mmol), Cul (203 mg, 1.07 mmol), and DMF (10 mL) was purged with nitrogen and stirred for one hour at 120 °C. The reaction was concentrated in vacuo and the residue suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatograph (PE/EA = 3/1 -1/1) to afford title the compound (40 mg, 20%). 1H NMR (400 MHz, DMSO-de) δ 3.98 (3H, s), 4.72 (2H, d, J= 6.8 Hz), 5.37 (1H, t, J= 8.4 Hz), 6.57 (1H, t, J = 1.6 Hz), 7.52 (1H, d, J= 6.8 Hz), 8.42 (1H, d, J= 6.4 Hz), 11.11 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 1.970 min. [M+H] Calc'd for Ci0H10N2O3, 207; Found, 207.
Example 10: 2-(hydroxymethyl)- -pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000068_0001
[00123] The title compound was prepared in 37% yield using methyl-2-
(hydroxymethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.76 (s, 2 H), 6.67 (s, 1 H), 7.68 (d, J=5.31 Hz, 1 H), 8.53 (d, J=5.31 Hz, 1 H), 11.63 (br. s., 1 H). [M+H] calc'd for C9H8N203, 193; found 193.
Example 11: methyl 2-cyclopro l-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000068_0002
[00124] The title compound was prepared in 54% yield using cyclopropylacetylene according to the procedure for the preparation of Example 4. 1H NMR (400 MHz,CDCl3): δ ppm 0.79 - 0.98 (m, 2 H), 1.00 - 1.17 (m, 2 H), 1.96 - 2.21 (m, 1 H), 4.02 (s, 3 H), 6.38 (s, 1 H), 7.51 (d, J=5.05 Hz, 1 H), 8.47 (d, J=5.05 Hz, 1 H), 9.38 (br. s., 1 H). [M+H] calc'd for Ci2H12N202, 217; found 217.
Example 12: 2-cyclopropyl-lH- rrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000068_0003
[00125] The title compound was prepared in 85% yield using methyl 2-cyclopropyl- lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5.1H NMR (400 MHz, DMSO-t ί): δ ppm 0.99 (dd, J=4.80, 2.27 Hz, 1H), 1.21 (dd, J=8.34, 2.53 Hz, 1H), 6.36 (d, J=1.77 Hz, 1H), 7.69 (d, J=5.56 Hz, 1H), 8.50 (d, J=5.56 Hz, 1H), 12.31 (br. s., 1 H) [M+H] calc'd for CnHi0N2O2, 203; found 203. Example 13: methyl 2-(l-hydroxycyclohexyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000069_0001
[00126] The title compound was prepared in 62% yield using 1-ethynylcyclohexanol according to the procedure for the preparation of example 4. 1H NMR (400 MHz, CDCI3): δ ppm 1.61 - 2.37 (m, 11 H), 4.03 (s, 3 H), 6.59 (d, J=2.27 Hz, 1 H), 7.54 - 7.78 (m, 1 H), 8.51 (d, J=4.80 Hz, 1 H), 9.73 (br. s., 1 H). [M+H] calc'd for Ci5H18N203, 275; found 275.
Example 14: 2-(l-hydroxycyclohexyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000069_0002
[00127] The title compound was prepared in 85% yield using methyl 2-(l- hydroxycyclohexyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.46 - 1.59 (m, 2 H), 1.59 - 1.96 (m, 8 H), 5.36 (s, 1 H), 6.50 (d, J=2.02 Hz, 1 H), 7.49 (d, J=5.05 Hz, 1 H), 8.41 (d, J=4.80 Hz, 1 H), 10.32 (br. s., 1 H), 13.81 (br. s., 1 H). [M+H] calc'd for
Ci4Hi6N203, 261; found 261.
Example 15: methyl 2-(4-methoxy-2-methylphenyl)-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000069_0003
[00128] The title compound was prepared in 23% yield using l-ethynyl-4-methoxy-
2-methylbenzene according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDC13): δ ppm 2.52 (s, 3 H), 3.87 (s, 3 H), 4.05 (s, 3 H), 6.86 - 7.00 (m, 3 H), 7.48 (d, J=8.08 Hz, 1 H), 7.63 (d, J=5.05 Hz, 1 H), 8.56 (d, J=5.31 Hz, 1 H), 9.61 (br. s., 1 H). [M+H] calc'd for Ci7Hi6N203, 297; found 297. Example 16: 2-(4-methoxy-2-methylphenyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000070_0001
[00129] The title compound was prepared in 95% yield using methyl 2-(4-methoxy-
2-methylphenyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.42 (s, 3 H), 3.81 (s, 3 H), 6.72 (s, 1 H), 6.85 - 7.02 (m, 2 H), 7.50 (dd, J=13.52, 6.69 Hz, 2 H), 8.45 (d, J=4.80 Hz, 1 H), 11.02 (br. s., 1 H), 13.59 - 13.76 (m, 1 H). [M+H] calc'd for Ci6H14N203 , 283; found 283.
Example 17: (+)-methyl 2-(l-hydroxyethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000070_0002
[00130] The title compound was prepared in 9% yield using (+)-propyn-3-ol according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CDC13): δ ppm 1.68 (3H, d, J= 6.4 Hz), 4.02 (3H, s), 5.18 (1H, q, J= 6.4 Hz), 6.61 (1H, s), 7.69 (1H, d, J= 4.8 Hz), 8.52 (1H, d, J= 4.8 Hz), 9.68 (1H, s). LCMS (mobile phase: 5-60%
Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.852 min. [M+H] calc'd for CiiHi2N203 , 221; found 221.
Example 18: (+)-2-(l-hydroxyethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000070_0003
[00131] The title compound was prepared in 68%> yield using (+)-methyl 2-(l- hydroxyethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.49 (3H, d, J= 6.4 Hz), 5.00 (1H, m), 5.50 (1H, s), 6.51 (1H, d, J= 2.0 Hz), 7.49 (1H, d, J= 5.2 Hz), 8.41 (1H, d, J = 4.8 Hz), 10.80 (1H, s). LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.688 min. [M+H] calc'd for Ci0Hi0N2O3, 207; found 207. Example 19: (+)-methyl 2-[hydroxy(phenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000071_0001
[00132] The title compound was prepared in 3% yield using (+)-l -phenyl-2-propyn- l-ol according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CDCls): δ ppm 3.96 (3H, s), 6.06 (IH, s), 6.54 (IH, s), 7.27-7.31 (3H, m), 7.33-7.40 (2H, m), 7.57 (IH, d, J= 5.2 Hz), 8.42 (IH, d, J= 5.2 Hz), 9.71 (IH, s). LCMS (mobile phase: 10-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.978 min. [M+H] calc'd for Ci6H14N203, 283; found 283.
Example 20: (+)-2-[hydroxy(phenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000071_0002
[00133] The title compound was prepared in 68%> yield using (+)-methyl 2-
[hydroxy(phenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 6.05 (IH, d, J= 4.0 Hz), 6.20 (IH, d, J= 4.8 Hz), 6.43 (IH, d, J= 1.2 Hz), 7.25-7.29 (IH, m), 7.33-7.37 (2H, m), 7.46-7.51 (3H, m), 8.42 (IH, d, J= 4.8 Hz), 10.94 (IH, s). LCMS (mobile phase: 5-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.217 min. [M+H] calc'd for Ci5H12N203 , 269; found 269. Example 21: (+)-Methyl 2-[hydroxy-(3-methylphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine- 7-carboxylate
Figure imgf000072_0001
[00134] The title compound was prepared in 27% yield using (+)-l-(3- methylphenyl)prop-2-yn-l-ol according to the procedure for the preparation of example 4. 1H NMR (400 MHz,CDCl3): δ ppm 2.36 (s, 4 H), 4.02 (s, 3 H), 6.08 (s, 1 H), 6.56 - 6.63 (m, 1 H), 7.14 - 7.20 (m, 1 H), 7.28 - 7.34 (m, 2 H), 7.61 (d, J=5.05 Hz, 1 H), 8.51 (d, J=5.05 Hz, 1 H), 9.68 (br. s., 1 H). [M+H] calc'd for Ci7Hi6N203, 297; found 297.
Example 22: (+)-2-[hydroxy-(3-methylphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000072_0002
[00135] The title compound was prepared in 90% yield using (+)-methyl 2-[hydroxy-
(3-methylphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.29 (s, 3 H), 6.00 (d, J=5.56 Hz, 1 H), 6.15 (d, J=5.05 Hz, 1 H), 6.39 - 6.50 (m, 1 H), 7.04 - 7.13 (m, 1 H), 7.24 (s, 3 H), 7.48 (s, 1 H), 8.40 (d, J=4.80 Hz, 1 H), 10.86 (br. s., 1 H), 13.75 (br. s., 1 H). [M+H] calc'd for Ci6H14N203, 283; found 283. Example 23: (+)-methyl 2-[hydroxy-(3-methoxyphenyl)methyl]-lH-pyrrolo[3,2- b]pyridine-7-carboxylate
Figure imgf000073_0001
[00136] The title compound was prepared in 27% yield using (+)-l-(3- methoxyphenyl)prop-2-yn-l-ol according to the procedure for the preparation of Example 4 1H NMR (400 MHz,CDCl3) δ ppm 3.81 (s, 3 H), 4.03 (s, 3 H), 6.10 (s, 1 H), 6.65 (s, 1 H), 6.85 - 6.95 (m, 1 H), 6.99 - 7.07 (m, 2 H), 7.29 - 7.36 (m, 2 H), 7.65 (d, J=5.31 Hz, 1 H), 8.51 (d, J=5.31 Hz, 1 H), 9.77 (br. s., 1 H). [M+H] calc'd for C17H16N2O4, 313; found 313.
Example 24: (+)-2-[hydroxy-(3-methoxyphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000073_0002
[00137] The title compound was prepared in 90% yield using (+)-methyl 2-[hydroxy-
(3-methoxyphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.74 (s, 3 H), 6.01 (d, J=5.31 Hz, 1 H), 6.19 (d, J=5.56 Hz, 1 H), 6.43 (s, 1 H), 6.83 (dd, J=8.08, 2.53 Hz, 1 H), 6.98 - 7.13 (m, 2 H), 7.26 (t, J=7.83 Hz, 1 H), 7.40 - 7.58 (m, 1 H), 8.40 (d, J=5.05 Hz, 1 H), 10.89 (br. s., 1 H), 13.77 (br. s., 1 H). [M+H] calc'd for Ci6H14N204, 299; found 299.
Example 25: (+)-methyl 2-(l-hydroxypropyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000073_0003
[00138] The title compound was prepared in 3%> yield using (+)-l -pentyn-3-ol according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CDC13): δ 0.94 (3H, t, J= 7.2 Hz), 1.84-1.88 (2H, m), 3.62 (IH, bs), 3.94 (3H, s), 4.85 (IH, t, J= 5.6 Hz), 6.46 (IH, s), 7.49 (IH, s), 8.36 (IH, s), 9.74 (IH, s). LCMS (mobile phase: 10-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.523 min. [M+H] calc'd for Ci2Hi4N203, 235; found 235.
Example 26: (+)-2-(l-hydroxypropyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000074_0001
[00139] The title compound was prepared in 50%> yield using (+)-methyl 2-(l- hydroxypropyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 0.92 (3H, t, J= 7.2 Hz), 1.72-1.89 (2H, m), 4.76-4.81(lH, m), 5.43 (IH, d, J= 5.6 Hz), 6.51 (IH, d, J= 2.0 Hz), 7.49 (IH, d, J= 5.2 Hz), 8.40 (IH, d, J= 5.2 Hz), 10.75 (IH, s). LCMS (mobile phase: 0- 60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.887 min. [M+H] calc'd for CiiH12N203, 221; found 221.
Example 27: 2-(l-hydroxycyclopentyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000074_0002
[00140] The title compound was prepared in 37%> yield using 1-ethynylcyclopropanol according to the procedure for the preparation of Examples 4 and 5. 1H NMR (400 MHz, DMSO-dg): δ ppm 1.71 - 2.15 (m, 8 H), 5.43 (s, 1 H), 6.52 (d, J=1.77 Hz, 1 H), 7.49 (d, J=4.80 Hz, 1 H), 8.42 (br. s., 1 H), 10.40 (br. s., 1 H), 13.81 (br. s., 1 H). [M+H] calc'd for Ci3Hi4N203 , 247; found 247. Example 28: methyl 2-cyclopentyl-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000075_0001
[00141] The title compound was prepared in 40% yield using 1-ethynylcyclopentane according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDC13): δ ppm 1.76 - 1.91 (m, 6 H), 2.12 - 2.27 (m, 2 H), 3.21 - 3.35 (m, 1 H), 4.04 (s, 3 H), 6.59 (d, J=1.01 Hz, 1 H), 7.57 (d, J=5.05 Hz, 1 H), 8.48 (d, J=5.05 Hz, 1 H), 9.28 - 9.55 (m, 1 H). [M+H] calc'd for Ci4H16N202 , 245; found 245.
Example 29: 2-cyclopentyl-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000075_0002
[00142] The title compound was prepared in 83% yield using 2-cyclopentyl-lH- pyrrolo[3,2-b]pyridine-7-carboxylic acid according to procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.56 - 1.84 (m, 6 H), 1.98 - 2.20 (m, 2 H), 3.36 - 3.42 (m, 1 H), 6.41 (s, 1 H), 7.39 - 7.49 (m, 1 H), 7.43 (d, J=4.55 Hz, 1 H), 8.35 (d, J=4.80 Hz, 1 H), 11.03 (br. s., 1 H), 13.61 (br. s., 1 H). [M+H] calc'd for Ci3Hi4N202, 231; found 231.
Example 30: (+)-methyl 2-(l-hydroxy-2-methylpropyl)-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000075_0003
[00143] The title compound was prepared in 7% yield using (+)-4-methyl-pentyn-3- ol according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CDC13): δ ppm 0.93 (6H, d, J= 6.8 Hz), 2.04-2.11 (1H, m), 3.98 (3H, s), 4.74 (1H, d, J = 6.0 Hz), 6.58 (1H, d, J= 2.0 Hz), 7.56 (1H, d, J= 5.2 Hz), 8.43 (1H, d, J= 5.2 Hz), 9.70 (1H, s). LCMS (mobile phase: 10-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.826 min. [M+H] calc'd for Ci3Hi6N203, 249; found 249. Example 31 : (+)-2-( 1 -hydroxy-2-methylpropyl)- 1 H-pyrrolo [3 ,2-b]pyridine-7-carboxylic acid
Figure imgf000076_0001
[00144] The title compound was prepared in 30% yield using (+)-methyl 2-(l- hydroxy-2-methylpropyl)-l H-pyrrolo [3, 2-b]pyridine-7-carboxylate according to procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.88 (6H, d, J = 6.8 Hz), 2.03-2.08 (1H, m), 4.63-4.64 (1H, m), 5.42-5.44 (1H, m), 6.52 (1H, d, J= 2.0 Hz), 7.50 (1H, d, J= 5.2 Hz), 8.42 (1H, d, J= 5.2 Hz), 10.76 (1H, s). LCMS (mobile phase: 0- 60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.175 min. [M+H] calc'd for Ci2H14N203, 235; found 235.
Example 32: (+)-methyl 2- [cyclopropyl(hydroxy)methyl]-l H-pyrrolo [3, 2-b]pyridine-7- carboxylate
Figure imgf000076_0002
[00145] The title compound was prepared in 7% yield using (+)-3- cyclopropylpropyn-3-ol according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CDC13): δ ppm 0.57-0.65 (2H, m), 0.76-0.83 (2H, m), 1.39-1.46 (1H, m), 4.09 (3H, s), 4.37 (1H, d, J= 8.4 Hz), 6.80 (1H, s), 7.68 (1H, bs), 8.59 (1H, br), 9.81 (1H, s). LCMS (mobile phase: 10-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.555 min. [M+H] calc'd for Ci3H14N203, 247; found 247. Example 33: (+)-2-[cyclopropyl(hydroxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000077_0001
[00146] The title compound was prepared in 30% yield using methyl 2-
[cyclopropyl(hydroxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.42- 0.53 (4H, m), 1.26-1.30 (1H, m), 4.31 (1H, t, J= 6.8 Hz), 5.53 (1H, d, J= 5.6 Hz), 6.57 (1H, d, J= 2.0 Hz), 7.50 (1H, d, J= 4.8 Hz), 8.42 (1H, d, J= 5.2 Hz), 10.68 (1H, s). LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.931 min. [M+H] calc'd for C12H12N2O3, 233; found 233.
Example 34: 2-[(3-methoxyphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000077_0002
[00147] A mixture containing methyl 2-[hydroxy-(3-methoxyphenyl)methyl]-lH- pyrrolo[3,2-b]pyridine-7-carboxylate (31 mg, 0.1 mmol), Et3SiH (160 μί, 1 mmol), and TFA (149 μί, 2 mmol) was stirred at 60 °C for 16 hrs. The reaction was concentrated in vacuo and purified by column chromatography (0-50% EtO Ac/Hex) to afford methyl-2-[(3- methoxyphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate, which was converted to the title compound (21 mg, 70%) according to procedure for Example 5. 1H NMR (400 MHz, DMSO-de): δ ppm 3.66 (s, 4 H), 4.12 (s, 2 H), 6.30 (s, 1 H), 6.73 (d, J=8.34 Hz, 1 H), 6.79 - 6.95 (m, 3 H), 7.15 (t, J=7.83 Hz, 1 H), 7.39 (d, J=4.80 Hz, 1 H), 8.30 (d, J=4.55 Hz, 1 H), 11.19 (br. s., 1 H), 13.60 (br. s., 1 H). [M+H] calc'd for Ci6H14N203, 283; found 283.
Example 35: methyl 2-[(3-methylphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000077_0003
[00148] The title compound was prepared in 74%> yield using methyl 2-[hydroxy-(3- methylphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 34. 1H NMR (400 MHz,CDCl3): δ ppm 2.33 (s, 3 H), 3.97 (s, 3 H), 4.16 (s, 2 H), 6.47 - 6.75 (m, 1 H), 7.07 (s, 3 H), 7.17 - 7.33 (m, 1 H), 7.50 - 7.70 (m, 1 H), 8.40 - 8.83 (m, 1 H), 9.18 - 9.49 (m, 1 H). [M+H] calc'd for Ci7H16N202, 281; found 283.
Example 36: 2-[(3-methylphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000078_0001
[00149] The title compound was prepared in 98% yield using methyl 2-[(3- methylphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.27 (s, 3 H), 4.13 - 4.24 (m, 2 H), 6.35 (s, 1 H), 7.03 (d, J=7.33 Hz, 1 H), 7.08 - 7.27 (m, 4 H), 7.45 (d, J=5.05 Hz, 1 H), 8.37 (d, J=5.05 Hz, 1 H), 11.25 (br. s., 1 H), 13.65 (br. s., 1 H). [M+H] calc'd for Ci6H14N202 , 267; found 267.
Example 37: (+)-methyl 2-(2-cyclopropyl-l-hydroxyethyl)-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000078_0002
[00150] A solution of 2-cyclopropylacetaldehyde (6.0 g, 71 mmol) in 15 mL THF was added to a solution of ethynylmagnesium bromide (0.5 M, 214 mL, 107 mmol) at 0 °C. After 1.5 h, saturated NH4C1 solution (75 mL) was added the mixture was extracted with EtOAc. The organic layers were successively washed water, brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (EA/PE = 1/5) to afford (+)-4-cyclopropylbutyn-3-ol (700 mg, 9%). 1H NMR (400 MHz, CDC13): δ ppm 0.03-0.17 (2H, m), 0.31-0.37 (2H, m), 0.71-0.76 (1H, m), 1.42-1.57 (2H, m), 2.33 (1H, d, J = 2.4 Hz), 4.29-4.32 (1H, m).
[00151] The title compound was prepared in 6% yield using (+)-4-cyclopropylbutyn-
3-ol according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CDC13): δ ppm 0.15-0.21 (2H, m), 0.48-0.58 (2H, m), 0.82-0.86 (1H, m), 1.85 (2H, t, J = 6.8 Hz), 4.04 (3H, s), 5.12 (1H, t, J= 6.8 Hz), 6.62 (1H, s), 7.61(1H, bs), 8.52 (1H, bs), 9.75 (1H, s). LCMS (mobile phase: 10-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.869 min. [M+H] calc'd for C14H16N2O3, 261; found 261.
Example 38: (+)-2-(2-cyclopropyl-l-hydroxyethyl)-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000079_0001
[00152] The title compound was prepared in 32%> yield using (+)-methyl 2-(2- cyclopropyl- 1 -hydroxyethyl)- 1 H-pyrrolo [3 ,2-b]pyridine-7-carboxylate according to procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.05- 0.15 (2H, m), 0.35-0.42 (2H, m), 0.85-0.89 (1H, m), 1.51-1.57 (1H, m), 1.80-1.87 (1H, m), 5.01-5.04 (1H, m), 6.78 (1H, s), 7.82 (1H, d, J= 5.6 Hz), 8.63 (1H, d, J= 3.6 Hz), 11.95 (1H, s). LCMS (mobile phase: 0-60% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.313 min. [M+H] calc'd for Ci3Hi4N203, 247; found 247.
Example 39: 2-(phenoxymethyl)-l H-pyrrolo [3, 2-b]pyridine-7-carboxylic acid
Figure imgf000079_0002
[00153] The title compound was prepared in 1%> yield using phenylpropargylether according to the procedure for the preparation of Examples 4 and 5. 1H NMR (400 MHz, DMSO-dg): δ ppm 5.33 (s, 2 H), 6.74 (s, 1 H), 6.90 - 6.99 (m, 1 H), 7.05 (d, J=8.59 Hz, 2 H), 7.29 - 7.37 (m, 2 H), 7.55 (d, J=4.80 Hz, 1 H), 8.45 (d, J=4.80 Hz, 1 H), 11.50 (br. s., 1 H), 13.75 (br. s., 1 H). [M+H] calc'd for Ci5Hi2N203, 269; found 269.
Example 40: methyl 2-(methoxymethyl)-l H-pyrrolo [3, 2-b]pyridine-7-carboxylate
Figure imgf000079_0003
[00154] The title compound was prepared in 17%> yield using methylpropargyl ether according to the procedure for the preparation of Example 4. 1H NMR (400 MHz,CDCl3): δ ppm 3.45 - 3.50 (m, 3 H), 4.07 (s, 3 H), 4.73 (s, 2 H), 6.84 (br. s., 1 H), 7.68 - 7.75 (m, 1 H), 8.55 (d, J=5.31 Hz, 1 H), 9.70 - 9.89 (m, 1 H). [M+H] calc'd for CnH12N203, 221; found 221.
Example 41: 2-(methoxymethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000080_0001
[00155] The title compound was prepared in 26% yield using methyl 2-
(methoxymethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.34 (s, 2 H), 4.65 (s, 2 H), 6.55 - 6.67 (m, 1 H), 7.52 (d, J=4.80 Hz, 1 H), 8.43 (d, J=4.80 Hz, 1 H), 11.23 (br. s., 1 H), 13.72 (br. s., 1 H). [M+H] calc'd for Ci0H10N2O3, 207; found 207.
Example 42: (+)-methyl 2-[hydroxy(oxan-4-yl)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000080_0002
[00156] The title compound was prepared in 32%> yield using (+)-l-(oxan-4-yl)-l- prop-2-yn-l-ol according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CDC13): δ ppm 1.47-1.57 (3H, m), 1.86-1.89 (1H, m), 2.03-2.10 (1H, m), 3.39-3.46 (2H, m), 3.98-4.07 (2H, m), 4.09 (3H, s), 4.82 (1H, d, J= 6.8 Hz), 6.64 (1H, s), 7.65(1H, d, J= 4.8 Hz), 8.55 (1H, d, J= 4.4 Hz), 9.75 (1H, s). LCMS (mobile phase: 10-95%
Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.433 min. [M+H] calc'd for Ci5H18N204, 291; found 291. Example 43: (+)-2-[hydroxy(oxan-4-yl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000081_0001
[00157] The title compound was prepared in 54% yield (+)-methyl 2-[hydroxy(oxan-
4-yl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, CD3OD): δ ppm 1.30-1.33 (1H, m), 1.43- 1.60 (3H, m), 1.94-2.01 (1H, m), 3.26-3.38 (2H, m), 3.82-3.89 (2H, m), 4.75 (1H, d, J= 6.0 Hz), 6.67 (1H, s), 7.80 (1H, d, J= 5.6 Hz), 8.41 (1H, d, J= 5.6 Hz). LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.873 min. [M+H] calc'd for Ci4Hi6N204, 277; found 277.
Example 44: 2-[(4-chlorophenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000081_0002
[00158] The title compound was prepared in 4%> yield using l-chloro-4-(prop-2-yn-l- yl)benzene according to the procedure for the preparation of Examples 4 and 5. 1H NMR (400 MHz, DMSO-de): δ ppm 4.22 (s, 2 H), 6.37 (s, 1 H), 7.37 (s, 4 H), 7.46 (d, J=4.80 Hz, 1 H), 8.37 (d, J=4.80 Hz, 1 H), 11.31 (br. s., 1 H), 13.61 - 13.73 (m, 1 H). [M+H] calc'd for Ci5HnN202Cl, 287; found 287.
Example 45: (+)-methyl 2-(l -hydroxy- l-phenylethyl)-l H-pyrrolo [3, 2-b]pyridine-7- carboxylate
Figure imgf000081_0003
[00159] The title compound was prepared in 31%> yield using (+)-2-phenyl-3-butyn-
2-ol according to the procedure for the preparation of example 4. 1H NMR (400 MHz, CDCI3): δ ppm 2.09 (s, 3 H), 4.01 (s, 3 H), 6.77 - 6.89 (m, 1 H), 7.28 - 7.41 (m, 5 H), 7.45 - 7.55 (m, 3 H), 7.65 (d, J=5.05 Hz, 1 H), 8.51 (d, J=5.05 Hz, 1 H), 9.69 (br. s., 1 H). [M+H] calc'd for Ci7H16N203, 297; found 297.
Example 46: (+)-2-(l-hydroxy- -phenylethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000082_0001
[00160] The title compound was prepared in 84% yield using (+)-methyl 2-(l- hydroxy- l-phenylethyl)-lH-pyrrolo [3, 2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.89 (s, 3 H), 6.36 (s, 1 H), 6.68 (d, J=2.02 Hz, 1 H), 7.20 - 7.26 (m, 1 H), 7.32 (t, J=7.58 Hz, 2 H), 7.42 (d, J=7.33 Hz, 2 H), 7.51 (d, J=4.80 Hz, 1 H), 8.45 (s, 1 H), 10.28 (br. s., 1 H), 13.80 (br. s., 1 H). [M+H] calc'd for Ci6H14N203, 283; found 283.
Example 47: (+)-methyl 2-[hydroxy-(2-methylpyrazol-3-yl)methyl]-lH-pyrrolo[3,2- b]pyridine-7-carboxylate
Figure imgf000082_0002
[00161] The title compound was prepared in 2%> yield using 1 -methyl- lH-pyrazole-5- carbaldehyde according to the procedure for the preparation of Example 37. 1H NMR (400
MHz, DMSO- e): δ ppm 3.86 (3H, s), 3.97 (3H, s), 5.93 (1H, d, J= 1.6 Hz), 6.19 (1H, d, J = 6.4 Hz), 6.34 (1H, d, J= 6.4 Hz), 6.59 (1H, d, J= 1.2 Hz), 7.29 (1H, d, J= 2.0 Hz), 7.56 (1H, d, J= 4.8 Hz), 8.43(1H, d, J= 4.8 Hz), 11.14 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.514 min. [M+H] calc'd for Ci4Hi4N403, 287; found 287. Example 48: (+)-2-[hydroxy-(2-methylpyrazol-3-yl)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000083_0001
[00162] The title compound was prepared in 65% yield using (+)-methyl 2-[hydroxy-
(2-methylpyrazol-3-yl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, CD3OD): δ ppm 3.93 (3H, s), 6.16 (1H, d, J= 1.6 Hz), 6.32 (1H, s), 6.65 (1H, d, J= 0.8 Hz), 7.42 (1H, d, J= 1.6 Hz), 7.80 (1H, d, J= 5.2 Hz), 7.48 (1H, d, J= 4.8 Hz). LCMS (mobile phase: 0-60%
Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.762 min. [M+H] calc'd for Ci3Hi2N403, 273; found 273.
Example 49: (+)-methyl 2-[hydroxy-(l-methylpyrazol-4-yl)methyl]-lH-pyrrolo[3,2- b]pyridine-7-carboxylate
Figure imgf000083_0002
[00163] The title compound was prepared in 3%> yield using 1 -methyl- lH-pyrazole-4- carbaldehyde according to the procedure for the preparation of Example 37. 1H NMR (400 MHz, DMSO-dg): δ ppm 3.78 (3H, s), 3.98 (3H, s), 5.91 (1H, d, J= 7.2 Hz), 5.97 (1H, d, J = 6.0 Hz), 6.51(1H, d, J= 1.6 Hz), 7.38 (1H, s), 7.52 (1H, d, J= 4.8 Hz), 7.55 (1H, s), 8.43 (1H, d, J= 4.8 Hz), 10.96 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.407 min. [M+H] calc'd for Ci4Hi4N403, 287; found 287. Example 50: (+)-2-[hydroxy-(l-methylpyrazol-4-yl)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000084_0001
[00164] The title compound was prepared in 70% yield using (+)-methyl 2-[hydroxy-
(l-methylpyrazol-4-yl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.78 (3H, s), 6.07 (1H, s), 6.72 (1H, s), 7.39 (1H, s), 7.58 (1H, s), 7.80 (1H, d, J= 5.6 Hz), 8.62 (1H, d, J= 5.6 Hz), 11.87 (1H, s). LCMS (mobile phase: 0%-60% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.686 min. [M+H] calc'd for Ci3Hi2N403, 273; found 273.
Example 51: methyl 2-(cyclopentylmethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000084_0002
[00165] The title compound was prepared in 8%> yield using prop-2-ynyl- cyclopentane according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, DMSO-dg): δ ppm 1.25-1.29 (2H, m), 1.50-1.54 (2H, m), 1.59-1.65 (2H, m), 1.69- 1.75 (2H, m), 2.27-2.34 (1H, m), 2.85 (2H, d, J = 7.2 Hz), 3.98 (3H, s), 6.43 (1H, d, J = 2.0 Hz), 7.46 (1H, d, J = 4.4 Hz), 8.38 (1H, d, J = 5.2 Hz), 11.10 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.929 min. [M+H] Calc'd for Ci5Hi8N202, 259; Found, 259. Example 52: 2-(cyclopentylmethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000085_0001
[00166] The title compound was prepared in 44% yield using methyl 2-
(cyclopentylmethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.22-1.28 (2H, m), 1.47-1.75 (6H, m), 2.25-2.32 (1H, m), 2.84 (2H, d, J = 7.2 Hz), 6.40 (1H, s), 7.44 (1H, d, J = 4.8 Hz), 8.36 (1H, d, J = 3.6 Hz), 11.06 (1H, s), 13.59 (1H, br).LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 4.194 min. [M+H] calc'd for Ci4Hi6N202, 245; found 245.
Example 53: methyl 2-(cyclohexylmethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000085_0002
[00167] The title compound was prepared in 24%> yield using prop-2-ynyl- cyclohexane according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, DMSO-dg): δ ppm 0.94-1.04 (2H, m), 1.12-1.25 (3H, m), 1.61-1.75 (6H, m), 2.74 (2H, d, J = 7.2 Hz), 3.98 (3H, s), 6.40 (1H, d, J = 2.0 Hz), 7.46 (1H, d, J = 5.2 Hz), 8.38 (1H, d, J = 4.8 Hz), 11.10 (1H, s). [M+H] calc'd for Ci6H20N2O2, 273; found 273.
Example 54: 2-(cyclohexylmethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000085_0003
[00168] The title compound was prepared in 42%> yield using methyl 2-
(cyclohexylmethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.93-0.99 (2H, m), 1.16-1.24 (3H, m), 1.60-1.72 (6H, m), 2.74 (2H, d, J= 7.0 Hz), 6.38 (1H, s), 7.45 (1H, d, J = 5.2 Hz), 8.37 (1H, d, J= 3.2 Hz), 11.15 (1H, s). LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 4.404 min. [M+H] calc'd for Ci5H18N202, 259; found 259.
Example 55: methyl 2-[[4-(trifluoromethyl)phenyl]methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000086_0001
[00169] 4-(trifluoromethyl)benzaldehyde (2.73 mL, 20 mmol) was added dropwise into round-bottom flask containing a solution of ethynylmagnesium bromide (50 mL, 25 mmol) in THF at 0 °C. After 30 min the reaction was quenched with aq. NH4C1. The mixture was taken up in EtOAc and washed successively with water, brine, and dried with Na2S04. The organic layers were concentrated in vacuo to afford l-[4- trifuoromethyl)phenyl]prop-2-yn-l-ol as a yellow oil (3.65 g, 91%).
[00170] To a vial containing l-[4-trifuoromethyl)phenyl]prop-2-yn-l-ol (1.65 g , 8.25 mmol) was added Et3SiH (3.98 mL, 25mmol) followed by TFA (3.83 mL, 50 mmol). The reaction was capped and allowed to stir at 60 °C for 16 hrs. The reaction was concentrated in vacuo and the residue purified by column chromatography (0-10% EtOAc/ hexanes gradient, 12g silica) to afford l-(prop-2-yn-lyl)-4-(trifluoromethyl)benzene (325 mg, 21%) as a clear oil.
[00171] The title compound was prepared in 17 % yield using l-(prop-2-yn-lyl)-4-
(trifluoromethyl)benzene according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDC13): δ ppm 4.00 (s, 3 H), 4.28 (s, 2 H), 6.59 - 6.68 (m, 1 H), 7.39 (d, J=8.08 Hz, 3 H), 7.56 - 7.67 (m, 4 H), 8.53 (d, J=4.80 Hz, 1 H), 9.33 (br. s., 1 H). [M+H] calc'd for Ci7Hi3N202, 335; found 335. Example 56: 2-[[4-(trifluoromethyl)phenyl]methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000087_0001
[00172] The title compound was prepared in 80% yield using methyl 2-[[4-
(trifluoromethyl)phenyl]methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 3.32 (s, 3 H), 4.33 (s, 2 H), 6.42 (s, 1 H), 7.47 (d, J=5.05 Hz, 1 H), 7.56 (d, J=8.08 Hz, 3 H), 7.68 (d, J=8.08 Hz, 3 H), 8.39 (s, 1 H), 11.38 (br. s., 1 H), 13.67 (br. s., 1 H). [M+H] calc'd for C16H11N2O2, 321; found 321.
Example 57: methyl 2-(2-cyanoethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000087_0002
[00173] The title compound was prepared in 5% yield using 4-cyano-l-butyne according to the procedure for the preparation of Example 4. 1H NMR (400 MHz,CDC13): δ ppm 2.84 (t, J=7.07 Hz, 2 H) 3.28 (t, J=7.20 Hz, 2 H) 4.06 (s, 3 H) 6.75 (s, 1 H) 7.68 (d, J=5.31 Hz, 1 H) 8.56 (d, J=5.05 Hz, 1 H) 9.58 - 9.87 (m, 1 H). [M+H] calc'd for
C12HH 3O2, 230; found 230.
Example 58: 2-(2-cyanoethyl)- -pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000087_0003
[00174] The title compound was prepared in 71% yield using methyl 2-(2- cyanoethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.98 (t, J=7.07 Hz, 2 H) 3.18 (t, J=7.07 Hz, 2 H) 6.56 - 6.59 (m, 1 H) 7.50 (d, J=4.80 Hz, 1 H) 8.41 (d, J=4.80 Hz, 1 H) 11.32 (d, J=1.26 Hz, 1 H) 13.71 (br. s., 1 H). [M+H] calc'd for C11H9N3O2, 216; found 216.
Example 59: 2-[(4-methoxyphenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000088_0001
[00175] To a vial containing l-[4-methoxy)phenyl]prop-2-yn-l-ol (1.62 g , 10.0 mmol), Et3SiH (1.91 mL, 12 mmol) in DCM (10 mL) at -78 °C was added BF3-Et20 (1.48 mL, 12 mmol) dropwise. The reaction was capped and allowed to stir at -78 °C for 2 hrs. The reaction was quenched with saturated NH4C1 and the aqueous layers were extracted with DCM. The combined organic layers were concentrated in vacuo and purified by column chromatography (0-5% EtOAc/ hexanes gradient, 12 g silica) to afford 1-methoxy- 4-(prop-2-yn-l-yl)benzene (400 mg, 27%) as a clear oil.
[00176] The title compound was prepared in 4%> yield using l-methoxy-4-(prop-2- yn-l-yl)benzene according to the procedure for the preparation of Examples 4 and 5. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H), 4.17 (s, 2 H), 6.37 (s, 1 H), 6.88 (d, J=8.08 Hz, 2 H), 7.27 (d, J=8.34 Hz, 2 H), 7.54 (br. s., 1 H), 8.42 (br. s., 1 H), 11.45 - 11.56 (m, 1 H). [M+H] calc'd for Ci6Hi4N203, 283; found 283.
Example 60: 2-[(4-fluorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000088_0002
[00177] The title compound was prepared in <1%> yield using l-fluoro-4-(prop-2-yn- l-yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, CD3OD): δ ppm 5.43 (2H, s), 6.95 (1H, s), 7.05-7.079 (4H, m), 8.02 (1H, br), 8.64 (1H, br). LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.416 min. [M+H] calc'd for Ci5HnFN203, 287; found 287. Example 61: methyl-2-[(4-methylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyrid
carboxylate
Figure imgf000089_0001
[00178] The title compound was prepared in <1% yield using l-methyl-4-(prop-2-yn- l-yloxy)benzene according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CD3OD): δ ppm 2.17 (3H, s), 3.96 (3H, s), 5.21 (2H, s), 6.64 (IH, s), 6.84 (2H, d, J= 8.8 Hz), 7.00 (2H, d, J= 8.4 Hz), 7.60 (IH, d, J= 5.2 Hz), 8.32 (IH, d, J= 4.8 Hz). [M+H] Calc'd for C17H16N2O3, 297; Found, 297.
Example 62: 2-[(4-methylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000089_0002
[00179] The title compound was prepared in 51 % yield using methyl-2-[(4- methylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, CD3OD): δ ppm 2.17 (3H, s), 5.33 (2H, s), 6.84-6.86 (3H, m), 7.02 (2H, d, J= 8.8 Hz), 7.94 (IH, d, J= 6.4 Hz), 8.50 (IH, d, J= 6.0 Hz). LCMS (mobile phase: 0-60% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 4.234 min. [M+H] Calc'd for Ci6Hi4N203, 283; Found, 283.
Example 63: methyl-2-[(4-chlorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000089_0003
[00180] The title compound was prepared in <1%> yield using l-chloro-4-(prop-2-yn- l-yloxy)benzene according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, CD3OD): δ ppm 4.09 (3H, s), 5.37 (2H, s), 6.80 (IH, s), 7.07-7.09 (2H, s), 7.30- 7.32 (2H, m), 7.75 (IH, d, J= 4.8 Hz), 8.47 (IH, d, J= 5.2 Hz). [M+H] Calc'd for
Ci6H13ClN203, 317; Found, 317.
Example 64: 2-[(4-chlorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000090_0001
[00181] The title compound was prepared in 75% yield using methyl-2-[(4- chlorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, CD3OD): δ ppm 5.32 (2H, s), 6.79 (IH, s), 6.96 (2H, d, J= 8.8 Hz), 7.20 (2H, d, J= 9.2 Hz), 7.84 (IH, d, J= 5.6 Hz), 8.45 (IH, br). LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 4.345 min. [M+H] Calc'd for Ci5HnClN203, 303; Found, 303.
Example 65: methyl 2-[(2-methylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000090_0002
[00182] The title compound was prepared in 2%> yield using l-methyl-2-(prop-2-yn- l-yloxy)benzene according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, DMSO-dg): δ ppm 2.19 (3H, s), 3.99 (3H, s), 5.34 (2H, s), 6.77 (IH, s), 6.86- 6.88 (IH, m), 7.08 (IH, d, J= 8.4 Hz), 7.16-7.18 (2H, m), 7.59 (IH, d, J= 5.2 Hz), 8.48 (IH, d, J= 4.8 Hz), 11.56 (IH, s). LCMS (mobile phase: 20-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.742 min. [M+H] calc'd for Ci7Hi6N203, 297; found 297.
Example 66: 2-[(2-methylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000090_0003
[00183] The title compound was prepared in 91% yield using methyl 2-[(2- methylphenoxy)methyl]-l H-pyrrolo [3, 2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.21 (3H, s), 5.41 (2H, s), 6.84-6.90 (2H, m), 7.05(1H, d, J= 8.4 Hz), 7.17-7.20 (2H, m), 7.75 (1H, d, J= 5.6 Hz), 8.59 (1H, d, J= 5.2 Hz), 12.08 (1H, s). LCMS (mobile phase: 0-60% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 4.218 min. [M+H] Calc'd for Ci6Hi4N203, 283; Found, 283.
Example 67: methyl 2-[[4-(trifluoromethyl)phenoxy]methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000091_0001
[00184] The title compound was prepared in 2%> yield using l-(prop-2-yn-l-yloxy)-4- trifluoromethylbenzene according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.99 (3H, s), 5.43 (2H, s), 6.83 (1H, d, J= 1.2 Hz), 7.27 (2H, d, J= 8.4 Hz), 7.60 (1H, d, J= 4.8 Hz), 7.70 (2H, d, J= 8.8 Hz), 8.50 (1H, d, J = 4.8 Hz), 11.63 (1H, s). LCMS (mobile phase: 20-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.876 min. [M+H] calc'd for Ci7Hi3N203F3, 351; found 351.
Example 68: 2- [[4-(trifluoromethyl)phenoxy]methyl]-l H-pyrrolo [3, 2-b]pyridine-7- carboxylic acid
Figure imgf000091_0002
[00185] The title compound was prepared in 85%> yield using methyl 2-[[4-
(trifluoromethyl)phenoxy]methyl] - 1 H-pyrrolo [3 ,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 5.43 (2H, s), 6.79 (1H, s), 7.25 (2H, d, J= 8.8 Hz), 7.58 (1H, d, J= 4.8 Hz), 7.69 (2H, d, J = 8.8 Hz), 8.48 (1H, d, J= 4.0 Hz), 11.62 (1H, s), 13.82 (1H, br). LCMS (mobile phase: 0- 60% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 4.575 min. [M+H] calc'd for Ci6HiiN203F3, 337; found 337. Example 69: methyl 2-(2-phenylethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000092_0001
[00186] The title compound was prepared in 33% yield using 4-phenyl-l-butyne according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDCI3): δ ppm 3.07 - 3.14 (m, 2 H) 3.16 - 3.25 (m, 2 H) 4.00 (s, 3 H) 6.62 (br. s., 1 H) 7.21 - 7.25 (m, 2 H) 7.28 - 7.39 (m, 3 H) 7.59 (br. s., 1 H) 8.49 (br. s., 1 H) 9.23 (br. s., 1 H). [M+H] calc'd for Ci7H16N202, 281; found 281.
Example 70: 2-(2-phenyleth -lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000092_0002
[00187] The title compound was prepared in 85% yield using methyl 2-(2- phenylethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.00 - 3.08 (m, 2 H) 3.11 - 3.20 (m, 2 H) 6.41 - 6.45 (m, 1 H) 7.16 - 7.23 (m, 1 H) 7.26 - 7.34 (m, 5 H) 7.45 (d, J=5.05 Hz, 2 H) 8.36 (d, J=5.05 Hz, 1 H) 11.21 (br. s., 1 H) 13.62 (br. s., 1 H). [M+H] calc'd for Ci6Hi4N202, 267; found 267.
Example 71: (+)-methyl 2-[(2-chlorophenyl)-hydroxymethyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000092_0003
[00188] The title compound was prepared in 33 > yield using (+)-l-(2-chlorophenyl)- prop-2-yn-l-ol according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDCI3): δ ppm 4.04 (s, 3 H), 6.53 (s, 1 H), 6.58 - 6.65 (m, 1 H), 7.29 - 7.36 (m, 2 H), 7.41 (d, J=2.02 Hz, 1 H), 7.61 (d, J=7.33 Hz, 1 H), 7.64 (d, J=5.05 Hz, 1 H), 8.51 (d, J=4.80 Hz, 1 H), 9.84 (br. s., 1 H). [M+H] calc'd for Ci6Hi3N203Cl, 317; found 317. Example 72: (+)-2-[(2-chlorophenyl)-hydroxymethyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000093_0001
[00189] The title compound was prepared in 88% yield using (+)-methyl 2-[(2- chlorophenyl)-hydroxymethyl]-l H-pyrrolo [3, 2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 6.12 (d, J=1.52 Hz, 1 H), 6.30 - 6.40 (m, 2 H), 7.33 - 7.45 (m, 2 H), 7.45 - 7.49 (m, 1 H), 7.53 (d, J=4.80 Hz, 1 H), 7.63 (dd, J=7.58, 1.77 Hz, 1 H), 8.42 (d, J=5.05 Hz, 1 H), 11.09 (br. s., 1 H), 13.80 (br. s., 1 H). [M+H] calc'd for Ci5HnN203Cl, 303; found 303.
Example 73: methyl 2-[(3-methylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000093_0002
[00190] The title compound was prepared in <1% yield using 3-fluoro-4-(prop-2-yn- l-yloxy)benzene according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, DMSO-de): δ 2.19 (3H, s), 3.99 (3H, s), 5.34 (2H, s), 6.77 (1H, s), 6.86-6.88 (1H, m), 7.08 (1H, d, J= 8.4 Hz), 7.16-7.18 (2H, m), 7.59 (1H, d, J= 5.2 Hz), 8.48 (1H, d, J= 4.8 Hz), 11.56 (1H, s). LCMS (mobile phase: 20-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.491 min. [M+H] Calc'd for Ci7H16N203, 297; Found, 297.
Example 74: 2-[(3-methylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000093_0003
[00191] The title compound was prepared in 88%> yield using methyl 2-[(3- methylphenoxy)methyl] - 1 H-pyrrolo [3 ,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.29 (3H, s), 5.36 (2H, s), 6.78-6.88 (4H, m), 7.17-7.22 (1H, m), 7.73 (1H, d, J= 7.2 Hz), 8.58 (1H, d, J= 7.2 Hz), 12.02 (1H, s). LCMS (mobile phase: 0-60% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.491 min. [M+H] Calc'd for Ci6Hi4N203, 283; Found, 283.
Example 75: methyl-2-(2,3dihydro-l-benzofuran-5-yloxyrnethyl)-lH-pyrrolo[3,2- b]pyridine-7-carboxylate
Figure imgf000094_0001
[00192] A mixture containing 2,3-dihydrobenzofuran-5-ol (3.12 mg, 23 mmol), 3- bromo-propyne (3.3 g, 28 mmol), and K2C03 (6.4 g, 46 mmol) in acetone (30 mL) was purged with nitrogen and stirred at 60 °C overnight. The reaction was concentrated in vacuo and the residue suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatograph (PE/EA = 50/1 -20/1) to afford 5-(prop-2-yn-l-yloxy)-2,3-dihydrobenzofuran (3.48 g, 86%>) as a yellow oil.
[00193] The title compound was prepared in <1% yield using 5-(prop-2-yn-l-yloxy)-
2,3-dihydrobenzofuran according to the procedure for the preparation of Example 9. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.15 (2H, t, J= 8.8 Hz), 3.99 (3H, s), 4.47 (2H, t, J = 8.8 Hz), 5.24 (2H, s), 6.67 (1H, d, J= 8.4 Hz), 6.74-6.79 (2H, m), 6.98 (1H, d, J= 2.8 Hz), 7.58 (1H, d, J= 4.8 Hz), 8.48 (1H, d, J= 5.2 Hz), 11.53 (1H, s). LCMS (mobile phase: 20- 95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.105 min. [M+H] Calc'd for Ci8Hi6N204, 325; Found, 325.
Example 76: 2-(2,3dihydro-l-benzofuran-5-yloxymethyl)-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000094_0002
[00194] The title compound was prepared in 88% yield using methyl-2-(2,3dihydro- l-benzofuran-5-yloxymethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.15 (2H, t, J= 8.4 Hz), 4.47 (2H, t, J= 8.4 Hz), 5.31 (2H, s), 6.68 (1H, d, J= 8.4 Hz), 6.75-6.81 (2H, m), 6.98 (1H, d, J= 2.4 Hz), 7.74 (1H, d, J= 5.2 Hz), 8.59 (1H, d, J= 5.6 Hz), 12.04 (1H, s). [M+H] Calc'd for Ci7H14N204, 311; Found, 311.
Example 77: methyl 2-[(2-chlorophenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000095_0001
[00195] The title compound was prepared in 74% yield using methyl 2-[(2- chlorophenyl)-hydroxymethyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 34. 1H NMR (400 MHz, CDC13): δ ppm 4.11 (s, 3 H), 4.42 (s, 2 H), 7.00 (s, 1 H), 7.28 - 7.38 (m, 3H), 7.45 - 7.51 (m, 1 H), 7.89 (d, J=6.06 Hz, 1 H), 8.62 (d, J=5.81 Hz, 1 H), 10.14 (br. s., 1 H). [M+H] Calc'd for Ci6H13ClN202, 301; Found, 301.
Example 78: 2-[(2-chlorophenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000095_0002
[00196] The title compound was prepared in 88% yield using methyl 2-[(2- chlorophenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.28 (s, 2 H), 6.14 (s, 1 H), 7.22 - 7.33 (m, 3 H), 7.35 - 7.51 (m, 2 H), 8.32 (d, J=5.05 Hz, 1 H), 11.32 (br. s., 1 H), 13.66 (br. s., 1 H). [M+H] Calc'd for Ci5HnClN202, 287; Found, 287.
Example 79: 2-[(3-fluorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000095_0003
[00197] The title compound was prepared in <1%> yield using l-fluoro-3-(prop-2-yn- l-yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.40 (2H, s), 6.79-6.84 (1H, m), 6.89-6.99 (3H, m), 7.33-7.39 (1H, m), 7.76 (1H, d, J= 4.8 Hz), 8.61 (1H, br), 12.11 (1H, s). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.321 min. [M+H] Calc'd for C15H11FN2O3, 287; Found, 287.
Example 80: 2-[(3-chlorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000096_0001
[00198] The title compound was prepared in <1% yield using l-chloro-3-(prop-2-yn- l-yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.42 (2H, s), 6.90 (1H, s), 7.05 (2H, d, J= 8.8 Hz), 7.18-7.19 (1H, m), 7.35 (1H, t, J= 8.4 Hz), 7.79 (1H, d, J= 5.2 Hz), 8.61-8.63 (1H, m), 12.18 (1H, s). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.432 min. [M+H] Calc'd for Ci5HnClN203, 303; Found, 303.
Example 81: 2-[(3,5-difluorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000096_0002
[00199] The title compound was prepared in <1%> yield using l,3-difluoro-5-(prop-2- yn-l-yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.40 (2H, s), 6.82-6.90 (4H, m), 7.75 (1H, d, J= 5.2 Hz), 8.60 (1H, d, J= 5.2 Hz), 12.07 (1H, s). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.385 min. [M+H] Calc'd for CisH^NzOs, 305; Found, 305.
Example 82: 2-[(3,5-dimethylphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000096_0003
[00200] The title compound was prepared in <1% yield using l,3-dimethyl-5-(prop-
2-yn-l-yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.24 (6H, s), 5.35 (2H, s), 6.62 (IH, s), 6.68 (2H, s), 8.83 (IH, d, J= 2.0 Hz), 7.75 (IH, d, J= 5.2 Hz), 8.59 (IH, d, J= 5.6 Hz), 12.06 (IH, s). LCMS (mobile phase: 5-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.490 min. [M+H] Calc'd for Ci6H16N203, 297; Found, 297.
Example 83: 2-[(3,5-dichlorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000097_0001
[00201] The title compound was prepared in <1% yield using l,3-dichloro-5-(prop-2- yn-l-yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.37 (2H, s), 6.79 (IH, s), 7.19 (3H, s), 7.59 (IH, s), 8.59 (IH, s, br), 11.59 (IH, s), 13.80 (IH, s). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.490 min. [M+H] Calc'd for Ci5H10Cl2N2O3, 337; Found, 337.
Example 84: (+)-2-(l-phenoxyethyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000097_0002
[00202] To a mixture containing (+)-3-butyn-2-ol (2.02 g, 29 mmol), TsCl (6.8 g, 36 mmol) in Et20 (30 mL) was added KOH (10.0 g, 174 mmol) at 0 °C. The mixture was stirred at 0 °C for 1.5 hours and filtered. The filtrate was concentrated in vacuo to afford (+)-(but-3-yn-2-yl)-4-methylphenylsulfonate (2.03 g, 31%) as a yellow oil. 1H NMR (400 MHz, CDC13): δ ppm 1.57 (3H, d, J= 6.8 Hz), 2.41-2.42 (IH, m), 2.45 (3H, s), 5.14-4.19 (IH, m), 7.34 (2H, d, J= 8.0 Hz), 7.82 (2H, d, J= 8.4 Hz).
[00203] To a mixture containing phenol (1.0 g, 10 mmol) and KOH (0.6 g, 10 mmol) in 95% EtOH (20 mL) was added (+)-(but-3-yn-2-yl)-4-methylphenylsulfonate (2.0 g, 9 mmol) at 0 °C. The mixture was heated at 65 °C overnight. H20 was added and the mixture was extracted with Et20. The organic layers were concentrated and purified by silica gel chromatography (PE/EA = 10/1) to afford (+)-(but-3-yn-2-yloxy)benzene (690 mg, 50%). 1H NMR (400 MHz, CDC13): δ ppm 1.66 (3H, d, J= 6.4 Hz), 2.46 (IH, d, J= 1.6 Hz), 4.85- 4.90 (IH, m), 6.96-7.02 (3H, m), 7.25-7.32 (2H, m).
[00204] The title compound was prepared in 10%> yield using (+)-(but-3-yn-2- yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-^): δ ppm 1.69 (3H, d, J= 6.4 Hz), 5.84-5.89 (IH, m), 6.59 (IH, s), 6.87-6.97 (3H, m), 7.21-7.26 (2H, m), 7.54 (IH, d, J= 4.8 Hz), 8.41-8.45 (IH, m), 11.48 (IH, s), 13.85 (IH, bs). LCMS (mobile phase: 5-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.266 min.
Example 85: (+)-2-(l-phenoxybutyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000098_0001
[00205] The title compound was prepared in <1%> yield using (+)-l-hexyn-3-ol according to the procedure for the preparation of Example 84. 1H NMR (400 MHz, DMSO- d6): δ ppm 0.94 (3H, t, J= 6.4 Hz), 1.38-1.54 (2H, m), 1.93-2.05 (2H, m), 5.71-5.74 (IH, m), 6.54 (IH, s), 6.85-6.96 (3H, m), 7.20-7.24 (2H, m), 7.53 (IH, s), 8.48-8.52 (IH, m), 11.45 (IH, s), 13.80 (IH, bs). LCMS (mobile phase: 5-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.597 min. [M+H] Calc'd for Ci8H18N203, 311; Found, 311.
Example 86: (+)-2-(3-methyl-phenoxybutyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000098_0002
[00206] The title compound was prepared in <1% yield starting from (+)-5-methlyl- l-hexyn-3-ol according to the procedure for the preparation of Example 84. 1H NMR (400 MHz, DMSC /e): δ ppm 0.95-0.99 (6H, m), 1.76-1.86 (2H, m), 1.97-2.052 (IH, m), 5.78- 5.81(1H, m), 6.57 (IH, s), 6.85-6.88 (IH, m), 6.97 (2H, d, J= 8.0 Hz), 7.20-7.24 (2H, m), 7.52 (IH, d, J= 4.0 Hz), 8.39-8.43 (IH, m). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.679 min. [M+H] Calc'd for Ci9H20N2O3, 325; Found, 325. Example 87: (+)-methyl 2-[(2-chlorophenyl)propoxyrnethyl])-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000099_0001
[00207] To a round-bottom flask charged with (+)- 1 -(2-chloro-phenyl)-prop-2-yn- 1 - ol (1.165 g, 7 mmol) in DMF was added NaH (336 mg, 8.4 mmol, 60% mineral oil suspension) portion-wise. The reaction was stirred for 30 min at ambient temperature under N2 atmosphere. 1-bromopropane was added dropwise at 0 °C and the reaction was allowed to warm to ambient temperature and stirred for 16 hrs. The reaction was quenched with saturated NH4C1 and extracted with EtOAc (2X). The combined organic layers were successively washed with water (2X), followed by brine, dried with Na2S04 and
concentrated in vacuo. The residue purified by silica gel chromatography (0-5%> gradient of EtOAc in hexanes) to afford (+)-l-(2-chlorophenyl)prop-2-yn-l-yl propyl ether(1.2g, 82%) as a light yellow oil.
[00208] The title compound was prepared in 15 > yield using (+)-l-(2- chlorophenyl)prop-2-yn-l-yl propyl ether according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDC13): δ ppm 1.00 (t, J=7.45 Hz, 3 H), 1.72 (dq, J=14.02, 6.95 Hz, 2 H), 3.55 (t, J=6.57 Hz, 2 H), 3.87 - 4.62 (m, 4 H), 4.03 (s, 3 H), 6.10 (s, 1 H), 6.60 (br. s., 1 H), 7.28 - 7.50 (m, 3 H), 7.52 - 7.75 (m, 2 H), 8.51 (br. s., 1 H), 9.71 (br. s., 1 H). [M+H] Calc'd for Ci9H19ClN203, 359; Found, 359.
Example 88: (+)-2-[(2-chlorophenyl)propoxymethyl])-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000099_0002
[00209] The title compound was prepared in 15%> yield using (+)-methyl 2-[(2- chlorophenyl)propoxymethyl])-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.90 (t, J=7.33 Hz, 3 H) 1.60 (m, 2 H) 3.40 - 3.52 (m, 2 H) 3.40 - 3.52 (m, 2 H) 3.54 - 3.64 (m, 1 H) 6.11 - 6.14 (m, 1 H) 6.24 (d, J=2.02 Hz, 1 H) 6.55 - 6.59 (m, 1 H) 7.35 - 7.45 (m, 2 H) 7.47 - 7.52 (m, 2 H) 7.54 (d, J=5.05 Hz, 1 H) 8.44 (d, J=4.80 Hz, 1 H) 11.33 (br. s., 1 H) 13.76 (br. s., 1 H). [M+H] Calc'd for C18H17CIN2O3, 345; Found, 345.
Example 89: methyl 2-[(2,4-dichlorophenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000100_0001
[00210] The title compound was prepared in 10% yield using 2,4-dichloro-l-(prop-2- yn-l-yl)benzene according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CDCI3): δ ppm 4.02 (s, 3 H), 4.31 (s, 2 H), 6.61 (s, 1 H), 7.20 - 7.23 (m, 1 H), 7.46 (d, J=1.77 Hz, 1 H), 7.61 (d, J=5.05 Hz, 1 H), 8.51 (d, J=5.31 Hz, 1 H), 9.54 (br. s., 1 H). [M+H] Calc'd for CigH^C^C^, 335; Found, 335.
Example 90: 2-[(2,4-dichlorophenyl)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000100_0002
[00211] The title compound was prepared in 88% yield using 5-methlyl-l-hexyn-3-ol according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO- d6) δ ppm 4.33 (s, 2 H) 6.24 (s, 1 H) 7.31 - 7.44 (m, 2 H) 7.49 (d, J=5.31 Hz, 1 H) 7.66 (s, 1 H) 8.39 (d, J=4.55 Hz, 1 H) 11.43 (br. s., 1 H) 13.70 (br. s., 1 H). [M+H] Calc'd for Ci5HioCi2N202, 321; Found, 321.
Example 91: methyl 2-(l-benzoi iran-2-yl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000100_0003
[00212] A mixture containing methyl 3-amino-2-chloroisonicotinate (372 mg, 2 mmol), 2-benzofuranyl methyl ketone (960 mg, 6 mmol), MgSO4 (120 mg, 1 mmol), and AcOH (150 μΐ,, 3mmol) in DMA was purged with N2 for 10 min. Pd(tBu3P)2 (101 mg, 0.2 mmol) and K3P04 (552 mg, 2.6 mmol) were added and the reaction sealed and heated at 140 °C for 16 hrs. The reaction mixture was taken up in EtOAc and washed successively with water (2X), brine, and dried with N2S04. The organic layers were concentrated in vacuo and the residue purified by column chromatography to afford the title compound (152 mg, 26%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.33 (s, 2 H), 6.24 (s, 1 H), 7.31 - 7.44 (m, 2 H), 7.49 (d, J=5.31 Hz, 1H), 7.66 (s, 1 H), 8.39 (d, J=4.55 Hz, 1 H), 11.43 (br. s., 1 H), 13.70 (br. s., 1 H). [M+H] Calc'd for Ci7Hi2N203, 293; Found, 293.
Example 92: 2-(l-benzoi ira -2-yl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000101_0001
[00213] The title compound was prepared in 75% yield using 5-methlyl-l-hexyn-3-ol according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO- d6) δ ppm 7.21 (s, 1 H) 7.32 (d, J=7.58 Hz, 1 H) 7.39 (s, 1 H) 7.62 (d, J=4.80 Hz, 1 H) 7.69 (d, J=8.08 Hz, 1 H) 7.74 (d, J=7.58 Hz, 1 H) 7.95 (s, 1 H) 8.54 (d, J=5.05 Hz, 1 H) 11.55 (br. s., 1 H) 13.88 (br. s., 1 H).
Example 93: 2-[(4-methoxyphenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000101_0002
[00214] The title compound was prepared in <1% yield using l-methoxy-4-(prop-2- yn-l-yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.69 (3H, s), 5.27 (2H, s), 6.72 (1H, s), 6.87-6.90 (2H, m), 6.97-7.00 (2H, m), 7.56-7.57 (1H, m), 8.47-8.53 (1H, m), 11.53 (1H, s), 13.78 (1H, br s). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.137 min. [M+H] Calc'd for Ci6H14N204, 299; Found, 299. Example 94: 2-[(2-chlorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000102_0001
[00215] The title compound was prepared in <1% yield using 2-chloro-(prop-2-yn-l- yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, CD3OD): δ ppm 5.41 (2H, s), 6.84 (IH, s), 6.88-6.91 (IH, m), 7.11-7.13 (IH, m), 7.17-7.21 (IH, m), 7.31-7.33 (IH, m), 7.85 (IH, br s), 8.46 (IH, br s). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.372 min. [M+H] Calc'd for Ci5HnClN203, 303; Found, 303.
Example 95: 2-[(2-fluorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000102_0002
[00216] The title compound was prepared in <1% yield using 2-fluoro-(prop-2-yn-l- yloxy)benzene according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.40 (2H, s), 6.78 (IH, s), 6.94-6.99 (IH, m), 7.14-7.21 (IH, m), 7.24-7.31 (IH, m), 7.33-7.35 (IH, m), 7.58-7.59 (IH, m), 8.47-8.49 (IH, m), 11.61 (IH, br), 13.61 (IH, br). LCMS (mobile phase: 5-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.300 min. [M+H] Calc'd for Ci5HnFN203, 287; Found, 287.
Example 96: 2-[(2-chloro-4-fluorophenoxy)methyl]-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000102_0003
[00217] The title compound was prepared in <1% yield using 2-chloro-4-fluoro-
(prop-2-yn-l-yloxy)benzene according to the procedure for the preparation of Examples and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.39 (2H, s), 6.83 (IH, s), 6.94-6.99 (IH, 7.11-7.19 (2H, m), 7.84-7.86 (IH, m), 8.46 (IH, br). LCMS (mobile phase: 5-95%
Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.633 min. [M+H] Calc'd for Ci5H10ClFN2O3, 321; Found, 321. Example 97: 2-{[4-(acetylamino)phenoxy]methyl}-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000103_0001
[00218] The title compound was prepared in <1% yield using N-[4-(prop-2-yn-l- yl)phenyl]acetamide according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.76 (3H, s), 5.32 (2H, s), 6.81 (IH, bs), 6.79 (IH, s), 6.82-6.85 (3H, m), 7.14 (IH, s), 7.28 (IH, d, J= 10.0 Hz), 7.73-7.77 (2H, m), 7.81 (IH, br), 9.83 (IH, s), 11.96 (IH, br). LCMS (mobile phase: 5-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.758 min. [M+H] Calc'd for Ci7H15N304, 326; Found, 326.
Example 98: 2-[(4-cyanophenoxy)methyl]-lH-pyrrolo[3,2-¾]pyridine-7-carboxyl
Figure imgf000103_0002
[00219] The title compound was prepared in <1% yield using 4-(prop-2-yn-l- yl)benzonitrile according to the procedure for the preparation of Examples 9 and 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.42 (2H, s), 6.79 (IH, s), 7.24 (2H, d, J= 9.2 Hz), 7.57-7.59 (IH, m), 7.83 (2H, d, J= 6.8 Hz), 8.48 (IH, d, J= 5.2 Hz), 11.62 (IH, s), 13.79 (IH, br). LCMS (mobile phase: 5-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.432 min. [M+H] Calc'd for Ci6HnN303, 294; Found, 294.
Example 99: 2-(pyrrolidin-l-ylcarbonyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000103_0003
[00220] To a round-bottom flask charged with pyruvic acid (693 μί, 10 mmol), DMF
(2 drops) in DCM (10 mL) was added SOCl2 (730 μΕ, 20 mmol) dropwise at 0 °C. The reaction was stirred at ambient temperature for 30min. Pyrrollidine (2.5 mL, 30 mmol) was added dropwise at 0 °C. The reaction was allowed to stir for lh at ambient temperature. The reaction was taken up in DCM and the organic layers were successively washed with water, brine, dried with Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (0-30% gradient of EtOAc in Hexanes) to afford l-(pyrrolidin-l- yl)propane-l,2-dione (335 mg, 24%).
[00221] The title compound was prepared in 34% yield using l-(pyrrolidin-l- yl)propane-l,2-dione according to the procedure for the preparation of Example 91, except the product was purified by prep-HPLC (10-95% ACN/water, 0.1% HC02H). 1H NMR (400 MHz, DMSO-dg): δ ppm 1.72 - 2.16 (m, 5 H), 3.58 (t, J=6.82 Hz, 2 H), 3.85 (t, J=6.69 Hz, 2 H), 7.11 - 7.38 (m, 1 H), 7.69 (d, J=4.80 Hz, 1 H), 8.61 (d, J=4.80 Hz, 1 H), 10.30 - 10.54 (m, 1 H), 13.90 - 14.19 (m, 1 H). [M+H] Calc'd for C13H13N3O3, 260; Found, 260.
Example 100: methyl 2-[(4-fluorophenyl)methyl]pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000104_0001
[00222] The title compound was prepared in <1% yield starting with 4- fluorobenzaldehyde according to the procedure for the preparation of Example 55 and 9. 1H NMR (400 MHz, CDCI3): δ ppm 3.99 (3H, s), 4.17 (2H, s), 6.58 (1H, s), 7.03 (2H, t, J= 8.4 Hz), 7.22-7.25 (2H, m), 7.56 (1H, d, J= 4.0 Hz), 8.51-8.53 (1H, m), 9.24 (1H, bs). LCMS (mobile phase: 10%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.573 min. [M+H] Calc'd for Ci6Hi3FN202, 285; Found, 285.
Example 101: 2-[(4-fluorophenyl)methyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000104_0002
[00223] The title compound was prepared in 61 > yield using methyl 2-[(4- fluorophenyl)methyl]pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.05 (2H, s), 6.36 (1H, s), 7.12-7.18 (2H, m), 7.36-7.51(2H, m), 8.38 (1H, m), 11.33 (1H, s), 13.69 (1H, bs). LCMS (mobile phase: 5-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.250 min. [M+H] Calc'd for C15HHFN2O2, 271; Found, 271.
Example 102: methyl 2-[l-(4-fluorophenyl)-l-hydroxyethyl]-lH-pyrrolo[3,2-¾]pyridine-7- carboxylate
Figure imgf000105_0001
[00224] The title compound was prepared in 15% yield using 2-(4-fluorophenyl)-3- butyn-2-ol according to the procedure for the preparation of Example 4. 1H NMR (400 MHz, CDC -d): δ ppm 2.08 (s, 3 H), 4.02 (s, 3 H), 6.81 (br. s., 1 H), 7.03 (t, J=8.72 Hz, 2 H), 7.46 (dd, J=8.72, 5.18 Hz, 2 H), 7.68 (br. s., 1 H), 8.52 (d, J=4.80 Hz, 1 H), 9.73 (br. s., 1 H). [M+H] Calc'd for Ci7Hi5FN203, 315; Found, 315.
Example 103: 2-[l-(4-fluorophenyl)-l-hydroxyethyl]-lH-pyrrolo[3,2-¾]pyridine-7- carboxylic acid
Figure imgf000105_0002
[00225] The title compound was prepared in 86%> yield using methyl 2-[l-(4- fluorophenyl)-l-hydroxyethyl]-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.89 (s, 3 H), 6.41 (s, 1 H), 6.67 (s, 1 H), 7.14 (t, J=8.84 Hz, 2 H), 7.45 (dd, J=8.84, 5.56 Hz, 2 H), 7.51 (d, J=5.05 Hz, 1 H), 8.45 (d, J=4.80 Hz, 1 H), 10.29 (br. s., 1 H), 13.81 (br. s., 1 H). [M+H] Calc'd for Ci6H13FN203, 301; Found, 301. Example 104: methyl 2-(l,2,3,4-tetrahydroquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000106_0001
[00226] To a round-bottom flask charged with pyruvic acid (1.39 mL, 20 mmol),
DMF (2 drops) in DCM (40 mL) was added SOCl2 (1.46 mL, 20 mmol) dropwise at 0 °C. The reaction was stirred at ambient temperature for 30min. DIEA (7.2 mL, 40 mmol) was added slowly at 0 °C followed by dropwise addition of 1,2, 3, 4-tetrahydroquino line (2.66g, 20 mmol). The reaction was allowed to stir for lh at ambient temperature. The reaction was taken up in DCM and the organic layers were successively washed with water, brine, dried with Na2S04, and concentrated in vacuo. The residue was purified by column
chromatography (0-30% gradient of EtOAc in Hexanes) to afford l-(3.4-dihydroquinolin-l- (2H)-yl)propane-l,2-dinone (480 mg, 30%).
[00227] The title compound was prepared in 10%> yield using l-(3.4-dihydroquinolin- l-(2H)-yl)propane-l,2-dinone according to the procedure for the preparation of Example 91, except the product was purified by prep-HPLC (20-80% ACN/water, 0.1% NH4Ac). 1H NMR (400 MHz, CDC13): δ ppm 2.06-2.13 (2H, m), 2.83-2.86 (2H, m), 4.01-4.05 (2H, m), 4.07 (3H, s), 6.44 (1H, s), 7.02-7.26 (3H, m), 7.26-7.27 (1H, m), 7.78 (1H, d, J= 4.4 Hz), 8.59 (1H, d, J= 4.8 Hz), 10.02 (1H, bs). LCMS (mobile phase: 20%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.363 min. [M+H] Calc'd for Ci9Hi7N303, 336; Found, 336.
Example 105: 2-(l ,2,3,4-tetrahydroquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000106_0002
[00228] The title compound was prepared in 65%> yield methyl 2-(l , 2,3,4- tetrahydroquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 1.95- 2.01 (2H, m), 2.81-2.85 (2H, m), 3.84-3.88 (2H, m), 6.52 (1H, s), 6.97-7.10 (2H, m), 7.19- 7.28 (2H, m), 7.63 (1H, d, J= 4.4 Hz), 8.52 (1H, d, J= 4.8 Hz), 11.11 (1H, bs), 13.93 (1H, bs). LCMS (mobile phase: 20%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.148 min. [M+H] Calc'd for Ci8Hi5N303, 322; Found, 322.
Example 106: methyl 2-(indolinylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000107_0001
[00229] The title compound was prepared in 2% yield starting with indoline according to the procedure for the preparation of Example 104. 1H NMR (400 MHz, DMSO-de): δ ppm 3.21-3.25 (2H, m), 4.01 (3H, s), 4.42-4.46 (2H, m), 7.09-7.13 (1H, m), 7.23-7.35 (2H, m), 7.74 (1H, d, J= 4.4 Hz), 8.21-8.23 (1H, m), 8.64 (1H, d, J= 4.8 Hz),l 1.11 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.741 min. [M+H] Calc'd for Ci8H15N303, 322; Found, 322.
Example 107: 2-(indolinylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000107_0002
[00230] The title compound was prepared in 40%> yield methyl 2-
(indolinylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.21-3.27 (2H, m), 4.48- 4.51 (2H, m), 7.09-7.14 (1H, m), 7.25-7.29 (3H, m), 7.71 (1H, d, J= 4.4 Hz), 8.16-8.23 (1H, m), 8.64 (1H, d, J= 4.8 Hz), 10.80 (1H, s). LCMS (mobile phase: 5%-95%
Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.365 min. [M+H] Calc'd for Ci7H13N303, 308; Found, 308.
Example 108: methyl 2-(piperidylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000107_0003
[00231] The title compound was prepared in 4% yield starting with piperidine according to the procedure for the preparation of Example 104. 1H NMR (400 MHz, DMSO-de): δ ppm 1.57-1.65 (6H, m), 3.53-3.64 (4H, m), 3.99 (3H, s), 6.89 (1H, s), 7.66 (1H, d, J= 4.8 Hz), 8.57 (1H, d, J= 4.8 Hz), 11.47 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.050 min. [M+H] Calc'd for Ci5H17N303, 288; Found, 288.
Example 109: 2-(piperidylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000108_0001
[00232] The title compoun was prepared in 25% yield methyl 2-
(piperidylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.54-1.64 (6H, m), 3.46- 3.63 (4H, m), 6.99 (1H, s), 7.80 (1H, d, J= 5.2 Hz), 8.66 (1H, d, J= 4.4Hz), 11.85 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.208 min. [M+H] Calc'd for Ci4Hi5N303, 274; Found, 274.
Example 110: 2-[l-(4-fluorophenyl)ethyl]-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000108_0002
[00233] To a vial containing methyl 2-[l-(4-fluorophenyl)-l-hydroxyethyl]-lH- pyrrolo[3,2-£]pyridine-7-carboxylate (31.4 mg, 0.1 mmol), and Et3SiH (79 μί, 0.5 mmol) was added TFA (76 μί, 1 mmol). The reaction was stirred at ambient temperature for 16hrs and concentrated in vacuo. The residue was taken up in MeOH(5 mL) followed by addition of Pd-C (50mg, 10%), and kept under 1 ATM of ¾ at ambient temperature for 2 hrs. The suspension was filtered through a pad of celite and concentrated in vacuo. The residue was converted to title compound in 46% yield according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.64 (d, J=7.07 Hz, 3 H), 4.49 - 4.62 (m, 1 H), 6.55 (s, 1 H), 7.12 (t, J=8.72 Hz, 2 H), 7.36 (dd, J=8.59, 5.56 Hz, 2 H), 7.46 (d, J=5.56 Hz, 1 H), 8.38 (d, J=4.80 Hz, 1 H), 11.03 - 11.15 (m, 1 H). [M+H] Calc'd for Ci6H13FN202, 275; Found, 275.
Example 111: methyl-2-(3-chloro-4-fluorobenzyl)- lH-pyrrolo[3,2-¾]pyridine-7- carboxylate
Figure imgf000109_0001
[00234] The title compound was prepared in 4% yield starting with 3-chloro-4- fluorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CDC13): δ ppm 4.00 (s, 3 H), 4.18 (s, 2 H), 6.56 - 6.63 (m, 1 H), 7.11- 7.31 (m, 2 H), 7.29-7.31 (m, 2 H), 7.61 (d, J=4.70 Hz, 1 H), 8.53 (s, 1 H), 9.35 (br. s., 1 H). [M+H] Calc'd for C16H12CIFN2O2, 319; Found, 319.
Example 112: 2-(3-chloro-4-fluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000109_0002
[00235] The title compound was prepared in 78% yield using methyl-2-(3-chloro-4- fluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.26 - 3.36 (m, 3 H), 4.19 - 4.26 (m, 2 H), 6.42 (s, 1 H), 7.32 - 7.41 (m, 2 H), 7.47 (d, J=4.80 Hz, 1 H), 7.59 (d, J=7.83 Hz, 1 H), 8.38 (d, J=5.05 Hz, 1 H), 11.35 (br. s., 1 H), 13.67 (br. s., 1 H). [M+H] Calc'd for Ci5Hi0ClFN2O2, 305; Found, 305. Example 113: methyl 2-(4-chloro-3-fluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7- carboxylate
Figure imgf000110_0001
[00236] The title compound was prepared in 11% yield starting with 4-chloro-3- fluorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CDCls): δ ppm 4.00 (s, 3 H), 4.19 (s, 2 H), 6.56 - 6.63 (m, 1 H), 6.92 - 7.11 (m, 2 H), 7.36 (t, J=7.83 Hz, 1 H), 7.58 (d, J=4.80 Hz, 1 H), 8.53 (d, J=5.05 Hz, 1 H), 9.30 (br. s., 1 H). [M+H] Calc'd for Ci6H12ClFN202, 319; Found, 319.
Example 114: 2-(4-chloro-3-fluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000110_0002
[00237] The title compound was prepared in 72% yield using methyl 2-(4-chloro-3- fluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.24 (s, 2 H), 6.43 (d, J=2.02 Hz, 1 H), 7.19 - 7.27 (m, 1 H), 7.42 (dd, J=10.48, 1.89 Hz, 1 H), 7.47 (d, J=4.80 Hz, 1 H), 7.52 (t, J=8.08 Hz, 1 H), 8.39 (d, J=5.05 Hz, 1 H), 11.35 (br. s., 1 H), 13.67 (br. s., 1 H). [M+H] Calc'd for Ci5H10ClFN2O2, 305; Found, 305.
Example 115: methyl 2-[(3-phenylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000110_0003
[00238] The title compound was prepared in 20%> yield starting with 3- phenylpyrrolidine according to the procedure for the preparation of Example 104. (400 MHz, CDCI3): δ ppm 2.15-2.27 (1H, m), 2.41-2.56 (1H, m), 3.49-3.61 (1H, m), 3.74- 3.89 (2H, m), 4.01-4.07 (4H, m), 4.17-4.44 (1H, m), 7.16 (1H, d, J= 16.8 Hz), 7.28-7.35 (3H, m), 7.36-7.39 (2H, m), 7.77-7.80 (1H, m), 8.64-8.67 (1H, m), 10.56 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.782 min. [M+H] Calc'd for C2oH19N303, 350; Found, 350.
Example 116: 2-[(3-phenylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000111_0001
[00239] The title compound was prepared in 82% yield methyl 2-[(3- phenylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 2.05- 2.17 (1H, m), 2.31-2.47 (1H, m), 3.46-3.57 (1.5H, m), 3.63-3.66 (0.5H, m), 3.83-3.88 (1H, m), 3.95-4.02 (0.5H, m), 4.07-4.12 (1H, m), 4.31-4.36 (0.5H, m), 7.24-7.40 (6H, m), 7.68- 7.71 (1H, m), 8.60-8.64 (1H, m), 10.45-10.49 (1H, m), 14.12 (1H, br). LCMS (mobile phase: 5%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.671 min. [M+H] Calc'd for Ci8Hi7N303, 336; Found, 336.
Example 117: methyl 2-[(4,4-dimethylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000111_0002
[00240] The title compound was prepared in 21 > yield starting with 4,4- dimethylpiperidine according to the procedure for the preparation of Example 104. 1H NMR (300 MHz, CDC13): δ ppm 1.07 (6H, s), 1.47-1.51 (4H, m), 3.78-3.93 (4H, m), 4.06 (3H, s), 7.01 (1H, s), 7.77 (1H, d, J= 4.8 Hz), 8.65 (1H, d, J= 4.8 Hz), 10.03 (1H, bs). LCMS (mobile phase: 10%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.407 min. [M+H] Calc'd for Ci7H2iN303, 316; Found, 316. Example 118: 2-[(4,4-dimethylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxyl
Figure imgf000112_0001
[00241] The title compound was prepared in 70% yield methyl 2-[(4,4- dimethylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 1.54- 1.64 (6H, m), 3.46-3.63 (4H, m), 6.99 (1H, s), 7.80 (1H, d, J= 5.2 Hz), 8.66 (1H, d, J = 4.4Hz), 11.85 (1H, s). LCMS (mobile phase: 5 %-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.208 min. [M+H] Calc'd for Ci4Hi5N303, 274; Found, 274.
Example 119: methyl 2-[( -phenylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate
Figure imgf000112_0002
[00242] The title compound was prepared in 12% yield starting with 3- phenylpiperidine according to the procedure for the preparation of Example 104. 1H NMR (400 MHz, CDC13): δ ppm 1.69-1.83 (3H, m), 1.86-1.99 (1H, m), 2.81-2.85 (2H, m), 2.89- 2.94 (1H, m), 3.96-3.99 (4H, m), 4.57-4.60 (1H, m), 6.95 (1H, s), 7.17-7.35 (5H, m), 7.66- 7.67 (1H, m), 7.78 (1H, d, J= 4.4 Hz), 8.57 (1H, br), 11.58 (1H, bs). LCMS (mobile phase: 20%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 3.323min. [M+H] Calc'd for C2iH2iN303, 364; Found, 364.
Example 120: 2-[(3-phen lpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000112_0003
[00243] The title compound was prepared in 50% yield methyl 2-[(3- phenylpiperidyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO- d6): δ ppm 1.55-2.05 (5H, m), 2.75-3.02 (2H, m), 3.32-3.38 (2H, m), 6.91 (1H, bs), 7.18-7.45 (5H, m), 7.68-7.72 (1H, m), 8.65 (1H, br), 11.88 (1H, bs). LCMS (mobile phase: 5%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.619min. [M+H] Calc'd for C20H19N3O3, 350; Found, 350.
Example 121: methyl 2-(2-l,2,3,4-tetrahydroisoquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000113_0001
[00244] The title compound was prepared in 35% yield starting with 1 ,2,3,4-
Tetrahydroisoquinoline according to the procedure for the preparation of Example 104. 1H NMR (400 MHz, CD3OD): δ ppm 2.88-2.91 (2H, m), 3.86-3.89 (2H, m), 3.94 (3H, s), 4.88 (2H, br), 6.96-7.09 (5H, m), 7.70 (1H, d, J= 4.8 Hz), 8.46 (1H, d, J= 4.4 Hz). LCMS (mobile phase: 10%-95% Acetonitrile-Water- 0.02% NH4Ac): purity is >95%, Rt = 2.468 min. [M+H] Calc'd for ¾Η17Ν303, 336; Found, 336.
Example 122: 2-(2-l,2,3,4-tetrahydroisoquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7- carboxylic acid
Figure imgf000113_0002
[00245] The title compound was prepared in 65%> yield methyl methyl 2-(2-l , 2,3,4- tetrahydroisoquinolylcarbonyl)pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ 2.93-2.95 (2H, m), 3.85-3.88 (2H, m), 4.82-4.89 (2H, m), 7.09-7.30 (5H, m), 7.70 (1H, d, J= 4.8 Hz), 8.61(1H, d, J= 4.8 Hz), 11.26-11.28 (1H, br). LCMS (mobile phase: 5%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.468 min. [M+H] Calc'd for ¾Η15Ν303, 322; Found, 322. Example 123: methyl 2-[(2,2-dimethylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]pyridine-7- carboxylate
Figure imgf000114_0001
[00246] The title compound was prepared in 35% yield starting with 2,2- dimethylpyrrolidine according to the procedure for the preparation of Example 104. 1H NMR (300 MHz, CDC13): δ ppm 1.62 (6H, s), 1.80-1.95 (2H, m), 1.99-2.06 (2H, m), 3.98- 4.02 (2H, m), 4.06 (3H, s), 7.09 (1H, d, J= 2.4 Hz), 7.78 (1H, d, J= 4.8 Hz), 8.64 (1H, d, J = 4.8 Hz), 10.22 (1H, bs). LCMS (mobile phase: 10%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 3.404 min. [M+H] Calc'd for Ci6Hi9N303, 302; Found, 302.
Example 124: 2-[(2,2-dimethylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylic acid
Figure imgf000114_0002
[00247] The title compound was prepared in 50%> yield methyl 2-[(2,2- dimethylpyrrolidinyl)carbonyl]pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (300 MHz, DMSO-^): δ ppm 1.52 (6H, s), 1.83-1.92 (4H, m), 3.83-3.86 (2H, m), 7.15 (1H, s), 7.72 (1H, d, J= 4.8 Hz), 8.62 (1H, d, J= 4.8 Hz), 10.73 (1H, bs). LCMS (mobile phase: 5%-95% Acetonitrile- Water- 0.02% NH4Ac): purity is >95%, Rt = 2.296 min. [M+H] Calc'd for Ci5H17N303, 288; Found, 288.
Example 125: methyl 2-(3,4-difluorobenz l)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate
Figure imgf000114_0003
[00248] The title compound was prepared in 17% yield starting with 3,4- difluorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CDC13): δ ppm 4.00 (s, 3H), 4.18 (s, 2H), 6.55-6.65 (m, 1H), 6.94-7.18 (m, 3H), 7.58 (d, J= 5.05 Hz, 1H), 8.53 (d, J= 5.05 Hz, 1H), 9.31 (br. s., 1H). [M+H] Calc'd for C16H12F2N2O2, 303; Found, 303.
Example 126: 2-(3,4-difluorobenz l)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000115_0001
[00249] The title compound was prepared in 87% yield using methyl 2-(3,4- difluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.22 (s, 2H), 6.33-6.46 (m, 1H), 7.20 (br. s., 1H), 7.31-7.45 (m, 2H), 7.47 (d, J= 4.80 Hz, 1H), 8.38 (d, J= 5.05 Hz, 1H), 11.34 (br. s., 1H),13.67 (br. s., 1H). [M+H] Calc'd for
Figure imgf000115_0002
289; Found, 289.
Example 127: methyl 2-(4-chloro-3-methoxybenzyl)-lH-pyrrolo[3,2-¾]pyridine-7- carboxylate
Figure imgf000115_0003
[00250] The title compound was prepared in <1% yield starting with 3-methoxy-4- chlorobenzaldehyde according to the procedure for the preparation of Example 59. 1H NMR (400 MHz, CDC13): δ ppm 3.87 (s, 3H), 4.04 (s, 3H), 4.23 (s, 2H), 6.76-6.90 (m, 2H), 7.35 (d, J= 8.08 Hz, 2H), 7.64-7.78 (m, 1H), 8.51 (d, J= 5.56 Hz, 1 H), 9.45-9.62 (m, 1H). [M+H] Calc'd for Ci7Hi5ClN203, 331; Found, 331. Example 128: 2-(4-chloro-3-methoxybenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000116_0001
[00251] The title compound was prepared in 12% yield using methyl 2-(4-chloro-3- methoxybenzyl)-lH-pyrrolo[3,2-b]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, CD3OD): δ ppm 3.80-3.92 (m, 3H), 4.31 (s, 2 H), 6.43-6.50 (m, 1H), 6.82-6.95 (m, 1H), 7.03-7.14 (m, 1H), 7.25-7.39 (m, 1H), 7.73-7.82 (m, 1H), 8.34-8.46 (m, 1H). [M+H] Calc'd for Ci6Hi3ClN203, 317; Found, 317.
Example 129: methyl 2-(3,4-dichlorobenz l)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate
Figure imgf000116_0002
[00252] The title compound was prepared in <5% yield starting with 3,4- dichlorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CDC13): δ ppm 4.02 (s, 3H), 4.19 (s, 2H), 6.62-6.79 (m, 1H), 7.11 (d, J = 10.11 Hz, 1H), 7.36 (m, 1H), 7.42 (d, J= 8.08 Hz, 1H), 7.60-7.68 (m, 1H), 8.48-8.59 (m, 1H), 9.31-9.46 (m, 1H). [M+H] Calc'd for Ci6Hi2Cl2N202, 335; Found, 335.
Example 130: 2-(3,4-dichlorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000116_0003
[00253] The title compound was prepared in 70% yield using methyl 2-(3,4- dichlorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.23 (s, 2H), 6.45 (d, J = 2.02 Hz, 1H), 7.32-7.38 (m, 1H), 7.48 (d, J= 4.80 Hz, 1H), 7.57 (d, J= 8.34 Hz, 1H), 7.63- 7.68 (m, 1H), 8.39 (d, J= 4.80 Hz, 1H), 11.32-11.46 (m, 1H), 13.68 (br. s., 1H). [M+H] Calc'd for C15H10CI2N2O2, 321; Found, 321.
Example 131: methyl 2-(3,4-dichloro-5-fluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7- carboxylate
Figure imgf000117_0001
[00254] The title compound was prepared in 13% yield starting with 3,4-dichloro-5- fluorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CDC13): δ ppm 4.02 (s, 3H), 4.19 (s, 2H), 6.65-6.74 (m, 1H), 6.98 (d, J = 7.33 Hz, 1H), 7.19 (s, 1H), 7.64 (d, J= 5.05 Hz, 1H), 8.55 (d, J= 5.30 Hz, 1H), 9.40 (br. s., 1H). [M+H] Calc'd for CigHnFC^C^, 353; Found, 353.
Example 132: 2-(3,4-dichloro-5-fluorobenz l)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000117_0002
[00255] The title compound was prepared in 80% yield using methyl 2-(3,4-dichloro-
5-fluorobenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.24 (s, 2H), 6.47-6.51 (m, 1H), 7.44-7.46 (m, 1H), 7.47-7.49 (m, 1H), 7.54-7.58 (m, 1H), 8.39 (d, J= 4.80 Hz, 1H), 11.33-11.42 (m, 1H), 13.63-13.73 (m, 1H). [M+H] Calc'd for
Figure imgf000117_0003
339; Found, 339. Example 133: methyl-2-(4-chloro-3-methylbenzyl)-lH-pyrrolo[3,2-¾]pyridine-7- carboxylate
Figure imgf000118_0001
[00256] The title compound was prepared in 6% yield starting with 3 -methyl -4- chlorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CD3OD): δ 2.37 (3H, s), 4.05 (3H, s), 4.23 (2H, s), 6.37 (1H, s), 7.13-7.16 (1H, m), 7.27 (1H, d, J= 2.0 Hz), 7.32 (1H, d, J= 8.0 Hz), 7.65 (1H, d, J= 5.2 Hz), 8.38 (1H, d, J= 5.2 Hz). [M+H] Calc'd for Ci7Hi5ClN202, 315; Found, 315.
Example 134: 2-(4-chloro-3-meth lbenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid
Figure imgf000118_0002
[00257] The title compound was prepared in 80% yield using methyl-2-(4-chloro-3- methylbenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.30 (3H, s), 4.23 (2H, s), 6.48 (1H, s), 7.19-7.21(1H, m), 7.34-7.36 (2H, m), 7.62 (1H, d, J= 5.6 Hz), 8.48 (1H, d, J= 5.2 Hz), 11.76 (1H, s). [M+H] Calc'd for Ci6H13ClN202, 301; Found, 301.
Example 135: methyl 2-[4-chloro-3-(trifluoromethyl)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7- carboxylate
Figure imgf000118_0003
[00258] The title compound was prepared in <5% yield starting with 3- trifluoromethyl-4-chlorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, DMSO-d6): δ 3.98 (3H, s), 4.33 (2H, s), 6.47 (1H, s), 7.51 (1H, d, J= 4.8 Hz), 7.66-7.69 (2H, m), 7.91 (1H, s), 8.42 (1H, d, J= 5.2 Hz), 11.46 (1H, s). [M+H] Calc'd for CnH^ClFsNzC^, 369; Found, 369.
Example 136: 2-[4-chloro-3-(trifluoromethyl)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7- carboxylic acid
Figure imgf000119_0001
[00259] The title compound was prepared in 65% yield using methyl-2-(4-chloro-3- trifluoromethylbenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.32 (2H, s), 6.48 (1H, s), 7.49 (1H, d, J= 5.2 Hz), 7.66-7.69 (2H, m), 7.90 (1H, s), 8.40 (1H, d, J= 4.4 Hz), 11.45 (1H, s). [M+H] Calc'd for
Figure imgf000119_0002
355; Found, 355.
Example 137: Methyl 2-[4-chloro-3-(cyclopropylmethoxy)benzyl]-lH-pyrrolo[3,2- ¾]pyridine-7-carboxylate
Figure imgf000119_0003
[00260] The title compound was prepared in <5% yield starting with 3-
(cyclopropylmethoxy)-4-chlorobenzaldehyde according to the procedure for the preparation of Example 55. 1 H NMR (400 MHz, CD30D): δ 0.33-0.36 (2H, m), 0.55-0.60 (2H, m), 1.24-1.27 (1H, m), 3.87 (2H, d, J = 6.4 Hz), 4.03 (3H, s), 4.21 (2H, s), 6.36 (1H, s), 6.84- 6.86 (1H, m), 7.01 (1H, d, J = 1.6 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.61 (1H, d, J = 5.2 Hz), 8.34 (1H, d, J = 5.2 Hz). [M+H] Calc'd for C20H19C1N2O3, 371; Found, 371. Example 138: 2-[4-chloro-3-(cyclopropylmethoxy)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7- carboxylic acid
Figure imgf000120_0001
[00261] The title compound was prepared in 65% yield using methyl-2-(4-chloro-3- trifluoromethylbenzyl)-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.33-0.36 (2H, m), 0.55-0.60 (2H, m), 1.22-1.26 (1H, m), 3.87 (2H, d, J= 6.4 Hz), 4.21 (2H, s), 6.48 (1H, s), 6.90-6.92 (1H, m), 7.21 (1H, d, J= 2.0 Hz), 7.34 (1H, d, J= 8.0 Hz), 7.61 (1H, d, J= 5.2 Hz), 8.47 (1H, d, J= 5.2 Hz), 11.39 (1H, s). [M+H] Calc'd for C19H17CIN2O3, 357; Found, 357.
Example 139: methyl-2-[4-chloro-3-(2,2,2-trifluoroethoxy)benzyl]-lH-pyrrolo[3,2- ¾]pyridine-7-carboxylate
Figure imgf000120_0002
[00262] The title compound was prepared in <5% yield starting with 3-(2,2,2- trifluoroethoxy)-4-chlorobenzaldehyde according to the procedure for the preparation of Example 55. 1H NMR (400 MHz, CD3OD): δ 4.06 (3H, s), 4.28 (2H, s), 4.58-4.64 (2H, m), 6.41 (1H, s), 7.01-7.04 (1H, m), 7.18 (1H, d, J= 2.0 Hz), 7.40 (1H, d, J= 8.4 Hz), 7.65 (1H, d, J= 4.8 Hz), 8.38 (1H, d, J= 5.2 Hz). [M+H] Calc'd for CisH^FsClNzOs, 399; Found, 399. Example 140: 2-[4-chloro-3-(2,2,2-trifluoroethoxy)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7- carboxylic acid
Figure imgf000121_0001
[00263] The title compound was prepared in 80% yield using methyl-2-[4-chloro-3-
(2,2,2-trifluoroethoxy)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-^): δ ppm 4.23 (2H, s), 4.81-4.88 (2H, m), 6.41 (1H, s), 7.02-7.05 (1H, m), 7.35 (1H, d, J= 1.2 Hz), 7.41 (1H, d, J= 8.0 Hz), 7.52 (1H, d, J= 5.2 Hz), 8.41 (1H, d, J= 4.8 Hz), 11.45 (1H, s).
[M+H] Calc'd for C17H12F3CIN2O3, 385; Found, 385.
Example 141: methyl-2-[4-chloro-3-(trifluoromethoxy)benzyl]-lH-pyrrolo[3,2-¾]pyridine- 7-carboxylate
Figure imgf000121_0002
[00264] The title compound was prepared in 8% yield starting with 3-
(trifluoromethoxy)-4-chlorobenzaldehyde according to the procedure for the preparation of Example 59. 1H NMR (400 MHz, CDC13): δ ppm 4.03 (s, 3H), 4.24 (s, 2H), 6.64-6.82 (m, 1H), 7.15 (d, J= 10.11 Hz, 1H), 7.46 (d, J= 8.08 Hz, 2H), 7.63-7.77 (m, 1H), 8.53 (d, J = 5.31 Hz, 1H), 9.40-9.57 (m, 1H). [M+H] Calc'd for C17H12F3CIN2O3, 385; Found, 385.
Example 142: 2-[4-chloro-3-(trifluoromethoxy)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7- carboxylic acid
Figure imgf000121_0003
[00265] The title compound was prepared in 92% yield using methyl-2-[4-chloro-3-
(trifluoromethoxy)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7-carboxylate according to the procedure for the preparation in Example 5. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.28 (s, 3H), 6.40-6.46 (m, 1H), 7.37-7.43 (m, 1H), 7.48 (d, J= 4.80 Hz, 1H), 7.58-7.65 (m, 3H), 8.39 (d, J= 4.80 Hz, 1H), 11.38 (br. s., 1H), 13.67 (s, 1H). [M+H] Calc'd for
Ci7H12ClN203, 371; Found, 371.
Example 143: 2-[4-chloro-benzyl]-N-methyl-lH-pyrrolo[3,2-¾]pyridine-7-carboxamide
Figure imgf000122_0001
[00266] To a vial charged with 2-(4-chlorobenzyl)-lH-pyrrolo[3,2-b]pyridine-7- carboxylic acid (75 mg, 0.262 mmol) in DMF (2 mL) was added HATU (150 mg, 0.393 mmol), DIEA (191 μί, 1 mmol) and MeNH2-HCl (26 mg, 0.393 mmol) . The reaction was allowed to stir for 16 h at ambient temperature. The crude mixture was purified by prep- HPLC (5-95% gradient of ACN in water with 0.1% HC02H) to afford the title compound as orange solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.81-2.92 (m, 3H), 4.12-4.27 (m, 2H), 6.28-6.37 (m, 1H), 7.36 (m, 5H), 8.32 (d, J= 5.05 Hz, 1H), 8.70-8.83 (m, 1H), 11.30 (br. s., 1H). [M+H] Calc'd for Ci6H14ClN30, 300; Found, 300.
Example 144 : 2- [4-chloro-3 -(trifluoromethoxy)benzyl] -N-methyl- 1 H-pyrrolo [3 ,2- ¾]pyridine-7-carboxamide
Figure imgf000122_0002
[00267] The title compound was prepared in 49%> yield using 2-[4-chloro-3-
(trifluoromethoxy)benzyl]-lH-pyrrolo[3,2-¾]pyridine-7-carboxylic acid according to the procedure for the preparation in Example 143. 1H NMR (400 MHz, CDC13): δ ppm 2.89- 3.20 (m, 3H), 4.05-4.14 (m, 1H), 4.24 (s, 2H), 6.60-6.80 (m, 1H), 7.05-7.18 (m, 1H), 7.41- 7.58 (m, 2H), 7.93-8.12 (m, 1H), 8.36 (br. s., 1H), 10.24 (s, 1H). [M+H] Calc'd for CnHoFsClNsOz, 384; Found, 384.
II. Biological Evaluation
Example 1: In Vitro Enzyme Inhibition Assay
[00268] This assay determines the ability of a test compound to inhibit JaridlA, JaridlB, JMJD2C, and JMJD2A demethylase activity. Baculovirus expressed JaridlA (GenBank Accession #NM_001042603, AAl-1090) was purchased from BPS Bioscience
(Cat#50110). Baculovirus expressed JaridlB (GenBank Accession #NM_006618, AA 2- 751) was purchased from BPS Bioscience (Cat # 50121) or custom made by
MolecularThroughput. Baculovirus expressed JMJD2C (GenBank Accession #BC143571, AA 2-372) was purchased from BPS Bioscience (Cat#50105). Baculovirus expressed JMJD2A (GenBank Accession #NM_014663, AA 1-350) was purchased from BPS Bioscience (Cat#50123).
JaridlA Assay
[00269] The enzymatic assay of JaridlA activity is based upon Time Resolved- Fluorescence Resonance Energy Transfer (TR-FRET) detection. The ability of test compounds to inhibit the activity of JaridlA was determined in 384-well plate format under the following reaction conditions: 1 nM JaridlA, 300 nM H3K4me3-biotin labeled peptide (Anaspec cat # 64357), 2 μΜ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij'35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μΜ sodium L-ascorbate, and 2 μΜ ammonium iron(II) sulfate. Reaction product was determined quantitatively by TR- FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-mono-or di-methylated histone H3 lysine 4 (H3K4mel-2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 25 nM and 1 nM, respectively.
[00270] The assay reaction was initiated by the following: 2 μΐ of the mixture of 900 nM H3K4me3-biotin labeled peptide and 6 μΜ alpha-ketoglutaric acid with 2 μΐ of 11 -point serial diluted inhibitor in 3%> DMSO was added to each well of plate, followed by the addition of 2 μΐ of 3 nM JaridlA to initiate the reaction. The reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 μΐ of 5 mM EDTA in LANCE detection buffer containing 50 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K4mel-2 antibody. Plates were read by EnVisionMultilabel Reader in TR-FRET mode (excitation at 320nm, emission at 615nm and 665nm) after 1 hour incubation at room temperature. A ratio was calculated (665/615) for each well and fitted to determine inhibition constant (IC50).
JaridlB Assay
[00271] The ability of test compounds to inhibit the activity of JaridlB was determined in 384-well plate format under the following reaction conditions: 0.8 nM JaridlB, 300 nM H3K4me3-biotin labeled peptide (Anaspec cat # 64357), 2 μΜ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μΜ sodium L-ascorbate, and 2 μΜ ammonium iron(II) sulfate. Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-mono-or di-methylated histone H3 lysine 4 (H3K4mel-2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 25 nM and 1 nM, respectively.
[00272] The assay reaction was initiated by the following: 2 μΐ of the mixture of 900 nM H3K4me3-biotin labeled peptide and 6 μΜ alpha-ketoglutaric acid with 2 μΐ of 11 -point serial diluted inhibitor in 3% DMSO was added to each well of the plate, followed by the addition of 2 μΐ of 2.4 nM JaridlB to initiate the reaction. The reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 μΐ of 5 mM EDTA in LANCE detection buffer containing 50 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K4mel-2 antibody. Plates were read by EnVisionMultilabel Reader in TR-FRET mode (excitation at 320nm, emission at 615nm and 665nm) after 1 hour incubation at room temperature. A ratio was calculated (665/615) for each well and fitted to determine inhibition constant (IC50).
JMJD2C Assay
[00273] The ability of test compounds to inhibit the activity of JMJD2C was determined in 384-well plate format under the following reaction conditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide (Anaspec cat # 64360), 2 μΜ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μΜ sodium L-ascorbate, and 2 μΜ ammonium iron(II) sulfate. Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.
[00274] The assay reaction was initiated by the following: 2 μΐ of the mixture of 900 nM H3K9me3-biotin labeled peptide and 6 μΜ alpha-ketoglutaric acid with 2 μΐ of 11 -point serial diluted inhibitor in 3% DMSO were added to each well of the plate, followed by the addition of 2 μΐ of 0.9 nM JMJD2C to initiate the reaction. The reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 μΐ of 5 mM EDTA in LANCE detection buffer containing 100 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody. Plates were read by EnVisionMultilabel Reader in TR-FRET mode (excitation at 320nm, emission at 615nm and 665nm) after 1 hour incubation at room temperature. A ratio was calculated (665/615) for each well and fitted to determine inhibition constant (IC50).
JMJD2A Assay
[00275] The ability of test compounds to inhibit the activity of JMJD2A was determined in 384-well plate format under the following reaction conditions: 2 nM JMJD2A, 300 nM H3K9me3-biotin labeled peptide (Anaspec cat # 64360), 2 μΜ alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μΜ sodium L-ascorbate, and 2 μΜ ammonium iron(II) sulfate. Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.
[00276] The assay reaction was initiated by the following: 2 μΐ of the mixture of 900 nM H3K9me3-biotin labeled peptide and 6 μΜ alpha-ketoglutaric acid with 2 μΐ of 11 -point serial diluted inhibitor in 3% DMSO were added to each well of plate, followed by the addition of 2 μΐ of 6 nM JMJD2A to initiate the reaction. The reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 μΐ of 5 mM EDTA in LANCE detection buffer containing 100 nM Phycolink Streptavidin- allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody. Plates were read by EnVisionMultilabel Reader in TR-FRET mode (excitation at 320nm, emission at 615nm and 665nm) after 1 hour incubation at room temperature. A ratio was calculated (665/615) for each well and fitted to determine inhibition constant (IC50).
[00277] The ability of the compounds disclosed herein to inhibit demethylase activity was quantified and the respective IC50 value was determined. Table 3 provides the IC50 values of various compounds disclosed herein.
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
carboxyl ic acid
Figure imgf000129_0001
carboxyl ic acid
Figure imgf000130_0001
Figure imgf000131_0001
carboxyl ic acid
Figure imgf000132_0001
Figure imgf000133_0001
lo[3,2-b]pyridine -7-carboxylate
Figure imgf000134_0001
Figure imgf000135_0001
Note: Biochemical assay IC50 data are designated within the following ranges:
Α: < 0.10 μΜ C: > 1.0 μΜ to < 10 μΜ
B: > 0.10 μΜ to < 1.0 μΜ D: > 10 μΜ
Example 2a: In Vitro Cell-based Assay - ZR-75-1 cell line
[00278] An assay to measure the degree of cellular inhibition of KDM5A and 5B was developed. This quantitative immuno-blotting assay measures the amount tri-methylated histone H3 at amino acid Lysine number 4, a specific substrate and product of the direct enzymatic activity of the histone demethylases KDM5A and KDM5B from extracts of the ZR-75-1 breast cancer cell line.
Assay Principle
[00279] This assay is a fluorometric immunoassay for the quantification of tri-methyl H3K4 extracted from cells treated with test compound and is used as a measure of the cellular inhibition of KDM5A/B.
Assay Method
[00280] ZR-75-1 (PTEN null, ER+) breast cancer cells numbering 50,000 (ATCC) were seeded into each well of a 96-well tissue culture treated plate and then exposed to an 1 1 point dilution of test compound with final concentration ranges of test compound ranging from 1250 μΜ to 10 nM. Cells were left in the presence of test compound for 72 hours. Extracts were prepared containing all of the cellular histone material using detergent based lysis and sonication methods. These lysates were subsequently normalized for total protein content using a colorimetric bicinchonic acid assay {MicroBCA Pierce/Thermo Scientific). Normalized cell extracts were then subjected to typical immuno-b lotting procedures using NuPage reagents {Life Technologies). Electrophoretically separated histones were then transferred and immobilized using polyvinylidene difluoride membrane (Immobilon-FL Millipore). The amount of tri-methylated lysine 4 of histone H3 was detected using an antibody specific to the tri-methylated state (Cell Signaling Technologies) and quantified on an infrared imager using a densitometry software package {Odyssey CLx, Image Studio, Li- Cor). This background subtracted densitometry value was reported as a ration of the GAPDH amount for that sample and then calculated as a percent of the DMSO treated sample. The software package XL-fit (IDBS) was then used to calculate a relative IC50 value for the dilution series of a given test compound according to the equation:
it = (D+((Vmax*(x n))/((x n)+(Km n)))).
Example 2b: In Vitro Cell-based Assay - KYSE-150 cell line
[00281] The primary cellular assay for JMJD2C inhibition is an assay which measures cellular proliferation via Bromodeoxyuridine (BrdU) incorporation after 168 hours of compound incubation. This assay is a quantitative ELISA assay measuring DNA
incorporation of BrdU during S-phase as a direct readout of cellular proliferation. The KYSE-150 cell line is a JMJD2C gene amplified cell line.
Assay Principle
[00282] This is a colorimetric immunoassay for the quantification of cell proliferation. Cells treated for 168 hours with test compounds are assayed for their ability to go through S-phase as a measure of their proliferative potential.
Assay Method
[00283] The human KYSE-150 (SMAD4 mut, TP53 mut) esophageal carcinoma cell line was seeded at 2,000 cells/well on a 96-well tissue culture treated plate. After an overnight incubation, cells were treated with a test compound in an 11 point dilution series with final concentrations ranging from 100 μΜ to 2 nM. Cells were then incubated in the presence of compound for 168 hours. After compound incubation, the cells were assayed using a BrdU Cell Proliferation ELISA (Roche). The cells were first incubated with BrdU labeling reagent for 2 hours. After 2 hours, these BrdU incorporated cells were fixed and denatured, probed with an anti-BrdU-Peroxidase antibody for 1.5 hours and washed. Finally, a tetramethylbenzidine peroxidase substrate was added to each well for 15 minutes followed by H2SO4 stop solution. The plate is read at 450nm, and the raw optical density data is transferred into XLFit (IDBS) for IC50 calculation using the formula: fit =
(D+((Vmax*(x n))/((x n)+(Km n)))) [00284] Table 4 provides the cellular IC5o values of various compounds disclosed herein.
Table 4
Figure imgf000137_0001
carboxylic acid
Figure imgf000138_0001
carboxamide
Figure imgf000139_0001
Note: Cellular assay IC50 data are designated within the following ranges:
Α: < 0.10 μΜ C: > 1.0 μΜ to < 10 μΜ
B: > 0.10 μΜ to < 1.0 μΜ D: > 10 μΜ
Example 3: In Vivo Xenograph Study
[00285] Time release pellets containing 0.72 mg 17-β Estradiol are subcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMI containing 10% FBS at 5% CO2, 37 °C. Cells are spun down and re-suspended in 50% RPMI (serum free) and 50%> Matrigel at 1X107 cells/mL. MCF-7 cells are subcutaneously injected
Figure imgf000139_0002
on the right flank 2-3 days post pellet implantation and tumor volume (length x width I ) is monitored bi-weekly. When tumors reach an average volume of -200 mm animals are randomized and treatment is started. Animals are treated with vehicle or compound daily for 4 weeks. Tumor volume and body weight are monitored bi-weekly throughout the study. At the conclusion of the treatment period, plasma and tumor samples are taken for
pharmacokinetic and pharmacodynamic analyses, respectively.
III. Preparation of Pharmaceutical Dosage Forms
Example 1: Oral Tablet
[00286] A tablet is prepared by mixing 48% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of low-substituted hydroxypropyl cellulose, and 2%> by weight of magnesium stearate. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 250-500 mg.

Claims

CLAIMS We Claim:
1. A compound having the structure of Formula (II),
Figure imgf000140_0001
or a pharmaceutically acceptable salt thereof,
wherein,
R1 is hydrogen or alkyl;
G is X-R 2 or X 1 -alkyl, wherein
X is a bond, alkylene, alkylene-O-, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or - S02-;
R is selected from carbocyclyl, heterocyclyl, aryl, or heteroaryl;
XI is a bond, -C(O)-, -C(0)-NH-, -NH-, -NH-C(O)-, -0-, -S-, or -S02-; and
R is hydrogen, halogen or alkyl.
2. The compound of claim 1, wherein R1 is hydrogen.
3. The compound of claim 1, wherein R3 is hydrogen.
4. The compound of claim 1, wherein G is X-R .
2
5. The compound of claim 4, wherein X is a bond and R is aryl.
6. The compound of claim 4, wherein X is alkylene and R is aryl.
7. The compound of claim 6, wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
8. The compound of claim 4, wherein X is a C1-C3 alkylene and R is aryl.
9. The compound of claim 4, wherein X is a bond and R is carbocyclyl.
10. The compound of claim 9, wherein R is C3-C7 carbocyclyl.
11. The compound of claim 10, wherein the carbocyclyl is a 1 -hydroxy carbocyclyl.
12. The compound of claim 4, wherein X is a bond and R is heteroaryl.
13. The compound of claim 4, wherein X is a bond and R is heterocyclyl.
14. The compound of claim 4, wherein X is alkylene and R is carbocyclyl.
15. The compound of claim 14, wherein alkylene is substituted with -OH, alkoxy, alkylamino, or dialkylamino.
16. The compound of claim 14, wherein R is C3-C7 carbocyclyl. 2
17. The compound of claim 4, wherein X is C1-C3 alkylene and R is carbocyclyl.
18. The compound of claim 17, wherein R is C3-C7 carbocyclyl.
19. The compound of claim 4, wherein X is alkylene and R is heteroaryl.
20. The compound of claim 19, wherein alkylene is substituted with -OH, alkoxy, alkyl or dialkylamino.
21. The compound of claim 4, wherein X is C1-C3 alkylene and R is heteroaryl.
22. The compound of claim 4, wherein X is alkylene and R is heterocyclyl.
23. The compound of claim 22, wherein alkylene is substituted with -OH, alkoxy, alkyl or dialkylamino.
24. The compound of claim 4, wherein X is C1-C3 alkylene and R is heterocyclyl.
2
25. The compound of claim 4, wherein X is -C(O)- and R is aryl.
26. The compound of claim 4, wherein X is -C(O)- and R is heteroaryl.
27. The compound of claim 4, wherein X is -C(O)- and R is carbocyclyl.
2
28. The compound of claim 27, wherein R is C3-C7 carbocyclyl.
2
29. The compound of claim 4, wherein X is -C(O)- and R is heterocyclyl.
30. The compound of claim 4, wherein X is -C(0)-NH- and R is aryl.
31. The compound of claim 4, wherein X is -C(0)-NH- and R is heteroaryl.
32. The compound of claim 4, wherein X is -C(0)-NH- and R is carbocyclyl.
2
33. The compound of claim 32, wherein R is C3-C7 carbocyclyl.
2
34. The compound of claim 4, wherein X is -C(0)-NH- and R is heterocyclyl.
2
35. The compound of claim 4, wherein X is -NH- and R is aryl.
36. The compound of claim 4, wherein X is -NH- and R is heteroaryl.
37. The compound of claim 4, wherein X is -NH- and R is carbocyclyl.
38. The compound of claim 37, wherein R is C3-C7 carbocyclyl.
39. The compound of claim 4, wherein X is -NH- and R is heterocyclyl.
40. The compound of claim 4, wherein X is -NH-C(O)- and R is aryl.
41. The compound of claim 4, wherein X is -NH-C(O)- and R is heteroaryl.
42. The compound of claim 4, wherein X is -NH-C(O)- and R is carbocyclyl.
2
43. The compound of claim 42, wherein R is C3-C7 carbocyclyl.
2
44. The compound of claim 4, wherein X is -NH-C(O)- and R is heterocyclyl.
2
45. The compound of claim 4, wherein X is -O- and R is aryl.
46. The compound of claim 4, wherein X is -O- and R is heteroaryl.
47. The compound of claim 4, wherein X is -O- and R is carbocyclyl.
48. The compound of claim 47, wherein R is C3-C7 carbocyclyl. 2
49. The compound of clai Lm 4, wherein X is -O- and R is heterocyclyl.
2
50. The compound of clai Lm 4, wherein X is -S- and R is aryl.
2
51. The compound of clai Lm 4, wherein X is -S- and R is heteroaryl.
52. The compound of clai Lm 4, wherein X is -S- and R is carbocyclyl.
53. The compound of clai Lm 52, wherein R is C3-C7 carbocyclyl.
54. The compound of clai Lm 4, wherein X is -S- and R is heterocyclyl.
2
55. The compound of clai Lm 4, wherein X is -SO2- and R is aryl.
2
56. The compound of clai Lm 4, wherein X is -SO2- and R is heteroaryl.
57. The compound of clai Lm 4, wherein X is -SO2- and R is carbocyclyl.
58. The compound of clai Lm 57, wherein R is C3-C7 carbocyclyl.
59. The compound of clai Lm 4, wherein X is -SO2- and R is heterocyclyl.
60. The compound of clai Lm 1 , wherein G is X^alkyl.
61. The compound of clai Lm 60, wherein X1 is a bond.
62. The compound of clai Lm 61, wherein the alkyl is a Cl-C4 alkyl.
63. The compound of clai Lm 62, wherein the alkyl is a 1-hydroxyalkyl.
64. The compound of clai Lm 61, wherein the alkyl is a C2-C4 1-hydroxyalkyl.
65. The compound of clai Lm 60, wherein X1 is -C(O)-.
66. The compound of clai Lm 65, wherein the alkyl is a Cl-C4 alkyl.
67. The compound of clai Lm 60, wherein X1 is -C(0)-NH-.
68. The compound of clai Lm 67, wherein the alkyl is a Cl-C4 alkyl.
69. The compound of clai Lm 60, wherein X1 is -NH-.
70. The compound of clai Lm 69, wherein the alkyl is a Cl-C4 alkyl.
71. The compound of clai Lm 60, wherein X1 is -NH-C(O)-.
72. The compound of clai Lm 71, wherein the alkyl is a Cl-C4 alkyl.
73. The compound of clai Lm 60, wherein X1 is -0-.
74. The compound of clai Lm 73, wherein the alkyl is a Cl-C4 alkyl.
75. The compound of clai Lm 60, wherein X1 is -S-.
76. The compound of clai Lm 75, wherein the alkyl is a Cl-C4 alkyl.
77. The compound of clai Lm 60, wherein X1 is -SO2-.
78. The compound of clai Lm 77, wherein the alkyl is a Cl-C4 alkyl.
79. The compound of clai Lm 4, wherein X is alkylene-O-.
80. The compound of clai Lm 4, wherein X is alkylene-O-, and R is aryl.
81. The compound of clai Lm 4, wherein X is alkylene-O-, and R is heteroaryl.
82. The compound of clai Lm 4, wherein X is alkylene-O-, and R is carbocyclyl.
2
83. The compound of claim 82, wherein R is C3-C7 carbocyclyl.
84. The compound of claim 4, wherein X is alkylene-O-, and R is heterocyclyl.
85. The compound of claim 79, wherein the alkylene is a C1-C3 alkylene.
86. A pharmaceutical composition comprising a compound of Formula (II), or a
pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
87. A method for inhibiting histone demethylase comprising the use of a compound of Formula (II), or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof.
88. A method for treating cancer in subject comprising administering to the subject in need thereof a composition comprising a compound of Formula (II), or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof.
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