WO2008008059A1 - Agents anti-cancer et leurs utilisations - Google Patents

Agents anti-cancer et leurs utilisations Download PDF

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Publication number
WO2008008059A1
WO2008008059A1 PCT/US2006/026935 US2006026935W WO2008008059A1 WO 2008008059 A1 WO2008008059 A1 WO 2008008059A1 US 2006026935 W US2006026935 W US 2006026935W WO 2008008059 A1 WO2008008059 A1 WO 2008008059A1
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alkyl
indol
pyridin
pharmaceutically
phenyl
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PCT/US2006/026935
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English (en)
Inventor
Martha Kelly
Younghee Lee
Bin Liu
Ted Fujimoto
Joel Freundlich
Bruce Dorsey
Gary A. Flynn
Arifa Husain
William R. Moore, Jr.
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Locus Pharmaceuticals, Inc.
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Priority to PCT/US2006/026935 priority Critical patent/WO2008008059A1/fr
Publication of WO2008008059A1 publication Critical patent/WO2008008059A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention is in the area of novel compounds and salts thereof, their syntheses, and their use as anti-cancer agents.
  • the cell cycle is a normal, highly regulated ordered set of events that culminates in cell growth and division.
  • the cell cycle progresses through a protein synthetic phase (Gl), a DNA synthetic phase (S) and a mitotic stage (G2/M).
  • Gl protein synthetic phase
  • S DNA synthetic phase
  • G2/M mitotic stage
  • Blocking the cell cycle with pharmacological inhibitors of key molecular targets that drive the cell cycle through mitosis is a strategy for inhibiting unchecked tumor proliferation.
  • Such inhibitors would be effective anti-cancer agents by slowing or halting tumor growth and proliferation.
  • G2/M anti-cancer agents in various stages of clinical development that block cell cycle progression at the Gl, S and the G2/M phase.
  • Compounds that block at G2/M include the anti-mitotic natural product 13-hydroxy-15-oxozoapatlin, the phosphatase inhibitors okadeic acid and sodium orthovanadate and the DNA intercalating agents imidazoacridinones.
  • Other G2/M blocking agents have unidentified molecular targets. Such agents include polyphenol resveratrol, thymoquinone and quinoxaline 1,4-dioxides.
  • Some cell cycle inhibitors also affect microtubule dynamics. These include the taxanes, Vinca alkaloids and combretastatins. hi addition to inhibiting the proliferation of cancer cells, these microtubule-targeted drugs have effects on the vasculature of cancer cells.
  • compounds that affect microtubule dynamics e.g., by inhibiting tubulin polymerization
  • will display antiangiogenic properties, and therefore be useful for the treatment of proliferative retinopathies such as diabetic retinopathy and macular degeneration. See, e.g., Jordan, M. A. and Wilson, L., Nature Rev. Cancer 4:253-65 (2004).
  • a need continues to exist for potent, small molecules that affect microtubule dynamics.
  • a first aspect of the present invention is directed to novel compounds of Formula J.
  • a second aspect of the present invention is directed to pharmaceutical compositions comprising at least one compound of Formula I, or a salt thereof, and one or more pharmaceutically-acceptable excipients.
  • a further aspect of the present invention is directed to a method of treating a condition that results from abnormal cell growth, cellular differentiation, tumor growth or invasion with one or more compounds of
  • a further aspect of the invention is directed to a method of treating cancer, particularly wherein the cancer is leukemia, soft-tissue sarcomas, or non-small cell lung, myeloma, colon, CNS, melanoma, ovarian, renal, prostate, breast, cervical or pancreatic cancer, particularly leukemia, prostate, non-small cell lung or colon cancer, with one or more compounds of
  • a further aspect of the invention is directed to hindering or blocking cell cycle progression by contacting one or more cells with one or more compounds of Formula /.
  • a further aspect of the invention is directed to a method of treating proliferative retinopathies, e.g., diabetic retinopathy and macular degeneration, with one or more compounds of Formula /.
  • a further aspect of the present invention is directed to a method of synthesizing compounds of Formula/. DETAILED DESCRIPTION OF THE INVENTION
  • Compounds of the present invention include compounds of Formula J:
  • a 1 is N or CR 1 , wherein R 1 is hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, nitro, cyano, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, amino, monoalkylamino, dialkylamino, formylamino, alkylcarbonylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyL dialkylaminocarbonylalkyl, sulfonylamino, alkylsulfonylamino, aminosulfonyl, aminosulfonyl, aminosulfonyl, alky
  • a 3 is N or CR 3 , wherein R 3 is hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, nitro, cyano, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, amino, monoalkylamino, dialkylamino, formylamino, alkylcarbonylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, sulfonylamino, alkylsulfonylamino, aminosulfonyl, monoalkylaminosulfonyl, dialky
  • a 5 is N or CR 5 ;
  • R 4 is 1-indolyl or 1-indazolyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl and dialkylaminocarbonylalkyl, or R 4 is adamantyl, or R 4 is selected from the group consisting of
  • R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano amino, monoalkylamino, dialkylamino, formylamino, alkylcarbonylamino, sulfonylamino, alkylsulfonylamino and phenyl, or any two adjacent R groups, together with the carbon atoms to which they are attached, form a 5- or 6-membered aromatic, heteroaromatic or fully or partially unsaturated non-aromatic ring, which ring has 0-2 oxygen atoms, 0-2 sulfur atoms, 0-3 nitrogen atoms and 2-6 carbon atoms, and which ring, together with the phenyl or pyridyl ring to.
  • bicyclic moiety which it is fused, forms a bicyclic moiety, wherein said bicyclic moiety is optionally substituted with one or two substituents independently selected from the group consisting of halo, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, nitro, cyano, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, amino, monoalkylamino, dialkylamino, foraiylamino, alkylcarbonylamino, alkoxycarbonylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, haloalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialky
  • X is Ar, HetAr or BiHetAr, wherein Ar is an aryl group having 6-10 carbons in the ring portion, HetAr is a 6-membered heteroaryl group having 1-3 nitrogen atoms in the ring portion, or HetAr is a 5-membered heteroaryl group having 0-4 nitrogen atoms in the ring portion and optionally having 1 sulfur atom or 1 oxygen atom in the ring portion, and BiHetAr is a heteroaryl group in which a 6-membered ring is fused either to a 5-membered ring or to a 6-membered ring, wherein in each case 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur;
  • Ar, HetAr and BiHetAr are each optionally substituted with one or two substituents independently selected from the group consisting of halo, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, nitro, cyano, aminoalkyl, monoalkylaminoalkyl, dialkylarninoalkyl, amino, monoalkylamino, dialkylamino, formylamino, alkylcarbonylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, sulfonylamino, alkylsulfony
  • a 1 , A 3 and A 5 are not all nitrogen;
  • R 1 , R 5 or R 6 is other than hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, nitro, aminoalkyl, monoalkylaminoalkyl or dialkylaminoalkyl; and
  • R 4 is selected from the group consisting of
  • R 4 is indol-4-yl optionally substituted with one or two substituents independently selected from the group consisting of halo, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, nitro, cyano, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, amino, monoalkylamino, , dialkylamino, formylamino, alkylcarbonylamino, alkoxycarbonylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, haloalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, sulfonylamin
  • the group X is directly bonded to the ring containing groups A 1 , A 3 and A 5 ("the A ring").
  • the linker L is a divalent radical bonded to both the A ring and the X group, and written such that the left end of the radical is bonded to the A ring, while the right end is bonded to the X group.
  • L is -S(O) 2 -NH-
  • the compound represented contains the following functionality: A ring-S(O) 2 -NH-X.
  • R a and R b are independently C 0-4 alkylene, meaning that independently each represents a diradical of a straight- or branched-chain alkane having 1-4 carbon atoms, or represents a covalent bond (the meaning of Co alkylene).
  • examples of -R a -N(R X )-R b -, -R a -S-R b - and -R a -0-R b - include -NH-, -N(CH 3 )-, -O-, -S-, -S-CH 2 -, -NH-CH 2 -, -N(CH 3 KH 2 -, -0-CH 2 -, -CH 2 S- and -CH 2 -O-CH 2 CH 2 -.
  • Suitable 5- and 6-membered aromatic, heteroaromatic or fully or partially unsaturated non-aromatic rings formed by adjacent R groups, together with the carbon atoms to which they are attached include cyclopentene, cyclopentadiene, raran, dihydrofuran, pyrrole, pyrroline, pyrazole, pyrazoline, imidazole, triazole, thiophene, dihydrothiophene, dithiole, dioxole, oxathiole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, oxathiazole, pyran, dihydropyran, dioxin, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazine, isoxazine, oxadiazine, oxathiazine and the like.
  • Each of these rings, together include
  • Suitable values of Ar include phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Each of these rings is optionally substituted as described above.
  • Suitable values of HetAr include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. Each of these rings is optionally substituted as described above. Additionally, the corresponding N-oxides of these rings are intended to be included.
  • Suitable values of BiHetAr groups include indolyl, benzofuranyl, benzo[b]thienyl, isoindolyl, isobenzo furanyl, benzo[c]thienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzo[l,3]dioxolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,4-c]pyridmyl, furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-c]pyridinyl, furo[3,2-b]pyridinyl, thieno[2,3
  • proviso (4) does not apply to a group of compounds in which the A ring is benzene.
  • One group of useful compounds of Formula / includes those wherein at least one of R 5 or R 6 is other than hydrogen.
  • Useful compounds of Formula I include those having an IC 50 of less than about 30 ⁇ M as measured by either of the assays described in Example 162; and those considered to be active compounds, as determined by any of the assays described in Examples 163 or 164.
  • Useful compounds of Formula / also include those having an IC 50 of less than about 20 ⁇ M in the assay described in Example 165.
  • the compounds are of Formula II:
  • R 7 , R 8 , R 9 , R 10 and R 11 are hydrogen, and the other two are independently selected from the group consisting of of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyano, amino, monoalkylamino, dialkylamino, formylamino, alkylcarbonylamino, alkoxycarbonylamino, sulfonylamino, alkylsulfonylamino and phenyl;
  • X is HetAr; n is 1; and R 1 , R 3 , R 5 , R 6 and L are defined as above.
  • One group of useful compounds in this embodiment includes those wherein:
  • R 1 is hydrogen or hydroxy
  • R 3 is hydrogen
  • R 5 is selected from the group consisting of hydrogen, benzyl and (C 1-4 alkoxy)benzyl
  • R 6 is selected from the group consisting of hydrogen, halo, hydroxyl, Ci -4 alkyl, halo(C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, benzyloxy, (C 1-4 alkoxy)benzyloxy, amino, HiOnO(C 1 ⁇ alkylamino, di(C 1-4 )alkylamino, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, benzyloxycarbonylamino, (C 1-4 alkyl)sulfonylamino, ureido, N-(C 1-4 alkyl)ureido, N-(Cw alkyl)ureido, N,N'-di(C 1-4 alkyl)ureido, N,N',N
  • X is selected from the group consisting of pyridinyl, 1-oxy-pyridinyl and pyrazinyl, each of which is optionally substituted with one or two substitutents selected from the group consisting of halo, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 )alkyl, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, cyano, carbamoyl, mono(C 1-4 alkyl)aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, morpholin-4-yl and formyloxy(C 1-4 )alkoxy(C 1-4 )alkyl.
  • useful compounds include those wherein R 1 , R 3 and R 5 are each hydrogen; and R 6 is other than hydrogen.
  • useful compounds include those wherein three of
  • R 7 , R 8 , R 9 , R 10 and R 11 are hydrogen, and the other two are independently selected from the group consisting of hydrogen, halo, phenyl, C 1-4 alkyl, halo(C 1-4 )alkyl, amino, mono(C 1-4 )alkylamino, di(C 1-4 )alkylamino and C 1-4 alkylsulfonylamino. More useful compounds include those wherein four of R 7 , R 8 , R 9 , R 10 and R 11 are hydrogen, and the other is selected from the group consisting of hydrogen, chloro, trifluoromethyl, dimethylamino, methylsulfonylamino and phenyl.
  • More useful compounds include those wherein R 7 , R 8 , R 9 , R 10 and R 11 , together with the phenyl ring to which they are attached, form a moiety selected from the group consisting of phenyl, 2-chloro ⁇ henyl, 3-phenylphenyl, 2-trifluoromethylphenyl,
  • useful R 1 include hydrogen.
  • useful R 3 include hydrogen.
  • useful R 5 include hydrogen.
  • useful R 6 include hydroxyl, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino and (C 1-4 alkyl)sulfonylamino. More useful R 6 include hydroxyl and (C 1-4 alkyl)carbonylamino, particularly hydroxyl.
  • useful L include -NH-, -N(R X )- and -C(O)-, wherein R x is C 1-6 alkyl. More useful L include -NH- and -C(O)-, particularly -NH-.
  • useful X include pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl and carbamoyl. More useful X include pyridyl, particularly 3-pyridyl.
  • one useful group of compounds includes those wherein R 1 , R 3 and R 5 are each hydrogen; R 6 is hydroxyl, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino or (C 1-4 alkyl)sulfonylamino; L is -NH-, -N(R X )- or -C(O)-, wherein R x is C 1-6 alkyl; and X is pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl and carbamoyl.
  • useful compounds include those wherein R is hydroxyl.
  • useful compounds include those wherein L is -NH-.
  • useful compounds include those wherein X is pyridyl, particularly 3-pyridyl.
  • the compounds are of Formula //:
  • one useful group of compounds are those wherein the bicyclic moiety is unsubstituted.
  • one useful group of compounds are those wherein
  • X is HetAr.
  • R 1 is hydrogen or hydroxy
  • R 3 is hydrogen
  • R 5 is selected from the group consisting of hydrogen, benzyl and (C 1-4 alkoxy)benzyl;
  • R 6 is selected from the group consisting of hydrogen, halo, hydroxyl, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, benzyloxy, (C 1-4 alkoxy)benzyloxy, amino, mono(C 1-4 )alkylamino, di(C 1 - 4 )alkylamino, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, hydroxy(C 1-4 allcyl)carbonylamino, benzyloxycarbonylamino, (C 1-4 alkyl)sulfonylamino, ureido, N-(C 1-4 alkyl)ureido, N-(C 1-4 alkyl)ureido, N,N'-di(C 1-4 alkyl)ureido, N,N',N'-tri(C 1-4 alkyl)
  • X is selected from the group consisting of pyridinyl, 1-oxy-pyridinyl, pyrirnidmyl and pyrazinyl, each of which is optionally substituted with one or two substitutents selected from the group consisting of halo, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C i -4 )alkyl, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, cyano, carbamoyl, mono(C 1-4 alkyl) aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, morpholin-4-yl and formyloxy(C 1-4 )alkoxy(C 1-4 )alkyl.
  • one useful group of compounds includes those wherein R 1 , R 3 and R 5 are each hydrogen; and R 6 is other than hydrogen.
  • useful bicylic moieties include indanyl, benzo[l,3]dioxolyl, l,3-dihydro-indol-2-onyl, quinolinyl, benzofuranyl, indazolyl, benzothienyl and indolyl, each of which is optionally substituted with one or two substitutents selected from the group consisting of halo, C 1-4 alkyl, cyano, C 2-5 alkanoyl and halo(C 2-5 )alkanoyl.
  • Benzimidazolyl may also be useful. More useful bicylic moieties include indan-5-yl, indan-4-yl, benzo[l ,3]dioxol-5-yl, benzo[l ,3]dioxol-4-yl, 1 ,3-dihydro-indol-2-on-4-yl, quinolin-8-yl, benzofuran-4-yl, indazol-4-yl, indazol-7-yl, benzo[b]thiophen- 4-yl, indol-7-yl, indol-5-yl, indol-6-yl and indol-4-yl, each of which is optionally substituted with one substitutent selected from the group consisting of fluoro, chloro, methyl, cyano and trifluoroacetyl.
  • More useful bicylic moieties include indan-5-yl, indan-4-yl, benzo[l,3]dioxol-5-yl, benzo[l,3]dioxol-4-yl, l,3-dihydro-indol-2-on-4-yl, quinolin-8-yl, benzofuran- 4-yl, indazol-4-yl, indazol-7-yl, benzo[b]thiophen-4-yl, l-methyl-indol-7-yl, indol-5-yl, indol-6-yl, indol-4-yl, 7-fluoro-indol-4-yl, 2-cyano-indol-4-yl, 2-methyl-indol-4-yl, 3-trifluoroacetyl-indol-4-yl, l-methyl-indol-4-yl and 3-chloro-indol-4
  • More useful bicylic moieties include indol-4-yl optionally substituted with one substitutent selected from the group consisting of halo, C 1-4 alkyl, C 2-5 alkanoyl and halo(C 2-5 )alkanoyl, and indol-4-yl optionally subsituted with cyano. More useful bicylic moieties include indol-4-yl optionally substituted once with chloro, fluoro, methyl or trifluoroacetyl. More useful bicylic moieties include indol-4-yl.
  • useful R 1 include hydrogen and hydroxy. More useful R 1 include hydrogen.
  • useful R 3 include hydrogen.
  • useful R 5 include hydrogen, benzyl and (C 1-4 alkoxy)benzyl. More useful R 5 include hydrogen.
  • useful R 6 include hydrogen, halo, hydroxyl, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy, benzyloxy, (C 1-4 alkoxy)benzyloxy, amino, mono(C 1-4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, hydroxy(C 1-4 alkyl)carbonylammo, benzyloxycarbonylamino, (C 1-4 alkyl)sulfonylamino, ureido, N-(C 1-4 alkyl)ureido, N'-(C 1-4 alkyl)ureido, N,N'-di(C 1-4 alkyl)ureido, N,N',N'-tri(C 1-4 alkyl)ureido, N',N'-di
  • R 6 More useful R 6 include hydrogen, halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, benzyloxy, (C 1-4 alkoxy)benzyloxy, amino, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, hydroxy(C 1-4 alkyl)carbonylamino, benzyloxycarbonylamiiio, (C 1-4 alkyl)sulfonylamino, N',N'-di(C 1-4 alkyl)ureido, carbamoyl, (C 1-4 alkoxy)carbonyl, cyano, nitro and 2-oxo-pyrrolidin-l-yl.
  • R 6 More useful R 6 include hydrogen, chloro, hydroxyl, methyl, methoxy, 4-methoxybenzyloxy, amino, acetylamino, propanoylamino, methoxycarbonylamino, hydroxyacetylamino, benzyloxycarbonylamino, methylsulfonylamino, N',N'-dimethylureido, carbamoyl, methoxycarbonyl, cyano, nitro and 2-oxo-pyrrolidin-l-yl.
  • useful R 6 also include hydroxyl. m this embodiment, useful R 6 also include (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino and (C 1-4 alkyl)sulfonylamino.
  • useful L include -NH-, -N(R X )-, -N(C(O)-CH 3 )-,
  • useful X when X is HetAr include pyridinyl
  • 1-oxy-pyridinyl and pyrazinyl each of which is optionally substituted with one or two substitutents selected from the group consisting of halo, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 )alkyl, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, cyano, carbamoyl, mono(C 1-4 alkyl)aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, morpholin-4-yl, thiomo ⁇ holin-4-yl, formyloxy(C 1-4 )alkoxy(C 1-4 )alkyl and piperidinyl.
  • substitutents selected from the group consisting of halo, C 1-4 alkyl, halo(C 1-4 )al
  • More useful X when X is HetAr include pyridin-2-yl, pyridin- 3-yl, l-oxy-pyridin-3-yl, pyridin-4-yl and pyrazinyl, each of which is optionally substituted with one or two substitutents selected from the group consisting of chloro, methyl, ethyl, hydroxy, hydroxymethyl, methoxy, amino, dimethylamino, cyano, carbamoyl, morpholin-4-yl, thiomorpholin-4-yl, (2-formyloxyethoxy)methyl and piperidin-1-yl.
  • More useful X when X is HetAr include pyridin-2-yl, pyridin-3-yl, 6-cyano-pyridin-3-yl, 6-chloro- pyridin-3-yl, 2-chloro-pyridin-3-yl, 6-hydroxy-pyridin-3-yl, 6-methyl-pyridin- 3-yl, 5-methyl-pyridin-3-yl, 2-ethyl-pyridin-3-yl, 6-hydroxymethyl-pyridin- 3-yl, 6-amino-pyridin-3-yl, 2-dimethylamino-pyridin-3-yl, 6-carbamoyl- pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-methoxy-pyridin-3-yl,
  • More useful X when X is HetAr include pyridyl optionally substituted by one substituent selected from the group consisting of methyl, cyano, chloro, hydroxy, hydroxymethyl, amino, methoxy and carbamoyl. More useful X when X is HetAr include pyridyl, particularly pyrid-3-yl.
  • One useful group of values for X include pyridinyl, 1-oxy-pyridinyl and pyrazinyl, each of which is optionally substituted with one substituted selected from the group consisting of halo, C 1-4 alkyl, hydroxy, hydroxy(C 1-4 )alkyl and amino, or one substituent selected from the group consisting of halo, C 1-4 alkyl, hydroxy, hydroxy(C 1-4 )alkyl, amino, C 1-4 alkoxy, cyano and carbamoyl.
  • Another useful group of values for X include pyridyl optionally substituted with one substituent selected from the group consisting of methyl, chloro, hydroxy, hydroxymethyl and amino.
  • one useful group of compounds includes those wherein R 5 is hydrogen; R 6 is hydroxyl, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino or (C 1-4 alkyl)sulfonylamino, particularly hydroxyl or (C 1-4 alkyl)carbonylamino; L is -NH-, -N(R X )- or -C(O)-, particularly -NH- or -C(O)-, more particuarly -NH-; and X is pyridyl, particuarly 3-pyridyl.
  • R 1 , R 3 and R 5 are each hydrogen; the bicylic moiety is indol-4-yl optionally substituted with one substitutent selected from the group consisting of halo, C 1-4 alkyl, cyano, C 2-5 alkanoyl and halo(C 2- 5)alkanoyl;
  • R 6 is selected from the group consisting of hydrogen, halo, hydroxyl, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, benzyloxy, (C 1-4 alkoxy)benzyloxy, amino, mono(C 1-4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino.
  • X is selected from the group consisting of pyridinyl, 1-oxy- pyridinyl and pyrazinyl, each of which is optionally substituted with one or two substitutents selected from the group consisting of halo, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 )alkyl, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, cyano, carbamoyl, mono(C 1-4 alkyl)aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, morpholin-4-yl, thiomorpholin-4-yl, formyloxy(C 1-4 )alkoxy(C 1-4 )alkyl, and piperidin-1-yl.
  • useful bicylic moieties include indol-4-yl.
  • useful R 6 include hydroxyl, (C 1-4 alkyl)carbonylamino,
  • R 6 include hydroxyl, acetylamino, methoxycarbonylamino and methylsulfonylamino .
  • useful L include -NH- and -C(O)-.
  • useful X include pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl, carbamoyl and morpholin-4-yl. More useful X include pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, chloro, methoxy, methyl, ethyl, carbamoyl and morpholin-4-yl. More useful X include pyridyl, particularly pyrid-3-yl. More useful X also include pyrid-4-yl.
  • one useful group of compounds includes those wherein:
  • R 1 and R 3 are each hydrogen; and R 5 and R 6 are each other than hydrogen.
  • one useful group of compounds includes those wherein: the bicyclic moiety is indol-4-yl or benzo[b]thiophen-4-yl; R 5 and R 6 are independently selected from the group consisting of (C 1-4 alkyl)sulfonylamino, (C 1-4 alkoxy)carbonylamino, (Ci -4 alkyl)carbonylamino, hydroxyl, benzyl and (C 1-4 alkoxy)benzyl; L is -NH- or -C(O)-; and
  • X is pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl and carbamoyl.
  • useful bicyclic moieties include indol-4-yl.
  • useful R 5 and R 6 include hydroxyl, benzyl and (C 1-4 alkoxy)benzyl. More useful R 5 include benzyl and methoxybenzyl. More useful R 6 include hydroxyl. [0077] In this group, useful L include -NH-.
  • useful X include pyridyl, particularly pyrid-3-yl.
  • one useful group of compounds includes those wherein:
  • R 3 , R 5 and R 6 are each hydrogen; and R 1 is other than hydrogen.
  • one useful group of compounds includes those wherein: the bicyclic moiety is indol-4-yl;
  • R 1 is selected from the group consisting of (C 1-4 alkyl)sulfonylamino, (C 1-4 alkoxy)carbonylarnino, (C 1-4 alkyl)carbonylarnino, hydroxyl and amino; L is -NH- or -C(O)-; and
  • X is pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, Ci -4 alkyl and carbamoyl.
  • useful R 1 include hydroxyl and amino.
  • useful L include -C(O)-.
  • useful X include pyridyl, particularly pyrid-3-yl.
  • one useful group of compounds are those wherein
  • X is Ar.
  • R 1 , R 3 and R 5 are each hydrogen; and R 6 is other than hydrogen.
  • R 1 is hydrogen or hydroxy
  • R 3 is hydrogen
  • R 5 is selected from the group consisting of hydrogen, benzyl and (C 1-4 alkoxy)benzyl; the bicylic moiety is indol-4-yl optionally substituted with one substitutent selected from the group consisting of halo, Ci -4 alkyl, cyano, C 2-5 alkanoyl and halo(C 2-5 )alkanoyl;
  • R 6 is selected from the group consisting of hydrogen, halo, hydroxyl, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, benzyloxy, (C 1-4 alkoxy)benzyloxy, amino, mono(Ci.
  • X is phenyl optionally substituted with one or two substitutents selected from the group consisting of halo, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 )alkyl, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, cyano, carbamoyl, mono(C 1-4 alkyl)aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, mo ⁇ holin-4-yl and formyloxy(C 1-4 )alkoxy(C 1-4 )alkyl.
  • useful bicylic moieties include indol-4-yl.
  • useful R 6 include (C 1-4 alkyl)sulfonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)carbonylamino and hydroxyl.
  • useful L include -NH- and -C(O)-.
  • useful X include phenyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl and carbamoyl.
  • R , R and R are each hydrogen; the bicyclic moiety is indol-4-yl;
  • R 6 is (C 1-4 alkyl)sulfonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)carbonylamino or hydroxyl;
  • L is -NH- or -C(O)-;
  • X is phenyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl and carbamoyl.
  • useful R 6 include hydroxyl.
  • useful L include -NH-.
  • useful X include phenyl and cyanophenyl.
  • the compounds are of Formula III:
  • R 5 include hydrogen.
  • R 5 is selected from the group consisting of hydrogen, benzyl and (C 1-4 alkoxy)benzyl; the bicylic moiety is indol-4-yl optionally substituted with one substitutent selected from the group consisting of halo, C 1-4 alkyl, cyano, C 2-5 alkanoyl and halo(C 2- s)alkanoyl;
  • R 6 is selected from the group consisting of hydrogen, halo, hydroxyl, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, benzyloxy, (C 1-4 alkoxy)benzyloxy, amino, mono(C 1-4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, benzyloxycarbonylamino, (C 1-4 alkyl)sulfonylamino, ureido, N-(C 1-4 alkyl)ureido, INF-(Ci -4 alkyl)ureido, N,N'-di(C 1-4 alkyl)ureido, N,N',N 1 -tri(C 1-4 alkyl)ureido, N',N'-di(C
  • X is selected from the group consisting of pyridinyl, 1-oxy-pyridinyl and pyrazinyl, each of which is optionally substituted with one or two substitutents selected from the group consisting of halo, C 1-4 alkyl, halo(C 1-4 )alkyl, hydroxy, hydroxy(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 )alkyl, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, cyano, carbamoyl, mono(C 1-4 alkyl)aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl, morpholin-4-yl and formyloxy(C 1-4 )alkoxy(C 1-4 )alkyl.
  • useful bicyclic moieties include indol-4-yl.
  • useful R 6 include (C 1-4 alkyl)sulfonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)carbonylamino, C 1-4 alkoxy and hydroxyl.
  • useful L include -NH- and -C(O)-.
  • useful X include pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl and carbamoyl.
  • R 5 is hydrogen; the bicyclic moiety is indol-4-yl;
  • R 6 is (C 1-4 alkyl)sulfonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)carbonylamino, C 1-4 alkoxy or hydroxyl;
  • L is -NH- or -C(O)-;
  • X is pyridyl optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl and carbamoyl.
  • useful R 6 include hydroxyl and C 1-4 alkoxy. More useful
  • R 6 include hydroxyl and methoxy.
  • useful L include -NH-.
  • useful X include pyridyl, particularly pyrid-3-yl.
  • the compounds are of Formula IV:
  • R 4 is adamantyl; n is 1; X is HetAr; and R 1 , R 3 -R 6 and L are defined as above.
  • useful R 1 include hydrogen.
  • useful R 3 include hydrogen.
  • useful R 5 include hydroxyl.
  • useful R 6 include hydrogen.
  • useful L include -C(H)(OH)- and -C(O)-.
  • useful X include pyridyl, particularly pyrid-3-yl.
  • the compounds are of Formula /F:
  • R 4 is 2-, 3- or 4-quinolinyl or 1-indolyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of halo, nitro and cyano; n is 1 ; X is HetAr; and R 1 , R 3 -R 6 and L are defined as above.
  • useful R 1 include hydrogen.
  • useful R 3 include hydrogen.
  • useful R 5 include hydrogen.
  • useful R 6 include hydroxyl.
  • useful L include -NH- and -C(O)-.
  • useful X include pyridyl and quinolin-3-yl. More useful X include pyridyl, particularly ⁇ yrid-3-yl. [0120] In one embodiment, the compounds are of Formula V:
  • one group of useful compounds includes those wherein R 1 , R 3 and R 5 are each hydrogen; and R 6 is other than hydrogen.
  • useful bicyclic moieties include indol-4-yl.
  • useful R 6 include (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)sulfonylamino, hydroxyl, and halo. More useful R 6 include acetylamino, methoxycarbonylamino, methylsulfonylamino, hydroxyl and bromo.
  • useful X include pyridinyl, pyrazinyl, pyrimidinyl, benzoxazol-2-yl and oxazolo[4,5-&]pyridin-2-yl, each of which is optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl, carbamoyl, amino, (C 1-4 alkyl)amino and di(C 1-4 alkyl)amino.
  • More useful X include pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, benzoxazol-2-yl and oxazolo[4,5-£]pyridin-2-yl, each of which is optionally substituted once with a substituent selected from the group consisting of C 1-4 alkoxy, halo, particularly chloro, and amino.
  • More useful X include pyridin-3-yl, 6-methoxy-pyridin-3-yl, 6-ethoxy-pyridin-3-yl, 6-chloro- pyridin-3-yl, pyridin-4-yl, 2-chloro-pyridin-4-yl, benzoxazol-2-yl, oxazolo[4,5-5]pyridin-2-yl and 2-amino-pyrimidin-4-yl.
  • one useful group of compounds includes those wherein:
  • R 1 , R 3 and R 5 are each hydrogen; the bicyclic moiety is indol-4-yl;
  • R 6 is (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)sulfonylamino, hydroxyl or halo;
  • X is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, benzoxazol-2-yl and oxazolo[4,5- ⁇ ]pyridin-2-yl, each of which is optionally substituted once with a substituent selected from the group consisting of cyano, halo, C 1-4 alkoxy, C 1-4 alkyl, carbamoyl, amino, (C 1-4 alkyl)amino and di(C 1-4 alkyl)amino.
  • useful R 6 include acetylamino, methoxycarbonylamino, methylsulfonylamino, hydroxyl and bromo.
  • useful X include pyridin-3-yl, pyridin-4-yl, pyrimidin-
  • one group of useful compounds includes those wherein R 1 , R 3 and R 5 are each hydrogen; and R 6 is other than hydrogen.
  • useful bicyclic moieties include indol-4-yl.
  • useful R 6 include (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)sulfonylamino and hydroxyl. More useful R 6 include acetylamino and methylsulfonylamino. More useful R 6 also include methoxycarbonylamino.
  • useful X include phenyl optionally substituted once or twice with a substituent independently selected from the group consisting of nitro, halo, C 1-4 alkyl, halo(C 1-4 )alkyl and methylenedioxy. More useful X include phenyl optionally substituted once or twice with a substituent independently selected from the group consisting of nitro, fiuoro, methyl, trifluoromethyl and methylenedioxy. More useful X include 3-nitrophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3-methylphenyl,
  • one useful group of compounds includes those wherein:
  • R 1 , R 3 and R 5 are each hydrogen; the bicyclic moiety is indol-4-yl;
  • R 6 is (C 1-4 alkyl)carbonylamino, (C 1-4 alkoxy)carbonylamino, (C 1-4 alkyl)sulfonylamino or hydroxyl;
  • X is phenyl optionally substituted once or twice with a substituent independently selected from the group consisting of nitro, halo, C 1-4 alkyl, halo(C 1-4 )alkyl and methylenedioxy.
  • useful R 6 include acetylamino and methylsulfonylamino.
  • useful X include phenyl optionally substituted once or twice with a substituent independently selected from the group consisting of nitro, halo, C 1-4 alkyl, halo(C 1-4 )alkyl, C 1-4 alkoxy and methylenedioxy. More useful X include 3-nitrophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-5- trifluoromethylphenyl and 3,4-methylenedioxyphenyl. [0137] Also useful are compounds of Formula VI:
  • R 12 is halo, particularly chloro or bromo, more particularly bromo.
  • a second aspect of the present invention is directed to pharmaceutical compositions comprising at least one compound of Formula/, wherein A 1 , A 3 , A 5 , R 4 , R 6 , L, n and X are as defined above, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically-acceptable excipients.
  • a further aspect of the present invention is directed to a method of treating a condition that results from abnormal cell growth, cellular differentiation, tumor growth or invasion by administering a pharmaceutically- effective amount of one or more compounds of Formula J, wherein A 1 , A 3 , A 5 , R 4 , R 6 , L, n and X are as defined above, to an animal.
  • a further aspect of the invention is directed to a method of treating cancer, particularly wherein the cancer is leukemia, soft-tissue sarcomas, or non-small cell lung, myeloma, colon, CNS, melanoma, ovarian, renal, prostate, breast, cervical or pancreatic cancer, particularly leukemia, prostate, non-small cell lung or colon cancer, by administering a pharmaceutically- effective amount of one or more compounds of Formula /, wherein A 1 , A 3 , A 5 , R 4 , R 6 , L, n and X are as defined above, to an animal.
  • a further aspect of the invention is directed to hindering or blocking cell cycle progression by contacting one or more cells, particularly cancerous cells, with one or more compounds of Formula /, wherein A 1 , A 3 , A 5 , R 4 , R 6 , L, n and X are as defined above.
  • Cancerous cells useful in this aspect of the invention include leukemia cells, soft-tissue sarcoma cells, and non-small cell lung, myeloma, colon, CNS, melanoma, ovarian, renal, prostate, breast, cervical and pancreatic cancer cells, particularly leukemia, prostate, non-small cell lung and colon cancer cells.
  • a further aspect of the invention is directed to a method of treating a proliferative retinopathy, particularly diabetic neuropathy or macular degeneration, by administering a pharmaceutically-effective amount of one or more compounds of Formula /, wherein A 1 , A 3 , A 5 , R 4 , R 6 , L, n and X are as defined above, to an animal.
  • a further aspect of the present invention is directed to a method of making compounds of Formula /, wherein A 1 , A 3 , A 5 , R 4 , R 6 , L, n and X are as defined above.
  • Examples. Examples of compounds include, but are not limited to, the following:
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabeled compound of the invention, administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur and isolating its conversion products from the urine, blood or other biological samples.
  • Some of the compounds disclosed herein may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers.
  • AU tautomers are intended to be encompassed by the present invention as well.
  • stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
  • chiral center refers to a carbon atom to which four different groups are attached, or a sulfur atom to which three different groups are attached, where the sulfur atom and its attached groups form a sulfoxide, sulfinic ester, sulfonium salt or sulfite.
  • enantiomer or “enantiomeric” refers to a molecule that is nonsuperimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which is optically inactive.
  • resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
  • enantiomeric excess refers to a mixture wherein one enantiomer is present in a greater concentration than its mirror image molecule.
  • the compounds of Formula / may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
  • alkyl refers to both straight and branched chain radicals of up to 10 carbons, unless the chain length is otherwise limited, such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, or decyl.
  • alkenyl is used herein to mean a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is otherwise limited, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2- methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
  • the alkenyl chain is 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length.
  • alkynyl is used herein to mean a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is otherwise limited, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • the alkynyl chain is 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length.
  • the unsaturated linkage i.e., the vinyl or ethenyl linkage, is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
  • alkoxy refers to any of the above alkyl groups linked to an oxygen atom. Typical examples are methoxy, ethoxy, isopropyloxy, sec- butyloxy, and t-butyloxy.
  • aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion. Typical examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl.
  • aralkyl or "arylalkyl” as employed herein by itself or as part of another group refers to C 1-6 alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
  • heteroaryl refers to groups having 5 to
  • heteroaryl groups are: thienyl, benzo[b]tliienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H " -indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,
  • saturated or partially unsaturated heterocycle refers to a saturated or partially unsaturated ring system having 5 to 14 ring atoms selected from carbon atoms and I 5 2, 3, or 4 oxygen, nitrogen, or sulfur heteroatoms.
  • Typical saturated examples include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperazinyl, quinuclidinyl, morpholinyl, and dioxacyclohexyl.
  • Typical partially unsaturated examples include pyrrolinyl, imidazolinyl, pyrazolinyl, dihydropyridinyl, tetrahydropyridinyl, and dihydropyranyl. Either of these systems can be optionally fused to a benzene ring.
  • heteroarylalkyl or “heteroaralkyl” as employed herein both refer to a heteroaryl group attached to an alkyl group. Typical examples include 2-(3-pyridyl)ethyl, 3-(2-furyl)-n-propyl, 3-(3-thienyl)-n-propyl, and 4- (l-isoquinolinyl)-ft-butyl.
  • cycloalkyl as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
  • cycloalkylalkyl or "cycloalkyl(alkyl)" as employed herein, by itself or as part of another group, refers to a cycloalkyl group attached to an alkyl group. Typical examples are 2-cyclopentylethyl, cyclohexylmethyl, cyclopentylmethyl, 3 -cyclohexyl-w -propyl, and 5-cyclobutyl-w-pentyl.
  • cycloalkenyl refers to cycloalkenyl groups containing 3 to 9 carbon atoms and 1 to 3 carbon-carbon double bonds. Typical examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclolieptadienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclononenyl, and cyclononadienyl.
  • halogen or "halo" as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine.
  • dialkylamine or "dialkylamino” as employed herein by itself or as part of another group refers to the group NH 2 wherein both hydrogens have been replaced by alkyl groups, as defined above.
  • hydroxyalkyl refers to any of the above alkyl groups wherein one or more hydrogens thereof are substituted by one or more hydroxyl moieties.
  • haloalkyl refers to any of the above alkyl groups wherein one or more hydrogens thereof are substituted by one or more halo moieties. Typical examples include fluoromethyl, difluoromethyl, trifluoromethyl, trichloroethyl, trifluoroethyl, fluoropropyl, and bromobutyl.
  • carboxyalkyl refers to any of the above alkyl groups wherein one or more hydrogens thereof are substituted by one or more carboxylic acid moieties.
  • heteroatom is used herein to mean an oxygen atom ("O"), a sulfur atom (“S”) or a nitrogen atom (“N”)- It will be recognized that when the heteroatom is nitrogen, it may form an NR a R b moiety, wherein R a and R b are, independently from one another, hydrogen or C 1 to C 8 alkyl, or together with the nitrogen to which they are bound form a saturated or unsaturated 5-, 6-, or 7-membered ring.
  • hydroxy and “hydroxyl” are used interchangeably to refer to the radical -OH.
  • pyridyl and “pyridinyl” are used interchangeably to refer to a monovalent radical of pyridine.
  • carbamoyl and “aminocarbonyl” are used interchangeably to refer to the radical NH 2 -C(O)-.
  • ureido and “aminocarbonylamino” are used interchangeably to refer to the radical NH 2 -C(O)-NH-.
  • the phrase "optionally substituted" when not explicitly defined refers to a group or groups being optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, nitro, trifluoromethyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylenedioxy, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 6-10 aryl, phenoxy, benzyloxy, 5-10 membered heteroaryl, C 1-6 aminoalkoxy, amino, mono ⁇ alkylamino, di(C 1-4 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonylalkyl, carboxy, C 2-6 hydroxyalkoxy, (C 1-6 )alkoxy(C
  • Preferred optional substituents include one or more substituents independently selected from the group consisting of nitro, hydroxy, carboxy, C 1-4 alkoxy, C 1-4 alkyl, halo, C 1-4 haloalkyl, C 1-4 alkylthio, thio, amino, and di(C 1-4 )alkylamino.
  • salts in the form of water- or oil-soluble or dispersible products
  • quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
  • 2-hydroxyethanesulfonate lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pahnoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl- D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides like benzyl and phenethyl bromides and others.
  • Preferred acids for forming acid addition salts include HCl, acetic acid, trifluoroacetic acid and fumaric acid.
  • compositions of the present invention include pharmaceutical compositions comprising a compound of Formula /, wherein A 1 , A 3 , A 5 , R 4 , R 6 , L, n and X are defined above, and one or more pharmaceutically acceptable excipients.
  • Preferred compositions of the present invention are pharmaceutical compositions comprising a compound selected from a preferred group of compounds of Formula /as defined above, and one or more pharmaceutically acceptable excipients.
  • compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
  • compositions of the present invention can be administered by any means that achieve their intended purpose.
  • administration can be by subcutaneous, intravenous, intramuscular, intraperitoneal, buccal, or ocular routes, rectally, parenterally, intrasystemically, intravaginally, topically (as by powders, ointments, drops or transdermal patch), or as an oral or nasal spray.
  • administration can be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the new pharmaceutical preparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, traga
  • disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions can be used, which can contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin.
  • stabilizers may be added.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts, alkaline solutions and cyclodextrin inclusion complexes.
  • Especially preferred alkaline salts are ammonium salts prepared, for example, with Tris, choline hydroxide, Bis-Tris propane, N-methylglucamine, or arginine.
  • One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention.
  • Useful cyclodextrins for this purpose are disclosed in U.S. Patent Nos. 4,727,064, 4,764,604, and 5,024,998.
  • suspensions of the active compounds as appropriate oily injection suspensions can be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, hi addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, rmcrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, rmcrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration may be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredients in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
  • suitable inert carriers include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant.
  • a compressed gas such as nitrogen or a liquefied gas propellant.
  • the liquefied propellant medium and indeed the total composition are preferably such that the active ingredients do not dissolve therein to any substantial extent.
  • the pressurized composition may also contain a surface-active agent.
  • the surface- active agent may be a liquid or solid non-ionic surface-active agent or may be a solid anionic surface-active agent. It is preferred to use the solid anionic surface-active agent in the form of a sodium salt.
  • a further form of topical administration is to the eye.
  • the compounds and compositions of the present invention are delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compounds are maintained in contact with the ocular surface for a sufficient time period to allow the compounds to penetrate the corneal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina and sclera.
  • the pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the drugs.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the drugs.
  • compositions of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art (see, for example, Prescott, Ed., Meth. Cell Biol. 14:33 (1976)).
  • Compounds of the present invention are useful for treating, inhibiting or preventing abnormal cell growth, cellular differentiation, tumor growth and invasion. They are effective against a broad range of cancers such as leukemia, non-small cell lung, myeloma, colon, CNS, melanoma, ovarian, renal, prostate, breast, cervical, soft-tissue sarcomas, pancreatic, especially leukemia, prostate, non-small cell lung and colon cancer. These cancers and conditions are merely meant to be illustrative and are by no means meant to be a limiting or exhaustive list.
  • the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.05 mg/kg to about 200 mg/kg, preferably from about 0.1 mg/kg to about 100 mg/kg body weight.
  • the compounds are preferably administered in compositions in which the compound is present in a concentration of about lmg/mL to about 250mg/mL (e.g., in a solution), or in an amount of about lmg to about 200mg, preferably about 5mg to about lOOmg (e.g., in one unit of a solid dosage form such as a tablet or capsule).
  • the compound of the present invention may comprise about 1 to about 50% (wt/wt), preferably about 5 to about 25% (wt/wt) of the tablet.
  • Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the present invention is also concerned with the syntheses of compounds of Formula/.
  • the synthesis starts with the preparation of Intermediate A(3) prepared as shown in Scheme 1, according to Effenberger, F. et al, Chem. Ber. 124:163-73 (1991).
  • a carbonyl linker can be introduced by the reaction of an aryl lithium reagent with a nitrile (in a similar manner to that described in Dickinson, R.P. et al, J. Med. Chem. 40:3442-52 (1997)) or a Weinreb amide as shown in Scheme 8.
  • Indoles and other groups can be attached to the core ring through the nitrogen using copper chemistry as shown in Scheme 10.
  • a nitrogen substituent can be introduced using the palladium catalyzed reaction of carbamic acid benzyl ester to an aryl bromide as shown in Scheme 11.
  • the benzyl ester can be removed, and the aniline derivatized with a variety of electrophiles.
  • a group such as acetamide, methyl carbamate or methanesulfonamide can be added directly to the aryl bromide as shown in Scheme 12.
  • 3,5-Dichlorobenzenethiol can serve as a starting material for compounds with a linker containing a sulfur, as shown in Scheme 15.
  • the thiol can be alkylated, or it can be coupled with an aromatic or heteroaromatic halide.
  • the oxidation state can be adjusted.
  • the dichloro compounds undergo Buchwald and Suzuki reactions in a manner analogous to the dibromointermediates.
  • the Suzuki reaction can be carried out on the dibromo-intermediate to give a monobrominated compound.
  • a carboxylic amide, a carbamate or a sulfonamide can be introduced by a copper-mediated addition reaction, as shown in Scheme 17.
  • Compounds containing an indole group can also be made by solid- phase synthesis.
  • 4-(3-Bromo-5-nitro-phenyl)-lH-indole prepared from 3,5-dibromonitrobenzene and indole-4-boronic acid, can be attached to a resin and derivatized. Cleavage from the resin with TBAF/THF gives the product.
  • l,3-dibromo-5-nitrobenzene (30.0 g, 107 mmol), freshly powdered potassium hydroxide (10.8 g, 192 mmol) and tetrabutylammonium bromide (3.42 g, 10.7 mmol) were dissolved in tetramethyl urea (TMU, 90 mL).
  • TMU tetramethyl urea
  • a solution ofp-methoxybenzyl alcohol (17.8 g, 128 mmol) in TMU (30 mL) was added drop-wise at room temperature over a period of 1 h. The mixture was stirred for 48 h at room temperature.
  • FC on silica gel 120 g, AcOEt/heptane 7:1 provided pure [3-benzyloxy-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- ⁇ henyl]-pyridin-3-yl-amine (1.85 g, 73%) as a white solid.
  • reaction solution was stirred at -5°C for 15 min and then a cooled solution of CuBr (3.94 g, 27.5 mmol) in concentrated HBr (11.5 niL) was added drop-wise over a period of 15 min.
  • the reaction mixture was stirred for 2 h at room temperature and was then neutralized with sat. NaHCO 3 solution.
  • the quenched mixture was diluted with water (50 mL).
  • the mixture was filtered and the filter cake was washed with AcOEt (300 mL). The layers of the filtrate were separated and the aqueous layer was extracted with AcOEt (3 x 200 mL).
  • Suzuki coupling A round bottom flask was charged with the boronic acid of 7-bromoindazole (144 mg, 0.89 mmol) and teixakistriphenylphosphine palladium (35 mg, 0.03 mmol). 1,2-Dimethoxyethane (4 mL) was added under argon and the mixture was stirred for 10 min at room temperature. A solution of 3-benzyloxy-5-bromo-phenyl)-pyridin-3-yl-amine (213 mg, 0.60 mmol) in DME (4.5 mL) and 2M aq Na 2 CO 3 (0.60 mL, 1.24 mmol) were added and the mixture was heated at reflux for 24 h.
  • the crude material was purified by flash chromatography (200 g SiO 2 , hexanes) to give a mixture of 2 mono- brominated indanes and a dibrominated indane (5.95 g, 68%) as yellow oil.
  • 6-bromo-6,7-dihydro-4-benzothio[b)phenone (2.80 g, 12.1 mmol), lithium bromide (2.37 g, 27.3 mmol), lithium carbonate (1.79 g, 24.2 ,mmol) and dry DMF.
  • the mixture was heated at reflux under argon for 3 h.
  • the solvent was removed under high vacuum and the residue was taken up in ice- water (30 mL) and acidified with IM HCl (40 mL) to pH 1.
  • the mixture was extracted with TBME (3x50 mL) and the combined organics were extracted with 10% NaOH solution (3x20 mL).
  • Suzuki coupling A 10 mL Schlenk flask was charged with (3-/j-methoxybenzyloxy-5-bromo-phenyl)-pyridin-3-yl-amine (200 mg, 0.46 mmol), trifluoro-methanesulfonic acid benzo[b]thiophen-4-yl ester (155 mg, 0.55 mmol), K 3 PO 4 (195 mg, 0.92 mmol) and dry THF (4 mL). The mixture was degassed for 10 min with argon and PdCl 2 (dppf) CH 2 Cl 2 complex (19 mg, 0.023 mmol) was added.
  • dppf PdCl 2
  • Aqueous 2M K 3 PO 4 (1.30 mL, 2.50 mmol) solution was added and the mixture was heated to 100°C and a solution of chloro(di-2-norbornylphosphino)(2'dimethylamino-l,r- biphenyl-2-yl)palladium (II) (35 mg, 0.06 mmol) in degassed dioxane (4 mL) was added.
  • the reaction mixture was stirred at 100°C for 5 h and was then cooled to room temperature.
  • the reaction mixture was diluted with AcOEt (30 mL) and brine (20 mL) and filtered over ⁇ yflo. The filtrate was transferred to a separatory funnel and the layers were separated.
  • the resin was filtered and washed with MeOH (4 x 3 mL), H 2 O (4 x 3 mL), THF (4 x 3 mL), MeOH (4x3 mL), methylene chloride (4 x 3 mL), and dried under high vacuum.
  • the resin was treated with 2% dimethylsulfide, 50% TFA/ methylene chloride (2 mL) for 50 min in a 20 mL glass vial.
  • the resin was filtered, washed with THF (4 x 3 mL), MeOH (4 x 3 mL), H 2 O (4 x 3 mL), DMF (3 x 4 mL), THF (4 x 3 mL), methylene chloride (4 x 3 mL) and dried in vacuo.
  • the resin was treated with 2% dimethylsulfide, 50% TFA/ methylene chloride (2 mL) for 20 min in a 20 mL glass vial.
  • the slurry of resin in cleavage cocktail was filtered through a fritted syringe to a 20 mL glass vial, washed with methylene chloride (2 x 1 mL), and the combined solution was evaporated by nitrogen blowing under mild heating to give the crude product which was confirmed by proton NMR and LC/MS analysis.
  • the crude product was passed through a short pad of silica gel using 5% MeOH in methylene chloride.
  • the combined fractions of product were concentrated, and the residue was further purified by prep SFC to obtain 3-(6-nitro-indol-l- yl)-5-(pyridin-3-ylamino)- ⁇ henol (4.3 mg, 0.012 mmol).
  • N-(3-pyridyl)acetamide (272 mg, 2 mmol), CuI (powdered, 190 mg, 1 mmol), cesium carbonate (651 mg, 2 mmol), 1,3-dibromobenzene (2.3 g, 10 mmol) in dioxane (10 mL) was added N,N'-dimethylethylenediarnme (176 mg, 2 mmol), then the mixture was heated to 110°C for 16 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite ® , and the filtrate was concentrated.
  • the tube was sealed and heated in a microwave reactor at 120 0 C for an hour.
  • the crude mixture was loaded directly to Celite ® , and purified by chromatography to afford the -[3-hydroxy- 5-(lH-indol-4-yl)-phenylamino]- ⁇ yridin-2-ol as a white solid (62 mg, 57.1%).
  • reaction mixture was diluted with a large amount of EtOAc, and filtered through Celite ® to remove palladium catalyst. The filtrate was concentrated, and the residue was taken up in dichloromethane, washed with brine, and dried over MgSO 4 . After filtration and concentration, the crude product was used directly in the next reaction.
  • the reaction mixture was heated to 110 0 C for 16 h. After cooling, the reaction mixture was filtered through a short pad of Celite ® , and the filtrate was concentrated. The residue was purified by silica gel column chromatography using 5% MeOH in methylene chloride to give a major fraction as a desired product which crystallized from a mixed solution of MeOH/ methylene chloride. The crystals were filtered and washed with methanol to give 115 mg of pure 3-bromo-5-(4-methoxy- benzyloxy)-phenyl]-pyridin-4-yl-amine.
  • 2-Adamantan-l-yl-4-bromo-phenol was prepared by the method of Charpentier, B. et al, J. Med. Chem. 35:4993-5006 (1995).
  • a solution of 2- adamantan-l-yl-4-bromo-phenol (0.800 g, 2.6 mmol) in methylene chloride was immersed in a -78°C bath.
  • the reaction was then diluted with collidine and DMF.
  • the t-butyldimethylsilyl triflate was then added via syringe and the reaction was allowed to warm to room temp.
  • the reaction mixture was poured into 50 niL of ice/H 2 O and then transferred to a 250 niL separatory funnel.
  • the layers were diluted with brine and extracted 2 X with brine, then DI water.
  • the organic layers were dried over Na 2 SO 4 and the compound was - Ill -
  • [3-adamantan-l-yl-4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-pyridin-3-yl- methanol (0.211 g, 0.617 mmol) was dissolved in 3 mL of and treated with 3 mL of IM tetrabutylammonium fluoride solution in THF. The reaction was allowed to stir overnight, then was quenched with 15-20 mL of water. Ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted again with of EtOAc. The organic layers were combined, dried with Na 2 SO 4 and concentrated to a red oil.
  • 3-Bromo-5-(pyridin-3-ylamino)-benzoic acid methyl ester was prepared from 3,5-dibromo-benzoic acid methyl ester and pyridin-3-ylamine in low yield as described for Example 36, except that the reaction was run at 13O 0 C. This material was converted to 3-(lH-indol-4-yl)-5-(pyridin-3- ylamino)-benzoic acid methyl ester by the method of Example 35.
  • 1,3,5-Tribromo-benzene (31.4 g, 100 mmol) was dissolved under argon in a flame dried three-neck flask in 1000 mL diethylether and the solution was cooled to -72°C.
  • a solution of 62 mL r ⁇ BuLi (1.6 M in hexane, 100 mmol) was added to the resulting suspension in such a fashion that temperature did not rise above -7O 0 C.
  • the mixture was stirred for 30 min at -75 0 C and the reaction was monitored by HPLC.
  • N-[3-bromo-5-(pyridme-3-carbonyl)-phenyl]-acetamide was converted to N-[3-(pyridine-3-carbonyl)-5-(l-triisopropylsilanyl-lH-indol-4-yl)-phenyl]- acetamide, and the triisopropylsilyl group was removed with tetra n-butylammonium fluoride to give N-[3-(lH-indol-4-yl)-5-(pyridine-3- carbonyl)-phenyl]-acetamide as described in Example 35.
  • N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-methanesulfonamide was converted to N-[3-(pyridme-3-carbonyl)-5-(l-triisopropylsilanyl-lH-indol-4- yl)-phenyl]-methanesulfonamide, and the triisopropylsilyl group was removed with tetra n-butylammonium fluoride to give N-[3-(lH-indol-4-yl)-5- (pyridine-3-carbonyl)-phenyl]-methanesulfonamide as described in Example 75.
  • N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-propionamide was converted to N-[3-(pyridine-3-carbonyl)-5-(l-triisopropylsilanyl-lH-indol-4-yl)- ⁇ henyl]- propionamide, and the triisopropylsilyl group was removed with tetra n-butylammonium fluoride to give N-[3-(lH-indol-4-yl)-5-(pyridine-3- carbonyl)-phenyl]-propionamide as described in Example 35.
  • a 50 mL tube was charged with (3,5-dibromo-phenyl)-pyridin-3-yl- methanone (2.55 g, 7.5 mmol), bis(pinacolato)diboron (1.26 g, 5.0 mmol), potassium acetate (1.47 g, 15.0 mmol) and Pd(d ⁇ f)Cl 2 -CH 2 Cl 2 (200 mg).
  • DMSO 15 mL was added, and the solution was degassed with nitrogen, then the tube was sealed.
  • the resin was filtered, washed with THF (4 x 3 mL), MeOH (4 x 3 mL), H 2 O (4 x 3 mL), DMF (5 x 3 mL), THF (4 x 3 mL), methylene chloride (4 x 3 mL) and dried in vacuo.
  • the resin was treated with 5 % DMS, 50% TFA/ methylene chloride (2 mL) for 20 min in a 20 mL glass vial.
  • the slurry of resin in the cleavage cocktail was filtered through a fritted syringe to a 20 mL glass vial, washed with methylene chloride (2 x 1 mL), and the combined solution was evaporated with a stream of nitrogen under mild heating to give the crude product.
  • the crude product was extracted with ethyl acetate and saturated sodium bicarbonate and the organic layer was dried and concentrated.

Abstract

La présente invention concerne le domaine des nouveaux composés et de leurs sels, leurs synthèses et leur utilisation comme agents anti-cancer. Les composés comprennent des composés représentés par la formule (I) : et des solvates, des hydrates et des sels pharmaceutiquement acceptables de ces composés, où A1 est N ou CR1 ; A3 est N ou CR3 ; A5 est N ou CR5 ; R1, R3, R6 et L sont définis dans la description ; n est 0 ou 1 ; et X est un groupe aryle facultativement substitué, ayant 6-10 carbones dans la partie cyclique, un groupe hétéroaryle à 6 chaînons, facultativement substitué, ayant 1-3 atomes d'azote dans la partie cyclique, un groupe hétéroaryle à 5 chaînons facultativement substitué, ayant 0-4 atomes d'azote dans la partie cyclique et ayant facultativement 1 atome de soufre ou 1 atome d'oxygène dans la partie cyclique, ou un groupe hétéroaryle facultativement substitué dans lequel un cycle à 6 chaînons est fusionné soit à un cycle à 5 chaînons, soit à un cycle à 6 chaînons, où, dans chaque cas, 1, 2, 3 ou 4 atomes de cycle sont des hétéroatomes indépendamment choisis parmi l'azote, l'oxygène et le soufre. Ils sont efficaces contre plusieurs types de cancers, notamment la leucémie, le cancer de la prostate, le cancer du poumon non à petites cellules et le cancer du côlon. Ils sont en outre utiles dans le traitement des rétinopathies prolifératives, telles que la neuropathie diabétique et la dégénérescence maculaire.
PCT/US2006/026935 2006-07-12 2006-07-12 Agents anti-cancer et leurs utilisations WO2008008059A1 (fr)

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US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
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