WO2008053319A1 - Amide resorcinol compounds - Google Patents

Amide resorcinol compounds Download PDF

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Publication number
WO2008053319A1
WO2008053319A1 PCT/IB2007/003270 IB2007003270W WO2008053319A1 WO 2008053319 A1 WO2008053319 A1 WO 2008053319A1 IB 2007003270 W IB2007003270 W IB 2007003270W WO 2008053319 A1 WO2008053319 A1 WO 2008053319A1
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compound
mmol
group
alkyl
added
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PCT/IB2007/003270
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French (fr)
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Sujin Cho-Schultz
Buwen Huang
Pei-Pei Kung
Scott Channing Sutton
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Pfizer Products Inc.
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Publication of WO2008053319A1 publication Critical patent/WO2008053319A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • 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
    • 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
    • C07D403/14—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 three or more hetero 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
    • C07D405/10—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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is directed to compounds, and pharmaceutically acceptable salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of HSP-90.
  • the compounds of the present invention are useful for modulating (e.g. inhibiting) HSP-90 activity and for treating diseases or conditions mediated by HSP-90, such as for example, disease states associated with abnormal cell growth such as cancer.
  • chaperones play important roles in cellular function by ensuring proper folding of proteins upon synthesis as well as their refolding under conditions of denaturing stress. By regulating the balance between protein synthesis and degradation, molecular chaperones are a significant part of the cellular response to stress. In addition, by regulating the proper folding of various cellular proteins, chaperones play an important role in regulating cellular functions such as cell proliferation and apoptosis. (See, e.g. Jolly, at al., J. Natl. Cancer Inst. 92: 1564-1572 (2000)).
  • HSPs Heat shock proteins
  • HSPs are a class of chaperones that accumulate in the cell in response to various environmental stresses, si.ch as hr-ai shock, oxidative stress, or the presence of alcohols or heavy molals.
  • HSPs may also play a significant role as chaperones for a variety of cellular proteins under stress-free conditions.
  • Members of the HSP family are classified according to their molecular weight (e.g. HSP-27, HSP-70, and HSP-90).
  • HSP-27, HSP-70, and HSP-90 Evidence of differential expression of HSPs in various stages of tumor progression suggests HSPs play a role in cancer. (See, e.g. Martin, et al., Cancer Res. 60:2232-2238 (2000)).
  • HSP-90 is a homodimer with ATPase activity and functions in a series of complex interactions with a variety of substrate proteins (Young, et al., J. Cell Biol. 154: 267-273 (2001)). HSP-90 is unique with regard to other chaperones, however, since most of its known substrate proteins are signal transduction proteins. Thus, HSP-90 plays an essential role in regulating cellular signal transduction networks. (See, e.g. Xu 1 et al., Proc. Natl. Acad. Sci 90:7074-7078 (1993)).
  • substrate proteins of HSP-90 include many mutated or over-expressed proteins implicated in cancer such as p53, Bcr- Ab1 kinase, RaM kinase, Akt kinase, Npm-Alk kinase p185 E * B2 transmembrane kinase, Cdk4, Cdk6, Wee1 (a cell cycle-dependent kinase), HER2/Neu (ErbB2), and hypoxia inducible factor-1 ⁇ (HIF-1 ⁇ ).
  • HSP-90 results in selective degradation of these important signaling proteins involved in apoptosis, cell proliferation, and cell cycle regulation (Holstein, et al., Cancer Res.
  • HSP-90 is an attractive therapeutic target because of the important roles played by these signaling proteins in disease states involving abnormal cell growth, such as cancer. It is thus desirable to discover and develop new inhibitors of HSP-90 activity that can provide a therapeutic benefit to patients suffering from disease states related to abnormal cell growth such as cancer.
  • Examples of compounds that inhibit HSP-90 include those described in U.S. provisional patent applications 60/677,268 (filed May 3, 2005), and 60/772,626 (filed Feb. 13, 2006), and in published patent applications WO 2005/000778, WO 2006/051808, and WO 2005/063222.
  • R 1 is halogen, (C 1 to C 6 ) alkyl, or H
  • R 2 is H, halogen, or -CH 3
  • R 3 is -CH 2 -NR 4 R 5 or -C(O)NR 6 R 7 ;
  • R 4 is H, (C 2 to C 6 ) alkyl, (C 1 to C 8 ) heteroalkyl, (C 3 to C 10 ) cycloalkyl, or (C 2 to C 9 ) cycloheteroalkyl, wherein each of said (C 2 to C 6 ) alkyl, (C 3 to C 10 ) cycloalkyl, and (C 2 to C 9 ) cycloheteroalkyl is optionally substituted with at least one R 8 group;
  • R 5 is H, (C 1 to C 6 ) alkyl, (C 1 to C 8 ) heteroalkyl, (C 3 to C 10 ) cycloalkyl, or (C 2 to C 9 ) cycloheteroalkyl wherein each of said (C 1 to C 6 ) alkyl, (C 3 to C 10 ) cycloalkyl, and (C 2 to C 9 ) cycloheteroalkyl is optionally substituted with at least one R 8 group; or R 4 and R 5 taken together with the N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to C 9 ) ccyycclloohheeteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 8 group;
  • R 6 is (C 3 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 3 to C 10 ) cycloalkyl, or (CH 2 J n -R 8 provided that R 8 is not -CH 3 or -CH 2 CH 3 , and wherein each of said (C 3 to C 6 ) alkyl and (C 3 to C 10 ) cycloalkyl is optionally substituted with at least one R 8 group;
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyi, wherein said (C 1 to C 6 ) alkyl is optionally substituted with at least one R 8 group; or R 6 and R 7 taken together with the N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 8 group; each R 8 is independently halogen, cyano, (C 1 to C 6 ) alkyl, (C 1 to C 8 ) alkoxy, (C 1 to C 8 ) heteroalkyl, -OH, -NR 1Oa R 1Ob , -C(O)NR 10a R 10b , -C(O)R 10a ,
  • -C(0)R 12a (C 6 to C 14 ) aryl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 10 ) cycloalkyl, wherein said (C 1 to C 6 ) alkyl is optionally substituted with at least one R 11 group, or R 1Oa and R 1Ob taken together with a N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group; R 11 is -NR 12a R 12b ; R 12a and R 12b are each independently H or (C 1 to C 6 ) alkyl; each n is independently 0, 1 , or 2; or a pharmaceutically acceptable salt thereof.
  • the invention provides compounds as described above wherein R 1 is halogen. In a further embodiment, R 1 is Cl or Br. In a further embodiment, R 1 is -CH 3 .
  • the invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
  • R 1 is halogen or -CH 3 ; or a pharmaceutically acceptable salt thereof.
  • R 1 is Cl.
  • R 4 and R 5 taken together with the N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to Cg) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 8 group.
  • R 4 is H.
  • R 5 is (C 1 to C 6 ) alkyl, (C 1 to C 8 ) heteroalkyl, (C 3 to C 10 ) cycloalkyl, or (C 2 to C 9 ) cycloheteroalkyl wherein each of said (C 1 to C 6 ) alkyl, (C 3 to C 10 ) cycloalkyl, and (C 2 to C 9 ) cycloheteroalkyl is optionally substituted with at least one R 8 group.
  • said (C 1 to C 6 ) alkyl is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
  • the present invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
  • R 1 is halogen or -CH 3 .
  • R 1 is Cl.
  • R 4 and R s taken together with the N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to Cg) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at feast one R 8 group.
  • R 4 is H.
  • R 5 is (C 1 to C 6 ) alkyl, (Ci to C 8 ) heteroalkyl, (C 3 to C 10 ) cycloalkyl, or (C 2 to C 9 ) cycloheteroalkyl wherein each of said (C 1 to C 6 ) alkyl, (C 3 to C 10 ) cycloalkyl, and (C 2 to C 9 ) cycloheteroalkyl is optionally substituted with at least one R 8 group.
  • said (C 1 to C 6 ) alkyl is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 C(CH 3 J 2 CH 3 , -CH(CH 3 J 2 , -CH(CH 2 CH 3 J 2 or -CH 2 C(CH 3 ) 3 .
  • the present invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
  • R 1 is halogen or -CH 3 .
  • R 1 is Cl.
  • R 6 and R 7 taken together with the N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to Cg) heteroaryl is optionally susbstituted with at least one R 8 group.
  • R 6 is (C 3 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 3 to C 10 ) cycloalkyl, or (CH 2 J n -R 8 provided that R 8 is not -CH 3 or -CH 2 CH 3 , and wherein each of said (C 3 to C 6 ) alkyl and (C 3 to C 10 ) cycloalkyl is optionally substituted with at least one R 8 group; and R 7 is H, (C 1 to C 6 ) alkyl, or (C 2 to C 8 ) alkenyl, wherein said (C 1 to C 6 ) alkyl is optionally substituted with at least one R 8 group.
  • the present invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
  • R 1 is halogen or -CH 3 .
  • R 1 can be Cl.
  • R 6 and R 7 taken together with the N atom to which they are bound form a (C 2 to Cg) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 8 group.
  • R 6 is (C 3 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 3 to C 10 ) cycloalkyl, or (CH 2 ) n -R 8 provided that R 8 is not -CH 3 or -CH 2 CH 3 , and wherein each of said (C 3 to C 6 ) alkyl and (C 3 to C 10 ) cycloalkyl is optionally substituted with at least one R 8 group; and R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, wherein said (C 1 to C 6 ) alkyl is optionally substituted with at least one R 8 group.
  • the present invention encompasses compounds of formula (I) as described above formed by any and all combinations of the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 1Oa , R 1Cb , R 11 , R 12a , R 12b , and n as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
  • the present invention also provides compounds of formula (II)
  • R 1 is halogen, (C 1 to C 6 ) alkyl, or H;
  • X is N, CH, or CR 2 ;
  • Y is N, CH, or CR 2 , provided that X and Y are not both N;
  • R is (C 1 to C 6 ) alkyl, (C 1 to C 8 ) heteroalkyl, (C 2 to C 9 ) heteroaryl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 14 ) aryl, or (C 3 to C 10 ) cycloalkyl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 9 ) heteroaryl, (C 3 to C 10 ) cycloalkyl, (C 2 to C 9 ) cycloheteroalkyl, and (C 6 to C 14 ) aryl is optionally substituted with at least one R 3 group where each R 3 is independently (C 1 to C 6 ) alkyl
  • R 1 is Cl or -CH 3 .
  • X is N and Y is CR 2 .
  • R 2 is -CH 3 , C 6 aryl, or -CH 2 -O-CH 3 .
  • the present invention encompasses compounds of formula (II) as described above formed by any and all combinations of the definitions of R 1 , R 2 , R 3 , X, and Y as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
  • the present invention also provides compounds of formula (III)
  • R 1 is halogen, (C 1 to C 6 ) alkyl, or H;
  • R 2 is -OR 3 Or-NR 4 R 5 ;
  • R 3 is (C 1 to C 6 ) alkyl;
  • R 4 and R 5 are each independently (C 1 to C 6 ) alkyl, or R 4 and R 5 , together with the N atom to which they are bound, form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 6 group; each R 6 is independently halogen, cyano, (C 1 to C 6 ) alkyl, (C 1 to C 8 ) alkoxy, (C 1 to C 8 ) heteroalkyl, or -OH; and R ⁇ is H or -CH 3 ; or a pharmaceutically acceptable salt thereof.
  • the present invention also provides compounds or salts as described above wherein the compound of formula (III) has the following structure:
  • R 1 is Cl and R 7 is H.
  • R 2 is -NR 4 R 5 or -OR 3 .
  • R 4 and R 5 are each independently (C 1 to C 6 ) alkyl.
  • R 4 and R 5 together with the N atom to which they are bound, form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to Cg) cycloheteroalkyl and (C 2 to Cg) heteroaryl is optionally susbstituted with at least one R 6 group.
  • the present invention also provides compounds or salts as described above wherein the compound of formula (III) has the following structure:
  • R 1 is Cl; and R 7 is H.
  • R 2 is -NR 4 R 5 or -OR 3 .
  • R 4 and R 5 are each independently (Ci to C 6 ) alkyl.
  • R 4 and R 5 together with the N atom to which they are bound, form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 6 group.
  • the present invention encompasses compounds of formula (III) as described above formed by any and all combinations of the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
  • the present invention also provides compounds of formula (IV)
  • R 1 is halogen, (C 1 to C 6 ) alkyl, or H;
  • R 2 and R 3 are each independently H, (C 1 to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 10 ) cycloalkyl, wherein each of said (C 1 to C 6 ) alkyl (C 2 to C 9 ) cycloheteroalkyl, and (C 3 to C 10 ) cycloalkyl is optionally substituted with at least one R 4 group; or R 2 and R 3 taken together with the N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to Cg) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 5 group; each R 4 is independently halogen, (C 3 to C 10 ) cycloalkyl, (C 2 to C 9
  • R 2 and R 3 are each independently H, (C 1 to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 10 ) cycloalkyl, wherein each of said (C 1 to C 6 ) alkyl (C 2 to C 9 ) cycloheteroalkyl, and (C 3 to C 10 ) cycloalkyl is optionally substituted with at least one R 4 group.
  • R 2 and R 3 taken together with the N atom to which they are bound form a (C 2 to C 9 ) cycloheteroalkyl group or a (C 2 to C 9 ) heteroaryl group, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 2 to C 9 ) heteroaryl is optionally susbstituted with at least one R 5 group.
  • R 5 group a further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
  • the present invention also provides compounds of formula (V)
  • R 1 is halogen, (C 1 to C 6 ) alkyl, or H;
  • R 2 is H, halogen, (C 1 to C 6 ) alkyl, (C 2 to C 9 ) heteroaryl, (C 2 to C 9 ) cycloheteroalkyl,
  • R 2 is halogen.
  • R 2 is (C 2 to C 9 ) heteroaryl.
  • R 2 is (Ci to C 6 ) alkyl.
  • the present invention encompasses compounds of formula (V) as described above formed by any and all combinations of the definitions of R 1 , R 2 , and R 3 as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
  • the present invention also provides a compound selected from the group consisting of:
  • the present invention further provides a pharmaceutical composition, comprising at least one compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention further provides a method of reducing abnormal cell growth in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of at least one compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof.
  • the abnormal cell growth is cancerous.
  • the present invention further provides a method of treating cancer in a mammal, comprising the step of administering to said mammal a therapeutically effective amount of at least one compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof.
  • the present invention further provides a method of inhibiting HSP-90 enzymatic activity, comprising contacting a HSP-90 enzyme with an HSP-90-inhibiting amount of at least one compound according to any one of the compounds described herein, or a pharmaceutically acceptable salt thereof .
  • the present invention further provides the use of a compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of abnormal cell growth in a mammal.
  • abnormal cell growth is cancerous.
  • the terms “comprising” and “including” are used in their open, non-limiting sense.
  • halo and/or halogen refer to fluorine, chlorine, bromine or iodine.
  • (C 1 to C 6 ) alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms. Examples of (C 1 to C 6 ) alkyl groups include methyl, ethyl, propyl, 2-propyl, ⁇ -butyl, /so-butyl, tert-butyl, pentyl, and the like.
  • (C 2 to C 6 ) alkyl refers to the corresponding saturated aliphatic hydrocarbon radicals of 2 to 6 carbon atoms, 3 to 6 carbon atoms, and 1 to 4 carbon atoms, respectively.
  • (C 2 to C 8 ) alkenyl means an alkyl moiety comprising 2 to 8 carbons having at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Such groups include both the E and Z isomers of said alkenyl moiety.
  • Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl.
  • (C 2 to C 8 ) alkynyl means an alkyl moiety comprising from 2 to 8 carbon atoms and having at least one carbon-carbon triple bond.
  • the carbon- carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, and 3- hexyne.
  • (C 1 to C 8 ) alkoxy means an O-alkyl group wherein said alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic.
  • alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic.
  • examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.
  • (C 1 to C 8 ) heteroalkyl refers to a straight- or branched-chain alkyl group having a total of from 2 to 12 atoms in the chain, including from 1 to 8 carbon atoms, and one or more atoms of which is a heteroatom selected from S, O, and N, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms.
  • the S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfides and sulfones, respectively.
  • the (C 1 to C 8 ) heteroalkyl groups in the compounds of the present invention can contain an oxo group at any carbon or heteroatom that will result in a stable compound.
  • -Exemplary (C 1 to C 8 ) heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers, primary, secondary, and tertiary alkyl amines, amides, ketones, esters, sulfides, and sulfones.
  • (C 6 to C 14 ) aryl means a group derived from an aromatic hydrocarbon containing from 6 to 14 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl.
  • (C 2 to C 9 ) heteroaryl means an aromatic heterocyclic group having a total of from 5 to 10 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
  • the heterocyclic groups include benzo-fused ring systems.
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indoiizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolin
  • the C 2 to C 9 heteroaryl groups may be C- attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • (C 2 to Cg) cycloheteroalkyl means a non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic group having a total of from 4 to 13 atoms in its ring system, and containing from 2 to 9 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
  • such C 2 to C 9 cycloheteroalkyl groups may contain an oxo substituent at any available atom that will result in a stable compound.
  • such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible.
  • a C 2 to C 9 cycloheteroalkyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone.
  • An example of a 4 membered cycloheteroalkyl group is azetidinyl (derived from azetidine).
  • An example of a 5 membered cycloheteroalkyl group is pyrrolidinyl.
  • An example of a 6 membered cycloheteroalkyl group is piperidinyl.
  • An example of a 9 membered cycloheteroalkyl group is indolinyl.
  • An example of a 10 membered cycloheteroalkyl group is 4H-quinolizinyl.
  • C 2 to Cg cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,
  • (C 3 to C 10 ) cycloalkyl group means a saturated or unsaturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 8 carbon ring atoms.
  • groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl.
  • (C 3 to C 6 ) cycloalkyl or “(C 4 to C 8 ) cycloalkyl” refer to the corresponding saturated or unsaturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 6 carbon ring atoms or from 4 to 8 carbon atoms, respectively.
  • cyano refers to a -C ⁇ N group.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. It is to be understood that in the compounds of the present invention when a group is said to be “unsubstituted,” or is “substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen.
  • a C 6 aryt group also called “phenyl” herein
  • phenyl substituted with one additional substituent
  • one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C 6 aryl ring (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4).
  • the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies.
  • a C 6 aryl group in the present compounds is said to be "disubstituted," one of ordinary skill in the art would understand it to mean that the C 6 aryl has 3 carbon atoms remaining that are unsubstituted.
  • solvate means a pharmaceutically acceptable solvate form of a compound of the present invention that retains the biological effectiveness of such compound.
  • solvates include, but are not limited to, compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
  • pharmaceutically acceptable salt means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.
  • pharmaceutically acceptable formulation means a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a carrier, diluent, and/or excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof.
  • Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art.
  • the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols.
  • fillers and extenders such as starch, sugars, mannitol, and silicic derivatives
  • binding agents such
  • Final pharmaceutical forms may be pills, tablets, powders, lozenges, saches, cachets, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain more than one compound according to the present invention. Alternatively, such formulations may contain one or more compounds of the present invention and one or more additional agents that reduce abnormal cell growth.
  • ⁇ SP-90-inhibiting amount refers to the amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, required to inhibit the enzymatic activity of HSP-90 in vivo, such as in a mammal, or in vitro.
  • the amount of such compounds required to cause such inhibition can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
  • inhibiting HSP-90 enzyme activity means decreasing the activity or functioning of the HSP-90 enzyme either in vitro or in vivo, such as in a mammal, such as a human, by contacting the enzyme with a compound of the present invention.
  • a therapeutically effective amount means an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof is a quantity sufficient to modulate or inhibit the activity of the HSP-90 enzyme such that a disease condition that is mediated by activity of the HSP-90 enzyme is reduced or alleviated.
  • treat refers to any treatment of an HSP-90 mediated disease or condition in a mammal, particularly a human, and include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition, e.g., relieving an inflammatory response without addressing the underlying disease or condition.
  • these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
  • abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells.
  • tumor cells tumor cells
  • tumors that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase
  • benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs any tumors that proliferate by receptor tyrosine kinases; any tumors that proliferate by aberrant serine/threonine kinase activation; benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs
  • tumors both benign and malignant, expressing an activated Ras oncogene
  • tumor cells both benign and malignant, in which the Ras protein is activated as a result of oncogenic mutation in another gene
  • benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs the abnormal growth of: tumor cells (tumors) that proliferate by expressing a mutated tyros
  • abnormal cell growth also refers to and includes the abnormal growth of cells, both benign and malignant, resulting from activity of the enzyme farnesyl protein transferase.
  • abnormal cell growth and “hyperproliferative disorder” are used interchangeably in this application.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound that are non- superimposable mirror images of one another.
  • racemic or “racemic mixture,” as used herein, refer to a 1:1 mixture of enantiomers of a particular compound.
  • diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
  • the compounds of the present invention are useful for modulating or inhibiting HSP-90 activity. Accordingly, these compounds are useful for the prevention and/or treatment of disease states associated with abnormal cell growth such as cancer, alone or in combination with other anti-cancer agents.
  • the compounds of the present invention may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( ), a solid wedge ( " ⁇ m ), or a dotted wedge ( —"""HI ).
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included.
  • the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom.
  • a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
  • the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
  • a compound of the invention contains an alkenyl or alkenylene group
  • geometric cisltrans (or ZJE) isomers are possible.
  • the compound contains, for example, a keto or oxime group or an aromatic moiety
  • tautomeric isomerism ('tautomerism') can occur.
  • Examples of tautomerism include keto and enol tautomers.
  • a single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • Salts of the present invention can be prepared according to methods known to those of skill in the art.
  • Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hex
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
  • Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • inventive compounds, agents and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labeled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an HSP-90 modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • a therapeutically effective amount i.e., an HSP-90 modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy
  • one compound of the present invention as an active ingredient
  • pharmaceutically suitable carriers which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • the pharmaceutical carriers employed may be either solid or liquid.
  • Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties.
  • a bioavailability enhancer such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol)
  • CMC carboxy-methylcellulose
  • PG propyleneglycol
  • PEG polyethyleneglycol
  • a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
  • a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
  • the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
  • a pharmaceutically acceptable salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable co-solvent or combinations of co-solvents. E ⁇ xamples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.
  • a compound of Formula I is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions that 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 ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds of the present invention may also be formulated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the co-solvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients.
  • These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs.
  • Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plural®, Peceol® Transcutol® and the like may be used.
  • the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
  • an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 0.1 mg to about 2000 mg, or from about 1 mg to about 1500 mg, or from about 5 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 20 mg to about 500 mg, or from about 30 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500mg.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, or from about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w%.
  • the compounds of the present invention may be administered to a mammal suffering from abnormal cell growth, such as a human, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, or four times a day, or even more frequently.
  • This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of any of the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth.
  • the abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of
  • the cancer is selected from lung cancer (NSCLC and SGLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers.
  • lung cancer NSCLC and SGLC
  • cancer of the head or neck ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers.
  • CNS central nervous
  • said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
  • This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti- hormones, and anti-androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers
  • the anti-tumor agent used in conjunction with a compound of the present invention and pharmaceutical compositions described herein is an anti-angiogenesis agent, kinase inhibitor, pan kinase inhibitor or growth factor inhibitor.
  • Preferred pan kinase inhibitors include SutentTM (sunitinib), described in U.S. Patent No. 6,573,293.
  • Anti-angiogenesis agents include but are not limited to the following agents, such as EGF inhibitors, EGFR inhibitors, VEGF inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9 (matrix-metalloprotienase 9) inhibitors.
  • EGF inhibitors include EGF inhibitors, EGFR inhibitors, VEGF inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9 (matrix-metalloprotienase 9) inhibitors.
  • VEGF inhibitors include for example, Avastin (bevacizumab), an anti- VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California. Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG 13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788 (Novartis), AZD-2171, VEGF Trap (Regeneron/Aventis), Vatalanib (also known as PTK-787, ZK-222584: Novartis & Schering AG), Macugen (pegaptanib octasodium, NX-1838, EYE-001, Pfizer In ⁇ /Gilead/Eyetech), IM862 (Cytran Inc.
  • Avastin bevacizumab
  • Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG 13736 (P
  • VEGF inhibitors useful in the practice of the present invention are described in U.S. Patent No. 6,534,524 and 6,235,764, both of which are incorporated in their entirety for all purposes. Additional VEGF inhibitors are described in, for example in WO 99/24440, in WO 95/21613, WO 99/61422, U.S. Patent 5,834,504, WO 98/50356, U.S. Patent 5,883,113 U.S. Patent 5,886,020, U.S. Patent 5,792,783, U.S.
  • anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, Vitaxin and combinations thereof.
  • antiproliferative agents that may be used in combination with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following: U.S. Patent 6,080,769; U.S. Patent 6,194,438; U.S. Patent 6,258,824; U.S. Patent 6,586447; U.S. Patent 6,071,935; U.S. Patent 6,495,564; and U.S. Patent 6,150,377; U.S. Patent 6,596,735; U.S. Patent 6,479,513; WO 01/40217; U.S. 2003-0166675.
  • PDGRr inhibitors include but are not limited to those disclosed in international patent application publication numbers WO 01/40217 and WO 04/020431, the contents of which are incorporated in their entirety for all purposes.
  • Preferred PDGFr inhibitors include Pfizer's CP-673,451 and CP-868,596 and its salts.
  • Preferred GARF inhibitors include Pfizer's AG-2037 (pelitrexol and its salts). GARF inhibitors useful in the practice of the present invention are disclosed in U.S. Patent 5,608,082 which is incorporated in its entirety for all purposes.
  • COX-II inhibitors which can be used in conjunction with a compound of Formula (I) and pharmaceutical compositions disclosed herein include CELEBREXTM (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381 , 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H-pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).
  • COX-I CELEBREXTM
  • the anti-tumor agent is celecoxib (U.S. Patent 5,466,823), valdecoxib (U.S. Patent 5,633,272), parecoxib (U.S. Patent 5,932,598), deracoxib (U.S. Patent 5,521,207), SD-8381 (U.S. Patent 6,034,256, Example 175), ABT- 963 (WO 02/24719), rofecoxib (CAS No. 162011-90-7), MK-663 (or etoricoxib) as disclosed in WO 98/03484, COX-189 (Lumiracoxib) as disclosed in WO 99/11605, BMS- 347070 (U.S.
  • Patent 6,180,651 NS-398 (CAS 123653-11-2), RS 57067 (CAS 17932-91- 3), 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1H-pyrrole, 2-(4-)
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs which inhibit the enzyme that makes prostaglandins (cyclooxygenase I and II), resulting in lower levels of prostaglandins
  • Salsalate Amigesic
  • Diflunisal Dolobid
  • lbuprofen Metoprofen
  • Orudis Nabumetone
  • Relafen Piroxicam
  • Naproxen Aleve, Naprosyn
  • Diclofenac Voltaren
  • lndomethacin Indocin
  • Sulindac Cl
  • Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof.
  • Targeted agents used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein include EGFr inhibitors such as lressa (gefitinib, AstraZeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux (cetuximab, lmclone Pharmaceuticals, Inc.), EMD-7200 (Merck AG), ABX-EGF (Amgen Inc.
  • EGFr inhibitors include lressa, Erbitux, Tarceva and combinations thereof.
  • anti-tumor agents include those selected from pan erb receptor inhibitors or ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer, Inc.), CI-1033 (canertinib, Pfizer, Inc.), Herceptin (trastuzumab, Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.), TAK-165 (Takeda), GW-572016 (lonafarnib, GlaxoSmithKline), GW-282974 (GlaxoSmithKline), EKB-569 (Wyeth), PKM 66 (Novartis), dHER2 (HER2 Vaccine, Corixa and GlaxoSmithKline), APC8024 (HER2 Vaccine, Dendreon), anti-HER2/neu bispecific antibody (Decof Cancer Center), B7.her2.lgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifunctional bispecific antibodies (University
  • Preferred erb selective anti-tumor agents include Herceptin, TAK-165, CP- 724,714, ABX-EGF, HER3 and combinations thereof.
  • Preferred pan erbb receptor inhibitors include GW572016, CI-1033, EKB-569, and Omitarg and combinations thereof.
  • Additional erbB2 inhibitors include those disclosed in WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, WO 95/19970, U.S. Patent 5,587,458, and U.S. Patent 5,877,305, each of which is herein incorporated by reference in its entirety.
  • ErbB2 receptor inhibitors useful in the present invention are also disclosed in U.S. Patents 6,465,449, and 6,284,764, and in WO 01/98277 each of which are herein incorporated by reference in their entirety.
  • anti-tumor agents may be selected from the following agents, BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen, Genta), Panitumumab (Abgenix/Amgen), Zevalin (Schering), Bexxar (Corixa/GlaxoSmithKline), Abarelix, Alimta, EPO 906 (Novartis), discodermolide (XAA-296), ABT-510 (Abbott), Neovastat (Aeterna), enzastaurin (EIi Lilly), Combrestatin A4P (Oxigene), ZO-6126 (AstraZeneca), flavopiridol (Aventis), CYC-202 (Cyclacel), AVE-8062 (Aventis), DMXAA (Roche/Antisoma), Thymitaq (Eximias), Temodar (temozolomide, Schering Plough) and Revilimd (Celegene) and combinations thereof.
  • anti-tumor agents may be selected from the following agents, CyPat (cyproterone acetate), Histerelin (histrelin acetate), Plenaixis (abarelix depot), Atrasentan (ABT-627), Satraplatin (JM-216), thalomid (Thalidomide), Theratope, Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamate paclitaxel), Targetin (bexarotine) and combinations thereof.
  • CyPat cyproterone acetate
  • Histerelin histrelin acetate
  • Plenaixis abarelix depot
  • ABT-627 Atrasentan
  • JM-216 thalomid (Thalidomide)
  • Theratope Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxi
  • anti-tumor agents may be selected from the following agents, Trizaone (tirapazamine), Aposyn (exisulind), Nevastat (AE-941), Ceplene (histamine dihydrochloride), Orathecin (rubitecan), Virulizin, Gastrimmune (G 17DT), DX-8951f (exatecan mesylate), Onconase (ranpirnase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and combinations thereof.
  • anti-tumor agents may be selected from the following agents, CeaVac (CEA), NeuTrexin (trimetresate glucuronate) and combinations thereof. Additional antitumor agents may be selected from the following agents, OvaRex (oregovomab), Osidem (IDM-1), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, Advexin (ING 201), Tirazone (tirapazamine), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, RSR13 (efaproxiral), Cotara (1311 chTNT Mb), NBI-3001 (IL-4) and combinations thereof.
  • Additional anti-tumor agents may be selected from the following agents, Canvaxin, GMK vaccine, PEG lnteron A, Taxoprexin (DHA/paciltaxel), and combinations thereof.
  • Other anti-tumor agents include Pfizer's MEK1/2 inhibitor PD325901, Array
  • mTOR inhibitors may also be utilized such as CCI-779 (Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573 (Ariad), HDAC inhibitors, SAHA (Merck Inc/Aton Pharmaceuticals) and combinations thereof.
  • Additional anti-tumor agents include aurora 2 inhibitor VX-680 (Vertex), and Chk1/2 inhibitor XL844 (Exilixis).
  • cytotoxic agents e.g., one or more selected from the group consisting of epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan) imatinib mesylate (Gleevec), and combinations thereof, may be used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein.
  • the invention also contemplates the use of the compounds of the present invention together with hormonal therapy, including but not limited to, exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin, TAP/Abbott/Takeda), anastrozole (Arimidex, Astrazeneca), gosrelin (Zoladex, AstraZeneca), doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex (AstraZeneca), Abarelix (Praecis), Trelstar, and combinations thereof.
  • exemestane Amasin, Pfizer Inc.
  • leuprorelin Louprorelin
  • anastrozole Arimidex, Astrazeneca
  • gosrelin Zoladex, AstraZeneca
  • doxercalciferol
  • the invention also relates to the use of the compounds of the present invention together with hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti- androgens such as bicalutamide, flutamide, mifepristone, nilutamide, CasodexTM (4 '-cyano- 3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl) propionanilide, bicalutamide) and combinations thereof.
  • hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti- androgens such as bicalutamide, flutamide, mifepri
  • the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • supportive care products e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • Particularly preferred cytotoxic agents include Camptosar, Erbitux, Iressa, Gleevec, Taxotere and combinations thereof.
  • topoisomerase I inhibitors may be utilized as anti-tumor agents: camptothecin; irinotecan HCI (Camptosar); edotecarin; orathecin (Supergen); exatecan (Daiichi); BN-80915 (Roche); and combinations thereof.
  • Particularly preferred toposimerase Il inhibitors include epirubicin (Ellence).
  • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi) or satrplatin and combinations thereof. Particularly preferred alkylating agents include Eloxatin (ox
  • Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine, EIi Lilly), fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostat
  • Antibiotics include intercalating antibiotics and include, but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.
  • Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere), paclitaxel and combinations thereof.
  • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan, and combinations thereof.
  • Preferred cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, SN-38, topotecan, and combinations thereof.
  • Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-la, interferon gamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof.
  • Other agents include filgrastim, lentinan, sizofilan,
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity.
  • agents include krestin, lentinan, sizofiran, picibanil, ubenimex and combinations thereof.
  • Millenium tretinoin, and combinations thereof.
  • Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, and combinations thereof.
  • Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof.
  • antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin and combinations thereof.
  • Anti-tumor agents capable of enhancing antitumor immune responses such as
  • CTLA4 cytotoxic lymphocyte antigen 4
  • CTLA4 may also be utilized, such as MDX-010 (Medarex) and CTLA4 compounds disclosed in U.S. Patent 6,682,736; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors.
  • CTLA4 antibodies that can be used in combination with compounds of the present invention include those disclosed in U.S. Patents 6,682,736 and 6,682,736 both of which are herein incorporated by reference in their entirety.
  • Gene therapy agents may also be employed as anti-tumor agents such as TNFerade
  • statins may be used in combination with a compound of the present invention and pharmaceutical compositions thereof.
  • HMG-CoA reducatase inhibitors may be selected from the group consisting of
  • Atorvastatin (LipitorTM, Pfizer Inc.), Pravastatin (PravacholTM, Bristol-Myers Squibb),
  • Lovastatin (MevacorTM, Merck Inc.), Simvastatin (ZocorTM, Merck Inc.), Fluvastatin (LescolTM, Novartis), Cerivastatin (BaycolTM, Bayer), Rosuvastatin (CrestorTM,
  • Atovorstatin and Lovastatin derivatives and combinations thereof.
  • Other agents useful as anti-tumor agents include Caduet.
  • Methods of Preparation Compounds of the present invention may be prepared using the general procedures described below, employing the techniques available in the art using starting materials that are readily available. The preparation of certain embodiments of the present invention is described in detail in the following examples, but those of ordinary skill in the art will recognize that the preparations described may be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non- exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.
  • DMF means di-methyl formamide
  • Me means methyl
  • TEA tri-ethyl amine
  • i-PrOH means isopropyl alcohol
  • HATU means 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium phosphorus pentafluoride
  • DMSO means di-methyl sulfoxide
  • EtOAc means ethyl acetate
  • Boc means t-butyloxycarbonyl
  • DCM means di-chloro methane
  • DME means di-methyl ether
  • MeOH means methanol
  • THF means tetrahydrofuran
  • DIEA means diisopropyl ethylamine
  • HOAc means acetic acid
  • NaOAc means sodium acetate
  • DMA means dimethyl amide
  • R3, R4, R5, R6 H, OH, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • R1, R2 substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • Amine 1.3 molar equivalent
  • DIEA 5 molar equivalent
  • HATU 1.1 molar equivalent
  • R H, substituted and unsubstituted alkyl, alkene, alkyn ⁇ , aryl, h ⁇ teroaryl, fused heterocycles.
  • R H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • X halogen, lower alkyl, substituted alkyl, trifluoromethyl
  • R1 , R2 H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • R H, substituted and unsubstituted alkyl, alke ⁇ e, alkyne, aryl, heteroaryl, fused heterocycles.
  • R1, R2 H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • R H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • R1, R2 H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • X Cl, Br, cyclopropyl, ethyl, vinyl General Procedure G16
  • R1 , R2 H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycl ⁇ s.
  • X Cl, Br, cyclopropyl, ethyl, vinyl
  • R1 , R2 H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
  • X Cl, Br, cyclopropyl, ethyl, vinyl
  • R substituted and unsubstituted alkyl
  • R H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocycles.
  • X Cl, Br, cyclopropyl, ethyl, vinyl
  • R H, substituted and u ⁇ substituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocyd ⁇ s.
  • R1, R2 H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocyd ⁇ s.
  • R1, R2 H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocycles.
  • R1, R2 H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocycles.
  • X Cl, Br, cyclopropyt, ethyl, vinyl
  • Examples 1 to 31 provide detailed synthetic steps for preparing several specific compounds of the present invention.
  • Table 1 shows additional compounds that were prepared as Examples 32 to 279 according to the general reaction schemes as described herein.
  • Examples 280 and 281 describe the biochemical and cellular assays used to assess the potency of the compounds shown in Examples 1 to 279.
  • Table 3 shows the biochemical and celluar assay values for compounds prepared as Example 1 to 279.
  • the compounds shown in the examples below may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( ), a solid wedge ( """ ⁇ - ), or a dotted wedge
  • Step 2 The compound obtained in Step 2 (100 mg, 0.46 mmol) was added to a solution of compound B in general procedure G10 (141 mg, 0.51 mmole), 4-methylmorpholine (700 mg, 7 mmol), N- ⁇ -dimethylaminopropylJ-N'-ethylcarbodiimide hydrochloride (177 mg, 0.93 mmol), and 1-hydroxy benzotriazole (125 mg, 0.93 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H 2 O (30 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 100 mL) was then added to extract the aqueous solution.
  • the compound prepared in Step 2 (0.55 mmol) was added to a solution of compound B in G10 (166 mg, 0.6 mmol), 4-methylmorpholine (1 ml, 9 mmol), N-(3- dimethylarninopropyl)-N'-ethylcarbodiimide hydrochloride (250 mg, 1.2 mmol), and 1- hydroxy benzotriazole (170 mg, 1.2 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H 2 O (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 100 mL) was then added to extract the aqueous solution.
  • Example 7 4-chloro-6-[(2- ⁇ 4-[(33-difluoroazetidin-1-yl)carbonyl]-2- methylph ⁇ nyl ⁇ pyrrolidin-1 -yl)carbonyl]benzene-13-diol
  • Lithium hydroxide hydrate (6 g, 142.3 mmol) was added to a solution of compound H1 (3.4 g, 7.1 mmol) in H 2 O (20 mL) and MeOH (15 ml_). The reaction mixture was heated to 4O 0 C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2 x 200 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white solid (3.03 g, 91.1% yield).
  • 3,3'-difluoroazetidine hydrochloride (44 mg, 0.34 mmol) was added to a solution of the compound prepared above (78 mg, 0.17 mmole), 4-methylmorpholine (0.37 ml, 3.4 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (64.5 mg, 0.34 mmol), and 1-hydroxy benzotriazole (45 mg, 0.34 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H 2 O (10 mL) was added to the reaction mixture to quench the reaction.
  • Example 8 4-chloro-6-[(2- ⁇ 4-[(33-dif1uoropyrrolidin-1 -yl)carbonyl]-2- methylphenyl ⁇ pyrrolidin-1-yl)carbonyl]benzene-13-diol
  • 3,3-Difluoro-pyrrolidine (59 mg, 0.41 mmol) was added to a solution of compound J1 in general procedure G14a (191 mg, 0.41 mmole), 4-methylmorpholine (0.9 ml, 8.2 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (158 mg, 0.82 mmol), and 1-hydroxy benzotriazole (111 mg, 0.82 mmol) in 10 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H 2 O (IO mL) was added to the reaction mixture to quench the reaction.
  • IO mL 1-hydroxy benzotriazole
  • Lithium hydroxide hydrate (6 g, 142.3 mmol) was added to a solution of compound H1 (3.4 g, 7.1 mmol) in H 2 O (20 mL) and MeOH (15 mL). The reaction mixture was heated to 40 0 C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2 x 200 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white solid (3.03 g, 91.1%yield).
  • 3,3'-difluoroazetidine hydrochloride (112 mg, 0.86 mmol) was added to a solution of the intermediate prepared above (200 mg, 0.43 mmole), 4-methylmorpholine (0.95 ml, 8.6 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol), and 1-hydroxy benzotriazole (117 mg, 0.86 mmol) in 6 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H 2 O (10 mL) was added to the reaction mixture to quench the reaction.
  • Example 10 4-chloro-6-[(2- ⁇ 3-[(3,3-dif1uoropyrrolidin-1 -yl)carbonyl]-2-methylphenyl ⁇ pyrrolidin-1 -yl)carbonyl]benze ⁇ e-1 ,3-diol
  • N-methylmorpholine (3 mL, 27 mmol), 1-hydroxybenzotriazole (0.48 g; 3.6 mmol), 1-(3- dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (0.70 g; 3.6 mmol) and diethylamine (0.15 mL, 1.4 mmol) were added.
  • the reaction mixture was stirred at room temperature for 6 days and EtOAc (20 mL) was added, washed with H 2 O (2 x 20 mL), with a saturated aqueous NaHCO 3 solution (2 x 20 mL), brine (15 mL), dried over Na 2 SO 4 and evaporated in vacuo to give crude compound 1d (268 mg).
  • Lithium hydroxide hydrate (720 mg, 17 mmol) was added to a solution of the compound from Step 3 in Example 18 (532 mg, 1.2 mmol) in H 2 O (3 mL) and MeOH (5 mL). The reaction mixture was heated to 40 0 C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2x150 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white foam (516 mg, quantitative yield).
  • Example 24 4-chloro-6- ⁇ [1 -(1 -hydroxy-1 -methylethyl)-1 -methyl-1 ,3-dihydro-2H- isoindol-2-yl]carbonyl ⁇ benzene-1,3-diol
  • Methyl magnesium bromide (0.5 mL, 117 mg, 0.33 mmol) was added to a solution of compound D in General Procedure G16 (200 mg, 0.45 mmol) in 6 mL of THF at room temperature, under nitrogen atmosphere. After addition, the color changed to orange clear, then light yellow clear. The reaction was stirred at room temperature for 12 hours (an orange clear solution).
  • Example 25 4-chloro-6- ⁇ [1 -(hydroxymethyl)-i ,3-dihydro-2H-isoindol-2- yl]carbonyl ⁇ benz ⁇ ne-1 ,3-diol
  • Lithium hydroxide hydrate (720 mg, 17 mmol) was added to a solution of the intermediate compound prepared in Step 1 above (532 mg, 1.2 mmol) in H 2 O (3 mL) and MeOH (5 mL). The reaction mixture was heated to 40 °C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2 x 150 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white foam (516 mg, quantitative yield).
  • the above compound was prepared using General Procuedure G18 as follows. Sodium hydride (27.3 mg, 60% dispersion in mineral oil) was added to a solution of the compound prepared in Example 25 (214 mg, 0.53 mmol) in 6 mL of DMF at room temperature, under N 2 . The reaction was stirred at room temperature for 20 minutes and then iodomethane (89.4 mg, in 1 mL of DMF) was added. The reaction was stirred at room temperature for 12hours. The reaction was checked by LC/MS. H 2 O (50 mL) was added to the mixture and EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to get a dark brown oil.
  • the Grignard reagent was cooled to 0°C and 1-vinyl-2-pyrrolidinone (9.53 g, 85.7 mmol) was added dropwise as a solution in THF (60 mL). After the addition was complete, the ice bath was removed and the reaction allowed to warm to room temperature. After 30 minutes at room temperature, TLC analysis showed the reaction to be complete. The reaction was cooled to 0°C and quenched by the dropwise addition of water (100 mL). The quenched reaction was further diluted with water (150 mL) and Et 2 O (300 mL) and transferred to a separatory funnel. To get separation of the layers, an aqueous solution of KH 2 PO 4 was added to adjust the pH to 6.
  • the reaction was then heated to 50 0 C for 15 minutes and allowed to cool to room temperature. After 2 hours longer at room temperature, the reaction was judged to be complete by LCMS analysis.
  • the reaction mixture was poured onto ice water and a liquid-liquid extraction was performed, extracting into EtOAc (4 x 150 mL).
  • the combined organic extract was washed with saturated aqueous NaHCO 3 (x3) and brine (x1), then dried over MgSO 4 . After removal of the solvent, the dark red oil was purified via flash chromatography eluting with a gradient of 10% to 80% EtOAc in PetEther.
  • 0.4 M solutions of the amines were prepared in anhydrous .dichloromethane.
  • a 0.4 M solution of the aldehyde (compound 6) was prepared in anhydrous dichlromethane.
  • a 0.1 M solution of acetic acid in anhydrous dichloromethane was prepared.
  • a 0.16 M suspension of NaBH(OAc) 3 in dichloromethane was prepared.
  • a set of 10 x 75 mm test tubes in an appropriately sized array was prepared. Using an Eppendorf pipette, 210 ⁇ L (0.084 mmol, 1.05 equiv.) of the amine solutions were placed into the appropriate test tubes.
  • Example 28 (5-Chloro-2,4-dihydroxy-phenyl)- ⁇ 2-[4-(3,3-difIuoro-pyrrolidin-1- ylmethyl)-phenyl]-pyrrolidin-1-yl ⁇ -methanone
  • a 0.20 M solution of the aldehydes (compound 10) was prepared in anhydrous DMSO.
  • a 0.6 M suspension of NaBH(OAc) 3 in anhydrous DMSO was prepared and sonicated until the solution was homogeneous.
  • a set of 10 x 75 mm test tubes was arranged in an appropriately sized array. Using an Eppendorf pipette, 200 ⁇ L (0.080 mmol, 1.0 equiv.) of the amine solutions were placed into the appropriate test tubes.
  • Using an Eppendorf pipette 400 ⁇ L (0.080 mmol, 1.0 equiv.) of the aldehyde solution was added to each test tube.
  • test tubes were sealed with parafilm and placed on a shaker at room temperature for 2 hours. Using an Eppendorf pipette, 333 ⁇ L (0.20 mmol, 2.5 equiv.) of the NaBH(OAc) 3 suspension was added to each of the test tubes. The test tubes were sealed with parafilm and placed on a shaker at room temperature for 1 hour. Using an Eppendorf pipette, 200 ⁇ L of methanol was added to each test tube. The test tubes were sealed with parafilm and placed on a shaker at room temperature for 1 hour. 267 ⁇ L DMSO (containing 0.01% BHT) was added to each test tube and the products were purified using reverse phase HPLC. The reaction was run on a 0.86 mmol scale and purification was accomplished via silica gel chromatography eluting with a gradient of 1% to 5% MeOH in DCM to afford 378 mg (100%) as a white solid.
  • DMSO containing 0.01% BHT
  • Example 29 4-chloro-6-[(2- ⁇ 4-[(33-difluoropyrrolidin-1-yl)carbonyl]-2- , . methylphenyl ⁇ pyrrolidin-1 -yl)carbonyl]benzene-13-diol
  • reaction solution was transferred via a syringe to a flask (flushed with N 2 ) containing a mixture of 4-bromo-3-methyl benzoic acid methyl ester (1.0 g, 4.56 mmol, 0.80 eq), palladium acetate (51 mg, 0.228 mmol, 0.04 eq), and tri-tert-butylphosphine tetrafluoroborate (83 mg, 0.285 mmol, 0.05 eq).
  • the resulting reaction mixture was stirred overnight. During the course of the reaction, the color of the reaction mixture became dark and precipitates were generated.
  • LCMS for the crude (5 minutes, positive APCI): T 3.969 min, 220.10, the desired prod-Boc.
  • Example 30 4-chloro-6-[(2- ⁇ 4-[(33-difluoroazetidin-1-yl)carbonyl]-2- fluorophenyl ⁇ pyrrolidin-1 -yl)carbonyl]benzene-13-diol
  • HSP-90 Compounds of the present invention were evaluated for potency against HSP-90 using a SPA (scintillation p/oximity assay) competition binding assay. Briefly, either full length or N-terminal HSP-90 that contains a 6-His tag on its C-terminus binds to copper on Yttrium-silicate scintiflant beads via the His-tag. Tritiated propyl-Geldanamycin (pGA), whose structure is shown below, is an analog of a natural inhibitor of HSP-90 called Geldanamycin.
  • pGA Tritiated propyl-Geldanamycin
  • Tritiated pGA which contains a tritiated propyl-amine group added at the #17 position, binds HSP-90 and brings the isotope into proximity with the beads.
  • 17-n-propylamino- Geldanamycin can be prepared as described in U.S. Patent No. 4,261,989, which is incorporated herein by reference.
  • a second tritiated compound that can also be used in this assay was made from the compound shown Example 61 is shown below and is designated as Compound A.
  • Compound A The "T” in the structure above indicates the position of the labeled tritiated hydrogen atoms.
  • This compound which can be made as described in Example 61, followed by standard hydrogenation methods using tritium gas, has a K d of 40 nM.
  • the beta signal emitted from the isotope excites the scintillant, which creates a measurable signal.
  • competitive compounds are added to the assay mixture, they compete with bound tritiated pGA or Compound A at the ATP-binding site on the N- terminal of HSP-90.
  • the signal is reduced (the beta-particles are no longer in proximity with the bead). This reduction in signal is used to quantify the extent to which the inhibitor/compound is competitive with pGA or Compound A.
  • the SPA assay for 3 H-pGA (designated G1) and Compound A (designated G2) binding to HSP-90 was performed in 96-well flat bottom white plates (Corning #3604).
  • typical reaction solutions contained 30 nM HSP-90 and 200 nM 3 H-pGA in binding buffer (100 mM Hepes, pH 7.5 and 150 mM KCI).
  • typical reaction solutions contained 5 nM HSP-90 and 50 nM of Compound A.
  • the 3 H-pGA was first diluted to 33% label with unlabeled pGA that was synthesized and purified to give a final concentration of 200 nM.
  • labeled Compound A was diluted with unlabeled Compound A to provide a ratio of labeled:unlabeled of 1:2 for a final concentration of 50 nM.
  • Inhibitors were added to the HSP- ⁇ O ⁇ H-pGA (or HSP-90/Compound A) solutions at eleven different concentrations for Kj determinations. The range of inhibitor concentrations were 100 ⁇ M, or an appropriate range, for solid samples and 10 ⁇ M for targeted library compounds and 4 mM liquid stocks. To determine percent inhibition, the compound was tested at 1 and 10 ⁇ M. The final DMSO in the samples was 4%.
  • Copper- Ysi beads (Amersham, #RPNQ0096) that have been diluted in binding buffer were added to each well to give a final concentration of 100 ⁇ g/well.
  • the plates were sealed, covered with a foil-covered lid and shaken for 30 minutes at room temperature.
  • the beads were allowed to settle for 30 minutes after which the plates were counted using a Packard TopCount NXT instrument. This procedure has also been adapted for medium throughput using a Beckman Biomek FX. Samples were run in duplicate and on two separate days to assure an accurate value of K 1 .
  • the corrected cpm's (actual cpm's minus background) were plotted vs. inhibitor concentration using GraphPad Prism software.
  • the IC 50 was then used to calculate the Ki by using the Cheng-
  • Ki ⁇ cl ⁇ IC n (Cl) 1 + ([hl]/Kd ⁇ hl ⁇ )
  • EL and EL 0 are the radioligand-HSP-90 complexes in the presence and absence of inhibitor, respectively.
  • EUEL 0 represents the fractional signal in the presence of inhibitor, lo, E 0 , and L 0 are the inhibitor, HSP-90, and radioligand concentrations, respectively.
  • K is the inhibition constant for the ligand, while KL is the binding affinity constant between the enzyme (HSP-90) and the ligand.

Abstract

The present invention is directed to amide resorcinol compounds and pharmaceutically acceptable salts and solvates thereof, their synthesis, and their use as HSP-90 inhibitors.

Description

AMIDE RESORCINOL COMPOUNDS
This application claims the benefit of United States Provisonal Patent Application No. 60/863,493 filed October 30, 2006, the disclosure of which is hereby incorporated by reference in its entirety. Field of the Invention
The present invention is directed to compounds, and pharmaceutically acceptable salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of HSP-90. The compounds of the present invention are useful for modulating (e.g. inhibiting) HSP-90 activity and for treating diseases or conditions mediated by HSP-90, such as for example, disease states associated with abnormal cell growth such as cancer.
Background
Molecular chaperones play important roles in cellular function by ensuring proper folding of proteins upon synthesis as well as their refolding under conditions of denaturing stress. By regulating the balance between protein synthesis and degradation, molecular chaperones are a significant part of the cellular response to stress. In addition, by regulating the proper folding of various cellular proteins, chaperones play an important role in regulating cellular functions such as cell proliferation and apoptosis. (See, e.g. Jolly, at al., J. Natl. Cancer Inst. 92: 1564-1572 (2000)). Heat shock proteins (HSPs) are a class of chaperones that accumulate in the cell in response to various environmental stresses, si.ch as hr-ai shock, oxidative stress, or the presence of alcohols or heavy molals. In addition to their role in protecting the cell from such environmental stresses, HSPs may also play a significant role as chaperones for a variety of cellular proteins under stress-free conditions. Members of the HSP family are classified according to their molecular weight (e.g. HSP-27, HSP-70, and HSP-90). Evidence of differential expression of HSPs in various stages of tumor progression suggests HSPs play a role in cancer. (See, e.g. Martin, et al., Cancer Res. 60:2232-2238 (2000)).
HSP-90 is a homodimer with ATPase activity and functions in a series of complex interactions with a variety of substrate proteins (Young, et al., J. Cell Biol. 154: 267-273 (2001)). HSP-90 is unique with regard to other chaperones, however, since most of its known substrate proteins are signal transduction proteins. Thus, HSP-90 plays an essential role in regulating cellular signal transduction networks. (See, e.g. Xu1 et al., Proc. Natl. Acad. Sci 90:7074-7078 (1993)). In particular, substrate proteins of HSP-90 include many mutated or over-expressed proteins implicated in cancer such as p53, Bcr- Ab1 kinase, RaM kinase, Akt kinase, Npm-Alk kinase p185E*B2 transmembrane kinase, Cdk4, Cdk6, Wee1 (a cell cycle-dependent kinase), HER2/Neu (ErbB2), and hypoxia inducible factor-1α (HIF-1α). Thus inhibition of HSP-90 results in selective degradation of these important signaling proteins involved in apoptosis, cell proliferation, and cell cycle regulation (Holstein, et al., Cancer Res. 61:4003-4009 (2001)). Accordingly, HSP-90 is an attractive therapeutic target because of the important roles played by these signaling proteins in disease states involving abnormal cell growth, such as cancer. It is thus desirable to discover and develop new inhibitors of HSP-90 activity that can provide a therapeutic benefit to patients suffering from disease states related to abnormal cell growth such as cancer. Examples of compounds that inhibit HSP-90 include those described in U.S. provisional patent applications 60/677,268 (filed May 3, 2005), and 60/772,626 (filed Feb. 13, 2006), and in published patent applications WO 2005/000778, WO 2006/051808, and WO 2005/063222.
Summary The present invention provides compounds of formula (I)
Figure imgf000003_0001
(I) wherein R1 is halogen, (C1 to C6) alkyl, or H; R2 is H, halogen, or -CH3; R3 is -CH2-NR4R5 or -C(O)NR6R7;
R4 is H, (C2 to C6) alkyl, (C1 to C8) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl, wherein each of said (C2 to C6) alkyl, (C3 to C10) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group;
R5 is H, (C1 to C6) alkyl, (C1 to C8) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl wherein each of said (C1 to C6) alkyl, (C3 to C10) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group; or R4 and R5 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) ccyycclloohheeteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R8 group;
R6 is (C3 to C6) alkyl, (C2 to C8) alkenyl, (C3 to C10) cycloalkyl, or (CH2Jn-R8 provided that R8 is not -CH3 or -CH2CH3, and wherein each of said (C3 to C6) alkyl and (C3 to C10) cycloalkyl is optionally substituted with at least one R8 group;
R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyi, wherein said (C1 to C6) alkyl is optionally substituted with at least one R8 group; or R6 and R7 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R8 group; each R8 is independently halogen, cyano, (C1 to C6) alkyl, (C1 to C8) alkoxy, (C1 to C8) heteroalkyl, -OH, -NR1OaR1Ob, -C(O)NR10aR10b, -C(O)R10a, -(CH2)n-(C3 to C10) cycloalkyl, -(CH2)n-(C2 to C9) heteroaryl, -(CH2)n-(C6 to C14) aryl, or -(CH2)π-(C2 to C9) cycloheteroalkyl, wherein each of said (C1 to C6) alkyl, (C1 to C8) alkoxy, (C3 to C10) cycloalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R9 group; each R9 is independently halogen, (C1 to C6) alkyl, -OH, (C1 to C8) heteroalkyl, (C1 to C8) alkoxy, -NR10aR10b, (C6 to C14) aryl, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl; R1Oa and R1Ob are each independently H, (C1 to C6) alkyl, (C1 to C8) heteroalkyl,
-C(0)R12a, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C3 to C10) cycloalkyl, wherein said (C1 to C6) alkyl is optionally substituted with at least one R11 group, or R1Oa and R1Ob taken together with a N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group; R11 is -NR12aR12b; R12a and R12b are each independently H or (C1 to C6) alkyl; each n is independently 0, 1 , or 2; or a pharmaceutically acceptable salt thereof.
In one embodiment, the invention provides compounds as described above wherein R1 is halogen. In a further embodiment, R1 is Cl or Br. In a further embodiment, R1 is -CH3. The invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
Figure imgf000004_0001
wherein R1 is halogen or -CH3; or a pharmaceutically acceptable salt thereof. In one embodiment, R1 is Cl. In a further embodiment, R4 and R5 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to Cg) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R8 group. In a further embodiment, R4 is H.
In a further embodiment R5 is (C1 to C6) alkyl, (C1 to C8) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl wherein each of said (C1 to C6) alkyl, (C3 to C10) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group. For example, said (C1 to C6) alkyl is -CH3, -CH2CH3, -CH2CH2CH3,
-CH2C(CH3)2CH3, -CH(CH3J2, -CH(CH2CH3)2 Or -CH2C(CH3J3. - A -
The present invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
Figure imgf000005_0001
wherein R1 is halogen or -CH3. For example, R1 is Cl. In one embodiment R4 and Rs taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to Cg) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at feast one R8 group. In another embodiment, R4 is H. In another embodiment R5 is (C1 to C6) alkyl, (Ci to C8) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl wherein each of said (C1 to C6) alkyl, (C3 to C10) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group. For example said (C1 to C6) alkyl is -CH3, -CH2CH3, -CH2CH2CH3, -CH2C(CH3J2CH3, -CH(CH3J2, -CH(CH2CH3J2 or -CH2C(CH3)3.
The present invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
Figure imgf000005_0002
wherein R1 is halogen or -CH3. In one embodiment R1 is Cl. In a further embodiment, R6 and R7 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to Cg) heteroaryl is optionally susbstituted with at least one R8 group.
In a further embodiment R6 is (C3 to C6) alkyl, (C2 to C8) alkenyl, (C3 to C10) cycloalkyl, or (CH2Jn-R8 provided that R8 is not -CH3 or -CH2CH3, and wherein each of said (C3 to C6) alkyl and (C3 to C10) cycloalkyl is optionally substituted with at least one R8 group; and R7 is H, (C1 to C6) alkyl, or (C2 to C8) alkenyl, wherein said (C1 to C6) alkyl is optionally substituted with at least one R8 group.
The present invention also provides compounds or salts as described above, wherein the compound of formula (I) has the following structure:
Figure imgf000006_0001
wherein R1 is halogen or -CH3. For example, R1 can be Cl.
In one embodiment R6 and R7 taken together with the N atom to which they are bound form a (C2 to Cg) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R8 group.
In a further embodiment R6 is (C3 to C6) alkyl, (C2 to C8) alkenyl, (C3 to C10) cycloalkyl, or (CH2)n-R8 provided that R8 is not -CH3 or -CH2CH3, and wherein each of said (C3 to C6) alkyl and (C3 to C10) cycloalkyl is optionally substituted with at least one R8 group; and R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, wherein said (C1 to C6) alkyl is optionally substituted with at least one R8 group.
It should be understood that the present invention encompasses compounds of formula (I) as described above formed by any and all combinations of the definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R1Oa, R1Cb, R11, R12a, R12b, and n as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
The present invention also provides compounds of formula (II)
Figure imgf000006_0002
(II) wherein R1 is halogen, (C1 to C6) alkyl, or H; X is N, CH, or CR2; Y is N, CH, or CR2, provided that X and Y are not both N; R is (C1 to C6) alkyl, (C1 to C8) heteroalkyl, (C2 to C9) heteroaryl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, or (C3 to C10) cycloalkyl, wherein each of said (C1 to C6) alkyl, (C2 to C9) heteroaryl, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, and (C6 to C14) aryl is optionally substituted with at least one R3 group where each R3 is independently (C1 to C6) alkyl, cyano, or (C6 to C14) aryl, or a pharmaceutically acceptable salt thereof.
In one embodiment, R1 is Cl or -CH3. In another embodiment X is N and Y is CR2. In another embodiment R2 is -CH3, C6 aryl, or -CH2-O-CH3.
It should be understood that the present invention encompasses compounds of formula (II) as described above formed by any and all combinations of the definitions of R1, R2, R3, X, and Y as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
The present invention also provides compounds of formula (III)
Figure imgf000007_0001
(III) wherein R1 is halogen, (C1 to C6) alkyl, or H; R2 is -OR3 Or-NR4R5; R3 is (C1 to C6) alkyl;
R4 and R5 are each independently (C1 to C6) alkyl, or R4 and R5, together with the N atom to which they are bound, form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R6 group; each R6 is independently halogen, cyano, (C1 to C6) alkyl, (C1 to C8) alkoxy, (C1 to C8) heteroalkyl, or -OH; and Rτ is H or -CH3; or a pharmaceutically acceptable salt thereof.
The present invention also provides compounds or salts as described above wherein the compound of formula (III) has the following structure:
Figure imgf000007_0002
In one embodiment R1 is Cl and R7 is H. In a further embodiment R2 is -NR4R5 or -OR3. In a further embodiment R4 and R5 are each independently (C1 to C6) alkyl.
In another embodiment R4 and R5, together with the N atom to which they are bound, form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to Cg) cycloheteroalkyl and (C2 to Cg) heteroaryl is optionally susbstituted with at least one R6 group.
The present invention also provides compounds or salts as described above wherein the compound of formula (III) has the following structure:
Figure imgf000008_0001
In one embodiment R1 is Cl; and R7 is H. In a further embodiment R2 is -NR4R5 or -OR3. In a further embodiment R4 and R5 are each independently (Ci to C6) alkyl. In another embodiment R4 and R5, together with the N atom to which they are bound, form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R6 group.
It should be understood that the present invention encompasses compounds of formula (III) as described above formed by any and all combinations of the definitions of R1, R2, R3, R4, R5, R6 and R7 as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
The present invention also provides compounds of formula (IV)
Figure imgf000008_0002
(IV) wherein R1 is halogen, (C1 to C6) alkyl, or H;
R2 and R3 are each independently H, (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, or (C3 to C10) cycloalkyl, wherein each of said (C1 to C6) alkyl (C2 to C9) cycloheteroalkyl, and (C3 to C10) cycloalkyl is optionally substituted with at least one R4 group; or R2 and R3 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to Cg) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R5 group; each R4 is independently halogen, (C3 to C10) cycloalkyl, (C2 to C9) heteroaryl, (C2 to C9) cycloheteroalkyl, or (C6 to C14) aryl, wherein each of said (C3 to C10) cycloalkyl, (C2 to C9) heteroaryl, (C2 to C9) cycloheteroalkyl and (C6 to C14) aryl is optionally substituted with at least one R5 group; and each R5 is independently halogen or (C1 to C6) alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment R1 is -CH3. In another embodiment R1 is Br. In a further embodiment R1 is Cl.
In a further embodiment R2 and R3 are each independently H, (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, or (C3 to C10) cycloalkyl, wherein each of said (C1 to C6) alkyl (C2 to C9) cycloheteroalkyl, and (C3 to C10) cycloalkyl is optionally substituted with at least one R4 group.
In a further embodiment R2 and R3 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R5 group. It should be understood that the present invention encompasses compounds of formula (IV) as described above formed by any and all combinations of the definitions of R1, R2, R3, R4, and R5, as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
The present invention also provides compounds of formula (V)
Figure imgf000009_0001
(V) wherein R1 is halogen, (C1 to C6) alkyl, or H;
R2 is H, halogen, (C1 to C6) alkyl, (C2 to C9) heteroaryl, (C2 to C9) cycloheteroalkyl,
(C6 to C14) aryl, or (C3 to C10) cycloalkyl, wherein each of said (C2 to C9) heteroaryl, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, and (C6 to C14) aryl is optionally substituted with at least one R3 group; and R3 is H, halogen, (C1 to C6) alkyl, cyano, (C1 to C8) alkoxy,
(C1 to C8) heteroalkyl, or -OH; or a pharmaceutically acceptable salt thereof. In one embodiment, R2 is halogen. In another embodiment R2 is (C2 to C9) heteroaryl. In a further embodiment R2 is (Ci to C6) alkyl.
It should be understood that the present invention encompasses compounds of formula (V) as described above formed by any and all combinations of the definitions of R1, R2, and R3 as described above, and further includes pharmaceutically acceptable salts and solvates thereof of any of said compounds.
The present invention also provides a compound selected from the group consisting of:
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000011_0004
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof.
The present invention further provides a pharmaceutical composition, comprising at least one compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
The present invention further provides a method of reducing abnormal cell growth in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of at least one compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof. In one embodiment the abnormal cell growth is cancerous.
The present invention further provides a method of treating cancer in a mammal, comprising the step of administering to said mammal a therapeutically effective amount of at least one compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of inhibiting HSP-90 enzymatic activity, comprising contacting a HSP-90 enzyme with an HSP-90-inhibiting amount of at least one compound according to any one of the compounds described herein, or a pharmaceutically acceptable salt thereof .
The present invention further provides the use of a compound according to any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of abnormal cell growth in a mammal. In one embodiment, such abnormal cell growth is cancerous. As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense.
The terms "halo" and/or "halogen" refer to fluorine, chlorine, bromine or iodine. The term "(C1 to C6) alkyl" refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms. Examples of (C1 to C6) alkyl groups include methyl, ethyl, propyl, 2-propyl, π-butyl, /so-butyl, tert-butyl, pentyl, and the like.
Similarly, terms such as "(C2 to C6) alkyl", "(C3 to C6) alkyl", and "(C1 to C4) alkyl" refer to the corresponding saturated aliphatic hydrocarbon radicals of 2 to 6 carbon atoms, 3 to 6 carbon atoms, and 1 to 4 carbon atoms, respectively. The term "(C2 to C8) alkenyl", as used herein, means an alkyl moiety comprising 2 to 8 carbons having at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Such groups include both the E and Z isomers of said alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. The term "allyl," as used herein, means a -CH2CH=CH2 group. The term, "C(R)=C(R)," as used herein, represents a carbon-carbon double bond in which each carbon is substituted by an R group.
As used herein, the term "(C2 to C8) alkynyl" means an alkyl moiety comprising from 2 to 8 carbon atoms and having at least one carbon-carbon triple bond. The carbon- carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, and 3- hexyne.
The term "(C1 to C8) alkoxy", as used herein, means an O-alkyl group wherein said alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.
The term "(C1 to C8) heteroalkyl" refers to a straight- or branched-chain alkyl group having a total of from 2 to 12 atoms in the chain, including from 1 to 8 carbon atoms, and one or more atoms of which is a heteroatom selected from S, O, and N, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfides and sulfones, respectively. Furthermore, the (C1 to C8) heteroalkyl groups in the compounds of the present invention can contain an oxo group at any carbon or heteroatom that will result in a stable compound. -Exemplary (C1 to C8) heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers, primary, secondary, and tertiary alkyl amines, amides, ketones, esters, sulfides, and sulfones.
The term "(C6 to C14) aryl", as used herein, means a group derived from an aromatic hydrocarbon containing from 6 to 14 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl. The terms "Ph" and "phenyl," as used herein, mean a -C6H5 group. The term "benzyl," as used herein, means a -CH2C6H5 group.
"(C2 to C9) heteroaryl", as used herein, means an aromatic heterocyclic group having a total of from 5 to 10 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. The heterocyclic groups include benzo-fused ring systems. .Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indoiizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quiπoxalinyl, naphthyridinyl, and furopyridiπyl. The C2 to C9 heteroaryl groups may be C- attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
"(C2 to Cg) cycloheteroalkyl", as used herein, means a non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic group having a total of from 4 to 13 atoms in its ring system, and containing from 2 to 9 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. Furthermore, such C2 to C9 cycloheteroalkyl groups may contain an oxo substituent at any available atom that will result in a stable compound. For example, such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible. In addition, it is to be understood that when such a C2 to C9 cycloheteroalkyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone. An example of a 4 membered cycloheteroalkyl group is azetidinyl (derived from azetidine). An example of a 5 membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6 membered cycloheteroalkyl group is piperidinyl. An example of a 9 membered cycloheteroalkyl group is indolinyl. An example of a 10 membered cycloheteroalkyl group is 4H-quinolizinyl. Further examples of such C2 to Cg cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4- ethylpiperazinyl, and 1-oxo-2,8,diazaspiro[4.5]dec-8-yl.
The term "(C3 to C10) cycloalkyl group" means a saturated or unsaturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 8 carbon ring atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl. Similarly, terms such as "(C3 to C6) cycloalkyl" or "(C4 to C8) cycloalkyl" refer to the corresponding saturated or unsaturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 6 carbon ring atoms or from 4 to 8 carbon atoms, respectively.
The term "cyano" refers to a -C≡N group. The term "substituted," means that the specified group or moiety bears one or more substituents. The term "unsubstituted," means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. It is to be understood that in the compounds of the present invention when a group is said to be "unsubstituted," or is "substituted" with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a C6 aryt group, also called "phenyl" herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C6 aryl ring (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a C6 aryl group in the present compounds is said to be "disubstituted," one of ordinary skill in the art would understand it to mean that the C6 aryl has 3 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies. The term "solvate", as used herein, means a pharmaceutically acceptable solvate form of a compound of the present invention that retains the biological effectiveness of such compound. Examples of solvates include, but are not limited to, compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds. The term "pharmaceutically acceptable salt," as used herein, means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.
The term "pharmaceutically acceptable formulation," as used herein, means a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a carrier, diluent, and/or excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof. Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art. For example, the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. Final pharmaceutical forms may be pills, tablets, powders, lozenges, saches, cachets, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain more than one compound according to the present invention. Alternatively, such formulations may contain one or more compounds of the present invention and one or more additional agents that reduce abnormal cell growth.
The term ΗSP-90-inhibiting amount" as used herein, refers to the amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, required to inhibit the enzymatic activity of HSP-90 in vivo, such as in a mammal, or in vitro. The amount of such compounds required to cause such inhibition can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
The term "inhibiting HSP-90 enzyme activity," as used herein, means decreasing the activity or functioning of the HSP-90 enzyme either in vitro or in vivo, such as in a mammal, such as a human, by contacting the enzyme with a compound of the present invention.
The term "therapeutically effective amount," as used herein, means an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, is a quantity sufficient to modulate or inhibit the activity of the HSP-90 enzyme such that a disease condition that is mediated by activity of the HSP-90 enzyme is reduced or alleviated. The terms "treat", "treating", and "treatment" refer to any treatment of an HSP-90 mediated disease or condition in a mammal, particularly a human, and include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition, e.g., relieving an inflammatory response without addressing the underlying disease or condition. With regard to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
The term "compound of the present invention" refers to any of the above- mentioned compounds, as well as those in the Examples that follow, and include those generically described or those described as species. The term also refers to pharmaceutically acceptable salts or solvates of these compounds. "Abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells. This includes, but is not limited to, the abnormal growth of: tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; any tumors that proliferate by receptor tyrosine kinases; any tumors that proliferate by aberrant serine/threonine kinase activation; benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs; tumors, both benign and malignant, expressing an activated Ras oncogene; tumor cells, both benign and malignant, in which the Ras protein is activated as a result of oncogenic mutation in another gene; benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papilloma virus (HPV), and restinosis. "Abnormal cell growth" also refers to and includes the abnormal growth of cells, both benign and malignant, resulting from activity of the enzyme farnesyl protein transferase.
The terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably in this application.
The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. In particular, the term "enantiomers" refers to two stereoisomers of a compound that are non- superimposable mirror images of one another. The terms "racemic" or "racemic mixture," as used herein, refer to a 1:1 mixture of enantiomers of a particular compound. The term "diastereomers", on the other hand, refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
Detailed Description
The compounds of the present invention are useful for modulating or inhibiting HSP-90 activity. Accordingly, these compounds are useful for the prevention and/or treatment of disease states associated with abnormal cell growth such as cancer, alone or in combination with other anti-cancer agents.
In accordance with a convention used in the art, the symbol ^ is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. In accordance with another convention, in some structural formulae herein the carbon atoms and their bound hydrogen atoms are
not explicitly depicted, e.g., ^ * *»- r reenprrαeisSfeinnttss a a m mpetthhuyll π grrnoiuinp, c ' ^ ^s represents an
ethyl group,
Figure imgf000018_0001
a cyclopentyl group, etc.
The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( ), a solid wedge ( "^^m ), or a dotted wedge ( —"""HI ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
Where a compound of the invention contains an alkenyl or alkenylene group, geometric cisltrans (or ZJE) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. Examples of tautomerism include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
Salts of the present invention can be prepared according to methods known to those of skill in the art. Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ- hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. The compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas. The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon-14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
The compounds of the present invention may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.
To treat or prevent diseases or conditions mediated by HSP-90, a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an HSP-90 modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
The pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavailability enhancer, such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation. If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable co-solvent or combinations of co-solvents. EΞxamples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
Proper formulation is dependent upon the route of administration selected. For injection, the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
Pharmaceutical preparations that 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 ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration intranasally or by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. The proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Furthermore, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plural®, Peceol® Transcutol® and the like may be used.
Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
It will be appreciated that the actual dosages of the agents of this invention will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions. For oral administration, an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
Furthermore, the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 0.1 mg to about 2000 mg, or from about 1 mg to about 1500 mg, or from about 5 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 20 mg to about 500 mg, or from about 30 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500mg.
Additionally, the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, or from about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w%. The compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof, may be administered to a mammal suffering from abnormal cell growth, such as a human, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, or four times a day, or even more frequently.
Those of ordinary skill in the art will understand that with respect to the compounds of the present invention, the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of any of the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth.
In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.
In one embodiment of the present invention the cancer is selected from lung cancer (NSCLC and SGLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers.
In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis. This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti- hormones, and anti-androgens.
In one embodiment of the present invention the anti-tumor agent used in conjunction with a compound of the present invention and pharmaceutical compositions described herein is an anti-angiogenesis agent, kinase inhibitor, pan kinase inhibitor or growth factor inhibitor. Preferred pan kinase inhibitors include Sutent™ (sunitinib), described in U.S. Patent No. 6,573,293. Anti-angiogenesis agents, include but are not limited to the following agents, such as EGF inhibitors, EGFR inhibitors, VEGF inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9 (matrix-metalloprotienase 9) inhibitors.
Preferred VEGF inhibitors, include for example, Avastin (bevacizumab), an anti- VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California. Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG 13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788 (Novartis), AZD-2171, VEGF Trap (Regeneron/Aventis), Vatalanib (also known as PTK-787, ZK-222584: Novartis & Schering AG), Macugen (pegaptanib octasodium, NX-1838, EYE-001, Pfizer Inα/Gilead/Eyetech), IM862 (Cytran Inc. of Kirkland, Washington, USA); and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California) and combinations thereof. VEGF inhibitors useful in the practice of the present invention are described in U.S. Patent No. 6,534,524 and 6,235,764, both of which are incorporated in their entirety for all purposes. Additional VEGF inhibitors are described in, for example in WO 99/24440, in WO 95/21613, WO 99/61422, U.S. Patent 5,834,504, WO 98/50356, U.S. Patent 5,883,113 U.S. Patent 5,886,020, U.S. Patent 5,792,783, U.S. Patent 6,653,308, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, all of which are herein incorporated by reference in their entirety.
Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, Vitaxin and combinations thereof.
Other antiproliferative agents that may be used in combination with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following: U.S. Patent 6,080,769; U.S. Patent 6,194,438; U.S. Patent 6,258,824; U.S. Patent 6,586447; U.S. Patent 6,071,935; U.S. Patent 6,495,564; and U.S. Patent 6,150,377; U.S. Patent 6,596,735; U.S. Patent 6,479,513; WO 01/40217; U.S. 2003-0166675. Each of the foregoing patents and patent applications is herein incorporated by reference in their entirety. PDGRr inhibitors include but are not limited to those disclosed in international patent application publication numbers WO 01/40217 and WO 04/020431, the contents of which are incorporated in their entirety for all purposes. Preferred PDGFr inhibitors include Pfizer's CP-673,451 and CP-868,596 and its salts.
Preferred GARF inhibitors include Pfizer's AG-2037 (pelitrexol and its salts). GARF inhibitors useful in the practice of the present invention are disclosed in U.S. Patent 5,608,082 which is incorporated in its entirety for all purposes.
Examples of useful COX-II inhibitors which can be used in conjunction with a compound of Formula (I) and pharmaceutical compositions disclosed herein include CELEBREX™ (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381 , 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H-pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib). Additonally, COX-II inhibitors are disclosed in U.S. patent applications US 2005-0148627 and US 2005-0148777, the contents of which are incorporated in their entirety for all purposes.
In a particular embodiment the anti-tumor agent is celecoxib (U.S. Patent 5,466,823), valdecoxib (U.S. Patent 5,633,272), parecoxib (U.S. Patent 5,932,598), deracoxib (U.S. Patent 5,521,207), SD-8381 (U.S. Patent 6,034,256, Example 175), ABT- 963 (WO 02/24719), rofecoxib (CAS No. 162011-90-7), MK-663 (or etoricoxib) as disclosed in WO 98/03484, COX-189 (Lumiracoxib) as disclosed in WO 99/11605, BMS- 347070 (U.S. Patent 6,180,651), NS-398 (CAS 123653-11-2), RS 57067 (CAS 17932-91- 3), 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1H-pyrrole, 2-(4-
Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole, or meloxicam.
Other useful inhibitors as anti-tumor agents used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein include aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit the enzyme that makes prostaglandins (cyclooxygenase I and II), resulting in lower levels of prostaglandins, include but are not limited to the following, Salsalate (Amigesic), Diflunisal (Dolobid), lbuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), lndomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol), Oxaprozin (Daypro) and combinations thereof.
Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof. Targeted agents used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein include EGFr inhibitors such as lressa (gefitinib, AstraZeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux (cetuximab, lmclone Pharmaceuticals, Inc.), EMD-7200 (Merck AG), ABX-EGF (Amgen Inc. and Abgenix Inc.), HR3 (Cuban Government), IgA antibodies (University of Eiiangen- Nuremberg), TP-38 (IVAX), EGFR fusion protein, EGF-vaccine, anti-EGFr immunoliposomes (Hermes Biosciences Inc.) and combinations thereof. Preferred EGFr inhibitors include lressa, Erbitux, Tarceva and combinations thereof.
Other anti-tumor agents include those selected from pan erb receptor inhibitors or ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer, Inc.), CI-1033 (canertinib, Pfizer, Inc.), Herceptin (trastuzumab, Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.), TAK-165 (Takeda), GW-572016 (lonafarnib, GlaxoSmithKline), GW-282974 (GlaxoSmithKline), EKB-569 (Wyeth), PKM 66 (Novartis), dHER2 (HER2 Vaccine, Corixa and GlaxoSmithKline), APC8024 (HER2 Vaccine, Dendreon), anti-HER2/neu bispecific antibody (Decof Cancer Center), B7.her2.lgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifunctional bispecific antibodies (University of Munich) and mAB AR-209 (Aronex Pharmaceuticals Inc) and mAB 2B-1 (Chiron) and combinations thereof.
Preferred erb selective anti-tumor agents include Herceptin, TAK-165, CP- 724,714, ABX-EGF, HER3 and combinations thereof. Preferred pan erbb receptor inhibitors include GW572016, CI-1033, EKB-569, and Omitarg and combinations thereof.
Additional erbB2 inhibitors include those disclosed in WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, WO 95/19970, U.S. Patent 5,587,458, and U.S. Patent 5,877,305, each of which is herein incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also disclosed in U.S. Patents 6,465,449, and 6,284,764, and in WO 01/98277 each of which are herein incorporated by reference in their entirety.
Additionally, other anti-tumor agents may be selected from the following agents, BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen, Genta), Panitumumab (Abgenix/Amgen), Zevalin (Schering), Bexxar (Corixa/GlaxoSmithKline), Abarelix, Alimta, EPO 906 (Novartis), discodermolide (XAA-296), ABT-510 (Abbott), Neovastat (Aeterna), enzastaurin (EIi Lilly), Combrestatin A4P (Oxigene), ZO-6126 (AstraZeneca), flavopiridol (Aventis), CYC-202 (Cyclacel), AVE-8062 (Aventis), DMXAA (Roche/Antisoma), Thymitaq (Eximias), Temodar (temozolomide, Schering Plough) and Revilimd (Celegene) and combinations thereof.
Other anti-tumor agents may be selected from the following agents, CyPat (cyproterone acetate), Histerelin (histrelin acetate), Plenaixis (abarelix depot), Atrasentan (ABT-627), Satraplatin (JM-216), thalomid (Thalidomide), Theratope, Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamate paclitaxel), Targetin (bexarotine) and combinations thereof.
Additionally, other anti-tumor agents may be selected from the following agents, Trizaone (tirapazamine), Aposyn (exisulind), Nevastat (AE-941), Ceplene (histamine dihydrochloride), Orathecin (rubitecan), Virulizin, Gastrimmune (G 17DT), DX-8951f (exatecan mesylate), Onconase (ranpirnase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and combinations thereof.
Further anti-tumor agents may be selected from the following agents, CeaVac (CEA), NeuTrexin (trimetresate glucuronate) and combinations thereof. Additional antitumor agents may be selected from the following agents, OvaRex (oregovomab), Osidem (IDM-1), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, Advexin (ING 201), Tirazone (tirapazamine), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, RSR13 (efaproxiral), Cotara (1311 chTNT Mb), NBI-3001 (IL-4) and combinations thereof. Additional anti-tumor agents may be selected from the following agents, Canvaxin, GMK vaccine, PEG lnteron A, Taxoprexin (DHA/paciltaxel), and combinations thereof. Other anti-tumor agents include Pfizer's MEK1/2 inhibitor PD325901, Array
Biopharm's MEK inhibitor ARRY-142886, Bristol Myers' CDK2 inhibitor BMS-387,032,
Pfizer's CDK inhibitor PD0332991 and AstraZeneca's AXD-5438, and combinations thereof.
Additionally, mTOR inhibitors may also be utilized such as CCI-779 (Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573 (Ariad), HDAC inhibitors, SAHA (Merck Inc/Aton Pharmaceuticals) and combinations thereof. Additional anti-tumor agents include aurora 2 inhibitor VX-680 (Vertex), and Chk1/2 inhibitor XL844 (Exilixis).
The following cytotoxic agents, e.g., one or more selected from the group consisting of epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan) imatinib mesylate (Gleevec), and combinations thereof, may be used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein.
The invention also contemplates the use of the compounds of the present invention together with hormonal therapy, including but not limited to, exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin, TAP/Abbott/Takeda), anastrozole (Arimidex, Astrazeneca), gosrelin (Zoladex, AstraZeneca), doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex (AstraZeneca), Abarelix (Praecis), Trelstar, and combinations thereof.
The invention also relates to the use of the compounds of the present invention together with hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti- androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex™ (4 '-cyano- 3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl) propionanilide, bicalutamide) and combinations thereof. Further, the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
Particularly preferred cytotoxic agents include Camptosar, Erbitux, Iressa, Gleevec, Taxotere and combinations thereof.
The following topoisomerase I inhibitors may be utilized as anti-tumor agents: camptothecin; irinotecan HCI (Camptosar); edotecarin; orathecin (Supergen); exatecan (Daiichi); BN-80915 (Roche); and combinations thereof. Particularly preferred toposimerase Il inhibitors include epirubicin (Ellence). Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi) or satrplatin and combinations thereof. Particularly preferred alkylating agents include Eloxatin (oxaliplatin).
Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine, EIi Lilly), fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti- metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4- dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid and combinations thereof.
Antibiotics include intercalating antibiotics and include, but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.
Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere), paclitaxel and combinations thereof.
Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan, and combinations thereof.
Preferred cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, SN-38, topotecan, and combinations thereof.
Immunologicals include interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-la, interferon gamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof. Other agents include filgrastim, lentinan, sizofilan,
TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y-muHMFG1), Provenge (Dendreon) and combinations thereof.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofiran, picibanil, ubenimex and combinations thereof.
Other anticancer agents that can be used in combination with a compound of the present invention include alitretinoin, ampligen, atrasentan bexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride.fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, Telcyta (TLK-286, Telik Inc.). Velcade (bortemazib,
Millenium), tretinoin, and combinations thereof.
Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, and combinations thereof. Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof.
Other antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin and combinations thereof. Anti-tumor agents capable of enhancing antitumor immune responses, such as
CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking
CTLA4 may also be utilized, such as MDX-010 (Medarex) and CTLA4 compounds disclosed in U.S. Patent 6,682,736; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors. Additionally, specific CTLA4 antibodies that can be used in combination with compounds of the present invention include those disclosed in U.S. Patents 6,682,736 and 6,682,736 both of which are herein incorporated by reference in their entirety.
Specific IGF1R antibodies that can be used in the combination methods of the present invention include those disclosed in WO 02/053596, which is herein incorporated by reference in its entirety.
Specific CD40 antibodies that can be used in the present invention include those disclosed in WO 03/040170 which is herein incorporated by reference in its entirety.
Gene therapy agents may also be employed as anti-tumor agents such as TNFerade
(GeneVec), which express TNFalpha in response to radiotherapy. In one embodiment of the present invention statins may be used in combination with a compound of the present invention and pharmaceutical compositions thereof.
Statins (HMG-CoA reducatase inhibitors) may be selected from the group consisting of
Atorvastatin (Lipitor™, Pfizer Inc.), Pravastatin (Pravachol™, Bristol-Myers Squibb),
Lovastatin (Mevacor™, Merck Inc.), Simvastatin (Zocor™, Merck Inc.), Fluvastatin (Lescol™, Novartis), Cerivastatin (Baycol™, Bayer), Rosuvastatin (Crestor™,
AstraZeneca), Lovostatin and Niacin (Advicor™, Kos Pharmaceuticals), derivatives and combinations thereof.
In a preferred embodiment the statin is selected from the group consisting of
Atovorstatin and Lovastatin, derivatives and combinations thereof. Other agents useful as anti-tumor agents include Caduet. Methods of Preparation Compounds of the present invention may be prepared using the general procedures described below, employing the techniques available in the art using starting materials that are readily available. The preparation of certain embodiments of the present invention is described in detail in the following examples, but those of ordinary skill in the art will recognize that the preparations described may be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non- exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.
In the following examples and preparations, "DMF" means di-methyl formamide, "Me" means methyl, "TEA" means tri-ethyl amine, "i-PrOH" means isopropyl alcohol, "HATU" means 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium phosphorus pentafluoride, "DMSO" means di-methyl sulfoxide, "EtOAc" means ethyl acetate, "Boc" means t-butyloxycarbonyl, "DCM" means di-chloro methane, "DME" means di-methyl ether, "MeOH" means methanol, "THF" means tetrahydrofuran, "DIEA" means diisopropyl ethylamine, "HOAc" means acetic acid, "NaOAc" means sodium acetate, "DMA" means dimethyl amide, "MTBE" means methyl tert-butyl ether, and "TFA" means tri-fluoro acetic acid.
General Procedure G2
Figure imgf000034_0001
P = H, CH3, CH2OCH3
R3, R4, R5, R6 = H, OH, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles. R1, R2 = substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles. Amine (1.3 molar equivalent) is added to a solution of acid (0.17 mmol), DIEA (5 molar equivalent), and HATU (1.1 molar equivalent) in 3 mL of DMF under a nitrogen atmosphere. The reaction is allowed to stir at room temperature for 12 hours. Saturated NaHCO3 is added to the reaction mixture to quench the reaction. EtOAc is then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 is filtered off and the filtrated is evaporated to give a brown oil residue. The residue is purified by silica gel chromatography (eluting with EtOAc and hexanes) to give the desired amide product. General Procedure G8
Figure imgf000035_0001
R = H, substituted and unsubstituted alkyl, alkene, alkynβ, aryl, hβteroaryl, fused heterocycles. General Procedure G8b
Figure imgf000035_0002
R = H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles. X= halogen, lower alkyl, substituted alkyl, trifluoromethyl
General Procedure G10
Figure imgf000035_0003
R1 , R2 = H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles. Geπeral Procedure G12
Figure imgf000036_0001
R = H, substituted and unsubstituted alkyl, alkeπe, alkyne, aryl, heteroaryl, fused heterocycles.
General Procedure G13
Chiral chromatography to separate two enantiomers. This separation was carried out using standard methods known to those skilled in the art, using the following chiral chromatography conditions: Chiralcel OJ-H 4.6x250 mm 5μ column; 13% or 40% MeOH @ 120bar or 140 bar, 2.5 mL/min.
General Procedure G14a
Figure imgf000036_0002
P= Me, CH2OCH3
R1, R2 = H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles. General Procedure G14d
Figure imgf000037_0001
P= Me, CH2OCH3
R = H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles.
X=CH3, Et, isopropyl, vinyl
General Procedure G15
Figure imgf000037_0002
R1, R2 = H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles. X= Cl, Br, cyclopropyl, ethyl, vinyl General Procedure G16
Figure imgf000038_0001
P= Me, CH2OCH3
R1 , R2 = H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocyclθs. X= Cl, Br, cyclopropyl, ethyl, vinyl
General Procedure G17
Figure imgf000038_0002
R1 , R2 = H, substituted and unsubstituted alkyl, alkene, alkyne, aryl, heteroaryl, fused heterocycles. X= Cl, Br, cyclopropyl, ethyl, vinyl
General Procedure G17a
Figure imgf000038_0003
Genβral Procedure G18
Figure imgf000039_0001
P= Me, CH2OCH3
R= substituted and unsubstituted alkyl
R = H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocycles. X= Cl, Br, cyclopropyl, ethyl, vinyl
General Procedure G19a (reductive amination)
Figure imgf000039_0002
NaBH4, iPrOH
Figure imgf000039_0003
General Procedure G19b (reductive amination)
Figure imgf000040_0001
, iPrOH
Figure imgf000040_0002
Figure imgf000040_0003
10
General Procedure G20a
Figure imgf000040_0004
R = H, substituted and uπsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocydβs.
X= Cl, Br, cyclopropyl, ethyl, vinyl General Procedure G20b
Figure imgf000041_0001
R1, R2 = H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocydβs.
X= Cl, Br, cyclopropyl, ethyl, vinyl
General Procedure G20c
Figure imgf000041_0002
R1, R2 = H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocycles.
X= Cl, Br, cyclopropyl, ethyl, vinyl General Procedure G21
Figure imgf000042_0001
R1, R2 = H, substituted and unsubstituted alkyl, alkoxy, alkene, alkyne, substituted and unsubstituted aryl, heteroaryl, fused heterocycles. X= Cl, Br, cyclopropyt, ethyl, vinyl
Examples
The examples below are intended to illustrate particular embodiments of the present invention and are not meant to limit the scope of the invention in any way. Examples 1 to 31 provide detailed synthetic steps for preparing several specific compounds of the present invention. Table 1 shows additional compounds that were prepared as Examples 32 to 279 according to the general reaction schemes as described herein. Examples 280 and 281 describe the biochemical and cellular assays used to assess the potency of the compounds shown in Examples 1 to 279. Table 3 shows the biochemical and celluar assay values for compounds prepared as Example 1 to 279.
The compounds shown in the examples below may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( ), a solid wedge ( """^- ), or a dotted wedge
( "" ). In the compounds shown in the examples below, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that the compound was prepared as a racemic mixture, or that the compound was prepared as a pure enantiomer but the absolute stereochemistry was not determined. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that the compound was prepared as a stereoisomer where the absolute stereochemistry was determined. In the compound shown in Example 61, the "T" indicates tritium.
Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, and used without further purification, unless indicated otherwise.
1H-NMR spectra were recorded on a Bruker instrument operating at 400 or 500 MHz. NMR spectra were obtained as DMSOd6 or CDCI3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or DMSO-d6 (2.50 ppm and 39.52 ppm). Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, when given, are reported in Hertz.
Example 1 : 4-chloro-6-{[2-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)pyrrolidin-1- yl]carbonyl}benzene-1 ,3-diol
Figure imgf000043_0001
The above compound was made using General Procedure G2 as described below. Step j lsoindoline (332 mg, 2.8 mmol) was added to a solution of N-(tert-butoxycarbonyl)-
D-Proline (500 mg, 2.3 mmole), DIEA (2 ml, 10 mmol), and HATU (972 mg, 2.56 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. Saturated NaHCO3 (30 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 100 mL) was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a brown oil residue. The residue was purified by silica gel chromatography (gradient elution 40→50% EtOAc in hexane) to give the desired product (700 mg, quantitative yield).
Figure imgf000043_0002
Step 2
Hydrogen chloride (6 mL, 24 mmol, 4 M in dioxane) was added to a solution of the compound obtained from Step 1 (700 mg, 2.32 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 12 hours to obtain a dark clear solution. The reaction was monitored by LC/M. The solvent was then evaporated to obtain a grey solid residue as the desired product. This compound was used for the next step reaction without further purification.
Figure imgf000044_0001
Step 3
The compound obtained in Step 2 (100 mg, 0.46 mmol) was added to a solution of compound B in general procedure G10 (141 mg, 0.51 mmole), 4-methylmorpholine (700 mg, 7 mmol), N-β-dimethylaminopropylJ-N'-ethylcarbodiimide hydrochloride (177 mg, 0.93 mmol), and 1-hydroxy benzotriazole (125 mg, 0.93 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (30 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 100 mL) was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a brown oil residue. The residue was purified by silica gel chromatography (gradient elution 40%→50% EtOAc in hexanes) to give the desired product (146.5 mg, 66.7% yield).
Figure imgf000044_0002
Step 4
Hydrogen chloride (1 mL, 4 mmol) was added to a solution of the compound obtained in Step 3 (73 mg, 0.15 mmol) in DCM (5 mL) at room temperature. After stirring at room temperature for 12 hours, the solvent was evaporated and DCM was added to obtain a light grey solid. The solid was collected and rinsed with DCM to give the desired final product (52 mg, 87% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.75 - 2.05 (m, 2 H) 2.18 - 2.34 (m, 2 H) 4.67 (d, J=20.72 Hz, 4 H) 4.92 (d, J=13.89 Hz, 1 H) 5.11 (d, J=13.89 Hz, 1 H) 6.57 (s, 1 H) 7.16 (s, 1 H) 7.21 - 7.48 (m, 5 H) 10.34 - 10.98 (m, 1 H).
Anal. Calcd for C20H19CIN2O4-I HCM H2O: C, 54.43; H, 5.02; N, 6.35. Found: C, 54.02; H, 4.76; N, 6.62. Example 2: 4-chloro-6-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}benzene- 1,3-diol
Figure imgf000045_0001
The above compound was prepared using General Procedure G2 as described below.
DIEA (0.8 mL, 4.3 mmol) was added to a solution of compound C in General Procedure G10 (120 mg, 0.43 mmol) and HATU (182 mg, 0.48 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 20 minutes (after a few minutes, solution turned from light yellow clear to light brown yellow clear). (R)-2-Methoxymethyl-pyrrolidine (MN-1634, 100 mg, 0.87 mmol in 15 mL of DMF) was added to the above reaction mixture via a syringe. The mixture was stirred at room temperature for 12hours. Saturated NaHCO3 (20 mL) was added to the mixture to stir. EtOAc (2X50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a brown yellow oil. Hydrogen chloride (1 mL, 4 mmol) was then added to a solution of the above compound (in 5 mL of DCM and 5 mL of methanol). The reaction was stirred at room temperature for 12hours. The solvent was then evaporated to obtain a brown solid residue. The mixture was then neutralized with saturated NaHCO3 (10 mL). EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a brown yellow oil. The residue was purified by silica gel chromatography (gradient elution 50→60% EtOAc in hexanes) to give the desired product as a white solid (92 mg, 74% yield over 2 steps).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (sc, J=8.10, 6.00, 1.20, 0.67, -12.30 Hz, 1 H) 1.68 (sc, J=12.60, 8.10, 7.75, 1.11, 0.70 Hz, 1 H) 2.06 (sc, J=8.10, 6.00, 1.20, 1.00, -12.30 Hz, 1 H) 2.06 (sc, J=12.60, 8.10, 7.75, 2.00, 1.11, 0.70 Hz, 1 H) 2.88 (sc, J=- 0.97 Hz, 3 H) 3.68 (sc, J=9.60, 8.60, 1.50, 1.20, 0.70, -0.97 Hz, 1 H) 3.70 (sc, J=10.00, 6.00, 1.50, 1.17, 1.11 Hz, 1 H) 3.79 (sc, J=9.60, 3.60, 1.50, 1.20, 0.70, -0.97 Hz, 1 H) 3.80 (sc, J=10.00, 6.00, 2.00, 1.50, 1.17, 1.11 Hz, 1 H) 4.59 (sc, J=8.60, 7.75, 3.60, 1.17, 1.00, 0.67 Hz, 1 H) 6.42 (sc, J=LOO Hz, 1 H) 7.30 (sc, J=LOO Hz, 1 H). Anal. Calcd for C13H16CINO4 «0.25H2O: C, 53.80; H, 5.73; N, 4.83. Found: C,
53.86; H, 5.72; N, 4.66. Example 3: 4-{[2-(4-bromophenyl)pyrrolidin-1 -yl]carbonyl}-6-chlorobenzenβ-1 ,3-diol
Figure imgf000046_0001
The above compound was made using General Procedure G8b as described below. DIEΞA (0.89 mL, 5.1mmol) was added to a solution of compound C in G10, (281 mg, 1 mmol) and HATU (425 mg, 1.1 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 20 minutes. After a few minutes, the solution turned from light yellow clear to light brown yellow clear. 2-(4-bromophenyl)pyrrolidine (230 mg, 1 mmol) was added to the above reaction mixture via a syringe. The mixture was stirred at room temperature for 12hours. Saturated NaHCO3 (20 mL) was added to the mixture to stir.
EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a brown oil (473 mg, 98% yield). This compound was used for the next step reaction without further purification.
Hydrogen chloride (2 mL, 8 mmol, 4M in dioxane) was added to a solution of the compound obtained above (145 mg, 0.3 mmol, in 5 mL of DCM and 5 mL of methanol).
The reaction was stirred at room temperature for 12 hours. The solvent was evaporated to obtain a brown solid residue. The mixture was neutralized with saturated NaHCO3 (10 mL). EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to provide a brown yellow oil. The residue was purified by silica gel chromatography (gradient elution 30→40% EtOAc in hexanes) to give the desired product as a white solid (100 mg, quantitative yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (d, J=6.06 Hz, 4 H) 3.59 (d, J=97.51 Hz, 2 H) 5.08 (s, 1 H) 6.36 - 6.69 (m, 1 H) 6.79 - 7.73 (m, 5 H) 10.47 (s, 2 H).
Anal. Calcd for C17H15CIBrNO3O-IH2O: C, 51.24; H, 3.84; N, 3.52. Found: C, 51.03; H, 3.96; N, 3.85. Example 4: 2-(5-chloro-2,4-dihydroxybenzoyl)-N,N-dimethylisoindoline-1- carboxamide
Figure imgf000047_0001
The above compound was made using General Procedure G8b as described below.
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole (68 mg, 0.32 mmol) was added to a solution of the compound obtained in Example 3 (130 mg, 0.32 mmol) in 6 mL of DME. The mixture was perged with N2 several times. Tetrakis (Triphenylphosphine) palladium (40 mg, 0.03 mmol) was added then Na2CO3 (0.5 mL, 2M) was added to the mixture. The mixture was heated and stirred at 85°C for 12hours.
H2O (20 mL) was added to the reaction mixture. EtOAc (2x 50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to give a brown yellow oil. The residue was purified by silica gel chromatography (gradient elution 40→50% EtOAc in hexanes) to give the desired product as a white solid (7 mg, 5% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 2.86 (s, 3 H) 3.38 (s, 3 H) 4.56 - 4.96 (m, 2 H) 6.24 (s, 1 H) 6.60 (s, 1 H) 7.06 - 7.73 (m, 5 H) 10.12 - 10.63 (m, 2 H). Example 5: 4-chloro-6-({2-[4-(1 H-pyrazol-4-yl)phenyl]pyrrolidin-1- yl}carboπyl)benzene-1 ,3-diol
Figure imgf000047_0002
The above compound was made using General Procedure G8b as described below.
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (287 mg, 0.98 mmol) was added to a solution of the compound obtained in Example 3 (473 mg, 0.98 mmol) in 6 mL of DME. The mixture was purged with N2 several times. Tetrakis (Triphenylphosphine) palladium (113 mg, 0.1 mmol) was added then Na2CO3 (1.5 mL, 2M) was added to the mixture. The mixture was heated and stirred at 85 0C for 12 hours. H2O (20 mL) was added to the reaction mixture. EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to give a brown yellow oil (504 mg, 90.3% yield).
Hydrogen chloride (1.75 mL, 7 mmol, 4M in dioxane) was added to a solution of the compound obtained above (267 mg, 0.47 mmol) in DCM/MeOH (10 mL, v:v; 1:1). The reaction was stirred at room temperature for 12 hours. The solvent was evaporated and then H2O (10 mL) was added. Saturated NaHCO3(aq) was then added to neutralize the aqueous solution. EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to provide a light brown yellow oil residue. The residue was purified by silica gel chromatography (gradient elution 60→70% EtOAc in hexanes) to give the desired product as a white solid (35 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 - 1.87 (m, 2 H) 2.21 - 2.39 (m, 1 H)
3.45 - 3.81 (m, 2 H) 4.11 (d, J=4.55 Hz, 1 H) 5.12 (s, 1 H) 6.51 - 7.08 (m, 2 H) 7.26 (d, J=28.29 Hz, 2 H) 7.52 (d, J=6.57 Hz1 2 H) 8.00 (s, 2 H) 10.49 (s, 2 H).
Anal. Calcd for C20H18CIN3O3O-SH2O: C, 61.15; H, 4.88; N, 10.70. Found: C, 60.90; H, 4.66; N, 10.36. Example 6: 4-chloro-6-{[1-(pyrrolidin-1-ylcarbonyl)-1,3-dihydro-2H-isoindol-2- yl]carbonyl}benzene-1 ,3-diol
Figure imgf000048_0001
The above compound was made using General Procedure G12 as described below. Step i
Pyrrolidine (55 mg, 0.7 mmol) was added to a solution of Boc(R,S)-1,3-dihydro-
2H-isoindole carboxylic acid (150 mg, 0.55 mmole), diisopropylethyl amine (0.5 ml, 2.8 mmol), and HATU (240 mg, 0.6 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. Saturated NaHCO3 (15 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 50 mL) was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a brown oil residue. This compound (tert-butyl 1-(pyrrolidine-1-carbonyl)isoindoline-2-carboxylate) was used for the next step reaction without further purification.
Figure imgf000049_0001
Step 2
Hydrogen chloride (3 ml_, 12 mmol; 4 M in dioxane) was added to a solution of the compound prepared in Step 1 (0.55 mmole) in DCM (5 mL) at room temperature. The reaction was heated and stirred at room temperature for 12 hours. The reaction mixture was evaporated to give an oil residue. The residue (isoindolin-1-yl(pyrrolidin-1- yl)methanone) was used for the next step reaction without further purification.
Figure imgf000049_0002
Step 3
The compound prepared in Step 2 (0.55 mmol) was added to a solution of compound B in G10 (166 mg, 0.6 mmol), 4-methylmorpholine (1 ml, 9 mmol), N-(3- dimethylarninopropyl)-N'-ethylcarbodiimide hydrochloride (250 mg, 1.2 mmol), and 1- hydroxy benzotriazole (170 mg, 1.2 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 100 mL) was then added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to give a brown oil residue. The residue was purified by silica gel chromatography (gradient elution 80→85% EtOAc in hexanes) to give the desired product as a white solid (153 mg, 58.5% yield) as the desired product.
Hydrogen chloride (1.5 mL, 6 mmol, 4M in dioxane) was added to a solution of this compound (153 mg, 0.32 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 12 hours. The solvent was then evaporated to obtain a brown solid residue. The mixture was then neutralized with saturated NaHCO3 (10 mL). EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a grey solid residue as the desired final product (110 mg, 0.28 mmol, 88.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 - 2.12 (m, 4 H) 2.76 - 3.26 (m, 2 H) 3.48 - 4.09 (m, 2 H) 4.66 - 4.96 (m, 2 H) 5.75 (d, J=6.06 Hz, 1 H) 6.57 (s, 1 H) 6.87 (s, 1 H) 7.16 - 7.71 (m, 4 H) 10.49 (s, 2 H)
Anal. Calcd for C20H19CIN2O4-CSH2O: C, 60.69; H, 5.09; N, 7.08. Found: C, 61.00; H, 4.92; N, 6.85.
Example 7: 4-chloro-6-[(2-{4-[(33-difluoroazetidin-1-yl)carbonyl]-2- methylphβnyl}pyrrolidin-1 -yl)carbonyl]benzene-13-diol
Figure imgf000050_0001
The above compound was made using General Procedure G14a as described below. Step 1
Lithium hydroxide hydrate (6 g, 142.3 mmol) was added to a solution of compound H1 (3.4 g, 7.1 mmol) in H2O (20 mL) and MeOH (15 ml_). The reaction mixture was heated to 4O0C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2 x 200 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white solid (3.03 g, 91.1% yield).
1H NMR (400 MHz, DMSO-D6) δ ppm 1.59 - 1.68 (m, 2 H) 1.77 - 1.86 (m, 2 H) 2.39 (s, 3 H) 3.31 - 3.38 (m, 6 H) 3.40 (s, 2 H) 3.43 (s, 2 H) 3.53 - 3.66 (m, 2 H) 5.26 (dd, .7=7.71 , 4.67 Hz, 1 H) 5.32 (s, 3 H) 7.34 (s, 1 H) 7.39 (d, J=7.83 Hz, 1 H) 7.74 (s, 2 H) 7.76 (s, 1 H) 12.80 (s, 1 H).
Figure imgf000050_0002
3,3'-difluoroazetidine hydrochloride (44 mg, 0.34 mmol) was added to a solution of the compound prepared above (78 mg, 0.17 mmole), 4-methylmorpholine (0.37 ml, 3.4 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (64.5 mg, 0.34 mmol), and 1-hydroxy benzotriazole (45 mg, 0.34 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (10 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 50 mL) was then added to extract the aqueous solution. The combined organic layer was dried, filtered, and evaporated to give a brown oil residue. This oil residue was used for the next step reaction without further purification. Hydrogen chloride (0.8 mL, 3.2 mmol; 4 M in dioxane) was added to a solution of the intermediate compound prepared above (0.17 mmole) in MeOH (5 mL). The reaction was stirred at room temperature for 12 hours. The reaction mixture neutralized with saturated NaHCO3 (aq) and then extracted with EtOAc (2 x 50 mL). The combined organic layers were dried, filtered, and evaporated to give a white solid (43 mg, 57% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 - 1.71 (m, 1 H) 1.75 - 2.12 (m, 3 H) 2.40 (s, 3 H) 3.45 - 3.89 (m, 2 H) 4.62 (d, J=115.45 Hz, 4 H) 5.13 - 5.44 (m, 1 H) 6.49 - 6.71 (m, 1 H) 6.96 - 7.69 (m, 4 H) 10.21 - 10.71 (m, 2 H)
Anal. Calcd for C22H21CIF2N2O4 «0.25H2O: C, 58.03; H, 4.76; N, 6.15. Found: C, 57.79; H, 4.75; N, 6.01.
Example 8: 4-chloro-6-[(2-{4-[(33-dif1uoropyrrolidin-1 -yl)carbonyl]-2- methylphenyl}pyrrolidin-1-yl)carbonyl]benzene-13-diol
Figure imgf000051_0001
The above compound was prepared using General Procedure G 14a as described below.
3,3-Difluoro-pyrrolidine (59 mg, 0.41 mmol) was added to a solution of compound J1 in general procedure G14a (191 mg, 0.41 mmole), 4-methylmorpholine (0.9 ml, 8.2 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (158 mg, 0.82 mmol), and 1-hydroxy benzotriazole (111 mg, 0.82 mmol) in 10 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (IO mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 100 mL) was then added to extract the aqueous solution. The combined organic layer was dried, filtered, and evaporated to give a brown oil residue. This oil residue is used for the next step reaction without further purification. Hydrogen chloride (2 mL, 8 mmol; 4 M in dioxane) was added to a solution of the intermediate prepared above (0.41 mmole) in MeOH (5 mL). The reaction was stirred at room temperature for 12 hours. Jhe reaction mixture neutralized with saturated NaHCO3 (aq) and then extracted with EtOAc (2 x 100 mL). The combined organic layers were dried, filtered, and evaporated to give white a solid (73 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 - 1.88 (m, 2 H) 1.89 - 2.15 (m, 2 H) 2.39 (s, 3 H) 3.43 - 3.84 (m, 4 H) 3.83 - 3.96 (m, 2 H) 5.06 - 5.38 (m, 1 H) 6.51 - 6.61 (m, 1 H) 7.15 - 7.50 (m, J=30.06, 21.98 Hz, 4 H) 10.25 (s, 1 H) 10.50 (s, 1 H).
Anal. Calcd for C23H23CIF2N2O4-CSH2O: C, 58.29; H, 5.10; N, 5.91. Found: C, 58.48; H, 4.99; N, 5.87.
Example 9: 4-chloro-6-[(2-{3-[(33-difluoropyrrolidin-1-yl)carbonyl]-2- mβthylphenyl}pyrrolidin-1 -yl)carbonyl]benzene-13-diol
Figure imgf000052_0001
The above compound was prepared using General Procedure G 14b as follows. Steo i
Lithium hydroxide hydrate (6 g, 142.3 mmol) was added to a solution of compound H1 (3.4 g, 7.1 mmol) in H2O (20 mL) and MeOH (15 mL). The reaction mixture was heated to 400C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2 x 200 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white solid (3.03 g, 91.1%yield).
1H NMR (400 MHz, DMSO-D6) δ ppm 1.56 - 1.70 (m, 1 H) 1.76 - 1.86 (m, 2 H) 2.32 - 2.44 (m, 1 H) 3.39 (s, 3 H) 3.43 (s, 3 H) 3.76 (t, J=7.07 Hz, 2 H) 5.11 - 5.24 (m, 1 H) 5.27 - 5.42 (m, 4 H) 7.06 (s, 1 H) 7.26 (t, ./=7.71 Hz, 1 H) 7.34 (s, 1 H) 7.46 (d, J=7.83 Hz, 1 H) 7.52 (d, J=7.58 Hz, 1 H) 12.86 (s, 1 H).
Anal. Calcd for C23H26CINO7: C, 59.55; H, 5.65; N, 3.02. Found: C, 59.18; H, 5.72; N, 3.16.
Figure imgf000052_0002
Step 2
3,3'-difluoroazetidine hydrochloride (112 mg, 0.86 mmol) was added to a solution of the intermediate prepared above (200 mg, 0.43 mmole), 4-methylmorpholine (0.95 ml, 8.6 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol), and 1-hydroxy benzotriazole (117 mg, 0.86 mmol) in 6 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (10 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 100 mL) was then added to extract the aqueous solution. The combined organic layer was dried, filtered, and evaporated to give a brown oil residue. This oil residue is used for the next step reaction without further purification. Hydrogen chloride (2 mL, 8.6 mmol; 4 M in dioxane) was added to a solution of the intermediate prepared above (0.43 mmole) in MeOH (5 mL). The reaction was stirred at room temperature for 12 hours. The reaction mixture was neutralized with saturated NaHCO3 (aq) and then extracted with EtOAc (2 x 100 mL). The combined organic layers were dried, filtered, and evaporated to give a white solid (43 mg, 57% yield). 1H NMR (400 MHz, DMSO-cfe) δ ppm 1.49 - 1.90 (m, 3 H) 1.93 - 2.01 (m, 1 H)
2.32 (s, 3 H) 3.45 - 3.85 (m, 2 H) 4.41 - 4.62 (m, J=M.87 Hz, 4 H) 5.26 - 5.38 (m, 1 H) 6.36 - 6.60 (m, 1 H) 7.11 - 7.28 (m, .7=5.56 Hz, 3 H) 7.36 - 7.53 (m, 1 H) 10.25 (s, 1 H) 10.47 (s, 1 H)
Anal. Calcd for C22H21CIF2N2O4O.25H2O: C, 58.03; H, 4.76; N, 6.15. Found: C1 57.68; H, 4.84; N, 5.96.
Example 10: 4-chloro-6-[(2-{3-[(3,3-dif1uoropyrrolidin-1 -yl)carbonyl]-2-methylphenyl} pyrrolidin-1 -yl)carbonyl]benzeπe-1 ,3-diol
Figure imgf000053_0001
The above compound was prepared using General Procuedure G14b as follows. To a reaction mixture of 3-{1-[5-chloro-2,4-bis(methoxymethoxy)benzoyl]pyrrolidin-2-yl}-2- methylbenzoic acid (100 mg, 0.22 mmol.) and 3,3-difluoropyrrolidine HCI (62mg, 0.43mmol) in 2.0 ml of DMF was added 4-Methylmorpholine (NMM) (0.24ml, 2.16 mmol.) and following N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (83mg, 0.43mmol) and 1 -hydroxy benzotriazole (58mg, 0.43mmol.). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc (200 ml) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) then concentrated by vacuum to give crude product which was ready to use for the next step of the reaction without further purification.
MOM deprotection: To a reaction solution of crude product from above in 5 mL of DCM and 3 mL of MeOH was added 4M HCI in Dioxane (1.1ml, 4.31 mmol.) dropwise. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated by vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) then concentrated by vacuum. The residue was purified by DT group to afford 69 mg as white solid (69% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (dd, J=11.75, 5.94 Hz, 2 H) 1.77 - 1.98 (m, 2 H) 2.24 (d, J=4.04 Hz, 3 H) 2.33 - 2.46 (m, 2 H) 3.44 - 3.59 (m, 2 H) 3.66 - 3.84 (m, 4 H) 3.93 (t, J=13.01 Hz, 1 H) 6.90 - 7.13 (m, 2 H) 7.16 - 7.28 (m, 2 H) 7.39 (d, J=7.58 Hz, 1 H) 10.20 (s, 1 H) 10.48 (s, 1 H).
Anal. Calc'd for C23H23CIF2N2O4O.66HOAc: C, 57.90; H, 5.12; N, 5.55. Found: C, 57.89; H, 5.02; N, 5.79.
Example 11 : 4-chloro-6-({2-[2-methyl-3-(pyrτolidin-1 -ylcarbonyl)phenyl]pyrrolidin-1 - yl}carbonyl) benzene-1,3-diol
Figure imgf000054_0001
The above compound was prepared using General Procuedure G14b as follows. To a reaction mixture of 3-{1-[5-chloro-2,4-bis(methoxymethoxy)benzoyl]pyrrolidin-2-yl}-2- methylbenzoic acid (100 mg, 0.22 mmol) and pyrrolidine (0.04 mL, 0.43mmol) in 2.0 mL of DMF was added 4-Methylmorpholine (NMM) (0.12mL, 1.08 mmol) and following N-(3- dimethylaminopropylJ-N'-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol) and 1- hydroxy benzotriazole (58 mg, 0.43 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) then concentrated by vacuum to give crude product which was ready to use for the next step of the reaction without further purification.
MOM deprotection: To a reaction solution of crude product from above in 5 mL of DCM and 3 mL of MeOH was added 4M HCI in Dioxane (1.1 mL, 4.31 mmol) dropwise. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated by vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) then concentrated by vacuum. The residue was purified by DT group to afford 78 mg as white solid (84% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (s, 2 H) 1.72 - 1.95 (m, 4 H) 2.22 (s, 3 H) 2.31 - 2.46 (m, 2 H) 2.77 (s, 1 H) 3.02 (s, 2 H) 3.42 - 3.54 (m, 2 H) 3.68 - 3.87 (m, 2 H) 6.91 (d, J=7.33 Hz, 1 H) 7.03 (t, J=6.32 Hz, 1 H) 7.12 - 7.26 (m, 2 H) 7.34 (d, J=7.33 Hz, 1 H) 10.18 (s, 1 H) 10.48 (s, 1 H).
Anal. Calcd for C23H25CIN2O4 «0.60HOAc: C, 62.52; H, 5.94; N, 6.03. Found: C, 62.51; H, 5.79; N, 6.23. Example 12: 4-({2-[3-(azetidin-1 -ylcarbonyl)-2-methylphenyl]pyrrolidin-1 - yl}carbonyl)-6-chlorobenzenβ-1,3-diol
Figure imgf000055_0001
The above compound was prepared using General Procuedure G14b as follows.
To a reaction mixture of 3-{1-[5-chloro-2,4-bis(methoxymethoxy)benzoyl]pyrrolidin-2-yl}-2- methylbenzoic acid (100 mg, 0.22 mmol) and Azetidine HCI (40 mg, 0.43 mmol) in 2.0 mL of DMF was added 4-Methylmorpholine (NMM) (0.24ml, 2.16 mmol) and following N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (83mg, 0.43mmol) and 1- hydroxy benzotriazole (58 mg, 0.43 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) then concentrated by vacuum to give crude product which was ready to use for the next step of the reaction without further purification. MOM deprotection: To a reaction solution of crude product from above in 5 mL of
DCM and 3 mL of MeOH was added 4M HCI in Dioxane (1.1 mL, 4.31 mmol) dropwise. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated by vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) then concentrated by vacuum. The residue was purified by DT group to afford 63 mg as white solid (70% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 - 1.66 (m, 2 H) 1.73 - 2.00 (m, 2 H) 2.12 - 2.25 (m, 2 H) 2.27 - 2.33 (m, 3 H) 2.34 - 2.44 (m, 2 H) 3.69 - 3.92 (m, 2 H) 3.92 - 4.09 (m, 3 H) 6.55 (s, 1 H) 7.03 - 7.12 (m, 1 H) 7.16 (t, J=7.58 Hz, 1 H) 7.22 (s, 1 H) 7.36 (d, J=7.58 Hz, 1 H) 10.19 (s, 1 H) 10.47 (s, 1 H).
Anal. Calcd for C22H23CIN2O4 «0.65HOAc: C, 61.65; H, 5.68; N, 6.17. Found: C, 61.65; H, 5.41; N, 6.45. Example 13: 2-(5-chloro-2,4-dihydroxybenzoyl)-N-ethylisoindolinβ-4-carboxamidβ
Figure imgf000055_0002
The above compound was prepared using General Procedure 15, as described below. Step j
To a solution of 2,3-dimethylbenzoic acid (50.2 g; 0.33 mol) in MeOH (1L) was added dropwise thionyl chloride (62 mL; 0.83 mol, exothermic). The reaction mixture was stirred at reflux overnight and allowed to cool to room temperature. Evaporation of the solvent in vacuo yielded compound 5 (53.3 g; 98%) as a yellow liquid.
1H-NMR (300 MHz, CDCI3): δ 2.34 (s, 3H), 3.45 (s, 3H), 3.90 (s, 3H), 7.15 (t, 1H), 7.28 (d, 1H), 7.62 (d, 1H).
Figure imgf000056_0001
Compound 5 (53.3 g; 0.32 mol) was dissolved in carbon tetrachloride (850 mL), under nitrogen. To the solution was added N-bromosuccinimide (115.5 g; 0.65 mol) and 2,2'-azobis(2-methyl-propionitrile (1.6 g; 0.010 mol). The reaction mixture was stirred at reflux for approximately 2 hours and the colour of this mixture changed from yellow to colorless. It was allowed to cool to room temperature and filtered off. The filtrate was evaporated in vacuo to give compound 6 (98.7 g; 96%) as a yellow liquid.
1H-NMR (300 MHz, CDCI3): δ 3.95 (s, 3H), 4.68 (s, 2H), 5.14 (s, 2H), 7.36 (t, 1H), 7.55 (dd, 1 H), 7.90 (dd, 1 H). GC-MS m/z = 322.
Figure imgf000056_0002
6 Step 3
To a solution of compound 6 (100.7 g 0.31 mol) in THF (1 L) was added benzylamine (34 mL; 0.31 mol), sodium carbonate (65.7 g; 0.62 mol) and tetrabutylammonium iodide (23g; 0.062 mol). The reaction mixture was stirred at room temperature overnight. H2O (750 mL) and EtOAc (250 mL) were added and the layers were separated. The organic layer was washed with H2O (3 x 250 mL), brine (150 mL), dried over Na2SO4 and evaporated in vacuo, which gave crude compound 7 (91.5 g) as an orange/brown solid. Purification was performed by column chromatography (Rf = 0.41; eluens: EtOAc/heptane 1:3; detection with U.V.) to give compound 7 (28.7 g; 35%) as an orange oil. 1H-NMR (300 MHz, CDCI3): δ 3.88 (s, 3H), 3.95 (s, 4H), 4.34 (s, 2H), 7.30 (m, 7H), 7.84 (d, 1H). LC-MS m/z = 268.2 [M+H].
Figure imgf000057_0001
7 Step 4
Compound 7 (28.7 g; 0.11 mol), dissolved in MeOH (500 mL) was added to a mixture of Pd/C-10% (s 7 g) in MeOH (300 mL) and hydrogenated at room temperature at
1 atmosphere for 7 days. The reaction mixture was filtered off over celite and the filtrate was evaporated in vacuo to give compound 8 (19.5 g) as an orange oil. 1H-NMR showed = 80% conversion.
1H-NMR (300 MHz, CDCI3): δ 3.90 (s, 1H), 4.25 (s, 2H), 4.45 (s, 2H), 7.28 (t, 1H), 7.42 (d, 1H), 7.85 (d, 1H). LC-MS m/z = 178.2 [M+H].
Figure imgf000057_0002
8 Step 5
To a solution of compound 8 (7.8 g; 3.5 mmol) in THF (150 mL) was added 5- chloro-2,4-bis(methoxymethoxy)benzoic acid (compound B in General Procedure G 10) (9.8 g; 35 mmol), 1-hydroxybenzotriazole (6.1 g; 46 mmol) and 1-(3-dimethylaminopropyl)- 3-ethyl carbodiimide hydrochloride (9.4 g; 49 mmol). The reaction mixture was stirred at room temperature overnight. EtOAc (150 mL) was added and washed with a saturated aqueous NaHCO3 solution (2 x 120 mL), brine (100 mL), dried over Na2SO4 and evaporated in vacuo to yield crude compound A (15.8 g) as a brown solid. The solid was stirred in diethyl ether for 1 hour and filtered off, dried on air and gave compound A (11.1 g; 73%) as a gray solid. 1H-NMR (300 MHz, CDCI3): complicated, a mixture of rotamers were observed.
LC-MS >99% purity.
Figure imgf000057_0003
Step 6
To a solution of compound A (11.0 g; 0.025 mol) in THF (250 mL) were added MeOH (120 mL), H2O (70 mL) and lithium hydroxide monohydrate (14.8 g; 0.35 mol). The reaction mixture was stirred at 5O0C overnight and the organic solvents of the mixture were evaporated in vacuo. The remaining aqueous layer was acidified to pH 1 with a 1 M HCI solution (aq.) and an oil was obtained. To this mixture was added EtOAc (500 mL) and a solid was precipitated, which was filtered off, yield = 5 g as a brown solid (batch 1). The layers of the filtrated were separated and organic layer was washed with brine (200 mL), dried over Na2SO4 and evaporated in vacuo to yield a dark brown solid (batch 2). This was combined with batch 1 and washed with CH2CI2. The residue was dried overnight on air and gave compound B (10.0 g; 95%) as a white solid.
1H-NMR (300 MHz, DMSO-d6): δ 3.29 (d, 3H), 3.43 (d, 3H), 4.68 (d, 2H), 4.94 (d, 2H), 5.21 (s, 2H), 5.33 (s, 2H), 7.10 (d, 1H), 7.50 (m, 3H), 7.84 (t, 1H). LC-MS >95% purity.
Figure imgf000058_0001
B
Step 7
Hydrogen chloride (2 mL, 4 M in dioxane) was added to a solution of compound B (50 mg, 0.11 mmol) in MeOH (5 mL). The reaction was stirred at room temperature for 12 hours (clear light yellow brown solution). The solvent was evaporated to obtain an oil. Saturated NaHCO3(aq) was then added to neutralize the reaction mixture. EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain an oil, then yophilized to obtain a white solid as the desired product C (24 mg, 60% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 3 H) 4.79 (d, J=25.26 Hz, 2 H) 5.00 (d, J=21.22 Hz, 2 H) 6.60 (d, J=4.29 Hz, 1 H) 7.23 (d, J=2.53 Hz, 1 H) 7.48 (t, J=8.21 Hz, 1 H) 7.63 (dd, J=37.77, 7.20 Hz, 1 H) 7.88 (t, J=7.83 Hz, 1 H) 10.31 (d, J=9.60 Hz, 1 H) 10.43 (s, 1 H). Anal. Calcd for C17Hi4CINO5: C, 58.72; H, 4.06; N, 4.03. Found: C, 58.86; H, 4.17; N, 3.98.
Figure imgf000059_0001
Step 8
Compound B (1.0 g; 2.6 mmol) was dissolved, under nitrogen, in THF (50 mL). 1- Hydroxybenzotriazole (0.46 g; 3.4 mmol), 1-(3-dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (0.70 g; 3.6 mmol) and a 2M solution of ethylamine in THF (1.3 mL; 2.6 mmol) were added. After 4 hours EtOAc (50 mL) was added to this mixture and washed with H2O (20 mL), with a saturated aqueous NaHCO3 solution (2 x 15 mL), brine (15 mL), dried over Na2SO4 and evaporated in vacuo to give crude compound (0.6 g). Purification was performed from CHCI3 and a solid was precipitated. The precipitate was collected to give compound 1a (315 mg, 30% yield) as a pale brown solid.
1H-NMR (300 MHz, DMSO-d6) showed a mixture of rotamers. LC-MS m/z = 405.0 [M+H].
Figure imgf000059_0002
1a
Step 9
Compound 1a (126 mg; 0.31 mol) was suspended in MeOH (15 mL) and acetyl chloride was added, untill a clear solution was obtained (exothermic). The reaction was stirred for 15 minutes, evaporated to dryness and gave the desired final product (88 mg; 79%) as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) d ppm 1.13 (t, J=7.07 Hz, 3 H) 3.14 - 3.25 (rrt, 2 H) 4.63 - 4.82 (m, 2 H) 4.87 - 5.08 (m, 2 H) 6.61 (s, 1 H) 7.00 - 7.29 (m, 1 H) 7.35 - 7.62 (m, 2 H) 7.58 - 7.83 (m, 1 H) 8.48 (t, J=5.56 Hz, 1 H) 9.80 - 10.73 (m, 2 H).
Anal. Calcd for C1βH17CIN2O4 «0.5 CHCI3: C, 52.84; H, 4.19; N, 6.66. Found: C, 52.82; H, 4.24; N, 6.66. Examplβ 14: 4-{[4-(azetidin-1 -ylcarbonyl)-1 ,3-dihydro-2H-isoindol-2-yl]carbonyl}-6- chlorobenzene-1,3-diol
Figure imgf000060_0001
The above compound was prepared using General Procedure G15 as follows. Step i
Compound B (0.50 g; 1.3 mmol) was dissolved, under nitrogen, in DMF (10 mL), N,N-diisopropylethylamine (2 mL, 12 mmol), 1-hydroxybenzotriazole (0.48 g; 3.6 mmol), 1- (3-dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (0.70 g; 3.6 mmol) and azetidine (0.10 mL, 1.4 mmol) were added. The reaction mixture was stirred overnight at room temperature. EtOAc (20 mL) was added, washed with H2O (2 x 15 mL), with a saturated aqueous NaHCO3 solution (2 x 20 mL), brine (15 mL), dried over Na2SO4 and evaporated in vacuo. The aqueous layer was extracted with CH2CI2 (20 mL) and the organic layer was washed with a saturated aqueous NaHCO3 solution (20 mL), dried over Na2SO4 and evaporated in vacuo to give the compound 1b (224 mg, 36%) as a white foam. LC-MS >99% purity.
Figure imgf000060_0002
1b
Step 2
Compound 1b (97 mg; 0.23 mol) was dissolved in CH2CI2 (5 mL) and == 8 drops of TFA were added. The colour of the reaction mixture changed from brown to green. The reaction mixture was stirred for 15 minutes and evaporated in vacuo. The solid was dissolved in warm EtOAc and heptane was added. A precipitate was obtained, which was filtered off and evaporated to dryness under high pressure, to give the desired final product (56 mg; 65%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 - 2.33 (m, 2 H) 3.92 - 4.30 (m, 4 H) 4.66 - 4.94 (m, 4 H) 6.60 (s, 1 H) 7.12 - 7.26 (m, 1 H) 7.31 - 7.62 (m, 3 H) 10.16 - 10.55 (m, 2 H).
Anal. Calcd for C19H17CIN2O4-O^ TFA: C, 58.90; H, 4.38; N, 7.08. Found: C, 58.93; H, 4.76; N, 7.21. Example 15: 4-chloro-6-{[4-(pyrrolidin-1 -ylcarbonyl)-1 ,3-dihydro-2H-isoindol-2- yl]carbonyl}benzene-1 ,3-diol
Figure imgf000061_0001
The above compound was prepared using General Procedure G15 as follows. Step i
Compound B (0.50 g; 1.3 mmol) was dissolved, under nitrogen, in DMF (10 mL), N-methylmorpholine (3 mL, 27 mmol), 1-hydroxybenzotriazole (0.48 g; 3.6 mmol), 1-(3- dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (0.70 g; 3.6 mmol) and pyrrolidine (0.12 mL, 1.4 mmol) were added. The reaction mixture was stirred overnight at room temperature. EtOAc (20 mL) was added, washed with H2O (2 x 20 mL), with a saturated aqueous NaHCO3 solution (2 x 15 mL), brine (15 mL), dried over Na2SO4 and evaporated in vacuo to give crude compound 1c (211 mg). This compound was dissolved in CH2CI2 and filtered off over silica. The silica was washed with a mixture of CH2CI2/MeOH 3% and the filtrate was evaporated in vacuo to give compound 1c (147; 23%yield) as a white foam. LC-MS >95% purity.
Figure imgf000061_0002
1c
Step 2
Compound 1c (97 mg; 0.23 mol) was suspended in MeOH (5 mL) and acetyl chloride was added, untill a clear solution was obtained (exothermic). The reaction was stirred for 10 minutes and evaporated to dryness, to give the desired product (70 mg; 79%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ pprn 1.69 - 2.07 (m, 4 H) 3.27 - 3.45 (m, 4 H) 4.65 - 4.90 (m, 4 H) 6.60 (s, 1 H) 7.19 (d, J=23.24 Hz1 1 H) 7.37 (d, J=10.86 Hz, 3 H) 10.13 - 10.61 (m, 2 H).
Anal. Calcd for C20H19CIN2O4*0.5 HCIO.5 H2O: C, 56,78; H, 5.12; N1 6.62. Found: C, 56.50; H, 4.84; N, 6.64. Example 16: 2-(5-chloro-2,4-dihydroxybenzoyl)-N,N-diethylisoindoline-4- carboxamidβ
Figure imgf000062_0001
The compound above was prepared using General Procedure G15 as follows.
Step j
Compound B (0.50 g; 1.3 mmol) was dissolved, under nitrogen, in DMF (10 mL),
N-methylmorpholine (3 mL, 27 mmol), 1-hydroxybenzotriazole (0.48 g; 3.6 mmol), 1-(3- dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (0.70 g; 3.6 mmol) and diethylamine (0.15 mL, 1.4 mmol) were added. The reaction mixture was stirred at room temperature for 6 days and EtOAc (20 mL) was added, washed with H2O (2 x 20 mL), with a saturated aqueous NaHCO3 solution (2 x 20 mL), brine (15 mL), dried over Na2SO4 and evaporated in vacuo to give crude compound 1d (268 mg). Purification was performed by column chromatography (twice; Rf = 0.48; eluens: CH2CI2/Me0H 3%; detection with U.V.) to give compound 1d (61 mg; 9%) as a white foam. LC-MS >93% purity.
Figure imgf000062_0002
1d
Step 2
Compound 1d (61 mg; 0.14 mol) was dissolved in MeOH (5 mL) and acetyl chloride was added, untill a clear solution was obtained (exothermic). The reaction was stirred for 15 minutes and evaporated to dryness, which gave crude product (61 mg) as a brown solid. This solid was dissolved in warm EtOAc and heptane was added. A precipitate was obtained, which was filtered off and evaporated to dryness under high pressure, to give the desired final product (43 mg; 79%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 - 1.08 (m, 3 H) 1.11 - 1.38 (m, 3 H)
3.06 - 3.23 (m, 2 H) 3.42 - 3.53 (m, 2 H) 4.64 (d, J=18.19 Hz, 2 H) 4.78 (d, J=27.28 Hz, 2 H) 6.59 (s, 1 H) 7.16 - 7.49 (m, 4 H) 10.18 - 10.33 (m, 1 H) 10.44 (s, 1 H).
Anal. Calcd for C2oH21CIN204 «0.75 HCI-0.25 H2O: C, 57.10;" H, 5.33; N, 6.66. Found: C, 56.97; H, 5.17; N, 6.62. Examplβ 17: N-allyl-2-(5-chloro-2,4-dihydroxybenzoyl)isoindoline-4-carboxamide
Figure imgf000063_0001
The compound above was prepared using General Procedure G15 as follows.
Stej
Compound B (0.50 g; 1.3 mmol) was dissolved, under nitrogen, in DMF (10 mL). N,N-diisopropylethylamine (2 mL, 12 mmol), 1-hydroxybenzotriazole (0.46 g; 3.4 mmol), 1- (3-dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (0.70 g; 3.6 mmol) and allylamine (0.11 mL, 1.4 mmol) were added. The reaction mixture was stirred overnight at room temperature. EtOAc (20 mL) was added, washed with H2O (2x15 mL), with a saturated aqueous NaHCO3 solution (2x15 mL) and brine (15 mL). The aqueous layer was extracted with CH2CI2 (15 mL) and the organic layer was washed with a saturated aqueous NaHCO3 solution (2x20 mL). The EtOAc layer was combined with the CH2CI2 layer, dried over Na2SO4 and evaporated in vacuo to yield crude compound 1e (258 mg) as a brown solid. This solid was dissolved in CH2CI2 and filtered off over silica. The silica was washed with a mixture of CH2CI2/Me0H 3% and the filtrate was evaporated in vacuo to give compound 1β (208; 38%) as a pale brown solid. LC-MS >95% purity.
Figure imgf000063_0002
Step 2
Compound 1e (211 mg; 0.57 mol) was dissolved in CH2CI2 (15 mL) and TFA (0.5 mL; 6.6 mmol) was added. The colour of the reaction mixture changed from orange to yellow. The reaction mixture was stirred overnight at room temperature and evaporated in vacuo, to give crude product as a pale brown solid. Purification was performed by column chromatography (eluens: EtOAc/heptane 3: 1 , detection with KMnO4) to give the desired product (56 mg; 65%) as a white solid.
1H-NMR (300 MHz, DMSO-d6): δ 3.85 (m, 2H), 4.85 (d, 2H), 5.05 (d, 1H), 5.21 (m, 2H), 6.66 (s, 1H), 7.25 (d, 1H), 7.54 (m, 2H), 7.78 (d, 1H), 8.74 (t, 1H), 10.35 (m, 2H).
Anal. Calcd for C19H17CIN2O4O.75 H2O: C, 59.07; H, 4.83; N, 7.25. Found: C, 59.24; H, 5.05; N, 6.47. Example 18: methyl 2-(5-chloro-2,4-dihydroxybenzoyl)isoindoline-1-carboxylate
Figure imgf000064_0001
The compound above was prepared using General Procedure G16 as follows. Step j
Methyliodide (350 mg, 2.2 mmol) was added to a solution of (R,S)-Boc-1,3- dihydro-2H-isoindole carboxylic acid (500 mg, 1.9 mmol) and potassium carbonate (830 mg, 6 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 12 hours. H2O (50 mL) was added to the reaction mixture and EtOAc was added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give an oil residue. The residue was purified by silica gel chromatography (gradient elution 20→30% EtOAc in hexanes) to give the desired intermediate product as a colorless oil (533 mg, quantitative yield).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.53 (s, 9 H) 3.77 (s, 3 H) 4.64 - 4.99 (m, 2 H) 5.53 (d, J=2.53 Hz, 1 H) 7.29 - 7.51 (m, 4 H).
Figure imgf000064_0002
Hydrogen chloride (8 mL, 32 mmol, 4M in dioxane) was added to a solution of the compound from Step 1 (532 mg, 1.9 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 12 hours. The reaction mixture was evaporated to give an oil residue. The residue was used for the next step reaction without further purification.
Figure imgf000064_0003
The compound from Step 2 (1.9 mmol) was added to a solution of 5-chloro-2,4- bis(methoxymethoxy)benzoic acid (compound B in General Procedure G10) (536 mg, 1.9 mmol), 4-methylmorpholine (3.4 mL, 30 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (770 mg, 4 mmol), and 1-hydroxy benzotriazole (550 mg, 4 mmol) in 15 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 150 mL) was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a brown oil residue. The residue was purified by silica gel chromatography (gradient elution 40→45% EtOAc in hexanes) to give the desired product as a white solid (532.3 mg, 64.2% yield).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.45 (s, 3 H) 3.54 (s, 3 H) 3.80 (s, 3 H) 4.66 (d, J=13.90 Hz, 1 H) 4.85 (dd, ./=14.15, 1.77 Hz, 1 H) 5.15 - 5.19 (m, 2 H) 5.27 (s, 2 H) 5.86 (d, J=2.02 Hz, 1 H) 7.06 (s, 1 H) 7.17 (dd, J=5.18, 3.41 Hz, 1 H) 7.29 - 7.35 (m, 2 H) 7.40 (s, 1 H) 7.48 (dd, J=5.18, 3.66 Hz, 1 H).
Figure imgf000065_0001
Step 4
Hydrogen chloride (0.4 ml_, 4 M in dioxane) was added to a solution of the compound from Step 3 (46 mg, 0.1 mmol) in methanol (5 mL). The reaction was stirred at room temperature for 12 hours under N2. The solvent was evaporated and the mixture was neutralized with saturated
NaHCO3(aq) and then EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, concentrated, and lyophilized to give a white powder as the desired final product (35 mg, 92% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 3 H) 4.79 (d, J=25.26 Hz, 2 H) 5.00 (d, J=21.22 Hz, 2 H) 6.60 (d, J=4.29 Hz, 1 H) 7.23 (d, J=2.53 Hz, 1 H) 7.48 (t, J=8.21 Hz, 1 H) 7.63 (dd, J=37.77, 7.20 Hz, 1 H) 7.88 (t, J=7.83 Hz, 1 H) 10.31 (d, J=9.60 Hz, 1 H) 10.43 (s, 1 H).
Anal. Calcd for C17H14CINO5 «0.25 H2O: C, 57.97; H, 4.15; N, 3.98. Found: C, 58.06; H, 4.17; N, 4.00. Example 19: 2-(5-chloro-2,4-dihydroxybenzoyl)-N-mβthylisoindolinβ-1-carboxamide
Figure imgf000065_0002
The above compound was prepared using General Procedure G16 as follows. Step i
Lithium hydroxide hydrate (720 mg, 17 mmol) was added to a solution of the compound from Step 3 in Example 18 (532 mg, 1.2 mmol) in H2O (3 mL) and MeOH (5 mL). The reaction mixture was heated to 400C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2x150 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white foam (516 mg, quantitative yield).
Figure imgf000066_0001
Step 2
Methylamine (110 mg, 3.56 mmol, 1.0 mL, 2 M in THF) was added to a solution of compound D in general procedure G16 (150 mg, 0.36 mmol), diisopropylethyl amine (0.3 ml, 1.8 mmol), and HATU (135 mg, 0.36 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (20 mL) was added to the reaction mixture to quench the reaction. EtOAc (2x100 mL) was then added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to give a brown oil residue. The residue was purified by silica gel chromatography (gradient elution 40→50% EtOAc in hexanes) to give the desired final product (66 mg, 54% yield over two steps).
1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (d, J=4.55 Hz, 3 H) 4.62 - 4.93 (m, 2 H) 5.56 (s, 1 H) 6.47 - 6.67 (m, 1 H) 7.12 - 7.49 (m, 5 H) 7.92 - 8.17 (m, 1 H) 10.32 - 10.65 (m, 2 H).
Anal. Calcd for C17H15CIN2O4-OJS H2O: C, 56.67; H, 4.62; N, 7.78. Found: C, 56.61; H, 4.37; N, 7.68.
Example 20: 2-(5-chloro-2,4-dihydroxybenzoyl)-N,N-dimethylisoindoline-1- carboxamide
Figure imgf000066_0002
The above compound was prepared using General Procedure G16 as follows. Dimethylamine (80 mg, 1.8 mmol, 2 M in THF) was added to a solution of the compound from Step 1 in Example 19 (compound D in general procedure G 16, 150 mg, 0.36 mmol), 4-methylmorpholine (360 mmol, 3.56 mmol), N-β-dimethylaminopropylJ-N1- ethylcarbodiimide hydrochloride (136 mg, 0.71 mmol), and 1-hydroxy benzotriazole (96 mg, 0-71 mmol) in 5 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2x100 mL) was then added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to give a brown yellow oil residue. The residue was used for the next step reaction without further purification.
Hydrogen chloride (2 mL, 8 mmol; 4 M in dioxane) was added to a solution of the compound prepared above (0.36 mmole) in DCM (5 mL). The reaction was stirred at room temperature for 12 hours. The reaction mixture neutralized with saturated NaHCO3 (aq) and then extracted with EtOAc (2x50 mL). The residue was purified by silica gel chromatography (gradient elution 50→60% EtOAc in hexanes).to give the desired final product (42 mg, 33% yield over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.86 (s, 3 H) 3.38 (s, 3 H) 4.56 - 4.96 (m, 2
H) 6.24 (s, 1 H) 6.60 (s, 1 H) 7.06 - 7.73 (m, 5 H) 10.12 - 10.63 (m, 2 H).
Anal. Calcd for C18H17CIN2O4O.25 CH3COOH: C, 59.13; H, 4.83; N, 7.45. Found:
C, 59.03; H, 4.62; N, 7.62.
Example 21 : N-(tert-butyl)-2-(5-chloro-2,4-dihydroxybenzoyl)isoindoline-1- carboxamidθ
Figure imgf000067_0001
The above compound was prepared using General Procedure G16 as follows. tert-Butylamine (76 mg, 1 mmol) was added to a solution of the compound from Step 1 in Example 19 (compound D in General Procedure G 16, 200 mg, 0.47 mmol), diisopropylethyl amine (0.4 ml, 2.4 mmol), and HATU (216 mg, 0.57 mmol) in 6 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (20 mL) was added to the reaction mixture to quench the reaction. EtOAc (2x100 mL) was then added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to give a brown oil residue. Hydrogen chloride (5 mL, 20 mmol; 4 M in dioxane) was added to a solution of the intermediate prepared above (0.47 mmole) in MeOH (5 mL). The reaction was stirred at room temperature for 12 hours. The reaction mixture was neutralized with saturated NaHCO3 (aq) and then extracted with EtOAc (2x100 mL). The combined organic layers were dried, filtered, and evaporated to give a light brown oil. DCM (10 mL) was added to the oil residue and a pinkish precipitate formed. The precipitant was collected and rinsed with more DCM to give the desired final product (130 mg, 70.5% yield over two steps).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (s, 9 H) 4.60 - 4.87 (m, 2 H) 5.54 (s, 1
H) 6,63 (s, 1 H) 7.14 - 7.42 (m, 5 H) 7.73 (s, 1 H) 10.28 (s, 1 H) 10.50 (s, 1 H) -
Anal. Calcd for C2oH2iCIN204 «0.3 CH2CI2-0.25 EtOAc: C, 58.63; H, 5.45; N, 6.42. Found: C, 58.58; H, 5.16; N, 6.76. Example 22: 2-(5-chloro-2,4-dihydroxybenzoyl)-N-ethyl-1-methylisoindolinβ-1- carboxamide
Figure imgf000068_0001
The above compound was prepared according to General Procedure G17 as follows.
4-methylmorpholine (557 mg), 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg), and 1-hydroxy-benzotriazole (75 mg) were added sequentially to a solution of compound G (synthesis in general procedure 17a, 120 mg, 0.28 mmol) and ethylamine (2.8 mmol, 1 mL of 1 M in THF) in DMF (7 mL). The reaction was stirred at room temperature for 12 hours. The reaction was checked by LC/MS. H2O (50 mL) was added to the reaction mixture to stir. EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain the intermediate compound as an oil. This oil was used for the next step reaction without further purification.
Hydrgen chloride (1.4 mL, 5.5 mmol, 4 M in dioxane) was added to a solution of the intermediate compound prepared above in DCM/MeOH (10 mL, v:v; 1:1). The reaction was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was neutralized with saturated NaHCO3. EtOAc (50 mL) was added to extract the aqueous solution. The organic layer was dried, filtered, and concentrated to obtain an oil residue. The residue was purified by reversed phase chromatography and the desired final product was collected (3 mg, 3% yield in two steps).
1H NMR (400 MHz, MeOD) δ ppm 1.05 (t, J=7.20 Hz, 3 H) 1.95 (s, 3 H) 3.02 - 3.18 (m, 2 H) 4.92 - 5.03 (m, 2 H) 6.55 (s, 1 H) 7.21 - 7.42 (m, 5 H). Example 23: methyl 2-(5-chloro-2,4-dihydroxybenzoyl)-1-methylisoindoline-1- carboxylate
Figure imgf000068_0002
The above compound was prepared using General Procedure 17a as follows. Step j
Sodium hydride (60 mg, 1.4 mmol, 60% dispersion in mineral oil) was added to a solution of compound D from General Procedure G16 (300 mg, 0.7 mmol) in DMF (5 ml_). The grey to white suspension was stirred at room temperature for 30 minutes. The solution turned to more clear yellow, lodomethane (202 mg, 1.4 mmol) was added in 1 mL of DMF. Solution turned into a clear yellow solution. The mixture was stirred at room temperature for 12 hours.
Saturated NH4CI (10 mL) and H2O (10 mL) were added to the reaction mixture.
EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain the desired intermediate product (178 mg, 55.6% yield). This compound was used for the next step reaction without further purification
Figure imgf000069_0001
Hydrogen chloride (0.5 mL, 2 mmol, 4 M in dioxane) was added to a solution of the intermediate compound prepared above in Step 1 (38 mg, 0.084 mmol) (a brown oil) in MeOH and DCM (5 mL; v:v; 1:1). The clear pale yellow solution was stirred at room temperature for 12 hours. The solvent was then evaporated. The mixture was then neutralized with saturated NaHCO3 and EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a brown oil. The residue was purified by silica gel chromatography (gradient elution 40→45% EtOAc in hexanes) to give the desired final product as a white solid (11 mg, 36% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (s, 3 H) 3.57 (s, 3 H) 4.62 (d, J=14.65 Hz, 1 H) 4.91 (d, J=14.40 Hz, 1 H) 6.61 (s, 1 H) 7.09 (s, 1 H) 7.18 - 7.43 (m, 4 H) 10.20 (s, 1 H) 10.48 (s, 1 H).
Example 24: 4-chloro-6-{[1 -(1 -hydroxy-1 -methylethyl)-1 -methyl-1 ,3-dihydro-2H- isoindol-2-yl]carbonyl}benzene-1,3-diol
Figure imgf000069_0002
The above compound was prepared using General Procuedure G 17a as follows.
Methyl magnesium bromide (0.5 mL, 117 mg, 0.33 mmol) was added to a solution of compound D in General Procedure G16 (200 mg, 0.45 mmol) in 6 mL of THF at room temperature, under nitrogen atmosphere. After addition, the color changed to orange clear, then light yellow clear. The reaction was stirred at room temperature for 12 hours (an orange clear solution).
Saturated NH4CI (aq) (10 ml_) was added to the reaction mixture to quench the reaction. NaOAc/HOAc was then added to neutralize the reaction mixture. Extracted the aqueous solution with EtOAc (2x50 ml_). The combined organic layer was dried, filtered, and concentrated to give a brown oil (170 mg). This compound was used for the next step reaction without further purification.
Hydrogen chloride (2 mL, 8 mmol, 4 M in dioxane) was added to a solution of the compound prepared above (170 mg) in MeOH (5 mL) (light black clear solution). The reaction was then stirred at room temperature for 12 hours.
The solvent was then evaporated. Saturated NaHCO3 (aq) was added to neutralize the aqueous solution. EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a light black oil. The residue was purified by silica gel chromatography (gradient elution 40— »50% EtOAc in hexanes) to give the desired final product as a white solid (85 mg, 53% yield over 2 steps).
1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (s, 3 H) 4.36 (s, 6 H) 5.45 (dd, J=111.28, 14.53 Hz, 2 H) 7.30 (s, 1 H) 7.80 (s, 1 H) 7.92 (d, J=4.55 Hz, 1 H) 8.03 (q, J=4.21 Hz, 3 H).
Example 25: 4-chloro-6-{[1 -(hydroxymethyl)-i ,3-dihydro-2H-isoindol-2- yl]carbonyl}benzβne-1 ,3-diol
Figure imgf000070_0001
The above compound was prepared using General Procedure G18 as follows.
Step 1
The compound prepared in Step 2 of Example 18 (1.9 mmol) was added to a solution of 5-chloro-2,4-bis(methoxymethoxy)benzoic acid (compound B in General Procedure G10) (536 mg, 1.9 mmol), 4-methylmorpholine (3.4 mL, 30 mmol), N-(3- dimethylarninopropyl)-N'-ethylcarbodiimide hydrochloride (770 mg, 4 mmol), and 1- hydroxy benzotriazole (550 mg, 4 mmol) in 15 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hours. H2O (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2x150 mL) was then added to extract the. aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered- • off and the filtrated was evaporated to give a brown oil residue. The residue was purified by silica gel chromatography (gradient elution 40→45% EtOAc in hexanes) to give the desired intermediate product as a white solid (532.3 mg, 64.2% yield).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.45 (s, 3 H) 3.54 (s, 3 H) 3.80 (s, 3 H) 4.66 (d, J=13.90 Hz, 1 H) 4.85 (dd, J=14.-\5, 1.77 Hz, 1 H) 5.15 - 5.19 (m, 2 H) 5.27 (s, 2 H) 5.86 (d, J=2.02 Hz, 1 H) 7.06 (s, 1 H) 7.17 (dd, J=5.18, 3.41 Hz, 1 H) 7.29 - 7.35 (m, 2 H) 7.40 (s, 1 H) 7.48 (dd, J=5.18, 3.66 Hz, 1 H).
Figure imgf000071_0001
Lithium hydroxide hydrate (720 mg, 17 mmol) was added to a solution of the intermediate compound prepared in Step 1 above (532 mg, 1.2 mmol) in H2O (3 mL) and MeOH (5 mL). The reaction mixture was heated to 40 °C for 12 hours. The mixture was evaporated and neutralized by HOAc-NaOAc buffer solution. EtOAc (2 x 150 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered, and concentrated to give the desired product as a white foam (516 mg, quantitative yield).
Figure imgf000071_0002
Step 3
Dicyclohexyl carbodiimide (118 mg) was added to a solution of the intermediate compound prepared in Step 2 above (white solid) and N-hydroxy succinimide (61 mg) in 10 mL of EtOAc at room temperature, under N2. Upon addition, the solution color turned into bright yellow (a little suspension) then color faded away and more suspension (pale yellow suspension). The suspension was stirred at room temperature for 12 hours. The white suspension was then filtered. The white precipitate was discarded the filtrate collected (almost colorless). Evaporated the filtrate to obtain a colorless oil, which was used for the next step reaction without further purification. This oil was then dissolved into a solution of THF (4 mL) and ethanol (2 mL). In an ice bath, under N2, sodium borohydride (21 mg) was added in this THF/ethanol solution. A pinkish suspension formed immediately. The reaction was warmed up to room temperature and stirred for 12 hours. The solvent was evaporated to obtain a solid residue. Saturated NH4CI (50 mL) was added to the residue and EtOAc (2 x 50 mL) was added to extract the aqueous solution. The organic layer was dried, filtered, and concentrated to give the desired final product (214 mg, quantitative yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (d, J=5.05 Hz, 1 H) 3.73 - 4.19 (m, 2 H) 4.51 - 5.37 (m, 3 H) 6.57 (s, 1 H) 7.18 - 7.52 (m, 5 H) 9.95 - 10.55 (m, 2 H). Example 26: 4-chloro-6-{[1-(methoxymβthyl)-1,3-dihydro-2H-isoindol-2- yl]carbonyl}benzene-1 ,3-diol
Figure imgf000072_0001
The above compound was prepared using General Procuedure G18 as follows. Sodium hydride (27.3 mg, 60% dispersion in mineral oil) was added to a solution of the compound prepared in Example 25 (214 mg, 0.53 mmol) in 6 mL of DMF at room temperature, under N2. The reaction was stirred at room temperature for 20 minutes and then iodomethane (89.4 mg, in 1 mL of DMF) was added. The reaction was stirred at room temperature for 12hours. The reaction was checked by LC/MS. H2O (50 mL) was added to the mixture and EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to get a dark brown oil. This oil residue was used for the next step reaction without further purification. Hydrogen chloride (2 mL, 4 M in dioxane) was added to a solution of the oil residue prepared above in 5 mL of MeOH. The mixture was stirred at room temperature for 12 hours. The solvent was then evaporated. Saturated NaHCO3 (10 mL) was added to neutralize the mixture. EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a brown oil. The residue was purified by silica gel chromatography (gradient elution 40→50% EtOAc in hexanes) to give the desired final product as a white solid (40 mg, 23% yield over 2 steps).
1H NMR (400 MHz, DMSO-de) δ ppm 3.26 - 3.32 (m, 3 H) 3.62 - 3.96 (m, 2 H) 4.37 - 4.84 (m, J=77.56 Hz, 2 H) 5.57 (d, J=8.08 Hz, 1 H) 6.55 - 6.60 (m, 1 H) 7.02 - 7.53 (m, J=41.18 Hz, 5 H) 10.26 (s, 1 H) 10.45 (s, 1 H).
Anal. Calcd for C17H16CINO4: C, 61.18; H, 4.83; N, 4.20. Found: C, 61.46; H, 5.28; N, 4.67. Example 27: (5-Chloro-2,4-dihydroxy-phenyl)-[2-(3-moφholin-4-ylmethyl-phenyl)- pyrrolidin-1 -ylj-methanone
Figure imgf000073_0001
The above compound was prepared using General Procedure G19a as follows.
Step 1
A 500 mL round bottom flask fitted with an addition funnel was charged with Reike Mg (2.5 g Mg, 100 mmol, suspension in 100 mL THF) and the resulting suspension cooled to 00C. 2-(4-bromophenyl)-1,3-dioxane (20.8 g, 85.7 mmol) was dissolved in THF (80 mL) and slowly added to the stirred suspension of Reike Mg over a period of 30 minutes. The ice bath was removed toward the end of the 30 minute period and the reaction was allowed to stir for an additional 30 minutes at room temperature. The formation of RMgBr was monitored by checking the LCMS of the MeOH quenched Grignard reagent. The Grignard reagent was cooled to 0°C and 1-vinyl-2-pyrrolidinone (9.53 g, 85.7 mmol) was added dropwise as a solution in THF (60 mL). After the addition was complete, the ice bath was removed and the reaction allowed to warm to room temperature. After 30 minutes at room temperature, TLC analysis showed the reaction to be complete. The reaction was cooled to 0°C and quenched by the dropwise addition of water (100 mL). The quenched reaction was further diluted with water (150 mL) and Et2O (300 mL) and transferred to a separatory funnel. To get separation of the layers, an aqueous solution of KH2PO4 was added to adjust the pH to 6. The aqueous layer was extracted with Et2O (x4). The combined organics were washed with aqueous NaHCO3 (x 1) and saturated NaCI (x 2) and then dried over MgSO4. After removal of the solvents, 17 grams of a red oil was obtained. This oil was purified by silica gel chromatography using a gradient of 5 to 30% EtOAc in Hexanes, holding at 30% for 5 CV, then a second gradinet from 30 to 75% EtOAc in Hexanes. Collection and concentration of the pure fractions afforded 4.5 grams (23%) of compound 2 in General Procedure 19a as a yellow oil.
1H NMR (400 MHz, CHLOROFORM-of) δ ppm 1.40 - 1.51 (m, 1 H) 1.96 - 2.12 (m, 2 H) 2.16 - 2.32 (m, 1 H) 2.89 - 3.03 (m, 2 H) 3.95 - 4.12 (m, 4 H) 4.22 - 4.34 (m, 2 H) 5.54 (s, 1 H) 7.36 - 7.46 (m, 1 H) 7.56 (d, J=7.55 Hz, 1 H) 7.86 (d, J=7.81 Hz, 1 H) 7.94 (s, 1 H). Step 2
A solution of compound 2 (4.5 g, 19 mmol) was dissolved in iPrOH (100 mL) and NaBH4 (1.5 g, 39 mmol) was added in small (0.2 g) portions until the full 1.5 g was added. The reaction was allowed to stir at room temperature for 24 hours at which time, LCMS indicated complete reduction. The reaction was then quenched by the addition of MeOH (100 mL). After stirring for 15 minutes, the solvents were removed in vacuo and more MeOH (100 mL) was added. The mixture was stirred for another 15 minutes and the MeOH removed on the rotovap again. A third round of MeOH treatment was conducted and the crude mixture was then placed on the h-vac for 16 hours. This crude material was taken to the next step without further purification and assuming 100% yield. The crude pyrrolidine (compound 3, 4.5 g, 19 mmol) was dissolved in DMA (25 mL)., 5-chloro-2,4- bis(methoxymethoxy)benzoic acid (compound 4, 5.26 g, 19 mmol) was dissolved in DMA (50 mL) and added to the amine solution. HOBt (2.82 g, 20.9 mmol), N-methylmorpholine (2.30 mL, 20.9 mmol) and EDCI (4.01 g, 20.9 mmol) were added sequentially and the reaction was stirred at room temperature for 5 minutes. The reaction was then heated to 500C for 15 minutes and allowed to cool to room temperature. After 2 hours longer at room temperature, the reaction was judged to be complete by LCMS analysis. The reaction mixture was poured onto ice water and a liquid-liquid extraction was performed, extracting into EtOAc (4 x 150 mL). The combined organic extract was washed with saturated aqueous NaHCO3 (x3) and brine (x1), then dried over MgSO4. After removal of the solvent, the dark red oil was purified via flash chromatography eluting with a gradient of 10% to 80% EtOAc in PetEther. The fractions were analyzed by TLC and those containing pure product were combined to afford compound 5 (7.15 g, 76%) as a yellow oil with 90% purity by UV detection - LCMS. The 1H NMR shows evidence of restricted rotation around the amide bond and peak doubling due to two conformations being present in approximately 1 : 1 ratio.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 - 1.49 (m, 2 H) 1.87 - 1.99 (m, 6 H) 2.07 (s, 6 H) 2.13 - 2.26 (m, 3 H) 2.26 - 2.41 (m, 2 H) 3.47 (s, 3 H) 3.52 (s, 3 H) 3.60 (s, 1 H) 3.83 (d, J=7.55 Hz, 1 H) 3.90 - 4.03 (m, 6 H) 4.19 - 4.31 (m, 4 H) 4.71 - 4.78 (m, 1 H) 5.15 (s, 2 H) 5.17 - 5.22 (m, 1 H) 5.22 - 5.27 (m, 3 H) 5.36 (dd, J=7.93, 3.90 Hz, 1 H) 5.39 (s, 1 H) 5.50 (s, 1 H) 6.82 (s, 1 H) 6.87 (d, J=7.55 Hz, 1 H) 7.03 (s, 1 H) 7.06 (s, 1 H) 7.16 (t, J=7.68 Hz, 1 H) 7.26 (d, 1 H) 7.29 - 7.35 (m, 4 H) 7.42 (s, 1 H). Step 3
To compound 5 (6.8 g, 14 mmol), was added a solution of 4 N HCI in 1,4-dioxane (200 mL). The reaction was allowed to stir for 5 hours at room temperature. The aldehyde product, when analyzed by LCMS, showed up as 2 peaks in various ratios but showed up as one spot by TLC. One peak had the MW of the desired aldehyde and the other was the methanol hemi-acetal fragment which has m/z = 360. The 1 ,4-dioxane was removed in vacuo and water (100 mL) was added. The product was extracted into Et2O (3 x 100 mL). The Et2O extract was washed with saturated aqueous NaHCO3 (x3, caution - foaming) and then brine (x 1). After drying over MgSO4 and removing the solvents 6 grams of the crude product was obtained as a brown oil. This oil was purified via flash chromatography eluting with a gradient of 12% to 70% EtOAc in Hexanes. The clean fractions were combined to afford 3.3 g of compound 6 (71%) as a white foam.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.85 - 2.00 (m, 2 H) 2.03 - 2.19 (m,
2 H) 2.50 (s, 1 H) 3.91 - 4.08 (m, 2 H) 5.32 (t, J=7A3 Hz, 1 H) 6.56 (s, 1 H) 7.46 - 7.63 (m,
3 H) 7.71 - 7.86 (m, 2 H) 10.01 (s, 1 H).
0.4 M solutions of the amines (morpholine in this example) were prepared in anhydrous .dichloromethane. A 0.4 M solution of the aldehyde (compound 6) was prepared in anhydrous dichlromethane. A 0.1 M solution of acetic acid in anhydrous dichloromethane was prepared. A 0.16 M suspension of NaBH(OAc)3 in dichloromethane was prepared. A set of 10 x 75 mm test tubes in an appropriately sized array was prepared. Using an Eppendorf pipette, 210 μL (0.084 mmol, 1.05 equiv.) of the amine solutions were placed into the appropriate test tubes. Using an Eppendorf pipette, 200 μL (0.080 mmol, 1.0 equiv.) of the aldehyde (compound 6) was placed into each test tube. Using an Eppendorf pipette, 80 μL (0.008 mmol, 0.1 equiv.) of the acetic acid solution was placed into each of the test tubes. The test tubes were sealed with parafilm and placed on a shaker at room temperature for 1 hour. Using an Eppendorf pipette, 750 μL (0.12 mmol, 1.5 equiv.) of the NaBH(OAc)3 solution was placed into each of the test tubes. The test tubes were sealed with parafilm and placed on a shaker at room temperature for 18 hours. Using an Eppendorf pipette, 500 μL of methanol was added to each of the test tubes. The test tubes were sealed with parafilm and placed on the shaker at room temperature for 1 hour. The volatiles were removed using a Speedvac™ or GeneVac™ apparatus. 1340 μL DMSO (containing 0.01% BHT) was added to each test tube to reach a final volume of 1400 μL and the products were purified via reverse phase HPLC. The reaction was run on a 0.38 mmol scale and purification was accomplished via silica gel chromatography eluting with a gradient of 1% to 5% MeOH in DCM to afford 100 mg (62%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ ppm, evidence of two rotational isomers, 1.75 (br m) 2.33 (br m) 3.07 (br m) 3.49 (br m) 3.74 (br m) 3.93 (br m) 4.30 (br m) 4.93 (br m) 5.14 (br m) 6.44 (br m) 6.61 (br m) 7.22 (br m) 7.40 (br m) 7.48 - 7.61 (br m) 8.32 (s, 1 H). When the sample is heated to 80°C inside the NMR probe, the two sets of peaks coalesce to one set but remain broad.
Example 28: (5-Chloro-2,4-dihydroxy-phenyl)-{2-[4-(3,3-difIuoro-pyrrolidin-1- ylmethyl)-phenyl]-pyrrolidin-1-yl}-methanone
Figure imgf000075_0001
The above compound was prepared using General Procedure 19b as follows. Step j
In a similar manner to the synthesis of compound 2 in Example 27, but starting with the commercial Grignard reagent compound 6 shown in General Procedure G19b (Rieke Metals), the 2-pyrroline (compound 7) was synthesized (4.0 g, 29%).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 - 1.56 (m, 1 H) 1.82 - 2.12 (m, 3 H) 2.77 - 3.00 (m, 2 H) 3.83 - 4.02 (m, 4 H) 4.06 - 4.23 (m, 2 H) 5.55 (s, 1 H) 7.45 (d, J=8.31 Hz, 2 H) 7.81 (d, J=8.31 Hz, 2 H). Step 2 In a similar manner to the synthesis of 2-[3-(1,3-dioxan-2-yl)phenyl]pyrrolidine
(compound 3 in Example 27), the para-substituted 2-arylpyrrolidine (compound 8) was prepared.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 - 1.50 (m, 2 H) 1.62 - 1.81 (m, 2 H) 1.89 - 2.16 (m, 2 H) 2.78 - 2.92 (m, 1 H) 2.94 - 3.04 (m, 1 H) 3.27 - 3.36 (m, 1 H) 3.85 - 3.96 (m, 2 H) 3.97 - 4.04 (m, 1 H) 4.05 - 4.20 (m, 2 H) 5.39 - 5.51 (m, 1 H) 7.22 - 7.40 (m, 4 H) Step 3
In a similar manner to the synthesis of 3-(1-(5-chloro-2,4- dihydroxybenzoyl)pyrrolidin-2-yl)benzaldehyde (compound 6 in Example 27), the para- substituted aldehyde was prepared (2.0 g, 77%).
1H NMR (300 MHz, DMSO-d6) δ ppm 1.69 - 1.99 (m, 3 H) 2.30 - 2.48 (m, J=7.54 Hz, 1 H) 3.48 - 3.91 (m, 2 H) 5.09 - 5.27 (m, 1 H) 6.51 (s, 1 H) 7.13 (s, 1 H) 7.47 (d, J=7.72 Hz, 2 H) 7.82 (d, J=8.10 Hz, 2 H) 9.91 - 10.12 (m, 2 H) 10.22 (s, 1 H). Step 4 0.40 M solutions of the amines (3,3-difluoropyrrolidine-HCI, in this example) were prepared in anhydrous DMSO. A 0.20 M solution of the aldehydes (compound 10) was prepared in anhydrous DMSO. A 0.6 M suspension of NaBH(OAc)3 in anhydrous DMSO was prepared and sonicated until the solution was homogeneous. A set of 10 x 75 mm test tubes was arranged in an appropriately sized array. Using an Eppendorf pipette, 200 μL (0.080 mmol, 1.0 equiv.) of the amine solutions were placed into the appropriate test tubes. Using an Eppendorf pipette, 400 μL (0.080 mmol, 1.0 equiv.) of the aldehyde solution was added to each test tube. The test tubes were sealed with parafilm and placed on a shaker at room temperature for 2 hours. Using an Eppendorf pipette, 333 μL (0.20 mmol, 2.5 equiv.) of the NaBH(OAc)3 suspension was added to each of the test tubes. The test tubes were sealed with parafilm and placed on a shaker at room temperature for 1 hour. Using an Eppendorf pipette, 200 μL of methanol was added to each test tube. The test tubes were sealed with parafilm and placed on a shaker at room temperature for 1 hour. 267 μL DMSO (containing 0.01% BHT) was added to each test tube and the products were purified using reverse phase HPLC. The reaction was run on a 0.86 mmol scale and purification was accomplished via silica gel chromatography eluting with a gradient of 1% to 5% MeOH in DCM to afford 378 mg (100%) as a white solid.
1H NMR (400 MHz, CHLOROFORM-cQ δppm 1.85 - 2.00 (m, 3 H) 2.00 - 2.13 (m, 1 H) 2.19 - 2.35 (m, 2 H) 2.34 - 2.49 (m, 1 H) 2.73 (dd, J=6.80 Hz x 2, 2 H) 2.88 (t, J=13.22 Hz, 2 H) 3.62 (s, 2 H) 3.87 - 3.97 (m, 1 H) 3.95 - 4.06 (m, 1 H) 5.24 (br. s., 1 H) 6.56 (s, 1 H) 7.22 (d, >7.30 Hz, 2 H) 7.30 (d, .7=7.05 Hz, 2 H) 7.52 (br. s., 1 H) 11.53 (br. s., 1 H).
Example 29: 4-chloro-6-[(2-{4-[(33-difluoropyrrolidin-1-yl)carbonyl]-2- , . methylphenyl}pyrrolidin-1 -yl)carbonyl]benzene-13-diol
Figure imgf000077_0001
The above compound was prepared using General Procedure G20b as follows.
Step i
To a solution of 1-boc-pyrrolidine (976 mg, 5.70 mmol, 1.0 eq) and (-)-sparteine
(1.34 g, 5.70 mmol, 1.0 eq) in 12 mL anhydrous MTBE at -780C in acetone/dry ice bath was added sec-butyl lithium (4.07 mL, 5.70 mmol, 1.0 eq, 1.4 M in cyclohexane) dropwise, keeping the temperature below -68°C. The resulting reaction solution was stirred for 3 hours at -78°C.
A solution of zinc chloride (6.84 mL, 3.42 mmol, 0.6 eq, 0.5 M in THF) was added to the above reaction dropwise with rapid stirring, keeping the temperature below -68°C. A light suspension was formed, and was stirred for 30 minutes at -78°C, and then warmed to room temperature. After stirring for an additional 30 minutes at room temperature, the reaction solution was transferred via a syringe to a flask (flushed with N2) containing a mixture of 4-bromo-3-methyl benzoic acid methyl ester (1.0 g, 4.56 mmol, 0.80 eq), palladium acetate (51 mg, 0.228 mmol, 0.04 eq), and tri-tert-butylphosphine tetrafluoroborate (83 mg, 0.285 mmol, 0.05 eq). The resulting reaction mixture was stirred overnight. During the course of the reaction, the color of the reaction mixture became dark and precipitates were generated. LCMS for the crude (5 minutes, positive APCI): T=3.969 min, 220.10, the desired prod-Boc.
To facilitate the filtration, NH4OH (0.35 mL) was added, and the mixture was stirred for 1 hour. The resulting slurry was filtered through Celite and washed with 60 mL
MTBE. The resulting filtrate was washed with 1 M HCI (50 mL), water (2 x 5OmL), dried over sodium sulfate, and concentrated to dryness. LCMS (5 minutes, positive APCI): T = 4.051 minutes, 146.10, the desired (prod - Boc) ion. The resulting residue was columned with hexanes:ethyl acetate (80:20) to afford the desired product as an oil (1.04 g, 71.4%).
Figure imgf000078_0001
tert-Butyl 2-[4-(methoxycarbonyl)-2-methylphenyl]pyrrolidine-1-carboxylate
(compound prepared in Step 1, 0.87 g, 2.70 mmol, 1.0 eq) was treated with LiOH (229 mg, 5.45 mmol, 2.0 eq, dissolved in 5 mL water) in 10 mL MeOH overnight. After removing solvents, the residue was dissolved in 20 mL, and the resulting solution was neutralized carefully with 1 M HCI to pH = 3-4. During the course of neutralizaiton, white precipitates were formed, and then filtered, and dried in oven under vacuum overnight to afford the desired product as a white powder (801 mg, 96%). LCMS (2 min, positive ESI): T=1.162 min, 250.20, (prod - t-Bu) ion. LCMS (2 min, negative ESI): T=1.163 min, 304.20, prod ion. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.78 (s, 1 H), 7.67 - 7.77 (m, 2 H), 7.05 -
7.19 (m, 1 H), 4.87 - 5.02 (m, 1 H), 3.42 - 3.64 (m, 2 H), 2.24 - 2.41 (m, 4 H), 1.71 - 1.89 (m, 2 H), 1.51 - 1.65 (m, 1 H), 1.38 (s, 3 H), 1.05 (s, 6 H).
To a 40 mL vial were charged 4-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-3- methylbenzoic acid (the intermediate prepared above, 200 mg, 0.655 mmol, 1.0 eq), HATU (274 mg, 0.720 mmol, 1.1 eq), 3,3-difluoropyrrolidine hydrochloride (113 mg, 0.786 mmol, 1.2 eq), and TEA (0.274 mL, 1.96 mmol, 3.0 eq, neat) in 6 mL anhydrous DMF. The resulting reaction mixture was heated at 600C for 16 hours. LCMS (2 min, positive ESI): T=1.285 min, 339.20, (prod - t-Bu) ion, clean UV and TIC; the reaction was completed. After removing solvent, the resulting residue was treated with 2 mL TFA for 3 hours at room temperature. LCMS (2 min, positive ESI): T=0.541 min, 295.20, the desired prod ion. The reaction was completed. The majority of the excess TFA was removed in vacuo, and the resulting residue was neutralized with 2 M Na2CO3 to pH=10. The neutralized solution was then concentrated to a oil residue. This compound was used for the next step reaction without further purification.
Figure imgf000078_0002
Step 3
A solution of 5-chloro-2,4-bis(methoxymethoxy)benzoic acid (compound C in General Procedure G10, 181 mg, 0.656 mmol, 1.0 eq), HATU (274 mg, 0.721 mmol, 1.1 eq), 3,3-difluoro-1-(3-methyl-4-pyrrolidin-2-ylbenzoyl)pyrrolidine (compound prepared in Step 2, 193 mg), and TEA (0.274 mL, 1.97 mmol, 3.0 eq, neat TEA) in 6 mL anhydrous DMF was heated at 600C for 16 hours. LCMS (2 min, positive ESI): T = 1.244 min, 553.20, the desired intermediate ion; T = 1.131 min, 457.20. After removing solvent, the resulting residue was treated with 4 M HCI in dioxane (2 mL, 8.0 mmol, 12.2 eq) for 3 hours. After removing solvent, the resulting residue was partitioned between ethyl acetate (50 mL) and aq NaHCO3 (50 mL). The organic phase was separated, washed with water (1x50 mL) and brine (1x50 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by silica gel chromatography (gradient elution 60→70% EtOAc in hexanes) to give the desired final product as a white solid (104 mg, 34%).
1H NMR (400 MHz, DMSO-d6) δ ppm: 10.47 (d, J=6.57 Hz, 2 H), 10.24 (br. s., 0.44 H), 10.18 (s, 0.42 H), 7.32 - 7.40 (m, 2 H), 7.29 (d, J=7.83 Hz, 1.65 H), 7.23 (s, 1 H), 7.14 (s, 0.5 H), 7.08 (d, J=8.08 Hz, 0.48 H), 6.55 (s, 1 H), 6.32 - 6.45 (m, 0.71 H), 5.25 (t, J=6.69 Hz, 1 H), 5.14 (br. s., 0.48 H), 3.89 (t, J=12.76 Hz, 2 H), 3.73 - 3.83 (m, 2 H), 3.64 - 3.73 (m, 2 H), 3.44 - 3.55 (m, 2 H), 2.32 - 2.46 (m, 5 H), 2.00 - 2.08 (m, 1 H), 1.76 - 1.95 (m, 3 H), 1.51 - 1.72 (m, 2 H). Anal. Calcd for C23H23CIFN2O4 «0.43CH2CI2«0.1 hexanes: C, 56.68; H, 5.03; N,
5.47. Found: C, 56.85; H, 5.08; N, 5.50.
Example 30: 4-chloro-6-[(2-{4-[(33-difluoroazetidin-1-yl)carbonyl]-2- fluorophenyl}pyrrolidin-1 -yl)carbonyl]benzene-13-diol
Figure imgf000079_0001
The above compound was prepared using General Procedure G20b as follows.
Step i
To a 40 mL vial were charged 4-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-3- methylbenzoic acid (compound from Step 2, Example 29, 200 mg, 0.655 mmol, 1.0 eq), HATU (274 mg, 0.720 mmol, 1.1 eq), 4,4-difluoropiperidine hydrochloride (124 mg, 0.786 mmol, 1.2 eq), and TEA (0.274 mL, 1.96 mmol, 3.0 eq, neat) in 6 mb anhydrous DMF. The resulting reaction mixture was heated at 60°C for 16 hours. LCMS (2 min, positive ESI): T=1.322 min, 353.20, (prod - t-Bu) ion, clean UV and TIC; the reaction was completed. After removing solvent, the resulting residue was treated with 2 mL TFA for 3 hours at room temperature. The majority of the excess TFA was removed in vacuo, and the resulting residue was neutralized with 2 M Na2CO3 to pH=10 The neutralized solution was then concentrated to an oil residue. This compound was used for the next step of the reaction without further purification.
Figure imgf000080_0001
Step 2
A solution of 5-chloro-2,4-bis(methoxymethoxy)benzoic acid (compound C in G 10, 181 mg, 0.656 mmol, 1.0 eq), HATU (274 mg, 0.721 mmol, 1.1 eq), 4,4-difluoro-1-(3- methyl-4-pyrrolidin-2-ylbenzoyl)piperidine (193 mg, crude from the compound prepared in Step 1 above) (202 mg, crude from the compound prepared in Step 2, Example 29), and TEA (0.274 mL, 1.97 mmol, 3.0 eq, neat TEA) in 6 mL anhydrous DMF was heated at 6O0C for 16 hours. After removing solvent, the resulting residue was treated with 4 M HCI in dioxane (2 mL, 8.0 mmol, 12.2 eq) for 3 hours. LCMS (2 min, positive ESI): T = 1.115 min, 479.20, the desired prod ion. After removing solvent, the resulting residue was partitioned between ethyl acetate (50 mL) and aqueous NaHCO3 (50 mL). The organic phase was separated, washed with water (1 x 50 mL) and brine (1 x 50 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by silica gel chromatography (gradient elution 60→70% EtOAc in hexanes) to give the desired final product as a white solid (245 mg, 78.1%yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.48 (d, J=6.57 Hz, 2 H), 10.25 (s, 0.40
H), 10.19 (s, 0.38 H), 7.37 (d, J=7.83 Hz, 1 H), 7.13 - 7.28 (m, 4 H), 7.01 - 7.10 (m, 1 H), 6.50 - 6.59 (m, 1.73 H), 6.35 (S, 0.44 H), 5.25 (t, J=6.69 Hz, 1 H), 5.18 (br. s., 0.47 H), 3.74 - 3.86 (m, 2 H), 3.64 - 3.74 (m, 2 H), 3.43 - 3.55 (m, 4 H), 2.30 - 2.47 (m, 5 H), 1.94 - 2.11 (m, 4 H), 1.77 - 1.94 (m, 2 H), 1.54 - 1.73 (m, 2 H). Anal. Calcd for C23H23CIFN2θ4'0.26CH2CI2«0.1 EtOAc: C, 58.10; H, 5.20; N, 5.49.
Found: C, 58.00; H, 5.42; N, 5.46. Example 31 : 4-chloro-6-[(2-{4-[(33-difluoroazetidin-1 -yl)carbonyl]-2- fluorophenyl}pyrrolidin-1-yl)carbonyl]benzene-13-diol
Figure imgf000081_0001
The above compound was prepared using General Procedure G20c as follows. Step 1
To a solution of 1-boc-pyrrolidine (976 mg, 5.70 mmol, 1.0 eq) and (-)-sparteine (1.34 g, 5.70 mmol, 1.0 eq) in 12 mL anhydrous MTBE at -78°C in acetone/dry ice bath was added sec-butyl lithium (4.07 mL, 5.70 mmol, 1.0 eq, 1.4 M in cyclohexane) dropwise, keeping the temperature below -680C. The resulting reaction solution was stirred for 3 hours at -78°C (light yellow clear solution).
A solution of zinc chloride (6.84 mL, 3.42 mmol, 0.6 eq, 1 M in ether) was added to the above reaction dropwise with rapid stirring, keeping the temperature below -68°C. A light suspension was formed, and was stirred for 30 minutes at -78°C, and then warmed up to 2O0C (yellow color faded, suspension). Methyl 4-bromo-3-fluorobenzoate (1.13 g, 4.84 mmol, 0.85 eq), palladium acetate
(51 mg, 0.228 mmol, 0.04 eq), and tri-tert-butylphosphine tetrafluoroborate (83 mg, 0.285 mmol, 0.05 eq) were added sequentially to the reaction. The resulting reaction mixture was stirred at room temperature overnight (after stirring for 20 minutes, the suspension solution turned from yellow to greenish). The reaction was checked by LC/MS. To facilitate the filtration, NH4OH (0.35 mL) was added, and the mixture was stirred for 1 hour. The resulting slurry was filtered through Celite and washed with 60 mL MTBE. The resulting filtrate was washed with 1 M HCI (50 mL), water (2 x 5OmL), dried over sodium sulfate, and concentrated to obtain a rose-red oil. Biotage was then used to purify the desired product. Fractions containing the desired product were then combined and evaporated to obtain a light brown oil (compound 6 in General Procedure G20c, 830 mg, 53% yield).
Figure imgf000081_0002
Step 2
Hydrogen chloride (3.2 ml_, 12.8 mmol, 4 M in dioxane) was added to a solution of 110646-169 (830 mg, 2.57 mmol) in DCM (5 mL) and MeOH (5 mL). The reaction mixture was stirred at room temperature for 12 hours (light brown clear solution). The solvent was then evaporated to obtain a pinkish solid residue. This compound was used for the next step of the reaction without further purification.
Figure imgf000082_0001
Step 3
4-methylmorpholine (2.8 mL, 25.7 mmol), 1,(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (984 mg, 5.1 mmol), and 1-hydroxy-benzotriazole (694 mg, 5.1 mmol) were added sequentially to a solution of the compound prepared in Step 2 above (513 mg, 2.6 mmol) and 5-chloro-2,4-bis(methoxymethoxy)benzoic acid (compound C in Generla Procedure G10, 710 mg, 2.6 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 12 hours. H2O (50 mL) was added to the reaction mixture. Adjusted pH to neutral and then extracted with EtOAc (2x100 mL). The combined organic layer was dried, filtered, and concentrated to get a light brown yellow oil. The residue was purified by silica gel chromatography (gradient elution 50→60% EtOAc in hexanes) to give the desired product as a white solid (580 mg). Lithium hydroxide (1.9 mL, 7.7 mmol, 4 M) was added to a solution of the compound prepared above (580 mg) in MeOH (10 mL). The mixture was heated at 45°C for 12 hours. Evaporated off the methanol. Acidified the aqueous solution with NaHCO3- HOAc buffer. EtOAc (2x100 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a colorless oil (290 mg, 24% yield).
Figure imgf000082_0002
Step 4
Hydrogen chloride (0.6 mL, 2.4 mmol, 4 M in dioxane) was added to a solution of the compound prepared in Step 3 above (126 mg, 0.23 mmol) in MeOH/DCM (6 mL; v:v; 1:1). The colorless clear solution was stirred at room temperature for 12 hours. Checked the reaction by LC/MS.
Evaporated all the solvent and saturated NaHCO3 (10 mL) was added to neutralize the mixture. EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a colorless oil. The residue was purified by silica gel chromatography (gradient elution 50→60% EtOAc in hexanes) to give the desired final product as a white solid (93 mg, 88% yield).
1H NMR (400 MHz, DMSO-d6) d ppm 1.60 - 1.99 (m, 3 H) 2.45 (d, J=1.77 Hz, 1 H) 3.38 - 3.61 (m, 1 H) 3.61 - 3.84 (m, 1 H) 4.29 - 4.54 (m, 2 H) 4.68 - 4.96 (m, 2 H) 5.30 (s, 1 H) 6.56 (s, 1 H) 7.22 (s, 1 H) 7.38 - 7.72 (m, 3 H) 10.45 (s, 2 H).
Anal. Calcd for C21H18CIF3N2O4 «0.25H2O: C, 54.91; H, 4.06; N, 6.10. Found: C, 54.94; H, 4.09; N, 5.86.
Table 1 δ ppm (bm) (bm) 7.19 (m)
δ ppm H) 2.33 - 4.04 1 H) (m, 2 H) H) 10.07
δ ppm - 2.38 2 H) (m, 1 H) (m, 1 H) (s, 1 H) 1 H) 10.48
δ 1.34 - (br m) - 3.09 (br - 4.21 5.55 - (br m) - 8.05 (br
Figure imgf000083_0001
δ 1.18- (brm) - 2.59 (br - 5.38 6.57 - (br m)
δ ppm 0.75 -' (brm) - 4.12 (br - 6.76 7.34 - (brm) δ ppm -1.92 0.8H) - 3.59 (bm, 1.2 5.24 (t, (s, 0.2H) 0.8 H) (m, 1 H) - -10.55
δ ppm (bm) 5.01- 7.17- 10.00-
δ ppm 2.06 - (m, 1 5.44 - H) 7.51 1 H) 7.97 1H) 8.70
ppm 6.53 (s, 1 4.08 (m, (s, 1 H), -1.93
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
δ ppm - 4.94 2 H) (m, 1 H) -7.56 1H) (m,
δ ppm -1.94 2 H) -4.99 1 H) (m, 4 H)
ppm -3.17 2 H) H) 7.20 - Hz, H)
δ ppm Hz,2 H) 7.23 (t, (t, J=9.60
Figure imgf000087_0001
δ ppm H) 1.82 (s, 1 2 H) (s, 1 H) 6.52 (s, 2
δ ppm H) 1.65 (s, 1 1 H) H) 4.05 (s, 1 1 H) H)
δ ppm Hz, 3 H) H) 2.01 (s, 2 (m, 1 H) H) 7.14 - (m, 1
Figure imgf000088_0001
δ ppm H) 2.29 (s, 4 4 H) H) 5.27 (s, 2
δ ppm H) 5.06 (s, 1 H) H) 5.84 (s, 1 1 H) 7.57 (s, 1 H)
δ ppm 1.18 (s, (s, 2 H) H) 2.37 3.16 (s, 1 H) 4.04 (s, 2 1 H) H) 8.17
δ ppm H) 1.66 - 2.40 (s, 3 1 H) Hz, 1 H) H)
Figure imgf000089_0001
Figure imgf000090_0001
1 H)
1
δ ppm 156 (s, (s, 2 H) H) 523 (s, 1 2 H)
1 H)
H) 1
δ ppm H) 189 19Hz, 3 3 H) 439 (s, 1 H) 2 H) Hz, 3 H)
1 H)
Figure imgf000091_0001
δ ppm H) 1.50 (s, 5 (s, 2 H) H) 3.16 (s, 2 1 H) H)
δ ppm 1.56 (s, (s, 3 H) H) 5.28 (d, 1 H) H)
ppm H) 2.05 (s, 1 2 H) H) 5.28 (s, 3 1 H)
Figure imgf000092_0001
δ ppm H) 1.83 (s, 3 3 H) H) 7.14 - (m, 1
δ ppm Hz, 1 H) 2 H) (m, 3 H) H) 7.20 Hz, 1 H) 7.60 (s,
δ ppm H) 2.03 3.16 (s, 1 4 H) H) 7.21 (s, 1 2 H)
Figure imgf000093_0001
164 1
δ ppm H) 1 90 (s, 2 3 H) H) 4 11 04 (s, 1 1 H) H) δ ppm O 39 (d, 1 H) H) 2 04 10 (s, 2 1 H) H) 733 (d, 1 H)
183
Figure imgf000094_0001
δ ppm 1.56 (s, (s, 4 H) H) 2.36 (s, 1 2 H) H) 6.93
δ ppm H) 1.90 (s, 2 2 H) H) 4.05 (s, 1 2 H)
δ ppm Hz, 1 H) Hz, 2 H) (m, (m, 1 J=7.42 2 H) 8.92 -
δ ppm H) 1.81 (s, 5 2 H) 3.26 (s, 1 H) 7.32
δ ppm H) 1.57 (s, 1 4 H) H) 2.97 (s, 1 3 H) 7.29
Figure imgf000095_0001
Figure imgf000096_0001
δ ppm H) 1.88 35 (s, 2 1 H) H) 4.35 (s, 1 1 H)
δ ppm H) 1.67 (s, 4 1 H) H) 3.33 (s, 1 4 H) H)
δ ppm H) 1.90 (s, 3 3 H) 1 H) 7.02 (s, 1
δ ppm H) 2.01 2.73 (s, 1 4 H) H) 3.47 (s, 1 1 H) H) 7.30
δ ppm Hz, (s, 3 H) H) 3.16 (s, 1 1 H) H) 8.12
Figure imgf000097_0001
δ ppm (s, 1 H) H) 2.02 (s, 1 1 H) H) 5.80 (s, 1 1 H)
δ ppm H) 2.31 Hz, 2 H) H) 7.17 - H) 7.38 (s, 1 H) 8.12 (s, (s, 1 H)
δ ppm H) 2.20 (s, 1 1 H) H) 6.53 (s, 1
Figure imgf000098_0001
Figure imgf000099_0001
δ ppm 1 39 (s, (s, 4 H) H) 3 16 05 (s, 1 3 H) H)
1
1 1
1
1
Figure imgf000100_0001
189
1
δ ppm H) 1 89 35 (s, 4 1 H) Hz, 2 H) 7 38
δ ppm H) 1 41 83 (s, 4 9 H) H) 275 (s, 2 1 H) 7 18
ppm H) 1 90 35 (s, 4 8 H) 4 05 52 (s, 1 3 H)
Figure imgf000101_0001
1
3
δ ppm H) 1 91 19 (s, 2 1 H) H) 405 34 (s, 1 2 H)
δ ppm H) 202 37 (s, 2 1 H) 4 05 (s, 1 2 H) 825
δ ppm 1 27 (d, 1 H) H) 1 92 (S14 37 (m, 1 6 84 - H) 8 02
Figure imgf000102_0001
Figure imgf000103_0001
δ ppm (s, 1 H) H) 1 89 (S, 1 2 H) H) 6 52 17 (s, 2
1 (s, 1
δ 2 07 (d, - 2 51 (m, 368 - 376 J=7 05 1 H) 722 (d, s , 1
δ 240 96 83 - 4 05 5 29 7 12 - (m, δ 242 96 86 - 3 99 1 H) s , 1 7 27 - (m, 1 δ 241 09 85 - 4 06 6 54 2 H) - 765 H)
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
δ ppm, (br m) 3.74 (br m) 4.93 (br m) 7.40 (br (s, 1 δ H) 1.06 - (m, 3 (s, 6 H) (m, 1 H) (m, 1 (m, 5
δ H) 1.96- 9 H) (br m, 5.21 - H) 7.12-
1.75 - (brm) 4.10- (br m) - 6.76 (br
Figure imgf000124_0001
Figure imgf000125_0002
Example 280: HSP-90 Biochemical Assay
Compounds of the present invention were evaluated for potency against HSP-90 using a SPA (scintillation p/oximity assay) competition binding assay. Briefly, either full length or N-terminal HSP-90 that contains a 6-His tag on its C-terminus binds to copper on Yttrium-silicate scintiflant beads via the His-tag. Tritiated propyl-Geldanamycin (pGA), whose structure is shown below, is an analog of a natural inhibitor of HSP-90 called Geldanamycin.
Figure imgf000125_0001
pGA
Tritiated pGA, which contains a tritiated propyl-amine group added at the #17 position, binds HSP-90 and brings the isotope into proximity with the beads. 17-n-propylamino- Geldanamycin can be prepared as described in U.S. Patent No. 4,261,989, which is incorporated herein by reference. A second tritiated compound that can also be used in this assay was made from the compound shown Example 61 is shown below and is designated as Compound A.
Figure imgf000126_0001
Compound A The "T" in the structure above indicates the position of the labeled tritiated hydrogen atoms. This compound, which can be made as described in Example 61, followed by standard hydrogenation methods using tritium gas, has a Kd of 40 nM.
The beta signal emitted from the isotope excites the scintillant, which creates a measurable signal. As competitive compounds are added to the assay mixture, they compete with bound tritiated pGA or Compound A at the ATP-binding site on the N- terminal of HSP-90. When a compound displaces the labeled pGA or Compond A, the signal is reduced (the beta-particles are no longer in proximity with the bead). This reduction in signal is used to quantify the extent to which the inhibitor/compound is competitive with pGA or Compound A. The SPA assay for 3H-pGA (designated G1) and Compound A (designated G2) binding to HSP-90 was performed in 96-well flat bottom white plates (Corning #3604). For G1 , typical reaction solutions contained 30 nM HSP-90 and 200 nM 3H-pGA in binding buffer (100 mM Hepes, pH 7.5 and 150 mM KCI). For G2, typical reaction solutions contained 5 nM HSP-90 and 50 nM of Compound A. For G1, the 3H-pGA was first diluted to 33% label with unlabeled pGA that was synthesized and purified to give a final concentration of 200 nM. For G2, labeled Compound A was diluted with unlabeled Compound A to provide a ratio of labeled:unlabeled of 1:2 for a final concentration of 50 nM. Inhibitors were added to the HSP-ΘO^H-pGA (or HSP-90/Compound A) solutions at eleven different concentrations for Kj determinations. The range of inhibitor concentrations were 100 μM, or an appropriate range, for solid samples and 10 μM for targeted library compounds and 4 mM liquid stocks. To determine percent inhibition, the compound was tested at 1 and 10 μM. The final DMSO in the samples was 4%. Copper- Ysi beads (Amersham, #RPNQ0096) that have been diluted in binding buffer were added to each well to give a final concentration of 100 μg/well. The plates were sealed, covered with a foil-covered lid and shaken for 30 minutes at room temperature. The beads were allowed to settle for 30 minutes after which the plates were counted using a Packard TopCount NXT instrument. This procedure has also been adapted for medium throughput using a Beckman Biomek FX. Samples were run in duplicate and on two separate days to assure an accurate value of K1.
For K1 determinations, the corrected cpm's (actual cpm's minus background) were plotted vs. inhibitor concentration using GraphPad Prism software. The data were fit to a generic IC50 equation, Y = Yl / (1 + [X]/IC50), where Yl = Y-intercept and [X] is the competing ligand/inhibitor. The IC50 was then used to calculate the Ki by using the Cheng-
Prusoff equation:
Ki{cl} = ICn(Cl) 1 + ([hl]/Kd{hl})
Where cl = cold ligand concentration (varies), [hi] = concentration of hot ligand (200 nM or 50 nM) and Kd{hl} = 240 nM (for 3H-pGA) or 40 nM (for Compound A). Error was calculated as follows: IC50 error / IC50 value = fractional error and fractional error * K1 value = K, error.
In the cases in which inhibitor binds to HSP-90 so tightly that the population of free inhibitor molecules is significantly depleted by formation of the enzyme-inhibitor complex, the above equation is no longer valid. This is normally true when the observed IC50 is about the same as the HSP-90 concentration. For a tight binding inhibitor, the following equation can be applied:
EL _ - (K^ + I0 - E0) + JjK?* + I0 -E0)2 + 4 X E0 X Kr EL0 Ix E0
Where Kfp ^ K1 x (1 + -^)
EL and EL0 are the radioligand-HSP-90 complexes in the presence and absence of inhibitor, respectively. EUEL0 represents the fractional signal in the presence of inhibitor, lo, E0, and L0 are the inhibitor, HSP-90, and radioligand concentrations, respectively. K, is the inhibition constant for the ligand, while KL is the binding affinity constant between the enzyme (HSP-90) and the ligand.
Example 281: HSP-90 Cellular Assay
Compounds of the present invention were evaluated for cell-based potency against HSP-90 using the Akt Luminex assay, which measures the turnover of the HSP-90 client protein Akt1. NCI-H1299 cells (ATCC Number: CRL-5803) were treated with serial dilutions of HSP-90 compounds for 24 hours. Cell lysates were then assayed to measure the loss of Akt1 expression thus determine cellular IC50 by Akt/PKB Beadmate (Upstate Catalog # 46-605) using a Luminex 100 system. Table 3: HSP-90 Biochemical and cellular assay data for compounds shown in Examples 1 to 279
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001

Claims

ClaimsWe claim:
1. A compound of formula (I)
Figure imgf000132_0001
(I) wherein:
R1 is halogen, (C1 to C6) alky), or H;
R2 is H, halogen, or -CH3;
R3 is -CH2-NR4R5 or -C(O)NR6R7;
R4 is H, (C2 to C6) alkyl, (C1 to C8) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl, wherein each of said (C2 to C6) alkyl, (C3 to C10) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group;
R5 is H, (C1 to C6) alkyl, (C1 to C8) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl wherein each of said (C1 to C6) alkyl, (C3 to C10) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group; or R4 and R5 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R8 group;
R6 is (C3 to C6) alkyl, (C2 to C8) alkenyl, (C3 to C10) cycloalkyl, or (CH2)n-R8 provided that R8 is not -CH3 or -CH2CH3, and wherein each of said (C3 to C6) alkyl and (C3 to C10) cycloalkyl is optionally substituted with at least one R8 group;
R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, wherein said (C1 to C6) alkyl is optionally substituted with at least one R8 group; or R6 and R7 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally susbstituted with at least one R8 group; each R8 is independently halogen, cyano, (C1 to C6) alkyl, (C1 to C8) alkoxy, (C1 to C8) heteroalkyl, -OH, -NR1OaR1Ob, -C(O)NR10aR10b, -C(O)R10a, -(CH2Jn-(C3 to C10) cycloalkyl, -(CH2)n-(C2 to C9) heteroaryl, -(CH2)n-(C6 to C14) aryl, or -(CH2Jn-(C2 to C9) cycloheteroalkyl, wherein each of said (C1 to C6) alkyl, (C1 to C8) alkoxy, (C3 to C10) cycloalkyl, (C6 to C14) aryl, (C2 to Cg) heteroaryl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R9 group; each R9 is independently halogen, (C1 to C6) alkyl, -OH, (C1 to C8) heteroalkyl, (C1 to C8) alkoxy, -NR1OaR1Ob, (C6 to C14) aryl, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl;
R1Oa and R1Ob are each independently H, (C1 to C6) alkyl, (C1 to C8) heteroalkyl, -C(O)R12a, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C3 to C10) cycloalkyl, wherein said (C1 to C6) alkyl is optionally substituted with at least one R11 group, or R1Oa and R1Ob taken together with a N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group;
R11 is -NR12aR12b;
R12a and R12b are each independently H or (C1 to C6) alkyl; and each n is independently 0, 1 , or 2; or a pharmaceutically acceptable salt thereof.
2. The compound or salt according to claim 1, wherein the compound of formula (I) has the following structure:
Figure imgf000133_0001
wherein:
R1 is halogen or -CH3.
3. The compound or salt according to claim 1, wherein: R1 is Cl; and R4 and R5 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally substituted with at least one R8 group.
4. The compound or salt according to claim 1, wherein: R1 is Cl; R4 is H; and R5 is (C1 to C6) alkyl, (C1 to C6) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl wherein each of said (C1 to C6) alkyl, (C3 to Ci0) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group.
5. The compound or salt according to claim 1, wherein the compound of formula (I) has the following structure:
Figure imgf000134_0001
wherein:
R1 is halogen or -CH3.
6. The compound or salt according to claim 5, wherein: R1 is Cl; and R4 and R5 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally substituted with at least one R8 group.
7. The compound according to claim 5, wherein: R1 is Cl; R4 is H; and R5 is (C1 to C6) alkyl, (C1 to C8) heteroalkyl, (C3 to C10) cycloalkyl, or (C2 to C9) cycloheteroalkyl wherein each of said (C1 to C6) alkyl, (C3 to C10) cycloalkyl, and (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R8 group.
8. The compound or salt according to claim 1, wherein the compound of formula (I) has the following structure:
Figure imgf000135_0001
wherein:
R1 is halogen or -CH3.
9. The compound or salt according to claim 8, wherein:
R1 is Cl; and
R6 and R7 taken together with the N atom to which they are bound form a (C2 to C9) cycloheteroalkyl group or a (C2 to Cg) heteroaryl group, wherein each of said (C2 to Cg) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally substituted with at least one R8 group.
10. The compound or salt according to claim 8, wherein: R1 is Cl;
R6 is (C3 to C6) alkyl, (C2 to C8) alkenyl, (C3 to C10) cycloalkyl, or (CH2Jn-R8 provided that R8 is not -CH3 or -CH2CH3, and wherein each of said (C3 to C6) alkyl and (C3 to C10) cycloalkyl is optionally substituted with at least one R8 group; and
R7 is H, (C1 to C6) alkyl or (C2 to C8) alkenyl, wherein said (C1 to C6) alkyl is optionally substituted with at least one R8 group.
11. The compound or salt according to claim 1, wherein the compound of formula (I) has the following structure:
Figure imgf000136_0001
wherein:
R1 is halogen or -CH3.
12. The compound or salt according to claim 11 , wherein:
R1 is Cl; and
R6 and R7 taken together with the N atom to which they are bound form a (C2 to Cg) cycloheteroalkyl group or a (C2 to C9) heteroaryl group, wherein each of said (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally substituted with at least one R8 group.
13. The compound or salt according to claim 11 , wherein:
R1 is Cl;
R6 is (C3 to C6) alkyl, (C2 to C8) alkenyl, (C3 to C10) cycloalkyl, or (CH2Jn-R8 provided that R8 is not -CH3 or -CH2CH3, and wherein each of said (C3 to C6) alkyl and (C3 to C10) cycloalkyl is optionally substituted with at least one R8 group; and
R7 is H, (C1 to C6) alkyl or (C2 to C8) alkenyl, wherein said (C1 to C6) alkyl is optionally substituted with at least one R8 group.
14. A pharmaceutical composition, comprising at least one compound or salt according to any of claims 1-13, and a pharmaceutically acceptable carrier or diluent.
15. Use of the compound or salt of any of claims 1 to 13, for the preparation of a medicament for the treatment of cancer in a mammal.
16. A method of treating cancer in a mammal comprising the step of administering to said mammal a therapeutically effective amount a compound or salt according, to any one of claims 1 to 13.
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