EP1276726A2 - Substituted phenyl farnesyltransferase inhibitors - Google Patents

Substituted phenyl farnesyltransferase inhibitors

Info

Publication number
EP1276726A2
EP1276726A2 EP01932712A EP01932712A EP1276726A2 EP 1276726 A2 EP1276726 A2 EP 1276726A2 EP 01932712 A EP01932712 A EP 01932712A EP 01932712 A EP01932712 A EP 01932712A EP 1276726 A2 EP1276726 A2 EP 1276726A2
Authority
EP
European Patent Office
Prior art keywords
methyl
imidazol
group
desired product
compound according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01932712A
Other languages
German (de)
English (en)
French (fr)
Inventor
Wei-Bo Wang
Michael L. Curtin
Stephen A. Fakhoury
Stephen L. Ii Gwaltney
Lisa A. Hasvold
Charles W. Hutchins
Qui Li
Nan-Horng Lin
Lissa Taka Jennings Nelson
Stephen J. O'connor
Hing L. Sham
Gerald M. Sullivan
Gary T. Wang
Xilu Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1276726A2 publication Critical patent/EP1276726A2/en
Withdrawn legal-status Critical Current

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D401/06—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 only aliphatic carbon atoms
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    • 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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the instant invention provides substituted phenyl compounds which inhibit farnesyltransferase, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
  • Ras oncogenes are the most frequently identified activated oncogenes in human tumors, and transformed protein Ras is involved in the proliferation of cancer cells.
  • the Ras must be famesylated by farnesyl pyrophosphate before this proliferation can occur, and farnesylation of Ras by farnesyl pyrophosphate is effected by protein farnesyltransferase. Inhibition of protein farnesyltransferase, and thereby farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate.
  • Ras and related proteins which are famesylated also partially mediates smooth muscle cell proliferation (Circulation, 1-3: 88 (1993)).
  • Inhibition of protein isoprenyl transferases, and thereby farnesylation of the Ras protein also aids in the prevention of intimal hyperplasia associated with restenosis and atherosclerosis, a condition which compromises the success of angioplasty and surgical bypass for obstructive vascular lesions.
  • A is L -M -L or alkylene, wherein the alkylene can be optionally substituted with one, two, or three substituents independently selected from the group consisting of amino,
  • L and L are independently absent or alkylene, wherein the alkylenes defining L and
  • L can be optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and oxo; with the proviso that at least one of L 1 or L 2 is present;
  • M 1 is selected from the group consisting of O, N(R 4 ), N(R 5 )SO 2 , SO 2 N(R 5 ), N(R 5 )C(O), C(O)N(R 5 ), OC(O), C(O)O, C(O), N(R 5 )C(O)O, OC(O)N(R 5 ), OC(O)O, N(R 5 )C(O)N(R 5 ), and S(O) t , wherein t is zero, one, or two; wherein, for the groups defining M , the left ends are attached to L and the right ends are
  • Q is absent or selected from the group consisting of O, N(R ), N(R )C(O), N(R 5 )SO 2 , and S(O) t ;
  • Q is absent or selected from the group consisting of alkylene, alkenylene, and alkynylene;
  • R is selected from the group consisting of halo, cycloalkyl, aryl, and heteroaryl;
  • R is a heteroaryl selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, and thiazolyl;
  • R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; and R is selected from the group consisting of hydrogen, alkyl, aryl, aryl
  • the instant invention discloses compounds of formula (II)
  • L is optionally substituted alkylene; L is optionally substituted alkylene; W and Y are N; and X and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to,
  • L is optionally substituted alkylene
  • L is optionally substituted alkylene
  • X, Y, and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to,
  • Example 519 and Example 521.
  • M 1 is O
  • L is optionally substituted alkylene
  • W is S
  • Y is N
  • X and Z are C(H).
  • Example 780 In another preferred embodiment of compounds of formula (II) are compounds wherein
  • M 1 is N(R 4 );
  • W is N
  • Y is N; and X and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to, 5-((benzyl((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile,
  • M 1 is N(R 4 );
  • Example 469 Example 469, Example 470,
  • Example 499 Example 500,
  • Example 524 Example 527,
  • Example 531 Example 532,
  • Example 549 In another preferred embodiment of compounds of formula (II) are compounds wherein
  • M 1 is N(R 4 );
  • W is S; Y is N; and
  • X and Z are C(H).
  • Example 580 Example 586,
  • Example 622 Example 646,
  • Example 725 Example 726
  • Example 730 Example 731,
  • Example 757 Example 758,
  • Example 779 Example 781,
  • Example 790 Example 791,
  • R is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, and a nitrogen protecting group;
  • X, Y and Z are C(H); or W is N or S, one of X, Y, or Z is C(H), and the remainder are
  • X and Z are C(H).
  • a compound which supports this embodiment includes, but is not limited to, 5-(hydroxy(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l -biphenyl)-2- carbonitrile.
  • W is S
  • Y is N
  • X and Z are C(H).
  • a compound which supports this embodiment includes, but is not limited to,
  • X, Y, and Z are C(H).
  • a compound which supports this embodiment includes, but is not limited to,
  • Q is absent or alkylene
  • R is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, and a nitrogen protecting group;
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; and
  • X is ⁇
  • Y and Z are C(H);
  • W is N or S, one of X, Y, or Z is C(H), and the remainder are C(H) or N; with the proviso that R is present when and only when W is N.
  • compounds of formula (IN) are compounds wherein
  • Y is ⁇ ; and X and Z are C(H).
  • X, Y, and Z are C(H).
  • Example 301 Example 301, Example 302,
  • Example 349 Example 350,
  • Example 360 Example 362
  • Example 370 Example 3701,
  • Example 375 Example 376
  • Example 380 Example 381
  • Example 397 Example 398,
  • Example 407 Example 408,
  • Example 412 Example 413,
  • Example 417 Example 418,
  • Example 425 Example 426,
  • Example 429 Example 430,
  • Example 434 Example 435,
  • Example 439 Example 440,
  • Example 444 Example 445,
  • Example 449 Example 451
  • Example 461 Example 462
  • Example 477 Example 478,
  • Example 503 Example 504
  • Example 508 Example 509
  • Example 513 Example 514,
  • Example 534 Example 535,
  • Example 540 Example 5401, Example 541,
  • W is S
  • Y is ⁇ ; and X, and Z are C(H).
  • Example 630 Example 630, Example 631,
  • Example 635 Example 636
  • Example 640 Example 640, Example 645,
  • Example 650 Example 650, Example 651,
  • Example 655 Example 656,
  • Example 660 Example 660, Example 661,
  • Example 665 Example 666,
  • Example 668 Example 669,
  • Example 672 Example 673,
  • Example 677 Example 678,
  • Example 682 Example 683,
  • Example 692 Example 693,
  • Example 697 Example 698,
  • Example 702 Example 703,
  • Example 705 Example 707,
  • Example 711 Example 712,
  • Example 716 Example 717,
  • Example 721 Example 722,
  • Example 735 Example 736
  • Example 764 Example 765,
  • Example 769 Example 770,
  • Example 784 Example 785,
  • Example 793 Example 794,
  • Q 1 is NCR 4 );
  • W is N
  • Y is N
  • X and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to,
  • X, Y, and Z are C(H).
  • Example 304 Example 305,
  • Example 340 Example 3401,
  • Example 544 and Example 545.
  • Q 1 is NCR 4 );
  • W is S; Y is N; and
  • X and Z are C(H).
  • Example 571 Example 572,
  • Example 583 Example 584,
  • Example 594 Example 595,
  • Example 599 Example 600,
  • Example 748 Example 749,
  • Q is S(O) t , wherein t is zero, one, or two;
  • X and Z are C(H).
  • compounds of formula (IV) are compounds wherein Q is S(O) t , wherein t is zero, one, or two;
  • X, Y, and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to, Example 347, and Example 356.
  • Q is S(O) t , wherein t is zero, one, or two; W is S;
  • Y is ⁇ ; and X and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to,
  • W is N
  • Y is N
  • X and Z are C(H).
  • a compound which supports this embodiment includes, but is not limited to, 4-cyano-N-((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)- benzenesulfonamide.
  • X, Y, and Z are C(H).
  • a compound which supports this embodiment includes, but is not limited to,
  • Q 1 is ⁇ (R 5 )SO 2 ;
  • W is S
  • Y is N
  • X and Z are C(H).
  • a compound which supports this embodiment includes, but is not limited to,
  • Example 802. In another preferred embodiment of compounds of formula (IN) are compounds wherein
  • X and Z are C(H).
  • X, Y, and Z are C(H).
  • W is S
  • Y is N
  • X and Z are C(H).
  • R is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, and a nitrogen protecting group;
  • X and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to, 5-(l-hydroxy-l-(l-methyl-lH-imidazol-5-yl)-3-phenyl-2-propynyl)-2'-methylCl, - biphenyl)-2-carbonitrile, 5-C1 -hydroxy- 1 -(1-methyl- lH-imidazol-5-yl)-3-phenylpropyl)-2 -methyl( 1,1 - biphenyl)-2-carbonitrile, and
  • Compounds which support this embodiment include, but are not limited to, Example 385, Example 386, and
  • W is S; Y is N; and
  • X and Z are C(H).
  • R A' is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group;
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; with the proviso that R A' is present when and only when W' is N.
  • R A' is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group;
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; with the proviso that R A' is present when and only when W' is N.
  • the instant invention discloses compounds of formula (Ni ⁇ i)
  • R is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group;
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy;
  • Q 1 is O; W'is ⁇ ;
  • X' and Z' are C(H).
  • a compound which supports this embodiment includes, but is not limited to,
  • W' is S; and X', Y', and Z' are C(H).
  • the instant invention discloses compounds of formula (LX)
  • R A' is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group;
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy;
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; and one of X and Y is C(H) and the other is C(H) or N.
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; and one of X and Y is C(H) and the other is C(H) or N.
  • the instant invention discloses compounds of formula (XII)
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; and one of X and Y is C(H) and the other is C(H) or N.
  • compounds of formula (XII) are compounds wherein c is zero;
  • X is C(H); Y is N; and
  • a compound which supports this embodiment includes, but is not limited to,
  • the instant invention discloses compounds of formula (XIIT)
  • R is absent or selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; and one of X and Y is C(H) and the other is C(H) or N.
  • R is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, and a nitrogen protecting group;
  • W is N or S, one of X, Y, or Z is C(H), and the remainder are C(H) or N; with the proviso that R is present when and only when W is N.
  • W is N
  • Y is N
  • X and Z are C(H).
  • Compounds which support this embodiment include, but are not limited to,
  • X, Y, and Z are C(H).
  • Compounds which support this embodiment are Example 367, Example 501, and Example 502.
  • In another preferred embodiment of compounds of formula (XIV) are compounds wherein
  • W is S
  • X, Y, and Z are C(H).
  • Example 760 and Example 761.
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (I).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (II).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (III).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (IV). In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (V).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (VI).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (VII).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (NET). In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (IX).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (X).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (XI). In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (XII).
  • the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (XIII).
  • the instant invention discloses a method of inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (XIN).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (I).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (II).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (III).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (IV).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (V).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (VI).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (V-3).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (VHI).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (IX).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (X).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (XI).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (XII).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (XIII).
  • the instant invention discloses a method for treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (XIV).
  • the instant invention discloses a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (II) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (III) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (IV) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (V) in combination with a pharmaceutically acceptable carrier. In another embodiment, the instant invention discloses a compound of formula (VI) in combination with a pharmaceutically acceptable carrier. In another embodiment, the instant invention discloses a compound of formula (VII) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (VIII) in combination with a pharmaceutically acceptable carrier. In another embodiment, the instant invention discloses a compound of formula (IX) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (X) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (XI) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (XII) in combination with a pharmaceutically acceptable carrier.
  • the instant invention discloses a compound of formula (XIII) in combination with a pharmaceutically acceptable carrier. In another embodiment, the instant invention discloses a compound of formula (XIV) in combination with a pharmaceutically acceptable carrier.
  • the instant invention provides substituted phenyl farnesyltransferase inhibitors. As used in the specification, the following terms have the meanings indicated.
  • alkanoyl refers to an alkyl group, as defined herein, or a substituted alkyl group, as defined herein, attached to the parent molecular group through a carbonyl, as defined herein.
  • alkoxy refers to an alkyl group, as defined herein, or a substituted alkyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • alkoxycarbonyl refers to an ester group; e.g., an alkoxy group as defined herein, attached to the parent molecular group through a carbonyl, as defined herein.
  • alkenyl refers to a monovalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbon-carbon double bond.
  • alkenylene refers to a divalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbon-carbon double bond.
  • alkyl refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons.
  • alkylene refers to a divalent straight or branched chain saturated hydrocarbon diradical having from one to six carbons.
  • alkylsulfonyl refers to an alkyl group, as defined herein, or a substituted alkyl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
  • alkynyl refers to a monovalent straight or branched chain hydrocarbon group having from two to six carbons and at least one carbon-carbon triple bond.
  • alkynylene refers to a divalent straight or branched chain hydrocarbon group having from two to six carbons and at least one carbon-carbon triple bond.
  • amino refers to -NH 2 or derivatives thereof formed by independent replacement of one or both hydrogen atoms thereon with a substituent or substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, and an amino protecting group.
  • aminosulfonyl refers to an amino group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
  • amino protecting group refers to selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures.
  • amino protecting groups include methoxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert- butoxycarbonyl (Boc), para-methoxybenzyloxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triphenylsilyl, and the like.
  • Preferred nitrogen protecting groups of the instant invention are benzyloxycarbonyl (Cbz), formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, benzoyl, tert-butoxycarbonyl (Boc), and triphenylmethyl (trityl).
  • aryl refers to groups containing at least one aromatic, carbocyclic ring.
  • Aryl groups of the instant invention are exemplified by phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, anthracenyl, acenaphthylenyl, dihydroacenaphthylenyl, and the like.
  • aryl groups of the instant invention can be optionally substituted with one, two, three, four, or five radicals independently selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyalkyl, hydroxyl, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, phenyl, heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,
  • the phenyl, the heteroaryl, and the heterocycloalkyl groups optionally substituting the aryl groups of the instant invention are attached to the aryl groups through either a covalent bond, an alkyl group, an oxygen atom, or a carbonyl group, as defined herein.
  • the phenyl, the heteroaryl, and the heterocycloalkyl groups optionally substituting the aryl groups of the instant invention can also be further substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy.
  • arylalkyl refers to an aryl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
  • arylsulfonyl refers to an aryl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
  • aryloyl refers to an aryl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
  • azido refers to -N 3 .
  • carbonyl refers to -C(O)-.
  • carboxyl refers to an amide; e.g., an amino group attached to the parent molecular group through a carbonyl group, as defined herein.
  • carboxyl refers to -CO 2 H or a derivative thereof formed by replacement of the hydrogen atom thereon by a carboxyl protecting group.
  • carboxyl protecting group refers to selectively introducible and removable groups which protect carboxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups.
  • carboxyl groups include methyl, ethyl, n-propyl, isopropyl, 1,1- dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), para-nitrobenzyl, para-methoxybenzyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, 2-tetrahydropyranyl 2- tetrahydrofuranyl, 2,2,2-trichloroethyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxy
  • cycloalkyl refers to a monovalent saturated cyclic hydrocarbon group of three to seven carbons.
  • the cycloalkyl groups of the instant invention can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxyl, phenyl, heteroaryl, heterocycloalkyl, and oxo.
  • phenyl, the heteroaryl, and the heterocycloalkyl groups optionally substituting the cycloalkyl groups of the instant invention can also be further substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy.
  • cycloalkylalkyl refers to a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
  • cycloalkyloyl refers to a cycloalkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
  • cycloalkylsulfonyl refers to a cycloalkyl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
  • halo or halide
  • heteroaryl refers to cyclic, aromatic five- and six- membered groups, wherein at least one atom is selected from the group consisting of nitrogen, oxygen, and sulfur, and the remaining atoms are carbon. The five-membered rings have two double bonds, and the six-membered rings have three double bonds.
  • Heteroaryls of the instant invention are exemplified by furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the like.
  • heteroaryl groups of the instant invention are connected to the parent molecular group through a carbon atom in the ring or, as exemplified by imidazole and pyrazolyl, through either a carbon atom or nitrogen atom in the ring.
  • heteroaryl groups of the instant invention can be optionally substituted with one, two, or three radicals independently selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyalkyl, hydroxyl, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, a nitrogen protecting group, phenyl, and a heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.
  • the phenyl and the heterocycloalkyl groups optionally substituting the heteroaryl groups of the instant invention are attached to the heteroaryl through either a covalent bond, an alkyl group, an oxygen, or a carbonyl group, as defined herein.
  • the phenyl and the heterocycloalkyl groups optionally substituting the heteroaryl groups of the instant invention can also be further substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy.
  • heteroaryl groups of the instant invention can also be fused to a phenyl ring, in which case the heteroaryl group can be connected to the parent molecular group through either the heteroaryl part or the phenyl part of the fused ring system.
  • Heteroaryl groups of this type are exemplified by quinolinyl, isoquinolinyl, benzodioxolyl, benzodioxinyl, and the like.
  • heteroarylalkyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
  • heteroaryloyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
  • heteroarylsulfonyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
  • heterocycloalkyl refers to cyclic, non-aromatic, four-, five-, six-, or seven-membered groups containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Heterocycloalkyl groups of the instant invention are exemplified by dihydropyridinyl, imidazolinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,3-dioxanyl.
  • the heterocycloalkyl groups of the instant invention can be attached through a carbon atom or nitrogen atom in the ring.
  • the heterocyalkalkyls of the instant invention can be optionally substituted one, two, or three substituents independently selected from the group consisting of optionally substituted alkyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxyl, cyano, halo, hydroxyalkyl, hydroxyl, a nitrogen protecting group, perfluoroalkyl, perfluoroalkoxy, oxo, phenyl, and heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, o
  • the phenyl and the heteroaryl groups optionally substituting the heterocycloalkyl groups of the instant invention can be attached through a covalent bond, an alkyl group, an oxygen atom, or a carbonyl group.
  • the phenyl and the heteroaryl groups optionally substituting the heterocycloalkyl groups of the instant invention can also be further substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy.
  • heterocycloalkyl also includes bicyclic groups in which the heterocycloalkyl ring is fused to a phenyl group, in which case the heterocycloalkyl group can be connected to the parent molecular group through either the heterocycloalkyl part or the phenyl part of the fused ring system.
  • Heterocycloalkyl groups of this type are exemplified by 1,3-benzodioxanyl, 1,3-benzodioxolyl, 2,4-dihydro-2H-l,4-benzoxazinyl, and the like.
  • heterocycloalkylalkyl refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
  • heterocycloalkyloyl refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
  • heterocycloalkylsulfonyl refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
  • hydroxyalkyl refers to a hydroxyl group attached to the parent molecular group through an alkyl group, as defined herein.
  • hydroxyl refers to -OH or a derivative thereof formed by replacement of the hydrogen atom thereon with a hydroxyl protecting group.
  • hydroxyl protecting group refers to selectively introducible and removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures.
  • hydroxyl protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, l,
  • Preferred hydroxyl protecting groups for the instant invention are acetyl, benzyl (Bn), benzoyl (Bz), and tert-butyl.
  • oxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
  • perfluoroalkoxy refers to a perfluoroalkyl group attached to the parent group through an oxygen atom.
  • perfluoroalkyl refers to an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
  • the compounds of the instant invention can exist as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to salts or zwitterionic forms of the compounds of the instant invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoro
  • amino groups in the compounds of the instant invantion can be quatemized with as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; benzyl and phenethyl bromides.
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulphuric, and phosphoric and organic acids such as oxalic, maleic, succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • salts cations based on lithium, sodium, potassium, calcium, magnesium, and aluminum and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N -dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • the compounds of the instant invention can also exist as pharmaceutically acceptable prodrugs.
  • pharmaceutically acceptable prodrug refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the instant invention.
  • prodrug represents compounds which are rapidly transformed in vivo to parent compounds of formulas (I)-(XlTf), for example, by hydrolysis in blood.
  • substituted alkyl refers to an alkyl group substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkanoyloxy, alkoxycarbonyl, alkoxy, alkoxyalkoxy, amino, carboxaldehyde, cycloalkyl, cyano, halo, hydroxyl, oxo, phenyl, heterocycloalkyl, and heteroaryl.
  • sulfonyl refers to -SO 2 -.
  • the instant invention contemplates stereoisomers and mixtures thereof. Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art. Tautomers can exist in the compounds of the instant invention.
  • the instant invention contemplates tautomers due to proton shifts from one atom to another atom of the same molecule generating two distinct compounds which are in equilibrium with each other.
  • tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule to provide two or more structurally distinct compounds which are in equilibrium with each other.
  • the compounds of the instant invention can be useful for the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic treatments conventionally administered to patients for treating cancer.
  • the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drags used in combination with or coincidently with the compound used.
  • compounds of the instant invention when used in the treatment of solid tumors, can be administered with chemotherapeutic agents such as alpha inteferon, COMP (cyclophosphamide, vincristine, methotrexate, and prednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone, and procarbazine), vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan,
  • the compounds of the instant invention can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • Parenterally adrninstered aqueous or oleaginous suspensions of the compounds of the instant invention can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, dilute acids or bases, dilute amino acid solutions, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the chemotherapeutic effect of parenterally administered compounds can be prolonged by slowing their absorption.
  • One way to slow the absorption of a particular compound is adminstering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides.
  • the rate of drug release can be controlled.
  • Transdermal patches also provide controlled delivery of the compounds.
  • the rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose.
  • Capsules, tablets and pills can also comprise buffering agents; and tablets and pills can be prepared with enteric coatings or other release- controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefor.
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents. Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds of the instant invention with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the instant invention.
  • the total daily dose of the compounds of the instant invention administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • Farnesyltransferase Inhibition Farnesyltransferase (FTase) or geranylgeranyltransferase I (GGTase I) fractions were isolated from bovine brains and purified by a series of methods which separate FTase from GGTase I and GGTase I from GGTase IT. The methods involved a partial purification of all three enzymes by precipitation from a beef brain homogenate with 30% to 50% saturated (NH 4 ) 2 S ⁇ 4 followed by chromatography on DEAE Sepharose.
  • HIC Hydrophobic Interaction Chromatography
  • Bovine FTase was assayed at 37 °C for 30 minutes in a volume of 100 ⁇ L containing 44 mM HEPES, pH 7.4, 26 mM MgCl 2 , 4.4 mM DTT, 18 mM KC1, 0.009% Triton X-100,
  • Example 291 was shown to possess an improved electrophysiological profile.
  • the compounds of the instant invention are useful for the treatment of diseased caused or exascerbated by farnesyltransferase.
  • these compounds are useful in the treatment of both primary and metastatic solid tumors and carcinomas of the breast; colon; rectum; lung; oropharynx; hypopharynx; esophagus; stomach; pancreas; liver; gallbladder; bile ducts; small intestine; urinary tract (kidney, bladder, and urothelium); female genital tract (cervix, uterus, and ovaries); male genital tract (prostate, seminal vesicles, and testes); endocrine glands (thyroid, adrenal, and pituitary); skin (hemangiomas, melanomas, and sarcomas); tumors of the brain, nerves, and eyes; meninges
  • the compounds and processes of the instant invention will be better understood in connection with the following synthetic schemes which illustrate methods by which the compounds can be prepared.
  • the compounds of the instant invention can be prepared by a variety of synthetic routes. Representative procedures are shown below in Schemes 1-19.
  • the groups a, b, c, A 1 , L 1 , L 2 , M 1 , Q 1 , Q 2 , R a , R b R 1 , R 2 , R 3 , R 4 , R 5 , W, W', X, X', Y, Y ⁇ Z, and Z' are defined above, and the groups M p , Q p , and Q p are defined below.
  • OAc for acetate
  • PyBop for benzotriazol-1-yl-oxy-tris- (pyrrolidino)phosphoniumhexafluorophosphate
  • DMAP for 4-(N,N-dimethylamino)pyridine
  • DME dimethoxyethane
  • DMF for N,N-dimethylformamide
  • DMSO for dimethylsulf oxide
  • EDC for l-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride
  • HOBt for 1-hydroxybenzotriazole hydrate
  • HPLC for high pressure liquid chromatography
  • LDA for lithium diisopropylamide
  • MTBE for methyl tert-butyl ether
  • TEA for triethylamine
  • TFA trifluoroacetic acid
  • THF for tetrahydrofuran.
  • organometallic nucleophiles include Grignard reagents, organolithium reagents, organozinc reagents, and organocadmium reagents.
  • the reaction temperature is about -78 °C to about 35 °C and depends on the method chosen. Reaction times are typically about 0.5 to about 4 hours.
  • Compounds of formula (1) can be converted to compounds of
  • compounds of formula (4) can be converted to compounds of formula (6) by treatment of the former with compounds of formula (5) in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or borane-pyridine in a solvent such as 1,2-dichloroethane, dichloromethane, chloroform, or carbon tetrachloride.
  • a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or borane-pyridine
  • a solvent such as 1,2-dichloroethane, dichloromethane, chloroform, or carbon tetrachloride.
  • the reaction temperature is about 0 °C to about 40 °C and depends on the method chosen. Reaction times are typically about 6 to about 24 hours.
  • Compounds of formula (6) can be converted to compounds of formula (II) by condensation of the former with compounds of formula (1) as described in Scheme 1.
  • compounds of formula (7) can be converted to compounds of formula (III) by sequential treatment of the former with a base such as tert-butyllithium, n- butyllithium, and lithium hexamethyldisilazide and compounds of formula (4) in a solvent such as THF, MTBE, or diethyl ether.
  • a base such as tert-butyllithium, n- butyllithium, and lithium hexamethyldisilazide and compounds of formula (4) in a solvent such as THF, MTBE, or diethyl ether.
  • the reaction temperature is about -78 °C to about 0 °C and depends on the method chosen. Reaction times are typically about 0.5 to about 2 hours.
  • Compounds of formula (HI) can be oxidized to compounds of formula (LTIa) by treatment of the same with an oxidizing agent such as manganese dioxide, potassium permanganate, potassium dichromate, or Jones reagent in a solvent such as dioxane, acetone, THF, or dichloromethane.
  • an oxidizing agent such as manganese dioxide, potassium permanganate, potassium dichromate, or Jones reagent in a solvent such as dioxane, acetone, THF, or dichloromethane.
  • the reaction temperature is about 0 °C to about 100 °C and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours.
  • compounds of formula (XIV) can be converted to compounds of formula (9) by sequential treatment of the former with a chlorinating agent such as SOCI 2 , PPt ⁇ /CC , PCI 5 , or PPI1 3 /NCS and ammonium hydroxide in a solvent such as dichloromethane, carbon tetrachloride, or chloroform.
  • a chlorinating agent such as SOCI 2 , PPt ⁇ /CC , PCI 5 , or PPI1 3 /NCS
  • ammonium hydroxide in a solvent such as dichloromethane, carbon tetrachloride, or chloroform.
  • the reaction temperature is about -10 °C to about 25 °C and depends on the method chosen. Reaction times are typically about 1 to about 12 hours.
  • Conversion of compounds of formula (9) to compounds of formula (IN) can be accomplished by the methods described in Scheme 2.
  • compounds of formula (HI) can be converted to compounds of formula (11) by treatment of the former with the chlorinating agent in a solvent such as dichloromethane, carbon tetrachloride, or chloroform.
  • the reaction temperature is about -10 °C to about 25 °C and depends on the method chosen. Reaction times are typically about 1 to about 12 hours.
  • Conversion of compounds of formula (11) to compounds of formula (IV), wherein t is 0, can be accomplished by treatment of the former with compounds of formula (12) in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine in a solvent such as dichloromethane, carbon tetrachloride, or chloroform.
  • the reaction temperature is about 20 °C to about 35 °C and depends on the method chosen. Reaction times are typically about 12 to about 24 hours. Conversion of compounds of formula (IN), wherein t is 0, to compounds of formula (IV), wherein, t is 1 or 2, can be accomplished by treatment of the former with an oxidizing agent such as m-CPBA, hydrogen peroxide, ⁇ aI ⁇ 4 , and NaOCl in a solvent such as dichloromethane, carbon tetrachloride, and chloroform.
  • the reaction temperature is about 20 °C to about 40 °C and depends on the method chosen. Reaction times are typically about 12 to about 72 hours.
  • compounds of formula (9) can be converted to compounds of formula (IV) by treatment of the former with compounds of formula (13) in the presence of a base such as DMAP, triethylamine, diisopropylethylamine, pyridine, or mixtures thereof in a solvent such as dichloromethane, chloroform, or carbon tetrachloride.
  • a base such as DMAP, triethylamine, diisopropylethylamine, pyridine, or mixtures thereof in a solvent such as dichloromethane, chloroform, or carbon tetrachloride.
  • the reaction temperature is about 20 °C to about 40 °C and depends on the method chosen. Reaction times are typically about 6 hours to about 24 hours.
  • compounds of formula (15), wherein Q p is an alkynyl Q precursor can be treated sequentially with a base such as tert-butyllithium, n-butyllithium, LD A, or lithium hexamethyldisilazide and compounds of formula (XIV) to provide compounds of formula (V), wherein Q is alkynylene, in a solvent such as THF, MTBE, dioxane, or diethyl ether.
  • the reaction temperature is about -78 °C to about 25 °C and depends on the method chosen. Reaction times are typically about 0.5 to about 24 hours.
  • Compounds of formula (V), wherein Q is alkynyl can be intraconverted to compounds of
  • reaction temperature is about 25 °C to about 40 °C and depends on the method chosen. Reaction times are typically about 2 to about 32 hours.
  • compounds of formula (21) can be converted to compounds of formula (22) by treatment with an oxidizing agent such as Dess-Martin periodinane, Mn ⁇ 2 , PCC, and K ⁇ C ⁇ O ⁇ in a solvent such as these reactions include dichloromethane, chloroform, and carbon tetrachloride.
  • the reaction temperature is about 0 °C to about 35 °C and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours.
  • Compounds of formula (22) can be condensed with compounds of formula (6) to provide compounds of formula (X) using the conditions described in Scheme 2.
  • compounds of formula (4) can be converted to compounds of formula (23) by treatment of the former with a sulfonium ylide such as trimethylsulfonium iodide in the presence of a base such as potassium hydroxide or sodium hydroxide in a solvent such as DMSO, DMF, or mixtures thereof.
  • a sulfonium ylide such as trimethylsulfonium iodide in the presence of a base such as potassium hydroxide or sodium hydroxide in a solvent such as DMSO, DMF, or mixtures thereof.
  • the reaction temperature is about 25 °C to about 80 °C and depends on the method chosen. Reaction times are typically about 1 to about 6 hours.
  • Compounds of formula (23) can be converted to compounds of formula compounds of formula (XI) by treatment of the former with catalytic base such as DMAP, pyridine, or diisopropylethylamine and compounds of formula (19) in solvents such as methanol, ethanol, or isopropanol.
  • catalytic base such as DMAP, pyridine, or diisopropylethylamine
  • solvents such as methanol, ethanol, or isopropanol.
  • the reaction temperature is about 35 °C to about 100 °C and depends on the method chosen. Reaction times are typically about 2 to about 24 hours.
  • Example 1A 6-fluoro-2 -meth yl( 1,1 -biphenyl)-3-carbaldehyde
  • 3-bromo-4-fluorobenzaldehyde 1.1 g, 5.9 mmol
  • 2-methylphenylboronic acid 9.05 mg, 6.6 mmol
  • palladium(H) acetate 23 mg, 6.6 mmol
  • 2M Na 2 CO 3 14 mL
  • triphenylphosphine 102 mg, 0.39 mmol
  • toluene 13 mL
  • the organic layer was concentrated, and the concentrate was purified by flash column chromatography on silica gel with 95:5/hexanes:ethyl acetate to provide the desired product.
  • Example IB (6-fluoro-2 -methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methanol ,
  • a solution of Example 87F (471.3 mg, 2.4 mmol) in THF (5 mL) at -75 °C was treated with 1.7M tert-butyllithium in pentane (1.7 mL, 2.88 mmol), stirred for 15 minutes, treated with Example 1 A (514 mg, 2.4 mmol) in THF (5 mL), stirred for 1 hour, warmed to 0 °C for 20 minutes, treated sequentially with methanol (3 mL) and IM tetrabutylammonium fluoride in THF C2.4 mL, 2.4 mmol), warmed to room temperature, stirred for 18 hours, poured into water (50 mL), and extracted with ethyl acetate.
  • Example IC 5 ((benzyloxy)(6-fluoro-2'methyl( 1 , 1 '-biphenyl)-3 -vDmethyl)- 1 -methyl- lH-imidazole hydrochloride
  • the concentrate was purified by preparative HPLC with 4:1/CH 3 CN:0.1% aqueous TFA to 0.1% aqueous TFA. The appropriate fractions were combined and concentrated. The concentrate was treated with saturated NaHCO 3 , and the resulting solution was extracted with ethyl acetate. The extract was dried (Na 2 SO 4 ), filtered, and concentrated. The concentrate was dissolved in 4M HCl in dioxane (2 mL), and the resulting solution was stirred for 2 hours and concentrated. This concentrate was dissolved in water and lyophilized to provide the desired product. MS (ESI(+)) m/z 387 (M+H) + ;
  • Example 2A 2 -methvKl .1 -biphenyl)-3-carbaldehyde
  • the desired product was prepared by substituting 3-bromobenzaldehyde for 3-bromo-4-fluorobenzaldehyde in Example 1 A.
  • the desired product was prepared by substituting Example 2 A for Example 1 A in Example IB.
  • Example 2C benzyl (2'-methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methyl ether hydrochloride
  • the desired product was prepared by substituting Example 2B for Example IB in
  • Example IC and purified by flash column chromatography on silica gel with 95:5:0.1/ethyl acetate:methanol:concentrated ammonium hydroxide. The appropriate fractions were concentrated, and the concentrate was dissolved in 4M HCl in dioxane (1.5 mL), stirred for 3 hours, and concentrated. The concentrate was treated with water and lyophilized to provide the desired product.
  • Example 3B 4-chloro-3-iodo-N-methoxy-N-methylbenzamide
  • EDC EDC
  • HOBt HOBt
  • N,O-dimethylhydroxylamine hydrochloride 1.26 g, 13 mmol
  • DMF DMF
  • Example 3E (6-chloro-2'-methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methanol
  • MS (DCI/NH 3 ) m z 313 (M+H) + ;
  • H NMR 300 MHz, CDCI 3 ) ⁇ 7.5-7.0 (m, 7H), 6.7 (s, IH), 5.9 (s, IH), 3.6 (d, 3H), 2.1 (d, 3H).
  • Example 3F 5-((benzyloxy)(6-chloro-2-methyl(l, -biphenyl)-3-yl)methyl)-l-methyl-lH-imidazole hydrochloride
  • the desired product was prepared by substituting Example 3E for Example IB in Example IC.
  • Example 4 2 -methyl-5-(( 1 -methyl- lH-imidazol-5-yl)(phenoxy)methyl)( 1 , 1 -biphenyl)-2-carbonitrile hydrochloride
  • Example 4A 5- ( hydroxyC 1 -methyl- lH-imidazol-5-yl)methyl)-2 -methvK 1 , 1 -biphenyl)-2-carbonitrile
  • the desired product was prepared by substituting Example 861 for Example 1 A in

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