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Withdrawn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)
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Withdrawn legal-status Critical Current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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    • C07D277/20—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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    • C07D401/10—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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    • C07D401/12—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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Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof, inhibit farnesyltransferase. Methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds are disclosed.

Description

SUBSTITUTED PHENYL FARNESYXTRANSFBRASE --NfflBITORS
Technical Field
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.
Background of The Invention
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.
Activation of 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. Because of this pivotal role played by farnesyltransferase in tumor formation and metastasis, compounds such as those reported in WO 97/36897, WO 97/36881, WO 97/36875, WO 97/36901, WO 99/17777, WO 99/18096, WO 99/20609, WO 99/27928, WO 99/27933, WO 99/27929, WO 99/28313, and WO 99/28314 have been the subject of current research.
However, there is still an ongoing need for farnesyltransferase inhibitors with modified or improved profiles of activity. Summary of The Invention
In its principle embodiment, therefore, the instant invention discloses compounds of formula (I)
(I), or pharmaceutically acceptable salts thereof, wherein
1 1 1 2
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,
1 2 3 hydroxyl, oxo, and -Q -Q -R ; with the proviso that when A is methylene, the methylene is substituted;
1 2 1
L and L are independently absent or alkylene, wherein the alkylenes defining L and
2
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;
M1 is selected from the group consisting of O, N(R4), N(R5)SO2, SO2N(R5), N(R5)C(O), C(O)N(R5), OC(O), C(O)O, C(O), N(R5)C(O)O, OC(O)N(R5), OC(O)O, N(R5)C(O)N(R5), 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
2 attached to L ;
Q is absent or selected from the group consisting of O, N(R ), N(R )C(O), N(R5)SO2, 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, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
In another embodiment, the instant invention discloses compounds of formula (II)
(H), or a pharmaceutically acceptable salt thereof, wherein
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; W is C(H)=C(H), X is N, and Y and Z are C(H); or W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X
2 and its right end attached to the carbon substituted with L ; and 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 C(H) or N; with the proviso that R is present when and only when W is N. In a preferred embodiment of compounds of formula (II) are compounds wherein M1 is O;
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,
4-(((4-cyanophenyl)(l-methyli-lH-imidazol-5-yl)methoxy)methyl)-2-(l-naphthyl)- benzonitrile,
4-((2-(4-cyanophenyl)-l-(l-methyl-lH-imidazol-5-yl)ethoxy)methyl)-2-(l- naphthyl)benzonitrile, 4-((l-(l-methyl-lH-imidazol-5-yl)-3-phenylpropoxy)methyl)-2-(l-naphthyl)- benzonitrile,
4-(((l-methyl-lH-imidazol-5-yl)(phenyl)methoxy)methyl)-2-(l-naphthyl)- benzonitrile, and 4-((l-(l-methyl-lH-imidazol-5-yl)-2-phenylethoxy)methyl)-2-(l-naphthyl)- benzonitrile.
In another preferred embodiment of compounds of formula (II) are compounds wherein M1 is O;
L is optionally substituted alkylene;
2
L is optionally substituted alkylene;
W is N=C(H); and
X, Y, and Z are C(H). Compounds which support this embodiment include, but are not limited to,
Example 516,
Example 517,
Example 518,
Example 519, and Example 521.
In another preferred embodiment of compounds of formula (II) are compounds wherein
M1 is O;
L is optionally substituted alkylene;
2 L is optionally substituted alkylene;
W is S;
Y is N; and
X and Z are C(H).
Compounds which support this embodiment include, but are not limited to, Example 775,
Example 776,
Example 777,
Example 778, and
Example 780. In another preferred embodiment of compounds of formula (II) are compounds wherein
M1 is N(R4);
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,
4-(((4-cyanobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2-(l- naphthyl)benzonitrile, 4-(((4-chlorobenzyl)(( 1 -methyl- lH-imidazol-5-yl)methyl)amino)methyl)-2-( 1- naphthyl)benzonitrile,
4-((((l-methyl-lH-imidazol-5-yl)methyl)(4-(trifluoromethoxy)benzyl)amino)- methyl)-2-(l-naphthyl)benzonitrile,
4-(((4-cyanobenzyl)(lH-imidazol-5-ylmethyl)amino)methyl)-2-(l-naphthyl)- benzonitrile,
5-(((2-cyclohexylethyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2 - methyl(l , 1 '-biphenyl)-2-carbonitrile,
4-(((2-cyclohexylethyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2-(l- naphthyl)benzonitrile, 4-(((cyclohexylmethyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2-(l- naphthyl)benzonitrile,
4-(((4-cyanobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2-(8- quinolinyl)benzonitrile,
4-(((3,4-dichlorobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2-(l- naphthyl)benzonitrile,
4-cyano-N-(4-cyanobenzyl)-N-(( 1 -methyl- 1 H-imidazol-5 -yl)methyl)-3 -( 1 - naphthyl)benzamide,
4-((((l-methyl-lH-imidazol-5-yl)methyl)(4-(trifluoromethyl)benzyl)amino)methyl)-2- ( 1 -naphthyl)benzonitrile, 4-(((4-cyano-3-(l-naphthyl)benzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)- methyl)benzoic acid,
N-(4-(((4-cyano-3-(l-naphthyl)benzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)- methyl)phenyl)acetamide,
4-((((l-methyl-lH-imidazol-5-yl)methyl)(4-(methylsulfonyl)benzyl)amino)methyl)-2- (l-naphthyl)benzonitrile,
4-cyano-N-(4-cyano-3-( 1 -naphthyl)benzyl)-N-((l -methyl- lH-imidazol-5-yl)- methyl)benzamide,
3 ,4-dichloro-N- (4-cyano-3 -(1 -naphthyl)benzyl)-N-(( 1 -methyl- lH-imidazol-5 -yl)- methyl)benzamide, 4-chloro-N-(4-cyano-3-(l-naphthyl)benzyl)-3-fluoro-N-((l-methyl-lH-imidazol-5- yl)methyl)benzamide, 5,6-dichloro-N-(4-cyano-3-(l-naphthyl)benzyl)-N-((l-methyl-lH-imidazol-5-yl)- methyl)nicotinamide,
4-cyano-N-(4-cyanobenzyl)-N-((l-methyl-lH-imidazol-5-yl)methyl)-3-(8- quinolinyl)-benz amide, 4-(((2-hydroxy-5-(trifluoromethoxy)benzyl)((l-methyl-lH-imidazol-5-yl)methyl)- amino)methyl)-2-( 1 -naphthyl)benzonitrile, methyl 6-(((4-cyano-3-(l-naphthyl)benzyl)((l-methyl-lH-imidazol-5-yl)methyl)- amino)-methyl)nicotinate, ethyl 4-((4-cyano-3-(l-naphthyl)benzyl)((l-methyl-lH-imidazol-5-yl)methyl)- amino)- 1-piperidinecarboxylate,
2 -methyl-5-(((l-methyl-lH-imidazol-5-yl)methyl)amino)(l, -biphenyl)-2- carbonitrile,
5-(benzyl((l -methyl- lH-imidazol-5-yl)methyl)amino)-2'-methyl(l , 1 -biphenyl)-2- carbonitrile, 4-(methyl((l-methyl-lH-imidazol-5-yl)methyl)amino)-2-(l-naphthyl)benzonitrile,
4-(allyl(( 1-methyl- lH-imidazol-5-yl)methyl)amino)-2-( 1 -naphthyl)benzonitrile,
5-((4-cyanobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)-2'-methyl(l, - biphenyl)-2-carbonitrile,
4-(((l-methyl-lH-imidazol-5-yl)methyl)(3-phenylpropyl)amino)-2-(l- naphthyl)benzonitrile,
4-((4-cyanobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)-2-(l-naphthyl)- benzonitrile,
4-(benzyl((l-methyl-lH-imidazol-5-yl)methyl)amino)-2-(l-naphthyl)benzonitrile,
4-(hexyl(( 1 -methyl- lH-imidazol-5-yl)methyl)amino)-2-( 1 -naphthyl)benzonitrile, 4-(((l-methyl-lH-inιidazol-5-yl)methyl)amino)-2-(l-naphthyl)benzonitrile,
N-(4-cyano-3 -( 1 -naphthyl)phenyl)-N- (( 1 -methyl- 1 H-imidazol-5 -yl)me thyl)- benzamide,
N-(6-cyano-2'-methyl(l , 1 -biphenyl)-3-yl)-N-((l-methyl-lH-imidazol-5-yl)methyl)- benzamide, 5-((3-cyanobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)-2'-methyl(l, - biphenyl)-2-carbonitrile,
4-(((( 1 -methyl- lH-imidazol-5-yl)(phenyl)methyl)amino)methyl)-2-( 1 - naphthyl)benzonitrile,
4-(((l-(l-methyl-lH-imidazol-5-yl)-2-phenylethyl)amino)methyl)-2-(l-naphthyl)- benzonitrile,
4-(((l-(l-methyl-lH-imidazol-5-yl)-3-phenylpropyl)amino)methyl)-2-(l-naphthyl)- benzonitrile, 4-(((2-(4-cyanophenyl)-l-(l-methyl-lH-imidazol-5-yl)ethyl)amino)methyl)-2-(l- naphthyl)benzonitrile,
4-((3-chlorobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)-2-(l-naphthyl)- benzonitrile, 4-(benzyl(lH-imidazol-5-ylmethyl)amino)-2-(l-naphthyl)benzonitrile,
4-((3-cyanobenzyl)(( 1 -methyl- lH-imidazol-5-yl)methyl)amino)-2-( 1 -naphthyl)- benzonitrile,
N-(4-cyano-3-(l-naphthyl)phenyl)-N-((l-methyl-lH-imidazol-5-yl)methyl)benzene- sulfonamide, methyl 4-((4-cyano((l-methyl-lH-imidazol-5-yl)methyl)-3-(l-naphthyl)anilino)- methyl)benzoate,
4-((4-cyano((l-methyl-lH-imidazol-5-yl)methyl)-3-(l-naphthyl)anilino)methyl)- benzoic acid,
5-(benzyl(lH-imidazol-5-ylmethyl)amino)-2'-methyl(l,r-biphenyl)-2-carbonitrile, methyl 3-((4-cyano(( 1 -methyl- lH-imidazol-5-yl)methyl)-3-(l -naphthyl)anilino)- methyl)benzoate,
4-(((4-cyanophenyl)( 1-methyl- lH-imidazol-5-yl)methyl)amino)-2-( 1 -naphthyl)- benzonitrile, and
6-(((4-cyano-3-(l-naphthyl)benzyl)((l-memyl-lH-imidazol-5-yl)methyl)amino)- methyl)nicotinonitrile.
In another preferred embodiment of compounds of formula (II) are compounds wherein
M1 is N(R4);
W is N=C(H); and X, Y and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
2 -methyl-5-((3-pyridinylamino)methyl)(l , 1 -biphenyl)-2-carbonitrile,
5-((benzyl(3-pyridinylmethyl)amino)methyl)-2'-methyl(l,r-biphenyl)-2-carbonitrile,
2-methyl-5-((3-pyridinylmethyl)amino)(l,r-biphenyl)-2-carbonitrile, 5-(benzyl(3-pyridinylmethyl)amino)-2'-methyl(l ,1 -biphenyl)-2-carbonitrile,
Example 322,
Example 328,
Example 329
Example 363 Example 364
Example 365
Example 390 Example 450,
Example 467,
Example 468,
Example 469, Example 470,
Example 471,
Example 472,
Example 473,
Example 474, Example 475,
Example 482,
Example 483,
Example 484,
Example 485, Example 490,
Example 491,
Example 492,
Example 493,
Example 494, Example 495,
Example 496,
Example 497,
Example 498,
Example 499, Example 500,
Example 520,
Example 522,
Example 523,
Example 524, Example 527,
Example 528,
Example 529,
Example 530,
Example 531, Example 532,
Example 548, and
Example 549. In another preferred embodiment of compounds of formula (II) are compounds wherein
M1 is N(R4);
W is S; Y is N; and
X and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
Example 578,
Example 580, Example 586,
Example 587,
Example 620,
Example 621,
Example 622, Example 646,
Example 706,
Example 723,
Example 724,
Example 725, Example 726,
Example 727,
Example 728,
Example 729,
Example 730, Example 731,
Example 738,
Example 739,
Example 740,
Example 741, Example 753,
Example 754,
Example 755,
Example 756,
Example 757, Example 758,
Example 759,
Example 779, Example 781,
Example 782,
Example 783,
. Example 786, Example 787,
Example 788,
Example 788,
Example 789,
Example 790, Example 791,
Example 807, and
Example 808.
In another embodiment, the instant invention discloses compounds of formula (III)
or a pharmaceutically acceptable salt thereof, wherein
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 W is C(H)=C(H), X is N, and Y and Z are C(H); or W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X
2 and its right end attached to the carbon substituted with L ; and 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
C(H) or N; with the proviso that R is present when and only when W is N. In a preferred embodiment of compounds of formula (HI) are compounds wherein W is N; Y is N; and
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.
In another preferred embodiment of compounds of formula (HI) are compounds wherein
W is S;
Y is N; and
X and Z are C(H).
A compound which supports this embodiment includes, but is not limited to,
5-(hydroxy(l ,3-thiazol-5-yl)methyl)-2 -methyl(l , 1 -biphenyl)-2-carbonitrile.
In another preferred embodiment of compounds of formula (III) are compounds wherein
W is N=C(H); and
X, Y, and Z are C(H).
A compound which supports this embodiment includes, but is not limited to,
5-(hydroxy(3-pyridinyl)methyl)-2'-methyl(l , 1 -biphenyl)-2-carbonitrile,
In another embodiment, the instant invention discloses compounds of formula (IV)
(IN), or a pharmaceutically acceptable salt thereof, wherein
2
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
W is C(H)=C(H), X is Ν, and Y and Z are C(H); or
W is C(H)=Ν or N=C(H), wherein each group is drawn with its left end attached to X
2 and its right end attached to the carbon substituted with L ; and 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 C(H) or N; with the proviso that R is present when and only when W is N. In a preferred embodiment of compounds of formula (IN) are compounds wherein
Q1 is O;
W is Ν;
Y is Ν; and X and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
2'-methyl-5-((l-methyl-lH-imidazol-5-yl)(phenoxy)methyl)(l, -biρhenyl)-2- carbonitrile,
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methoxy(l,l'-biphenyl)-2- carbonitrile,
5-((benzyloxy)(l-methyl-lH-irnidazol-5-yl)methyl)-3'-phenyl(l, -biphenyl)-2- carbonitrile,
(2-(9-antrιryl)-4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)benzonitrile,
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-isopropyl(l, -biphenyl)-2- carbonitrile,
4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l,2-dihydro-5-acenaphth- ylenyl)benzonitrile ,
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-chloro(l, -biphenyl)-2- carbonitrile, 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, -biphenyl)-2- carbonitrile,
4-((cyclohexylmethoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile,
4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(8-quinolinyl)- benzonitrile,
4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(4-quinolinyl)- benzonitrile,
4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(5-quinolinyl)- benzonitrile, 4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(5-isoquinolinyl)- benzonitrile,
4-(((4-cyanobenzyl)oxy)(lH-imidazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile,
4-((l-methyl-lH-imidazol-5-yl)((4-nitrobenzyl)oxy)methyl)-2-(l-naphthyl)- benzonitrile, 4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-iodobenzonitrile,
4-(((3-chloro-4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile, 4-(((4-cyano-3-iodobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile, methyl 4-(((4-cyano-3 -( 1 -naphthyl)phenyl)(l -methyl- lH-imidazol-5-yl)methoxy)- methyl)benzoate, 4-((l-methyl-lH-imidazol-5-yl)((4-(trifluoromethyl)benzyl)oxy)methyl)-2-(l- naphthyl)benzonitrile,
4-(((4-chlorobenzyl)oxy)( 1 -methyl- lH-imidazol-5 -yl)methyl)-2-( 1 -naphthyl)- benzonitrile,
4-((l-methyl-lH-imidazol-5-yl)((4-(trifluoromethoxy)benzyl)oxy)methyl)-2-(l- naphthyl)benzonitrile,
4-((l-methyl-lH-imidazol-5-yl)((3-(trifluoromethyl)benzyl)oxy)methyl)-2-(l- naphthyl)benzonitrile,
4-(((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methoxy)methyl)- benzoic acid, 4-(((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methoxy)methyl)-
N,N-dimethylbenzamide,
4-(((2,4-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile,
4-((l-methyl-lH-imidazol-5-yl)((4-(methylsulfonyl)benzyl)oxy)methyl)-2-(l- naphthyl)benzonitrile,
4-(((2,6-dichloro-4-pyridinyl)methoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile,
4-(((3-bromo-4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile, 6-(((4-cyano-3-(l -naphthyl)phenyl)(l-methyl- lH-imidazol-5-yl)methoxy)methyl)- nicotinonitrile,
4-(((4-cyano-3-fluorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile,
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)(l, -biphenyl)-2-carbonitrile, 4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile,
4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(3-thienyl)benzonitrile,
5-((benzyloxy) ( 1 -methyl- 1 H-imidazol-5 -yl)methyl)-3 -methyl( 1 , 1 -biphenyl)-2- carbonitrile,
4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(2-naphthyl)benzonitrile, 5-((benzyloxy)( 1 -methyl- lH-imidazol-5-yl)methyl)-4'-methyl(l , 1 -biphenyl)-2- carbonitrile, 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-phenyl(l,r-biphenyl)-2- carbonitrile,
5-((benzyloxy)( 1 -methyl- lH-imidazol-5-yl)methyl)-2 ',5 -dimethyl(l , 1 -biphenyl)-2- carbonitrile, 4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile,
4-(((2-methoxy-5-nitrobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)-benzonitrile,
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -ethyl(l,l'-biphenyl)-2- carbonitrile,
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2',3'-dimethyl(l,r-biphenyl)-2- carbonitrile,
4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-cyclohexylbenzonitrile,
4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(5,6,7,8-tetrahydro-l- naphthalenyl)benzonitrile,
4-((benzyloxy) ( 1 -methyl- lH-imidazol-5 -yl)methyl)-2-(2-methyl- 1 -naphthyl)- benzonitrile,
2-(l-anthryl)-4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)benzonitrile,
4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(4-isoquinolinyl)benzonitrile, 4-((benzyloxy)(l-(ethoxymethyl)-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile,
4-(((4-cyanobenzyl)oxy)(l-(ethoxymethyl)-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile,
5-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-phenyl(l, - biphenyl)-2-carbonitrile,
4-(((4-cyanobenzyl)oxy)(l-(3-hydroxypropyl)-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile,
4-(((4-fluoro-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methoxy)methyl)- benzonitrile, 5-(((3-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,r- biphenyl)-2-carbonitrile,
5-(((4-(tert-butyl)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l , 1 '- biphenyl)-2-carbonitrile,
5-(((3-iodobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,r-biphenyl)- 2-carbonitrile, 5-(((4-fluorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l, - biphenyl)-2-carbonitrile,
5-(((4-bromobenzyl)oxy)(l-methyl- lH-imidazol-5-yl)methyl)-2'-methyl(l , 1 - biphenyl)-2-carbonitrile, 5-(((3-chlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l'- biphenyl)-2-carbonitrile,
(2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((4-nitrobenzyl)oxy)methyl)(l, - biphenyl)-2-carbonitrile,
5-(((2-methoxy-5-nitrobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl- (l,l'-biphenyl)-2-carbonitrile,
(2'-methyl-5-((l-methyl-lH-imidazol-5-yl)((3-(trifluoromethyl)benzyl)oxy)methyl)- (1,1 -biphenyl)-2-carbonitrile,
5-(((2,6-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile, 5-(((3,4-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((2-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,r- biphenyl)-2-carbonitrile,
(2'-methyl-5-(((4-methylbenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)(l, - biphenyl)-2-carbonitrile,
(2 -methyl-5-(((3-methylbenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)(l,l - biphenyl)-2-carbonitrile,
5-(((2,5-difluorobenzyl)oxy)( 1 -methyl- lH-imidazol-5-yl)methyl)-2 -methyl( 1,1 - biphenyl)-2-carbonitrile, methyl 4-(((6-cyano-2'-methyl(l,r-biphenyl)-3-yl)(l-methyl-lH-imidazol-5- yl)methoxy)-methyl)benzoate,
5-(((3 ,5-difluorobenzyl)oxy)( 1-methyl- lH-imidazol-5-yl)methyl)-2 -methyl( 1 , 1 - biphenyl)-2-carbonitrile,
5-(((2-chlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l, - biphenyl)-2-carbonitrile,
5-(((4-chlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l , 1 - biphenyl)-2-carbonitrile,
5-(((3-methoxybenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile, (2'-methyl-5-(((2-methylbenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)(l,l - biphenyl)-2-carbonitrile, 5-(((3-fluorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((2,6-dichloro-4-pyridinyl)methoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 - methyl( 1 , 1 -biphenyl)-2-carbonitrile, 5-(((2-fluorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,r- biphenyl)-2-carbonitrile,
(2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((4-(trifluoromethyl)benzyl)oxy)- methyl)(l ,1 '-biphenyl)-2-carbonitrile,
5-(((3,5-dimethylbenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((4-fluoro-2-(trifluoromethyl)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'- methyl-( 1 , 1 -biphenyl)-2-carbonitrile,
(2'-methyl-5-((l-methyl-lH-imidazol-5-yl)((2-nitrobenzyl)oxy)methyl)(l,l - biphenyl)-2-carbonitrile, (2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((3-(trifluoromethoxy)benzyl)oxy)- methyl)( 1 , 1 -biphenyl)-2-carbonitrile,
4-(((6-cyano-2'-methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methoxy)- methyl)-6-methylisophthalonitrile,
5-(((2'-cyano(l, -biphenyl)-4-yl)methoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 - methyl(l , 1 -biphenyl)-2-carbonitrile, methyl 3-(((6-cyano-2'-methyl(l,l -biphenyl)-3-yl)(l-methyl-lH-imidazol-5- yl)methoxy)-methyl)benzoate,
5-(((3,4-difluorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l'- biphenyl)-2-carbonitrile, (2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((3,4,5-trimethoxybenzyl)oxy)methyl)-
(1,1 -biphenyl)-2-carbonitrile,
(2'-methyl-5-((l-methyl-lH-imidazol-5-yl)(8-quinolinylmethoxy)methyl)(l, - biphenyl)-2-carbonitrile,
5-(((3,5-dimethoxybenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile,
(2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((4-(methylsulfonyl)benzyl)oxy)- methyl)( 1 , 1 -biphenyl)-2-carbonitrile,
5-(((6-chloro-l,3-benzodioxol-5-yl)methoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 - methyl( 1 , 1 -biphenyl)-2-carbonitrile, 5-(((4-isopropylbenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,r- biphenyl)-2-carbonitrile, 5-(((3,4-dimethylbenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((4-(benzyloxy)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile, 5-(((6-fluoro-4H-l,3-benzoώoxin-8-yl)methoxy)(l-methyl-lH-imidazol-5- yl)methyl)-2 -methyl(l , 1 -biphenyl)-2-carbonitrile,
5-(((2,4-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((3,5-dimethylbenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile,
5-(((5-(tert-butyl)-l,2,4-oxadiazol-3-yl)methoxy)(l-methyl-lH-imidazol-5- yl)methyl)-2 -methyl(l , 1 -biphenyl)-2-carbonitrile,
5-(((4-iodobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, -biρhenyl)- 2-carbonitrile, 5-(((l,l'-biρhenyl)-4-ylmethoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((2-(4-chlorophenyl)- 1 ,3-thiazol-4-yl)methoxy)(l-methyl- lH-imidazol-5-yl)- methyl)-2'-methyl(l , 1 -biphenyl)-2-carbonitrile,
5-(((5-(2-methoxyphenyl)-l,2,4-oxadiazol-3-yl)methoxy)(l-methyl-lH-imidazol-5- yl)methyl)-2'-methyl(l, -biρhenyl)-2-carbonitrile,
5-(((4-chloro-2-nitrobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile, methyl 5-(((6-cyano-2'-methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)- methoxy)methyl)-2-furoate, 2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((5-(4-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)methoxy)methyl)(l , 1 -biphenyl)-2-carbonitrile, methyl 8-(((6-cyano-2'-methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5- yl)methoxy)methyl)-4H-l,3-benzodioxine-6-carboxylate,
(2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((6-nitro-4H-l,3-benzodioxin-8- yl)methoxy)methyl)(l , 1 -biphenyl)-2-carbonitrile,
2'-methyl-5-((l-methyl-lH-imidazol-5-yl)((5-(3-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)methoxy)methyl)(l,l'-biphenyl)-2-carbonitrile,
5-(((5-acetyl-2-methoxybenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 - methyl(l , 1 -biphenyl)-2-carbonitrile, 2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((5-ρhenyl-l,2,4-oxadiazol-3-yl)- methoxy)methyl) (1,1 -biphenyl)-2-carbonitrile, 5-(((5-(4-methoxyphenyl)-l,2,4-oxadiazol-3-yl)methoxy)(l-methyl-lH-imidazol-5- yl)methyl)-2'-methyl(l, -biphenyl)-2-carbomtrile,
5-(((5-(3-methoxyphenyl)-l,2,4-oxadiazol-3-yl)methoxy)(l-methyl-lH-imidazol-5- yl)methyl)-2'-methyl(l,l'-biphenyl)-2-carbonitrile, 2'-memyl-5-((l-methyl-lH-imidazol-5-yl)((2-(4-(trifluorornethyl)ρhenyl)-l,3-thiazol-
4-yl)methoxy)methyl)(l , 1 -biphenyl)-2-carbonitrile,
2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((5-methyl-3-isoxazolyl)methoxy)methyl)- (1,1 -biphenyl)-2-carbonitrile,
(2-methyl-5-((l-methyl-lH-imidazol-5-yl)((2-methyl-l-naphthyl)methoxy)methyl)- (l,l'-biρhenyl)-2-carbonitrile,
(2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((2,3,5,6-tetramethylbenzyl)oxy)methyl)- (1,1 -biphenyl)-2-carbonitrile,
(2'-methyl-5-((l-methyl-lH-irnidazol-5-yl)((4-(trifluoromethoxy)benzyl)oxy)- methyl)(l , 1 -biphenyl)-2-carbonitrile, 5-(((5,6-dichloro-3-ρyridinyl)methoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2- methyl(l , 1 -biphenyl)-2-carbonitrile,
5-(((3-chloro-5-(trifluoromethyl)-2-pyridinyl)methoxy)(l-methyl-lH-imidazol-5-yl)- methyl)-2'-methyl(l, -biphenyl)-2-carboni-rile,
2-methyl-5-((l-methyl-lH-imidazol-5-yl)(2-naphthylmethoxy)methyl)(l,r- biphenyl)-2-carbonitrile,
5-(((3-bromobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile,
5-(((2-bromobenzyl)oxy)(l-methyl-lH-irnidazol-5-yl)methyl)-2 -methyl(l, - biphenyl)-2-carbonitrile, 5-(((2,6-difluorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l - biphenyl)-2-carbonitrile,
5-(((2-fluoro-4-(trifluoromemyl)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'- methyl(l , 1 -biphenyl)-2-carbonitrile,
4-(((6-cyano-2 -methyl(l , 1 -biphenyl)-3-yI)(l-methyl- lH-imidazol-5-yl)methoxy)- methyl)-benzamide,
4-(((6-cyano-2'-methyl(l,r-biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methoxy)- methyl)-N-methylbenzamide,
4-(((6-cyano-2 -methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methoxy)- methyl)-N,N-dimethylbenzamide, 5-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -formyl(l, - biphenyl)-2-carbonitrile, 5-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-(trifluoromethyl)- (1,1 '-biphenyl)-2-carbonitrile,
2',4'-dichloro-5-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)(l, - biphenyl)-2-carbonitrile, 2-(l-benzothien-2-yl)-4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)- benzonitrile,
5 -(((4-cyanobenzyl)oxy)( 1 -methyl- 1 H-imidazol-5 -yl)methyl)-2 '-(hydroxymethyl)- (1,1 -biphenyl)-2-carbonitrile,
2 -cyano-5'-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)(l, - biphenyl)-2-carboxylic acid,
4-(((3,4-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(8-quinolinyl)- benzonitrile,
4-(((3-fluoro-4-(trifluoromethyl)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2- (8-quinolinyl)benzonitrile, 4-(((4-fluoro-3-(trifluoromethyl)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-
(8-quinolinyl)benzonitrile,
4-(((4-cyano-3-(8-quinolinyl)phenyl)(l-methyl-lH-imidazol-5-yl)methoxy)methyl)- benzoic acid,
6-(((4-cyano-3-(8-quinolinyl)phenyl)(l-methyl-lH-imidazol-5-yl)methoxy)methyl)- nicotinamide,
6-(((4-cyano-3-(8-quinolinyl)phenyl)(l-methyl-lH-imidazol-5-yl)methoxy)methyl)- nicotinic acid,
4-(((3-chloro-5-(trifluoromethyl)-2-pyridinyl)methoxy)(l-methyl-lH-imidazol-5- yl)methyl)-2-(8-quinolinyl)benzonitrile, 6-(((4-cyano-3 -(8 -quinolinyl)phenyl) ( 1 -methyl- 1 H-imidazol-5 -yl)methoxy)methyl)- nicotinonitrile,
5-(((3,4-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-(trifluoro- methyl)(l , 1 '-biphenyl)-2-carbonitrile,
5-(((3-fluoro-4-(1rifluoromethyl)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'- (trifluoromethyl)( 1 , 1 -biphenyl)-2-carbonitrile,
5-(((4-fluoro-3-(trifluoromethyl)benzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 - (trifluoromethyl)(l , 1 -biphenyl)-2-carbonitrile,
6-(((6-cyano-2'-(txifluoromethyl)(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)- methoxy)methyl)nicotinonitrile, 4-(((3-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile,
4-(((4-bromobenzyl)oxy)( 1 -methyl- lH-imidazol-5-yl)methyl)-2-(l -naphthyl)- benzonitrile,
4-(((6-cyano-2'-methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methoxy)- methyl)-benzoic acid,
4-((l-methyl-lH-imidazol-5-yl)((3-chlorobenzyl)oxy)methyl)-2-(l-naρhthyl)- benzonitrile,
5-(((4-cyano-3-( 1 -naphthyl)phenyl)( 1 -methyl- lH-imidazol-5-yl)methoxy)methyl)-2- pyridinecarbonitrile,
4-((l-methyl-lH-imidazol-5-yl)((4-azidobenzyl)oxy)methyl)-2-(l-naphthyl)- benzonitrile, methyl 6-(((6-cyano-2'-(trifluoromethyl)(l,l -biphenyl)-3-yl)(l-methyl-lH-imidazol-
5-yl)methoxy)methyl)nicotinate,
5-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2',3'-dimethyl(l, - biphenyl)-2-carbonitrile,
2',3'-dichloro-5-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)(l, - biphenyl)-2-carbonitrile,
6-(((2 3'-α-ichloro-6-cyano(l,r-biphenyl)-3-yl)(l-methyl-lH-imidazol-5- yl)methoxy)-methyl)nicotinonitrile,
6-(((6-cyano-2',3'-dimethyl(l,l'-biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)- methoxy)methyl)nicotinonitrile, and 4-((4-cyanophenoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile.
In another preferred embodiment of compounds of formula (IV) are compounds wherein
Q1 is O; W is N=C(H); and
X, Y, and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
6-(((4-cyano-3-(l-naphthyl)phenyl)(3-pyridinyl)methoxy)methyl)nicotinonitrile,
Example 296, Example 297,
Example 298,
Example 299,
Example 300,
Example 301, Example 302,
Example 303,
Example 306, Example 310,
Example 311,
Example 331,
Example 332, Example 344,
Example 345,
Example 346,
Example 348,
Example 349, Example 350,
Example 351,
Example 352,
Example 353,
Example 354, Example 355,
Example 357,
Example 358,
Example 359,
Example 360, Example 362,
Example 366,
Example 368,
Example 369,
Example 370, Example 371,
Example 372,
Example 373,
Example 374,
Example 375, Example 376,
Example 377,
Example 378,
Example 379,
Example 380, Example 381,
Example 382,
Example 383, Example 384,
Example 389,
Example 391,
Example 392, Example 393,
Example 394,
Example 395,
Example 396,
Example 397, Example 398,
Example 399,
Example 400,
Example 401,
Example 402, Example 403,
Example 404,
Example 405,
Example 406,
Example 407, Example 408,
Example 409,
Example 410,
Example 411,
Example 412, Example 413,
Example 414,
Example 415,
Example 416,
Example 417, Example 418,
Example 419,
Example 420,
Example 421,
Example 422, Example 423,
Example 424,
Example 425, Example 426,
Example 427,
Example 428,
Example 429, Example 430,
Example 431,
Example 432,
Example 433,
Example 434, Example 435,
Example 436,
Example 437,
Example 438,
Example 439, Example 440,
Example 441,
Example 442,
Example 443,
Example 444, Example 445,
Example 446,
Example 447,
Example 448,
Example 449, Example 451,
Example 453,
Example 454,
Example 455,
Example 456, Example 457,
Example 458,
Example 459,
Example 460,
Example 461, Example 462,
Example 463,
Example 464, Example 465,
Example 466,
Example 476,
Example 477, Example 478,
Example 479,
Example 480,
Example 481,
Example 503, Example 504,
Example 505,
Example 506,
Example 507,
Example 508, Example 509,
Example 510,
Example 511,
Example 512,
Example 513, Example 514,
Example 525,
Example 526,
Example 533,
Example 534, Example 535,
Example 537,
Example 538,
Example 539,
Example 540, Example 541,
Example 542, and
Example 547.
In another preferred embodiment of compounds of formula (IN) are compounds wherein Q1 is O;
W is S;
Y is Ν; and X, and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
5-((benzyloxy)(l ,3-thiazol-5-yl)methyl)-2'-methyl(l , 1 -biphenyl)-2-carbonitrile,
4-(((4-cyanobenzyl)oxy)(l,3-thiazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile,
6-(((4-cyano-3-(l-naphthyl)phenyl)(l,3-thiazol-5-yl)methoxy)methyl)nicotinonitrile,
Example 552,
Example 553,
Example 554
Example 555
Example 556
Example 557
Example 558
Example 559
Example 563
Example 567
Example 568
Example 589
Example 590
Example 602
Example 603
Example 604
Example 606
Example 607
Example 608
Example 609
Example 610
Example 611
Example 612
Example 613
Example 615
Example 616
Example 617
Example 618
Example 619
Example 623
Example 625
Example 626 Example 627,
Example 628,
Example 629,
Example 630, Example 631,
Example 632,
Example 633,
Example 634,
Example 635, Example 636,
Example 637,
Example 638,
Example 639,
Example 640, Example 645,
Example 647,
Example 648,
Example 649,
Example 650, Example 651,
Example 652,
Example 653,
Example 654,
Example 655, Example 656,
Example 657,
Example 658,
Example 659,
Example 660, Example 661,
Example 662,
Example 663,
Example 664,
Example 665, Example 666,
Example 667,
Example 668, Example 669,
Example 670,
Example 671,
Example 672, Example 673,
Example 674,
Example 675,
Example 676,
Example 677, Example 678,
Example 679,
Example 680,
Example 681,
Example 682, Example 683,
Example 684,
Example 685,
Example 686,
Example 687, Example 688,
Example 689,
Example 690,
Example 691,
Example 692, Example 693,
Example 694,
Example 695,
Example 696,
Example 697, Example 698,
Example 699,
Example 700,
Example 701,
Example 702, Example 703,
Example 704,
Example 705, Example 707,
Example 709,
Example 710,
Example 711, Example 712,
Example 713,
Example 714,
Example 715,
Example 716, Example 717,
Example 718,
Example 719,
Example 720,
Example 721, Example 722,
Example 732,
Example 733,
Example 734,
Example 735, Example 736,
Example 737,
Example 762,
Example 763,
Example 764, Example 765,
Example 766,
Example 767,
Example 768,
Example 769, Example 770,
Example 771,
Example 772,
Example 773,
Example 784, Example 785,
Example 792,
Example 793, Example 794,
Example 796,
Example 797,
Example 798, Example 799,
Example 800,
Example 801, and
Example 806.
In another preferred embodiment of compounds of formula (IN) are compounds wherein
Q1 is NCR4);
W is N;
Y is N; and
X and Z are C(H). Compounds which support this embodiment include, but are not limited to,
(2'-methyl-5-((l-methyl-lH-imidazol-5-yl)((4-nitrobenzyl)amino)methyl)(l,r- biphenyl)-2-carbonitrile,
4-(((4-cyanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile, 5-(((l-benzoyl-4-piperidinyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl-
(1,1 -biphenyl)-2-carbonitrile,
4-((l-methyl-lH-imidazol-5-yl)((4-(methylsulfonyl)benzyl)amino)methyl)-2-(l- naphthyl)benzonitrile,
5-((benzylamino)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, -biphenyl)-2- carbonitrile,
5-(((cyclohexylmethyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile,
5-(((4-cyanobenzyl)amino)( 1 -methyl- lH-imidazol-5-yl)methyl)-2'-methyl( 1,1 - biphenyl)-2-carbonitrile, 5-((((6-cyano-2'-methyl(l, -biphenyl)-3-yl)methyl)amino)(l-methyl-lH-imidazol-5- yl)methyl)-2'-methyl(l, -biphenyl)-2-carbonitrile,
5-((ethyl(4-nitrobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l, - biphenyl)-2-carbonitrile,
5-(((4-cyanobenzyl)(ethyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl- (l,l'-biphenyl)-2-carbonitrile,
4-(((4-cyanobenzyl)(methyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile, 4-((butyl(4-cyanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile,
4-(( 1 -methyl- lH-imidazol-5-yl)(phenethylamino)methyl)-2-( 1 -naphthyl)benzonitrile,
4-(((3-bromo-4-cyanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile,
4-(((3 -chloro-4-cy anobenzyl) amino) ( 1 -methyl- 1 H-imidazol-5 -yl)methyl)-2-( 1 - naphthyl)benzonitrile,
4-(((l-(4-cyanophenyl)ethyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile, 4-(((4-cyano-3-iodobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyl)benzonitrile, methyl 4-((((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)- amino)methyl)benzoate,
4-((((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)amino)- methyl)benzoic acid,
4-(((4-chlorobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile,
4-(((3,4-dichlorobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile, 4-((((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)amino)- methyl)-N-methylbenzamide, ethyl 4-(((4-cyano-3-(l -naphthyl)phenyl)( 1 -methyl- lH-imidazol-5-yl)methyl)- amino)- 1 -piperidinecarboxylate,
6-((((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)amino)- methyl)nicotinonitrile, methyl 6-((((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)- amino)methyl)nicotinate,
N-(4-((((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)amino)- methyl)phenyl)acetamide, benzyl 4-(((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)- amino)- 1 -piperidinecarboxylate,
4-((( 1 -benzyl-4-piperidinyl)amino) ( 1 -methyl- 1 H-imidazol-5 -yl)methyl)-2-( 1 - naphthyl)benzonitrile, tert-butyl 4-(((4-cyano-3-(l -naphthyl)phenyl)( 1 -methyl- lH-imidazol-5-yl)methyl)- amino)- 1 -piperidinecarboxylate,
4-((( 1 -benzoyl-4-piperidinyl)amino)( 1 -methyl- 1 H-imidazol-5 -yl)methyl)-2-( 1 - naphthyl)benzonitrile, 4-((((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)amino)- methyl)benzamide,
4-((l-methyl-lH-imidazol-5-yl)(((l-methyl-2-oxo-l,2-dihydro-4-pyridinyl)methyl)- amino)methyl)-2-(l-naphthyl)benzonitrile, 4-((4-cyanoanilino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile, and
4-((3-cyanoanilino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile.
In another preferred embodiment of compounds of formula (IN) are compounds wherein Q1 is Ν(R4);
W is N=C(H);
X, Y, and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
Example 304, Example 305,
Example 308
Example 309
Example 312
Example 313 Example 314
Example 315
Example 316
Example 317
Example 318 Example 319
Example 320
Example 321
Example 323
Example 324 Example 325
Example 326
Example 327
Example 330
Example 333 Example 334
Example 335
Example 336 Example 337,
Example 338,
Example 339,
Example 340, Example 341,
Example 342,
Example 343,
Example 452,
Example 544, and Example 545.
In another preferred embodiment of compounds of formula (IN) are compounds wherein
Q1 is NCR4);
W is S; Y is N; and
X and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
Example 561,
Example 562, Example 565,
Example 566,
Example 569,
Example 570,
Example 571, Example 572,
Example 573,
Example 574,
Example 575,
Example 576, Example 577,
Example 579,
Example 581,
Example 582,
Example 583, Example 584,
Example 585,
Example 588, Example 591,
Example 592,
Example 593,
Example 594, Example 595,
Example 596,
Example 597,
Example 598,
Example 599, Example 600,
Example 601,
Example 708,
Example 747,
Example 748, Example 749,
Example 750,
Example 751,
Example 752,
Example 803, and Example 804.
In another preferred embodiment of compounds of formula (IV) are compounds wherein
Q is S(O)t, wherein t is zero, one, or two;
W is N; Y is N; and
X and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
4-(((4-cyanobenzyl)sulfanyl)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)- benzonitrile, and
4-(((4-cyanobenzyl)sulf onyl) ( 1 -methyl- lH-imidazol-5 -yl)methyl)-2-( 1 -naphthyl)- benzonitrile.
In another preferred embodiment of compounds of formula (IV) are compounds wherein Q is S(O)t, wherein t is zero, one, or two;
W is N=C(H); and
X, Y, and Z are C(H). Compounds which support this embodiment include, but are not limited to, Example 347, and Example 356.
In another preferred embodiment of compounds of formula (IN) are compounds wherein
Q is S(O)t, wherein t is zero, one, or two; W is S;
Y is Ν; and X and Z are C(H). Compounds which support this embodiment include, but are not limited to,
Example 605, and
Example 614.
In another preferred embodiment of compounds of formula (IN) are compounds wherein Q1 is Ν(R5)SO2;
W is N;
Y is N; and
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.
In another preferred embodiment of compounds of formula (IV) are compounds wherein
Q1 is N(R5)SO2; W is N=C(H); and
X, Y, and Z are C(H).
A compound which supports this embodiment includes, but is not limited to,
Example 543.
In another preferred embodiment of compounds of formula (IN) are compounds wherein
Q1 is Ν(R5)SO2;
W is S;
Y is N; and
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
Q is absent;
W is Ν; Y is Ν; and
X and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
(2 -methyl-5-((l-methyl-lH-imidazol-5-yl)(3-oxo-4-(3-(trifluoromethoxy)phenyl)-l- piperazinyl)methyl)(l , 1 -biphenyl)-2-carbonitrile, and tert-butyl l-((4-cyano-3-(l-naphthyl)phenyl)(l-methyl-lH-imidazol-5-yl)methyl)-4- piperidinylcarbamate.
In another preferred embodiment of compounds of formula (IN) are compounds wherein
Q is absent;
W is Ν=C(H); and
X, Y, and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
Example 307, and
Example 546.
In another preferred embodiment of compounds of formula (IV) are compounds wherein
Q is absent;
W is S;
Y is N; and
X and Z are C(H).
Compounds which support this embodiment include, but are not limited to,
Example 564, and
Example 805.
In another embodiment, the instant invention discloses compounds of formula (V)
(N), or a pharmaceutically acceptable salt thereof, wherein
R is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, and a nitrogen protecting group; β
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 W is C(H)=C(H), X is N, and Y and Z are C(H); or
W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X and its right end attached to the carbon substituted with L ; and 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
C(H) or N; with the proviso that R is present when and only when W is N. In a preferred embodiment of compounds of formula (V) are compounds wherein 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-(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
4-(l-hydroxy-l-(l-methyl-lH-imidazol-5-yl)-3-phenyl-2-propynyl)-2-(l- naphthyl)benzonitrile.
In another preferred embodiment of compounds of formula (V) are compounds wherein
W is N=C(H); and X, Y, and Z are C(H).
Compounds which support this embodiment include, but are not limited to, Example 385, Example 386, and
Example 387.
In another preferred embodiment of compounds of formula (V) are compounds wherein
W is S; Y is N; and
X and Z are C(H).
Compounds which support this embodiment include, but are not limited to, Example 641,
Example 642, and
Example 643.
In another embodiment, the instant invention discloses compounds of formula (VI)
(VI), or pharmaceutically acceptable salts thereof, wherein W' is N or S; and one of X', Y', or Z' is C(H), and the remainder are C(H) or N;
R A' is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group; and
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.
In another embodiment, the instant invention discloses compounds of formula (VII)
(vπ), or pharmaceutically acceptable salts thereof, wherein W'is N or S; and one of X', Y', or Z' is C(H), and the remainder are C(H) or N;
R A' is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group; and
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. In another embodiment, the instant invention discloses compounds of formula (Niϊi)
(vm), or pharmaceutically acceptable salts thereof, wherein a is zero to six; W'is N or S; and one of X', Y', or Z' is C(H), and the remainder are C(H) or N;
A'
R is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group; and
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;
A' with the proviso that R is present when and only when W' is N.
In a preferred embodiment of compounds of formula (NIII) are compounds wherein
Q1 is O; W'is Ν;
Y'is Ν; and
X' and Z' are C(H).
A compound which supports this embodiment includes, but is not limited to,
4-(((4-cyanobenzyl)oxy)(l-trityl-lH-imidazol-4-yl)methyl)-2-(l- naphthyl)benzonitrile.
In another preferred embodiment of compounds of formula (VIE) are compounds wherein
Q1 is O;
W'is S; and X', Y', and Z' are C(H).
Compounds which support this embodiment include, but are not limited to,
5-((benzyloxy)(3-thienyl)methyl)-2'-methyl(l , 1 -biphenyl)-2-carbonitrile, and
6-(((4-cyano-3-(l-naphthyl)phenyl)(3-thienyl)methoxy)methyl)nicotinonitrile.
In another embodiment, the instant invention discloses compounds of formula (LX)
(IX), or pharmaceutically acceptable salts thereof, wherein W' is N or S; and one of X', Y', or Z' is C(H), and the remainder are C(H) or N;
R A' is absent or selected from the group consisting of hydrogen, optionally substituted alkyl, alkoxycarbonyl, hydroxyl, and a nitrogen protecting group; and
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;
A' with the proviso that R is present when and only when W is N.
or pharmaceutically acceptable salts thereof, wherein b is two to six; r>
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.
In another embodiment, the instant invention discloses compounds of formula (XI)
(XI), or pharmaceutically acceptable salts thereof, wherein
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.
In another embodiment, the instant invention discloses compounds of formula (XII)
(XH), or pharmaceutically acceptable salts thereof, wherein a is zero to six; c is zero to two;
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.
In a preferred embodiment of compounds of formula (XII) are compounds wherein c is zero;
X is C(H); Y is N; and
Q1 is O.
A compound which supports this embodiment includes, but is not limited to,
5-(l -(benzyloxy)-2-( lH-imidazol- 1 -yl)ethyl)-2 -methyl ( 1 , 1 -biphenyl)-2-carbonitrile.
In another embodiment, the instant invention discloses compounds of formula (XIIT)
or pharmaceutically acceptable salts thereof, wherein
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.
In another embodiment, the instant invention discloses compounds of formula (XIV)
or a pharmaceutically acceptable salt thereof, wherein 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 W is C(H)=C(H), X is N, and Y and Z are C(H); or
W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X
2 and its right end attached to the carbon substituted with L ; and 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 C(H) or N; with the proviso that R is present when and only when W is N.
In a preferred embodiment of compounds of formula (XIV) are compounds wherein
W is N;
Y is N; and
X and Z are C(H). Compounds which support this embodiment include, but are not limited to,
(2'-methyl-5-((l-methyl-lH-imidazol-5-yl)carbonyl)(l, -biphenyl)-2-carbonitrile,
4-((l-methyl-lH-irnidazol-5-yl)carbonyl)-2-(8-quinolinyl)benzonitrile, and
5-((l-methyl-lH-imidazol-5-yl)carbonyl)-2'-(trifluoromethyl)(l, -biphenyl)-2- carbonitrile. In another preferred embodiment of compounds of formula (XIN) are compounds wherein
W is Ν=C(H); and
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; and
X, Y, and Z are C(H).
Compounds which support this embodiment are Example 624,
Example 760, and Example 761.
In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (I).
In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (II).
In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (III).
In another embodiment, 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).
In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (VI).
In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (VII).
In another embodiment, 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).
In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (X).
In another embodiment, 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).
In another embodiment, the instant invention discloses a method for inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (XIII).
In another embodiment, the instant invention discloses a method of inhibiting farnesyltransferase comprising administering a pharmaceutically acceptable amount of a compound of formula (XIN).
In another embodiment, 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).
In another embodiment, 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). In another embodiment, 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).
In another embodiment, 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).
In another embodiment, 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).
In another embodiment, 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). In another embodiment, 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).
In another embodiment, 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).
In another embodiment, 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). In another embodiment, 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).
In another embodiment, 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).
In another embodiment, 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).
In another embodiment, 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).
In another embodiment, 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). In another embodiment, the instant invention discloses a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the instant invention discloses a compound of formula (II) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the instant invention discloses a compound of formula (III) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the instant invention discloses a compound of formula (IV) in combination with a pharmaceutically acceptable carrier.
In another embodiment, 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.
In another embodiment, 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.
In another embodiment, the instant invention discloses a compound of formula (X) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the instant invention discloses a compound of formula (XI) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the instant invention discloses a compound of formula (XII) in combination with a pharmaceutically acceptable carrier.
In another embodiment, 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.
Detailed Description of The Invention
The instant invention provides substituted phenyl farnesyltransferase inhibitors. As used in the specification, the following terms have the meanings indicated.
The term "alkanoyl," as used herein, 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.
The term "alkoxy," as used herein, 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.
The term "alkoxycarbonyl," as used herein, 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. The term "alkenyl," as used herein, refers to a monovalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbon-carbon double bond.
The term "alkenylene," as used herein, refers to a divalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbon-carbon double bond.
The term "alkyl," as used herein, refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons. The term "alkylene," as used herein, refers to a divalent straight or branched chain saturated hydrocarbon diradical having from one to six carbons.
The term "alkylsulfonyl," as used herein, 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.
The term "alkynyl," as used herein, refers to a monovalent straight or branched chain hydrocarbon group having from two to six carbons and at least one carbon-carbon triple bond.
The term "alkynylene," as used herein, refers to a divalent straight or branched chain hydrocarbon group having from two to six carbons and at least one carbon-carbon triple bond.
The term "amino," as used herein, refers to -NH2 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.
The term "aminosulfonyl," as used herein, refers to an amino group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
The terms "amino protecting group," or "nitrogen protecting group," as used herein, refer to selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of 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). The term "aryl," as used herein, 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. The 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. 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.
The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
The term "arylsulfonyl," as used herein, refers to an aryl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
The term "aryloyl," as used herein, refers to an aryl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
The term "azido," as used herein, refers to -N3.
The term "carbonyl," as used herein, refers to -C(O)-. The term "carboxamido," as used herein, refers to an amide; e.g., an amino group attached to the parent molecular group through a carbonyl group, as defined herein.
The term "carboxyl," as used herein, refers to -CO2H or a derivative thereof formed by replacement of the hydrogen atom thereon by a carboxyl protecting group.
The term "carboxyl protecting group," as used herein, 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. Examples of 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, methoxyethoxymethyl, arylalkoxyalkyl benzyloxymethyl l,l-dimethyl-2- propenyl, 3-methyl-3-butenyl, allyl, and the like. Preferred carboxyl protecting groups of the instant invention are alkyl and arylalkyl. The term "cyano," as used herein, refers to -CN.
The term "cycloalkyl," as used herein, 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. The 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.
The term "cycloalkylalkyl," as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein. The term "cycloalkyloyl," as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
The term "cycloalkylsulfonyl," as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein. The terms "halo" or "halide," as used herein, refer to F, Cl, Br, or I. The term "heteroaryl," as used herein, 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. The 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. The 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. The 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. The term "heteroarylalkyl," as used herein, refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein. The term "heteroaryloyl," as used herein, refers to a heteroaryl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein. The term "heteroarylsulfonyl," as used herein, refers to a heteroaryl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein. The term "heterocycloalkyl," as used herein, 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. The four-membered rings have zero double bonds, the five-membered rings have zero or one double bonds, and the six- and seven- membered rings have zero, one, or two double bonds. 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, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, and triazinyl. 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. The term "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.
The term "heterocycloalkylalkyl," as used herein, refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
The term "heterocycloalkyloyl," as used herein, refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
The term "heterocycloalkylsulfonyl," as used herein, refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
The term "hydroxyalkyl," as used herein, refers to a hydroxyl group attached to the parent molecular group through an alkyl group, as defined herein.
The term "hydroxyl," as used herein, refers to -OH or a derivative thereof formed by replacement of the hydrogen atom thereon with a hydroxyl protecting group.
The term "hydroxyl protecting group," as used herein, refers to selectively introducible and removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures. Examples of 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,l-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para- methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxyl protecting groups for the instant invention are acetyl, benzyl (Bn), benzoyl (Bz), and tert-butyl. The term "oxo," as used herein, refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
The term "perfluoroalkoxy," as used herein, refers to a perfluoroalkyl group attached to the parent group through an oxygen atom.
The term "perfluoroalkyl," as used herein, 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. The term "pharmaceutically acceptable salt," as used herein, 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, trifluoroacetic, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, 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. Examples of 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. Pharmaceutically acceptable 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. The term "pharmaceutically acceptable prodrug," as used herein, 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.
The term "prodrug," as used herein, represents compounds which are rapidly transformed in vivo to parent compounds of formulas (I)-(XlTf), for example, by hydrolysis in blood.
The term "substituted alkyl," as used herein, 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. The term "sulfonyl," as used herein, refers to -SO2-.
Asymmetric centers exist in the compounds of the instant invention. 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. The term "tautomer" as used herein 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.
According to methods of treatment, 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. When using the compounds of the instant invention for chemotherapy, 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. For example, when used in the treatment of solid tumors, compounds of the instant invention 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, thalidomide, SP-PG, and the like. For example, a tumor may be treated conventionally with surgery, radiation or chemotherapy and a compound of the instant invention with subsequent compound adminsteration of the compound to extend the dormancy of micrometastases and to stabilize and inhibit the growth of any residual primary tumor.
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. The term "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. Among the 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. Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, 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. Conversely, absorption enhancers can be used to increase absorption. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, 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.
Determination of Biological Activity
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 (NH4)2Sθ4 followed by chromatography on DEAE Sepharose. A Hydrophobic Interaction Chromatography (HIC) media, Fractogel-Phenyl (EM Industries) was used to separate FTase from GGTase; and chromatography of each enzyme on MonoQ (Pharmacia) resulted in further purification of the enzymes. The catalytic purity of each enzyme was assayed separately with substrate acceptor proteins specific for that enzyme.
After quickly freezing in liquid nitrogen, the various prenyl transferases were stored at -80 °C.
Bovine FTase was assayed at 37 °C for 30 minutes in a volume of 100 μL containing 44 mM HEPES, pH 7.4, 26 mM MgCl2, 4.4 mM DTT, 18 mM KC1, 0.009% Triton X-100,
3 3 256 nM [ H]-famesyl pyrophosphate, triammonium salt ([ HJ-FPP, 759 GBq/mmol, New England Nuclear), 100 nM biotin- -ras peptide (American Peptide Company), and FTase (12.5 μg/mL total protein). Reactions are initiated by the addition of FTase and stopped by the addition of 75 μL of a 1.43 mg/mL suspension of streptavidin SPA (Scintillation Proximity Assay) beads (Amersham) in 0.2M sodium phosphate, pH 4, containing 1.5M MgCl2, 0.5% BSA and 0.05% sodium azide. The quenched reactions stood for 1 hour before analysis in a Packard TopCount scintillation counter. Purified compounds were dissolved in 100% ethanol and diluted 10-fold into the assay. The percent inhibition of the compounds of the instant invention at 10" M was then measured.
The percent inhibition of representative compounds of the instant invention are shown in Table 1.
Table 1 Inhibitory Potencies of Representative Compounds
Representative compounds of the instant invention were also tested for cardiovascular liability (see Journal of Cardiovascular Pharmacology, 607-618: 37 (2001)). Example 291 was shown to possess an improved electrophysiological profile.
As shown by the data in Table 1, the compounds of the instant invention, including but not limited to those specified in the examples, are useful for the treatment of diseased caused or exascerbated by farnesyltransferase. As farnesyltransferase inhibitors, 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 (astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, and meningiomas); solid tumors arising from hematopoietic malignancies (leukemias and chloromas); plasmacytomas; plaques; tumors of mycosis fungoides; cutaneous T-cell lymphoma/leukemia; lymphomas including Hodgkin's and non-Hodgkin's lymphomas; prophylaxis of autoimmune diseases (rheumatoid, immune and degenerative arthritis); ocular diseases (diabetic retinopathy, retinopathy of prematurity, comeal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration, and hypoxia); skin diseases (psoriasis, hemagiomas and capillary proliferation within atherosclerotic plaques).
Synthetic Methods
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, A1, L1, L2, M1, Q1, Q2, Ra, Rb R1, R2, R3, R4, R5, 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. It will be readily apparent to one of ordinary skill in the art that the compounds can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will also be apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of a, b, c, A1, L1, L2, M1, Q1, Q2, Ra, Rb R1, R2, R3, R4, R5, W, W', X, X', Y, Y', Z, and Z' to successfully complete the syntheses of compounds of the instant invention. Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: OAc for acetate; PyBop for benzotriazol-1-yl-oxy-tris- (pyrrolidino)phosphoniumhexafluorophosphate; DMAP for 4-(N,N-dimethylamino)pyridine; DME for 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 for trifluoroacetic acid; and THF for tetrahydrofuran.
Scheme 1
(1) (2)
formula (II) As shown in Scheme 1, compounds of formula (1) can be converted to compounds of
2 formula (2), wherein L is optionally substituted alkylene, by treatment of the former with an organometallic nucleophile in a solvent such as THF, dioxane, MTBE, or diethyl ether. Representative 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
2 formula (2), wherein L is alkylene, by treatment of the former with a reducing agent in a solvent such as THF, dioxane, or diethyl ether. Representative reducing agents include LiAlH4 and NaBIL. 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 (2) can be converted to compounds of formula (II) by treatment of the former with compounds of formula (3), wherein M p is an M precursor such as halo, in the presence of silver(I) oxide in a solvent such as dichloromethane, carbon tetrachloride, or chloroform. The reaction temperature is about 20 °C to about 40 °C and depends on the method chosen. Reaction times are typically about 6 to about 48 hours.
As shown in Scheme 2, 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. 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.
Scheme 3
(7) (4) formula (HI)
As shown in Scheme 3, 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. 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. 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.
formula (HI) (8)
formula (IV) As shown in Scheme 4, compounds of formula (III) can be treated with compounds of formula (8), wherein Q p is a Q precursor such as halo, under the conditions described in Scheme 1 to provide compounds of formula (IV).
Scheme 5
formula (XIV) (9)
formula (IV) As shown in Scheme 5, compounds of formula (XIV) can be converted to compounds of formula (9) by sequential treatment of the former with a chlorinating agent such as SOCI2, PPt^/CC , PCI5, or PPI13/NCS and 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.
formula (HI) (11)
/ SH
Cϊ
Rd
(12)
formula (IN) As shown in Scheme 6, 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, ΝaIθ4, 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. formula (IV) As shown in Scheme 7, 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. 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.
Scheme 8
(11) (14) formula (IV) As shown in Scheme 8, compounds of formula (11) can be converted to compounds of formula (IV) by treatment of the former with compounds of formula (14), wherein R is an alcohol, thiol, or a primary or secondary amine, in the presence of a base such as diisopropylethylamine, pyridine, or triethylamine in a solvent such as dichloromethane, carbon tetrachloride, or chloroform. The reaction temperature is about 30 °C to about 100 °C and depends on the method chosen. Reaction times are typically about 1 to about 12 hours.
Scheme 9
formula (XIV) (15) formula (V)
As shown in Scheme 9, 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
2 formula (V), wherein Q is alkylene or alkenylene, by hydrogenation in the presence of palladium catalysts such as Pd BaSθ4, Pd/CaCO3, and Pd/C in a solvent such as methanol, ethanol, or isopropanol. The 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.
Scheme 10
formula (VI) As shown in Scheme 10, compounds of formula (16) can be converted to compounds of formula (17) and subsequently to compounds of formula (VI) by the methods described in Scheme 1.
Scheme 11
(4) (5) (6)
formula (VI) As shown in Scheme 11, compounds of formula (4) can be converted to compounds of formula (6) and subsequently to compounds of formula (VI) by the methods described in Scheme 2.
(18) (4) formula (Vπ)
As shown in Scheme 12, compounds of formula (18) can be converted to compounds of formula (VH) by the methods described in Scheme 3. formula (VIH) As shown in Scheme 13, compounds of formula (Hla) can be converted to compounds of formula (VIH) by the methods described in Schemes 4 through 8.
Scheme 14
formula (VII) (15) formula (IX)
As shown in Scheme 14, compounds of formula (VH) can be converted to compounds of formula (IX) by treatment with compounds of formula (15) under the conditions described in Scheme 9.
formula (X) As shown in Scheme 15, compounds of formula (19) can be reacted with oxirane to provide compounds of formula (21), wherein b is 2, which can be converted to compounds of formula (X) by treatment with compounds of formula (3) under the conditions described in Scheme 1.
(21) (22)
formula (X) As shown in Scheme 16, compounds of formula (21) can be converted to compounds of formula (22) by treatment with an oxidizing agent such as Dess-Martin periodinane, Mnθ2, PCC, and K^C^Oγ 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.
Scheme 17
formula (XI) As shown in Scheme 17, 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. 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. 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.
formula (XI) formula (XH)
As shown in Scheme 18, compounds of formula (XI) can be converted to compounds of formula (XH) using the conditions described in Schemes 4 through 8. Scheme 19
formula (XI) (15) formula (XHI)
As shown in Scheme 19, compounds of formula (XI) can be converted to compounds of formula (XHI) by treatment of the former with compounds of formula (15) under the conditions described in Scheme 9.
The instant invention will now be described in connection with other particularly preferred embodiments of Schemes 1-19, which are not intended to limit its scope. On the contrary, the instant invention covers all alternatives, modifications, and equivalents which are included within the scope of the claims. Thus, the following examples will illustrate an especially preferred practice of the instant nvention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.
It will be evident to one skilled in the art that the instant invention is not limited to the forgoing examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. Thus, it is desired that the examples be considered as illustrative and not restrictive, reference being made to the claims, and that all changes which come within the meaning and range of equivalency of the claims be embraced therein.
Example 1 5-((benzyloxy)(6-fluoro-2,methyl(l, -biphenyl)-3-yl)methyl)-l-methyl-lH-imidazole hydrochloride
Example 1A 6-fluoro-2 -meth yl( 1,1 -biphenyl)-3-carbaldehyde A mixture of 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 Na2CO3 (14 mL), and triphenylphosphine (102 mg, 0.39 mmol) in toluene (13 mL) was heated to 100 °C for 90 minutes with vigorous stirring, and cooled to room temperature to provide two separate layers. 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.
MS (DCI/NH3) m z 214 (M+H)+ and 232 (M+NH4)+; 1H NMR (300 MHz, CDC13) δ 10.0 (s, IH), 8.95 ( , IH), 8.83 (dd, IH), 7.40-7.15 (m, 5H), 2.2 (s, 3H).
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. The extract was washed sequentially with saturated N-1HCO3, water, and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 96.5:2.5:1 to 89:10:1 ethyl acetate/methanol/ concentrated ammonium hydroxide to provide the desired product. MS (DCINH3) m/z 297 (M+H)+;
!H NMR (300 MHz, CD3OD) δ 7.6 (s, IH), 7.45 (m, IH), 7.35-7.10 (m, 5H), 6.55 (s, IH), 5.90 (s, IH), 3.65 (s, 3H), 2.15 (s, 3H), 1.90 (s, IH).
Example IC 5 -((benzyloxy)(6-fluoro-2'methyl( 1 , 1 '-biphenyl)-3 -vDmethyl)- 1 -methyl- lH-imidazole hydrochloride A solution of Example IB (133 mg, 0.45 mmol) in DMF (1 mL) at -3 °C was treated with a 60% oily sodium hydride (28 mg, 0.68 mmol), stirred for 1 hour, treated with (bromomethyl)benzene (60 μL, 0.5 mmol), stirred for 18 hours at room temperature, treated with water, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by preparative HPLC with 4:1/CH3CN:0.1% aqueous TFA to 0.1% aqueous TFA. The appropriate fractions were combined and concentrated. The concentrate was treated with saturated NaHCO3, and the resulting solution was extracted with ethyl acetate. The extract was dried (Na2SO4), 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)+;
1H NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 7.6-7.2 (m, 12H), 5.95 (s, IH), 4.55 (q, 2H), 3.75 (s, 3H), 2.15 (s, 3H);
Anal, calcd for C25H24ClFN2O-1.25H2θ: C, 67.41; H, 6.00; N, 6.29. Found: C, 67.48; H, 5.85; N 6.13.
Example 2 benzyl (2 -methyl(l,l -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methyl ether, hydrochloride
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. MS (DCINH3) m/z 214 (M+NE ) ;
1H NMR (300 MHz, CDC13) δ 10.1 (s, IH), 7.85 (m, 2H), 7.6 (m, 2H), 7.35-7.2 (m, 4H), 2.25 (s, 3H).
Example 2B (2 -methyl(l,l -biρhenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methanol
The desired product was prepared by substituting Example 2 A for Example 1 A in Example IB.
MS (DCI/NH3) m/z 279 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 7.6 (s, IH), 7.5-7.1 (m, 7H), 6.55 (s, IH), 5.95 (s, IH), 3.7 (s, 3H), 2.2 (s, 3H).
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.
MS (ESI(+)) m/z 369 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 7.8-7.2 (m, 13H), 5.95 (s, IH), 4.6 (q, 2H), 3.75 (s, 3H), 2.2 (s, 3H);
Anal, calcd for C25H25ClN2O-1.35H2O: C, 69.95; H, 6.50; N, 6.53. Found: C, 69.89, H, 6.23; N, 6.78.
Example 3 5-((benzyloxy)(6-chloro-2-methyl(l,r-biphenyl)-3-yl methyl)-l-methyl-lH-imidazole hydrochloride
Example 3A
4-chloro-3-iodobenzoic acid A solution of 3-amino-4-chlorobenzoic acid (8.6 g, 50 mmol) in 2:1 3M HCl/acetone (150 mL) at -3 °C was treated dropwise with sodium nitrite (3.8 g, 55 mmol) in water (30 mL), stirred for 30 minutes, treated with potassium iodide (14.5 g, 87.5 mmol) in water (50 mL), stirred for 15 minutes at 0 °C and at room temperature for 2 hours, and treated with water (500 mL) and excess NaHCO3 to provide a solid. The solid was collected by filtration and recrystalized from 20% methanol/water to provide the desired product. MS (DCI/NH3) m/z 282 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 13.35 (br s, IH), 8.4 (d, IH), 7.95 (dd, IH), 7.7 (d, IH).
Example 3B 4-chloro-3-iodo-N-methoxy-N-methylbenzamide A mixture of Example 3A (2.82 g, 10 mmol), EDC (2.11 g, 11 mmol), HOBt (1.68 g, 11 mmol), and N,O-dimethylhydroxylamine hydrochloride (1.26 g, 13 mmol) in DMF (30 mL) was stirred until all of the reagents dissolved, treated with triethylamine (2.54 mL, 18 mmol), stirred for 3 days at room temperature, treated with l:l/ethyl acetate:water, stirred for 1 hour, poured into water, and extracted with ethyl acetate. The extract was washed sequentially with 2M Na2CO3, water, and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:l/hexanes:efhyl acetate to provide the desired product. MS (DCI/NH3) m/z 343 (M+NH-4)+; H NMR (300 MHz, CDC13) δ 8.2 (d, IH), 7.65 (dd, IH), 7.5 (s, IH), 3.55 (s, 3H), 3.35 (s, 3H).
Example 3C
6-chloro-N-methoxy-N,2'-dimethyl(l , 1 '-biphenyl)-3-carboxamide A mixture of Example 3B (2.61 g, 8.02 mmol), 2-methylphenylboronic acid (1.20 g, 8.82 mmol), (1,1 -bis(diphenylphosphino)ferrocene)dichloropalladium (H) (196 mg, 0.24 mmol), CsF (2.44 g, 16.14 mmol), and DME (40 mL) was heated to reflux for 18 hours, cooled to room temperature, treated with diethyl ether, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 7:3/hexanes:ethyl acetate to provide the desired product. MS (DCI/NH3) m/z 307 (M+NIL ; H NMR (300 MHz, CDC13) δ 7.7-7.1 (m, 7H), 3.55 (s, 3H), 3.35 (s, 3H), 2.1 (s, 3H).
Example 3D
6-chloro-2'-methyl(l, -biphenyl)-3-carbaldehyde A solution of Example 3C (1.167 g, 4 mmol) in THF (10 mL) at -10 °C was treated dropwise with IM lithium aluminum hydride in THF (4.4 mL, 3.3 mmol), stirred for 2 hours, treated sequentially with THF/water (1 mL:0.17 mL), 4M NaOH (0.17 mL), and water (0.5 mL), warmed to room temperature, and extracted with l:l/ethyl acetate:hexanes. The extract was dried (Na2SO4), filtered through a pad of silica gel, and concentrated to provide material of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m z 230 (M+H)+; H NMR (300 MHz, CDCI3) δ 10.0 (s, IH), 7.9-7.1 (m, 7H), 2.1 (s, 3H).
Example 3E (6-chloro-2'-methyl(l, -biphenyl)-3-yl)(l-methyl-lH-imidazol-5-yl)methanol The desired product was prepared by substituting Example 3D for Example 1 A in Example IB. MS (DCI/NH3) m z 313 (M+H)+; H NMR (300 MHz, CDCI3) δ 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.
MS (ESI(+)) m/z 403 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 7.7 (dd, IH), 7.5 (dt, IH), 7.4-7.1 (m, 10H), 5.95 (s, IH), 4.6 (q, 2H), 3.75 (d, 3H), 2.1 (s, 3H); Anal, calcd for C, 65.52; H, 5.74; N, 6.11. Found: C, 65.49; H, 5.77; N, 6.18.
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
Example IB.
MS (DCI/NH3) m/z 304 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 7.85 (dd, IH), 7.6-7.1 (m, 6H), 6.55 (s, IH), 6.0 (s, IH), 3.7 (s, 3H).
Example 4B 2 -methyl-5-((l-methyl-lH-imidazol-5-yl)(phenoxy)methyl)(l,l -biphenyl)-2-carbonitrile A solution of Example 4A (106 mg, 0.35 mmol), phenol (38.5 mg, 0.35 mmol), and triphenylphosphine (139.2 mg, 0.525 mmol) in THF (2 mL) was treated with diethyl azodicarboxylate (90 μL, 0.525 mmol), stirred for 24 hours, poured into water, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 96.5:2.5: 1/ethyl acetate:methanol:concentrated ammonium hydroxide to provide the desired product. MS (ESI(+)) m/z 380 (M+H)+;
XH NMR (300 MHz, CDCI3) δ 7.8-6.9 (m, 12H), 6.7 (s, IH), 6.35 (s, IH), 3.6 (s, 3H).
Example 4C 2 -methyl-5-((l-methyl-lH-imidazol-5-yl)(phenoxy)methyl)(l, -biphenyl)-2-carbonitrile hydrochloride
A solution of Example 4B (82 mg ) in 4M HCl in dioxane (2 mL) was stirred for 2 hours and concentrated. The concentrate was treated with water (2 mL) and lyophilized. The product was purified by HPLC with continuous 20% to 100%:0.1%TFA/water: CH3CN. The appropriate fractions were combined, adjusted to pH 7-8 with NaHCO3, and extracted with ethyl acetate. The extract was dried (NaSO4), filtered, and concentrated. The concentrate was dissolved in 4M HCl in dioxane (0.5 mL), stirred for 3 hours, and concentrated. The concentrate was treated with water and lyophilized to provide the desired product. MS (ESI(+)) m z 380 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 8.05 (d, 2H), 7.75-6.95 (m, 13H), 3.8 (s, 3H), 3.55 (s, IH), 2.0 (s, 3H);
Anal, calcd for C25H22ClN3O-2.6H2O: C, 64.76; H, 5.93; N, 9.06. Found: C, 64.90; H, 5.40; N, 7.60.
Example 5 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2,-methoxy(l, -biphenyl)-2-carbonitrile hydrochloride
Example 5A ethyl 6-cyano-2 -methoxy( 1 , 1 -biphenyl)-3 -carboxylate The desired product was prepared by substituting ethyl 3-bromo-4-cyanobenzoate and 2-methoxyphenylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1 A. MS (DCI/NH3) m/z 299 (M+NE ; H NMR (300 MHz, CDC13) δ 8.1 (m, 2H), 7.8 (d, IH), 7.45 (m, IH), 7.25 (dd, IH), 7.05 (m, 2H), 4.4 (q, 2H), 3.8 (s, 3H), 1.4 (t, 3H).
Example 5B
5-(hvdroxymethyl)-2 -methoxy(l,r-biphenyl -2-carbonitrile A solution of Example 5A (389 mg, 1.38 mmol) in THF (3 mL) was treated sequentially with calcium chloride (312 mg, 2.76 mmol), absolute ethanol (4 mL), and sodium borohydride (209 mg, 5.52 mol), stirred for 48 hours, treated with water (1 mL) and 2M HCl (2 mL) to break up any solid, and extracted with diethyl ether. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The product was purified by flash column chromatography on silica gel with 1:1 ethyl/acetate ".hexanes to provide the desired product.
MS (DCI/NH3) m/z 357 (M+NH4)+; H NMR (300 MHz, CD3OD) δ 7.75 (d, IH), 7.45 ( , 3H), 7.25 (dd, IH), 7.15-7.0 ( , 2H),
4.7 (s, 2H), 3.8 (s, 3H).
Example 5C 5-formyl-2 -methoxy(l, -biρhenyl)-2-carbonitrile A solution of oxalyl chloride (0.25 mL, 2.76 mmol) in dichloromethane (2 mL) at
-78 °C was treated with DMSO (0.4 mL, 5.52 mmol), stirred for 20 minutes, treated with Example 5B (331 mg, 1.38 mmol) in dichloromethane (3 mL), stirred for 3 hours at -78 °C, treated with triethylamine (0.77 mL, 5.52 mmol), warmed to room temperature, poured into diethyl ether (20 mL), washed sequentially with water, saturated NaHCO3, water, and brine, dried (Na2SO4), filtered, and concentrated to provide material of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 255 (M+NH4)+;
1H NMR (300 MHz, CDCI3) δ 10.1 (s, IH), 7.95 (m, 3H), 7.45 (dt, IH), 7.3 (dd, IH), 7.15- 7.0 (m, 2H), 3.85 (s, 3H).
Example 5D 5-(hydroxy(l-methyl-lH-imidazol-5-yl)methyl)-2'-methoxy(l,r-biphenyl)-2-carbonitrile
The desired product was prepared by substituting Example 5C for Example 1 A in Example IB.
MS (DCI/NH3) m/z 320 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 7.8 (d, IH), 7.7-7.4 (m, 3H), 7.3-6.9 (m, 3H), 6.6 (s, IH), 6.0 (s, IH), 3.8 (s, 3H), 3.7 (s, 3H).
Example 5E 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methoxy(l,r-biphenyl)-2-carbonitrile hydrochloride A mixture of Example 5D (113 mg, 0.35 mmol), silver (I) oxide (91 mg, 0.39 mmol),
(bromomethyl)benzene (0.05 mL, 0.42 mmol), and dichloromethane (15 mL) was stirred for 36 hours in darkness, filtered through a pad of diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated ammonium hydroxide. The appropriate fractions were concentrated, and the concentrate was dissolved in 4M HCl in dioxane (1 mL), stirred for 3 hours, and concentrated. The concentrate was treated with water and lyophilized to provide the desired product. MS (ESI(+)) m/z 410 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.0 (s, IH), 8.0-7.0 (m, 12H), 6.0 (s, IH), 4.55 (q, 2H), 3.75 (s, 3H), 3.65 (s, 3H).
Example 6 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-3'-(phenyl)(l,r-biphenyl)-2-carbonitrile hydrochloride
Example 6A 3-(dihydroxyboryl)-l , 1 '-biphenyl A solution of 1.7M tert-butyllithium in pentane (12.6 mL, 21.5 mmol) in diethyl ether (65 mL) at -78 °C was treated with 3-bromo-l,l'-biphenyl (2 g, 8.6 mmol) in diethyl ether (20 mL), stirred for 1 hour, treated with triisopropylborate (5 L, 21.5 mmol), warmed to room temperature over 1 hour, poured into 2M NaOH (200 mL), stirred for 15 minutes, cooled, adjusted to pH 1 with concentrated HCl, and extracted with diethyl ether and ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated to provide material of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 198 (M+H)+.
Example 6B ethyl 6-cyano-3 -(phenyl)(l. -biphenyl)-3-carboxylate The desired product was prepared by substituting 3-bromo-4-cyanoethylbenzoate and Example 6A for 3-bromo-4-fluorobenzaldehyde and 2-methoxyphenylboronic acid, respectively, in Example 1A, and purified by flash column chromatography on silica gel with 95:5/hexanes:ethyl acetate.
MS (DCI/NH3) m z 345 (M+NH4)+;
1H NMR (300 MHz, CDCI3) δ 8.25 (d, IH), 7.9-7.3 (m, 10H), 4.45 (q, 2H), 1.4 (t, 3H).
Example 6C 5-(hvdroxymethyl)-3'-(phenyl)(l, -biphenyl)-2-carbonitrile
The desired product was prepared by substituting Example 6B for Example 5 A in Example 5B.
MS (DCI/NH3) m z 303 (M+NI N";
1H NMR (300 MHz, CD3OD) δ 8.1-7.3 (m, 12H), 4.8 (s, 2H).
Example 6D 5-f ormyl-3 '-(phenylX 1 , 1 ,-biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 6C for Example 5B in Example 5C, and purified by flash column chromatography on silica gel with 7:3/hexanes:ethyl acetate.
MS (DCI/NH3) m/z 301 (M+NH4)+; H NMR (300 MHz, CDC13) δ 10.15 (s, IH), 8.1-7.35 (m, 12H).
Example 6E 5-(hydroxy(l -methyl- lH-imidazol-5-yl)methyl)-3 '-(phenyl)Cl , 1 -biphenyl)-2-carbonitrile
The desired product was prepared by substituting Example 6D for Example 1 A in Example IB. 1H NMR (300 MHz, CDC13) δ 7.8-7.3 (m, 12H), 6.75 (s, IH), 6.0 (s, IH), 3.6 (s, 3H), 3.4-3.0 (br s, IH).
Example 6F 5-((benzyloxy)( 1 -methyl- lH-imidazol-5-yl)methyl)-3 -(phenyl)Cl , 1 -biphenyl -2-carbonitrile hydrochloride The desired product was prepared by substituting Example 6E for Example 5D in Example 5E.
MS (ESI(+)) m/z 456 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 8.1-7.3 (m, 12H), 6.1 (s, IH), 4.6 (q, 2H), 3.8 (s, 3H);
Anal, calcd for C3ιH26ClN3O-2.3H2O: C, 69.56; H, 5.80; N, 7.85. Found: C, 69,43; H, 5.50; N, 8.32.
Example 7
(2-(9-anthryl)-4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)benzonitrile hydrochloride
Example 7A 9-anthrylboronic acid The desired product was prepared by substituting 9-bromoanthracene for
3-bromo-l,l'-biphenyl in Example 6 A, and purified by flash column chromatography on silica gel with 9:l/hexanes:ethyl acetate to 7:3/hexanes:ethyl acetate. MS (DCI/NH3) m/z 268 (M+2NH4)+.
Example 7B ethyl 3-(9-anthryl)-4-cyanobenzoate The desired product was prepared by substituting ethyl 3-bromo-4-cyanobenzoate and Example 7A for 3-bromo-4-fluorobenzaldehyde and 2-methoxyphenylboronic acid, respectively, in Example 1 A, and purified by flash column chromatography on silica gel with 9:l/hexanes:ethyl acetate.
MS (DCI/NH3) m/z 369 (M+NH4)+;
1H NMR (300 MHz, CDCI3) δ 8.6 (s, IH), 8.35 (dd, IH), 8.25-7.95 (m, 3H), 7.85-7.3 (m,
6H), 4.4 (q, 2H), 1.4 (t, 3H).
Example 7C
2-(9-anthryl)-4-(hydroxymethyl)benzonitrile The desired product was prepared by substituting Example 7B for Example 5A in Example 5B.
MS (DCI/NH3) m/z 327 (M+NILN"; H NMR (300 MHz, CD3OD) δ 8.65 (s, IH), 8.17 (s, IH), 8.12 (s, IH), 8.0 (d, IH), 7.8-7.6 (m, 2H), 7.6-7.4 (m, 6H), 4.8 (s, 2H).
Example 7D 2-(9-anthryl)-4-formylbenzonitrile The desired product was prepared by substituting Example 7C for Example 5B in Example 5C, and purified by flash column chromatography on silica gel with 7:3/hexanes:ethyl acetate. MS (DCI/NH3) m z 325 (M+Nftt ; 1H NMR (300 MHz, CDC13) δ 10.2 (s, IH), 8.15 (s, IH), 8.3-7.8 (m, 5H), 7.6-7.35 (m, 6H).
Example 7E
2-(9-anthryl)-4-(hychOxy(l-methyl-lH-imidazol-5-yl)methyl)benzonitrile The desired product was prepared by substituting Example 7D for Example 1 A in Example IB and purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated ammonium hydroxide. MS (DCI/NH3) m z 390 (M+H)+.
Example 7F 2-(9-anthryl)-4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)benzonitrile hydrochloride The desired product was prepared by substituting Example 7E and dichloromethane for Example IB and DMF, respectively, in Example IC. MS (ESI(+)) m/z 480 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.8 (s, IH), 8.3-8.2 (m, 2H), 7.9 (dd, IH), 7.7-7.3 (m, 14H), 6.1 (s, IH), 4.65 (q, 2H), 3.8 (s, 3H).
Example 8
5-((benzyloxy)( 1 -methyl- lH-imidazol-5-yl)methyl)-2 -isopropyK 1 , 1 -biphenyl)-2-carbonitrile hydrochloride
Example 8A 2-isopropylphenylboronic acid
A mixture of magnesium (720 mg, 30 mmol) and diethyl ether (15 mL) was treated with a small aliquot of l-bromo-2-isopropylbenzene, stirred for 30 minutes, treated dropwise with 2-bromoisopropylbenzene (4.978 g, 25 mmol) in diethyl ether (10 mL), stirred at reflux for 1 hour, cooled to room temperature, added to a solution of triisopropylborate (6.4 mL, 27.5 mmol) in diethyl ether (15 mL ) at -78 °C, warmed to room temperature, treated with 4M NaOH (10 mL), stirred for 10 minutes, poured into water, washed with diethyl ether, adjusted to pH 1 with concentrated HCl, and extracted with diethyl ether. The extract was dried (Na SO4), filtered, and concentrated to provide material of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m z 182 (M+NH4)+.
Example 8B ethyl 6-cyano-2'-isopropyl(l,l -biphenyl)-3-carboxylate The desired product was prepared by substituting ethyl 3-bromo-4-cyanobenzoate and Example 8A for 3-bromo-4-fluorobenzaldehyde and 2-methoxyphenylboronic acid, respectively, in Example 1 A. and purified by flash column chromatography on silica gel with 9: l/hexanes:ethyl acetate.
MS (DCI/NH3) m/z 311 (M+NH4)+; HNMR (300 MHz, CDC13) δ 8.1 (dd, IH), 8.05 (d, IH), 7.8 (d, IH), 7.48 (s, IH), 7.42 (s,
IH), 7.25 (m, IH), 7.15 (d, IH), 4.4 (q, 2H), 2.7 (sept., IH), 1.4 (t, 3H), 1.25 (dd, 6H).
Example 8C
5-(hydroxymethyl)-2 -isopropyK 1 , 1 -biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 8B for Example 5 A in Example 5B.
MS (DCI/NH3) m/z 269 (M+NH- "1"; 1H NMR (300 MHz, CD3OD) δ 7.8 (d,lH), 7.6-7.35 (m, 4H), 7.25 (dt, IH), 7.1 (d, IH), 4.7 (s, 2H), 2.7 (sept., IH), 1.15 (dd, 6H).
Example 8D 5-formyl-2 -isopropyl(l, -biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 8C for Example 5B in Example 5C.
MS (DCI/NH3) m/z 267 (M+NH4)+;
!H NMR (300 MHz, CDC13) δ 10.1 (s, IH), 8.0-7.8 (m, 3H), 7.48 (s, IH), 7.45 (s, IH), 7.3
(m, IH), 7.15 (d, IH), 2.7 (sept., IH), 1.2 (dd, 6H).
Example 8E
5-(hydroxy(l-methyl-lH-imidazol-5-yl)methyl)-2 -isopropyl(l,r-biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 8D for Example 1 A in Example IB, and purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated a monium hydroxide. MS (DCI/NH3) m/z 332 (M+H)+; 1H NMR (300 MHz, CDC13) δ 7.8-6.9 ( , 7H), 6.75 (s, IH), 6.0 (s, IH), 3.6 (s, 3H), 2.7 (sept., IH), 1.1 (dd, 6H).
Example 8F
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -isopropyl(l, -biphenyl)-2-carbomtrile hydrochloride
The desired product was prepared by substituting Example 8E for Example 5D in
Example 5E, and purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated ammonium hydroxide.
MS (ESI(+)) m/z 422 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 8.05 (dd, IH), 7.7-7.1 (m, 11H), 6.1 (s, IH),
4.6 (q, 2H), 3.75 (s, 3H), 2.65 (sept., IH), 1.05 (dd, 6H);
Anal, calcd for C28H28C1N3O-0.85H2O: C, 71.05; H, 6.32; N, 8.88. Found: C, 71.15; H,
6.36; N, 8.01.
Example 9
4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l,2-dihydro-5- acenaphthylenyPbenzomtrile hydrochloride
Example 9A 1 ,2-dihydro-5-acenaphthylenylboronic acid
The desired product was prepared by substituting 5-bromo-l,2-dihydroacenaphthylene for 3-bromo-l,l -biphenyl in Example 6A. MS (DCI/NH3) m/z 216 (M+NH4)+; H NMR (300 MHz, CD3OD) δ 7.55 (dd, 2H), 7.45 (t, IH), 7.25 (dd, 2H), 3.4 (s, 4H).
Example 9B ethyl 4-cvano-3-(l ,2-dihydro-5-acenaphthylenyl)benzoate The desired product was prepared by substituting ethyl 3-bromo-4-cyanobenzoate and Example 9A for 3-bromo-4-fluorobenzaldehyde and 2-methoxyphenylboronic acid, respectively, in Example 1 A, and purified by flash column chromatography on silica gel with 3:l/hexanes:ethyl acetate. MS (DCI/NH3) m/z 345 (M+NH4)+; 1H NMR (300 MHz, CDC13) δ 8.25 (d, IH), 8.15 (dd, IH), 7.9 (d, IH), 7.5-7.25 (m, 5H), 4.4 (q, 2H), 3.5 (s, 4H), 1.4 (t, 3H).
Example 9C 2-( 1 ,2-dihydro-5-acenaphthylenyl)-4-(hydroxymethyl)benzonitrile
The desired product was prepared by substituting Example 9B for Example 5 A in Example 5B.
MS (DCI/NH3) m/z 303 (M+NILt ;
1H NMR (300 MHz, CD3OD) δ 7.6 (t, 2H), 7.45-7.25 (m, 5H), 7.35 (d, IH), 4.75 (s, 2H), 3.45 (s, 4H).
Example 9D 2-(l,2-dihydro-5-acenaphthylenyl)-4-formylbenzonitrile The desired product was prepared by substituting Example 9C for Example 5B in Example 5C, and purified by flash column chromatography on silica gel with 7:3/hexanes:ethyl acetate. MS (DCI/NH3) m/z 301 (M+NH4)+;
!H NMR (300 MHz, CDC13) δ 10.15 (s, IH), 8.1 (d, IH), 8.0 (t, 2H), 7.5-7.25 (m, 5H), 3.45 (s, 4H).
Example 9E 2-( 1 ,2-dihydro-5 -acenaphthylenylV 4-(hvdroxy ( 1 -methyl- lH-imidazol-5 - vDmethyDbenzonitrile The desired product was prepared by substituting Example 9D for Example 1 A in Example IB, and purified by flash column chromatography on silica gel with 95 5:l/ethyl acetate:methanol:concentrated ammonium hydroxide. MS (DCI/NH3) m z 366 (M+H)+;
!H NMR (300 MHz, CDC13) δ 7.85 (d, IH), 7.65 (s, IH), 7.55 (m, IH), 7.5-7.3 (m, 5H), 6.75 (s, IH), 6.0 (s, IH), 3.7 (s, IH), 3.6 (s, 3H), 3.45 (s, 4H).
Example 9F 4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l,2-dihydro-5- acenaphthylenypbenzonitrile hydrochloride The desired product was prepared by substituting Example 9E for Example 5D in Example 5E, and purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated ammonium hydroxide. MS (ESI(+)) m/z 456 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 8.2-7.2 (m, 13H), 6.1 (s, IH), 4.6 (q, 2H), 3.8
(s, 3H), 3.5 (s, 4H);
Anal, calcd for C3ιH26ClN3O-1.5H O: C, 71.61; H, 5.64; N, 8.08. Found: C, 71.62; H, 5.35;
N, 8.26.
Example 10 5-(( benzyloxyXl -methyl- lH-imidazol-5-yl)methyl)-2 -chloro( 1 , 1 -biphenyl)-2-carbonitrile hydrochloride
Example 10A
2-chloro-6-(methoxycarbonyl)(l, -biphenyl)-3-carboxylic acid The desired product was prepared by substituting dimethyl 2-iodoterephthalate and 2- chlorophenylboronic acid and for Example 3B and 2-methylphenylboronic acid, respectively, in Example 3C to provide material of sufficient purity for use without further purification.
Example 10B 2'-chloro-6-(methoxycarbonyl)(l, -biphenyl)-3-carboxylic acid A solution of Example 10A in THF (100 mL) was treated with IM LiOH (33 mL), stirred for 4 days, concentrated, treated with water, and adjusted to pH 1 with 4M HCl to precipitate a first crop of desired product. This first crop was recrystallized from 1 : 1 ethanol/water and filtered. The filtrate was concentrated to remove the ethanol and extracted with ethyl acetate. The extract was washed water and brine, dried (Na2SO4), filtered, and concentrated to provide a second crop material of sufficient purity for subsequent use without further purification. !H NMR (300 MHz, CDC13) δ 8.2 (dd, IH), 8.1 (d, IH), 8.05 (d, IH), 7.45 (m, IH), 7.35 (m, 2H), 7.25 (m, IH), 3.7 (s, 3H).
Example 10C methyl 2 -chloro-5-(hydroxymethyl)(l,l -biphenyl)-2-carboxylate A solution of Example 10B (6.29 g, 21.64 mmol) in THF (30 mL) at 0 °C was treated with 10M borane-dimethylsulfide in THF (4.4 mL, 43.28 mmol), stirred for 24 hours, treated with additional borane-dimethylsulfide (2 mL), stirred for 24 hours, treated dropwise with 4:l/THF:water (25 mL), stirred for 1 hour, and treated with 3M HCl (50 mL) to form two separate layers. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was washed sequentially with 2M Na2CO3, water, and brine, dried (Na2SO4), filtered, and concentrated. The product was purified by flash column chromatography on silica gel with 3:1 to 3:2/hexanes:ethyl acetate to provide the desired product.
MS (DCI/NH3) m z 294 (M+NH4)+.
Example 10D methyl 2 -chloro-5-formyl(l .1 -biphenyl)-2-carboxylate The desired product was prepared by substituting Example IOC for Example 5B in Example 5C, and purified by flash column chromatography on silica gel with 75:25/hexanes:ethyl acetate. MS (DCI/NH3) m z 292 (M+NH4)+;
*H NMR (300 MHz, CDC13) δ 10.1 (s, IH), 8.15 (dd, IH), 8.0 (dd, 2H), 7.8 (d, IH), 7.5 (m, IH), 7.35 (m, IH), 3.7 (s, 3H).
Example 10E methyl 2 -chloro-5-(hvdroxy(l-methyl-lH-imidazol-5-yl)methyl)(l,l -biphenyl)-2- carboxylate The desired product was prepared by substituting Example 10D for Example 1A in Example IB, and purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated ammonium hydroxide. MS (DCI/NH3) m/z 356 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 8.0 (dd, IH), 7.6-6.9 (m, 6H), 6.6 (s, IH), 6.0 (s, IH), 3.65 (s, 3H), 3.6 (s, 3H).
Example 10F methyl 5-((benz yloxy) ( 1 -methyl- lH-imidazol-5 -yl methyl -2 -chloro( 1 , 1 -biphenvD-2- carboxylate The desired product was prepared by substituting Example 10E for Example 5D in Example 5E, and purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated ammonium hydroxide. MS (DCI/NH3) m/z 447 (M+H)+; H NMR (300 MHz, CDC13) δ 8.05 (dd, IH), 7.6-7.1 (m, 11H), 6.9 (s, IH), 5.6 (s, IH), 4.55 (s, 2H), 3.65 (s, 3H), 3.45 (s, 3H).
Example 10G 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2,-chloro(l, -biphenyl)-2-carboxylic acid A solution of Example 10F (835 mg, 1.87 mmol) in methanol (10 mL) was treated with 4M NaOH, heated to reflux for 4 hours, cooled, concentrated, poured into 0.5M H3PO4 in diethyl ether, and extracted with 4:10/chloroform:isopropyl alcohol. The extract was dried (Na2SO4), filtered, and concentrated to provide material of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 433 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 8.1 (s, IH), 7.7-7.2 (m, 11H), 6.85 (s, IH), 5.6 (s, IH), 4.55 (s, 2H), 3.45 (s, 3H).
Example 10H
5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2'-chloro(l '-biphenyl)-2-carboxamide
A slurry of Example 10G (794 mg, 1.83 mmol), EDC (385 mg, 2.01 mmol), and HOBt (271 mg, 2.01 mmol) in DMF (4 mL) was stirred until a clear solution resulted, treated with concentrated ammonium hydroxide (0.62 mL, 9.15 mmol), stirred for 24 hours, treated with ethyl acetate, washed sequentially with 0.5M H3PO4, saturated NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
1H NMR (300 MHz, CD3OD) δ 7.95 (s, IH), 7.8-7.2 (m, 11H), 6.65 (s, IH), 5.75 (s, IH), 4.55 (s, 2H), 3.55 (s, 3H), 3.0 (s, IH), 2.85 (s, IH).
Example 101 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -chloro(l, -biphenyl)-2-carbonitrile hydrochloride A solution of Example 10H (519 mg, 1.20 mmol) in THF (2.5 mL) at 0 °C was treated with triethylamine (1 mL, 7.08 mmol), stirred for 10 minutes, treated with trifluoroacetic anhydride (0.5 mL, 3.60 mmol), stirred for 40 minutes, warmed to room temperature, stirred for 1 hour, poured onto ice, treated with concentrated ammonium hydroxide /THF until a clear solution formed, poured into water, and extracted with diethyl ether. The extract was washed with brine, and the washes were back-extracted with diethyl ether. The extract was dried (Na SO4), filtered, and concentrated. The product was purified by flash column chromatography on silica gel with 95:5:l/ethyl acetate:methanol:concentrated ammonium hydroxide. The appropriate fractions were concentrated, and the concentrate was dissolved in 4M HCl in dioxane (1 mL), stirred for 3 hours, and concentrated. The concentrate was treated with water and lyophilized to provide the desired product. MS (ESI(+)) m/z 414 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.2 (s, IH), 8.1 (d IH), 7.8-7.45 (m, 5H), 7.4-7.2 (m, 6H), 6.1 (s, IH), 4.6 (q, 2H), 3.75 (s, 3H); Anal, calcd for C25H2ιCl2N3O-0.7H2O-0.35TFA: C, 61.38; H, 4.56; N, 8.36. Found: C, 61.47; H, 4.62; N, 8.09.
Example 11 5-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l, -biphenyl)-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 4A for Example IB in Example IC.
MS (ESI(+)) m/z 394 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 8.05 ( d, IH), 7.7 (dd, IH), (d, IH), 7.4-7.2 (m, IH), 6.05 (s, IH), 4.6 (q, 2H), 3.75 (s, 3H), 2.15 (s, 3H);
Anal, calcd for C26H24C1N3O-0.75H2O: C, 70.42; H, 5.80; N, 9.48. Found: C, 70.44; H, 5.86; N, 8.90.
Example 12
(2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((4-nitrobenzyl)amino)methyl)(l,r-biphenyl)-2- carbonitrile
Example 12A 5-(amino(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(lJ -biphenyl)-2-carbonitrile A suspension of Example 4A (0.3 g, 1.0 mmol) in dichloromethane (3 mL) was cooled to 0 °C, treated with a solution of thionyl chloride (240 mg, 2.0 mmol) in dichloromethane (2 mL), stirred 30 minutes, warmed to room temperature, stirred 4 hours, cooled to 0 °C, treated with concentrated ammonium hydroxide (5 mL), warmed to room temperature, stirred for 16 hours, and concentrated. The concentrate was treated with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:l/dichloromethane:methanol to provide the desired product.
Example 12B
(2 -methyl-5-((l-methyl- lH-imidazol-5-yl)((4-nitrobenzyl)amino)methyl)( 1 , 1 -biphenyl)-2- carbonitrile A solution of Example 12A (100 mg, 0.33 mmol) in 1,2-dichloroethane (2 mL) was treated with 4-nitrobenzaldehyde (94 mg, 0.62 mmol) and acetic acid (150 mg, 2.5 mmol), stirred for 30 minutes, treated with sodium triacetoxyborohydride (265 mg, 1.25 mmol), and stirred for 16 hours. The mixture was diluted with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was treated with dichloromethane (5 mL) and a solution of 4M HCl in dioxane (1 mL), stirred for 30 minutes, and concentrated. The concentrate was treated with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2/dichloromethane: methanol to provide the desired product.
MS (ESI(+)) m/z 438 (M+H)+;
1H NMR (300 MHz, CDC13) δ 8.20 (d, 2H), 7.78 (d, IH), 7.50-7.29 (m, 8H), 7.20-7.17 (m,
IH), 6.88 (s, IH), 4.95 (s, IH), 3.89 (abq, 2H), 3.53 (s, 3H), 2.17 (s, 3H), 2.05 (s, IH).
Example 13 4-(((4-cyanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile dihydrochloride
Example 13 A
4-(amino(l -methyl- lH-imidazol-5-yl)methyl)-2-( 1 -naphthyPbenzonitrile A suspension of Example 89D (0.5 g, 1.48 mmol) in dichloromethane (10 mL) at 0 °C was treated with thionyl chloride (0.65 mL, 8.85 mmol), stirred for 30 minutes, warmed to room temperature, stirred for 1.5 hours, and concentrated. The concentrate was treated with dichloromethane (3 mL), and the resulting solution was added to a solution of concentrated ammonium hydroxide (10 mL) at 0 °C. This solution was stirred for 30 minutes, warmed to room temperature, stiπ'ed for 2 hours, and concentrated. The concentrate was treated with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9: l/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m z 339 (M+H)+;
1H NMR (300 MHz, CDC13) δ 7.95 (dd, 2H), 7.84 (d, IH), 7.57-7.42 (m, 8H), 6.86 (d, IH), 5.32 (d, IH), 3.59 (d, 3H).
Example 13B
4-(((4-cvanobenzyl)armno)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile dihydrochloride The desired product was prepared by substituting 4-formylbenzonitrile and Example 13A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 454 (M+H)+; 1H NMR (400 MHz, CDC13) δ 7.96-7.93 (m, 2H), 7.83 (d, IH), 7.60-7.38 (m, 12H), 6.89- 6.88 (m, IH), 4.96 (d, IH), 3.90-3.80 (m, 2H), 3.53 (d, 3H).
Example 14 4-((cvclohexylmethoxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l-naphthyl)benzonitrile hydrochloride A suspension of Example 89D (68 mg, 0.2 mmol) in dichloromethane (4 mL) at 0 °C was treated with thionyl chloride (48 mg, 0.4 mmol), stirred for 30 minutes, warmed to room temperature, stirred for 1.5 hours, treated with cyclohexylmethanol and N,N- diisopropylethylamine, warmed to 35 °C, stirred for 16 hours, and concentrated. The concentrate was treated with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2/dichloromethane:methanol, treated with dichloromethane and IM HCl in diethyl ether, and concentrated to provide the desired product.
MS (ESI(+)) m/z 436 (M+H)+;
!H NMR (500 MHz, CDC13) δ 7.98-7.91 (m, 2H), 7.84-7.82 (m, IH), 7.60-7.40 (m, 8H), 6.81 (d, IH), 5.50 (d, IH), 3.52 (d, 3H), 3.29 (d, 2H), 1.77-1.63 (m, 6H), 1.27-1.10 (m, 3H), 0.99- 0.92 (m, 2H).
Example 15
(2'-methyl-5-((l-methyl-lH-imidazol-5-yl)(3-oxo-4-(3-(trifluoromethoxy phenyl)-l- piperazinyl)methyl)(l,l -biphenyl)-2-carbonitrile dihydrochloride
Example 15 A tert-butyl 2-oxoethylcarbamate A solution of tert-butyl allylcarbamate (5.0 g, 31 mmol) in dichloromethane (200 mL) and methanol (25 mL) at -78 °C was treated with ozone until green, treated with zinc (4.0 g, 61.0 mmol) and acetic acid (4 mL), stirred for 16 hours, filtered through a pad of silica gel, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
Example 15B tert-butyl 2-(3-(trifluoromethoxy)anilino)ethylcarbamate A solution of 3-(trifluoromethoxy)aniline (4.45 g, 25 mmol) in 1,2-dichloroethane
(100 mL) was treated with Example 15A (4.0 g, 25 mmol) and acetic acid (9.0 g, 150 mmol), stirred for 30 minutes, treated with sodium triacetoxyborohydride (15.9 g, 75 mmol), stirred for 16 hours, and concentrated. The residue was treated with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:l/hexanes:ethyl acetate to provide the desired product. 1H NMR (300 MHz, CDC13) δ 7.14 (t, IH), 6.55-6.48 (m, 2H), 6.40 (s, IH), 4.78 (s, IH), 4.31 (s, IH), 3.42-3.36 (m, 2H), 3.28-3.22 (m, 2H), 1.45 (s, 9H).
Example 15C tert-butyl 2-((chloroacetyl)-3-(trifluoromethoxy anilino ethylcarbamate A solution of Example 15B (1.5 g, 4.68 mmol) in ethyl acetate (20 mL) at 0 °C was treated with chloroacetyl chloride (0.38 mL, 5.6 mmol) and saturated NaHCO3 (20 mL), and stirred for 2 hours to provide two layers. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
MS (ESI(+)) m/z 397 (M+H)+;
!H NMR (300 MHz, CDC13) δ 7.51 (t, IH), 7.31-7.28 (m, 2H), 7.20 (s, IH), 4.88-4.87 (m,
IH), 3.87-3.81 (m, 4H), 3.39-3.32 (m, 2H), 1.41 (s, 9H).
Example 15D tert-butyl 3-oxo-4-(3-(trifluoromethoxy)phenyl)-l-piperazinecarboxylate A solution of Example 15C (1.7 g, 4.4 mmol) in DMF (10 mL) at 0 °C was treated with cesium carbonate (1.4 g, 4.3 mmol), warmed to room temperature, stirred for 16 hours, treated with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10:1 to 2:l/hexanes:ethyl acetate to provide the desired product. XH MR (300 MHz, CDCI3) δ 7.44 (t, IH), 7.28-7.13 (m, 3H), 4.84-4.74 (m, 4H), 4.27 (s, 2H), 1.50 (s, 9H).
Example 15E l-(3-(trifluoromethoxy)phenyl)-2-piperazinone hydrochloride A solution of Example 15D (1.2 g, 3.3 mmol) in ethyl acetate (10 mL) at room temperature was treated with IM HCl in diethyl ether (20 mL), stirred for 30 minutes, and concentrated to provide 0.98 g of the desired product of sufficient purity for subsequent use without further purification.
Example 15F (2 -methyl-5-((l-methyl-lH-imidazol-5-yl)(3-oxo-4-(3-(trifluoromethoxy)phenyl)-l- piperazinvDmethyl) (1,1 -biphenyl)-2-c arbonitrile dihydrochloride A suspension of Example 4A (30 mg, 0.1 mmol) in dichloromethane (2 mL) at 0 °C was treated with thionyl chloride (0.15 mL, 2.05 mmol), stirred for 30 minutes, warmed to room temperature, stirred for 3.5 hours, and concentrated. The concentrate was treated with a solution of Example 15E (35 mg, 0.12 mmol) in acetonitrile (2 mL) and N,N- diisopropylethylamine(100 μL, 0.57 mmol), warmed to 80 °C, stirred for 3 hours, diluted with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 95:5/dichloromethane:methanol. The appropriate fractions were dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 546 (M+H)+;
*H NMR (400 MHz, CDC13) δ 7.76 (d, IH), 7.54 (dd, IH), 7.47 (d, IH), 7.44-7.12 (m, 9H), 7.08 (s, IH), 4.73 (s, IH), 3.76-3.67 (m, 2H), 3.62 (s, 3H), 3.33 (q, 2H), 2.97-2.82 (m, 2H), 2.16 (d, 3H).
Example 16 5-((( 1 -benzoyl-4-piperidinyl)amino)( 1 -methyl- lH-imidazol-5-yl)methyl -2'-methyl( 1 , 1 - biphenyl)-2-carbonitrile dihydrochloride
The desired product was prepared by substituting l-benzoyl-4-piperidinone for 4- nitrobenzaldehyde in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS CESIC+)) m/z 490 (M+H)+;
1H NMR (400 MHz, CDCI3) δ 7.73 (d, IH), 7.43 (dd, IH), 7.41-7.24 (m, 10H), 7.18 (d, IH), 6.72 (s, IH), 5.11 (s, IH), 4.51 (s, IH), 3.76-3.70 (m, IH), 3.57 (s, 3H), 2.95 (s, 2H), 2.75- 2.70 ( , IH), 2.17 (s, 3H), 1.99-1.65 (m, 3H), 1.50-1.26 (m, 2H).
Example 17
4-((l-methyl-lH-imidazol-5-yl)((4-(methylsulfonyl)benzyl)amino)methyl)-2-(l- naphthyDbenzonitrile dihydrochloride The desired product was prepared by substituting 4-(methylsulfonyl)-benzaldehyde for 4-nitrobenzaldehyde in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 507 (M+H)+; 1H NMR (400 MHz, CDC13) δ 7.94 (dd, 2H), 7.88-7.82 (m, 3H), 7.59-7.38 (m, 10H), 6.88 (d, IH), 4.97 (s, IH), 3.92-3.83 (m, 2H), 3.54 (d, 3H), 3.01 (s, 3H), 2.25 (s, IH).
Example 18 4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(8-quinolinyl)benzonitrile dihydrochloride The desired product was prepared by substituting 8-quinolinylboronic acid for Example 43B in Example 43C. MS (ESI(+)) m z 456 (M+H)+; 1H NMR (400 MHz, CDCI3) δ 8.85-8.83 (m, IH), 8.22 (dd, IH), 7.93 (dd, IH) 7.83 (d, IH), 7.75 (dd, IH), 7.66-7.61 (m, 4H), 7.57-7.54 (m, IH), 7.46-7.42 (m, 4H), 7.01 (s, IH), 5.70 (s, IH), 4.67-4.60 (m, 2H), 3.50 (s, 3H).
Example 19 4-(((4-cyanobenzyl)oxy)(l-methyl-lH-imidazol-5-yl)methyl)-2-(4-quinolinyl)benzonitrile dihydrochloride
Example 19A 4-iodoquinorme A solution of 4-chloroquinoline (5.0 g, 30.56 mmol) in 2-butanone (40 mL) at room temperature was treated with sodium iodide (23 g, 153 mmol) and 47% hydriodic acid (20 mL), heated to reflux for 8 hours, cooled to room temperature, adjusted to pH 7 with saturated NaHCO3, and extracted with ethyl acetate. The extract was concentrated, and the concentrate was purified by flash column chromatography on silica gel with 4:l/hexanes:ethyl acetate to provide the desired product. MS (ESI(+)) m/z 256 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 8.46 (d, IH), 8.06-8.00 (m, 3H), 7.79-7.73 (m, IH), 7.66-7.61 (m, IH).
Example 19B
4-quinolinylboronic acid The desired product was prepared by substituting Example 19A for Example 43A in Example 43B.
1H NMR (300 MHz, DMSO-d6) δ 8.86 (d, IH), 8.75 (s, IH), 8.25 (dd, IH), 8.25 (dd, IH), 8.00 (dd, IH), 7.76-7.70 (m, IH), 7.62-7.56 (m, IH).
Example 19C 4-(((4-c yanobenzvDoxy ( 1 -methyl- 1 H-imidazol-5 -yl)methyl -2-(4-quinolinyl benzonitrile dihydrochloride The desired product was prepared by substituting Example 19B for Example 43B in Example 43C. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 456 (M+H)+;
1H NMR (400 MHz, CDC13) δ 9.03 (dd, IH), 8.23 (d, IH), 7.90 (d, IH), 7.80-7.75 (m, IH), 7.67-7.32 (m, 10H), 6.98 (d, IH), 5.70 (d, IH), 4.63 (abq, 2H), 3.46 (s, 3H).
Example 20
5-((5-(hydroxymethyl)-lH-irnidazol-l-yl)methyl)-2 -methyl( r-biphenyl)-2-carbonitrile
Example 20A 5-(bromomethyl)-2 -methyK 1 , 1 -biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 86H for Example 61 A in
Example 6 IB.
*H NMR (300 MHz, CDC13) δ 7.72 (d, IH), 7.47 (dd, IH), 7.40 (d, IH), 7.39-7.26 (m, 3H), 7.22-7.18 (m, IH), 4.50 (s, 2H), 2.20 (s, 3H).
Example 20B
( 1 -trityl- lH-imidazol-4-yl methanol A solution of lH-imidazol-5-ylmethanol hydrochloride (1.37 g, 10.2 mmol) and triethylamine (3.55 mL, 25.5 mmol) in DMF (7 mL) at room temperature was treated with a solution of triphenylmethyl chloride (3.0 g, 10.7 mmol) in DMF (14 mL), stirred for 3 days, poured into ice water, and filtered. The filter cake was washed with ice water and dried in a vacuum oven for 16 hours to provide the desired product of sufficient purity for subsequent use without further purification.
!H NMR (300 MHz, CDCI3) δ 7.45-7.34 (m, 10H), 7.11-7.07 (m, 6H), 6.72-6.71 (m, IH), 4.86 (t, IH), 4.33 (d, 2H).
Example 20C (l-trityl-lH-imidazol-4-yl methyl acetate A solution of Example 20B (3.5 g, 10.3 mmol) in pyridine (20 mL) at room temperature was treated with acetic anhydride (2.0 mL, 21.2 mmol), stirred for 2 days, cooled, treated with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. !H NMR (300 MHz, CDC13) δ 7.42 (d, IH), 7.35-7.31 (m, 9H), 7.15-7.10 (m, 6H), 6.88-6.87 (m, IH), 5.01 (s, 2H), 2.07 (s, 3H).
Example 20D (l-((6-cvano-2 -methyl(l,r-biphenyl)-3-yl)methyl)-lH-imidazol-5-yl)methyl acetate hydrobromide A solution of Example 20C (2.39 g, 6.25 mmol) in ethyl acetate (15 mL) at 60 °C was treated with Example 20A (1.79 g, 6.25 mmol), stirred for 16 hours, cooled to room temperature, and filtered. The filtrate was reheated to 60 °C, stirred for 16 hours, cooled to room temperature, and filtered a second time. The combined solids were dissolved in methanol (20 mL), heated to 60 °C, stirred for 6 hours, cooled to room temperature, filtered, and washed with hexanes to provide the desired product of sufficient purity for subsequent use without further purification.
Example 20E
5-((5-(hydroxymethyl - lH-imidazol- l-yl)methyl)-2 -methyl ( 1 , 1 ,-biphenyl)-2-carbonitrile A solution of Example 20D in 3:1 THF/water at 0 °C was treated with lithium hydroxide monohydrate (840 mg, 19.1 mmol), stirred for 2 hours, and extracted with ethyl acetate. The extract was concentrated, and the concentrate was purified by flash column chromatography on silica gel with 9:l/dichloromethane:methanol to provide the desired product.
MS (ESI(+)) m z 304 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 7.72 (d, IH), 7.53 (s, IH), 7.37-7.09 (m, 6H), 7.01 (s, IH), 5.34 (s, 2H), 4.52 (s, 2H), 2.14 (s, 3H).
Example 21 2 -methyl-5-((5-((3-oxo-4-(3-(trifluoromethoxy)phenyl)-l-piperazinyl)methyl)-lH-imidazol- 1 - vDmethyl) (1,1 '-biphenvD-2-carbonitrile dihydrochloride
Example 21A
5-((5-formyl-lH-imidazol-l-yl)methyl)-2 -methyl(l, -biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 20E for Example 37A in Example 37B.
MS (ESI(+)) m z 302 (M+H)+; 1H NMR (300 MHz, CDCI3) δ 9.76-9.75 (m, IH), 7.88 (s, IH), 7.79 (s, IH), 7.72 (d, IH), 7.38-7.12 (m, 6H), 5.61 (s, 2H), 2.13 (s, 3H). Example 2 IB 2 -methyl-5-((5-((3-oxo-4-(3-(trifluoromethoxy phenyl)-l-piperazinyl)methyl)-lH-imidazol- 1 - vDmethyl) (1,1 -biphenyl)- 2-carbonitrile dihydrochloride The desired product was prepared by substituting Example 21 A and Example 15E for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 546 (M+H)+;
1H NMR (300 MHz, CDC13) δ 7.74 (d, IH), 7.60 (s, IH), 7.44-7.11 (m, 9H), 7.06 (s, 2H), 5.38 (s, 2H), 3.52 (dd, 2H), 3.44 (s, 2H), 3.28 (s, 2H), 2.74 (dd, 2H), 2.13 (s, 3H).
Example 22 2-methyl-5-((5-(((l-methyl-2-oxo-l,2-dihydro-6-quinolinyl)arrrino)methyl)-lH-imidazol-l- yl)methyl)(l,l -biphenyl)-2-carbonitrile dihydrochloride
Example 22A 6-amino-l-methyl-2(lH)-quinolinone A solution of l-methyl-6-nitro-2(lH)-quinolinone in ethanol (5 mL) at room temperature was treated with Pd/C (10 mg), stirred under 1 atmosphere of hydrogen gas for 16 hours, filtered through a pad of diatomaceous earth (Celite®), and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
Example 22B 2'-methyl-5 -( (5 -( ( ( 1 -mefhyl-2-oxo- 1 ,2-dihydro-6-quinolinyl)amino)methyl - lH-imidazol- 1 - yPmethylX 1 , 1 '-biphenyl)-2-carbonitrile dihydrochloride
The desired product was prepared by substituting Example 21 A and Example 22A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 460 (M+H)+;
1H NMR (300 MHz, CDC13) δ 7.74-7.69 (m, IH), 7.62-7.55 (m, IH), 7.47 (d, IH), 7.36-7.00 (m, 9H), 6.79 (dd, IH), 6.67-6.65 (m, IH), 5.35-5.29 (m, 2H), 4.18 (d, 2H), 3.67 (s, 3H), 3.62-3.56 (m, IH), 2.10 (m, 3H).
Example 23
5-((benzylamino)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l,r-biphenyl)-2-carbonitrile The desired product was prepared by substituting benzaldehyde for 4-nitrobenzaldehyde in Example 12B. MS (ESI(+)) m/z 393 (M+H)+;
*H NMR (300 MHz, CDC13) δ 7.75 (d, IH), 7.46 (dd, IH), 7.39-7.26 (m, 10H), 7.19 (d, IH), 6.82 (s, IH), 4.93 (s, IH), 3.76 (abq, 2H), 3.52 (s, 3H), 2.18 (s, 3H).
Example 24 5-(((cyclohexylmethyl armno)(l-methyl-lH-imidazol-5-yl)methyl)-2'-methyl(l,l -biphenyl)-
2-carbonitrile The desired product was prepared by substituting cyclohexylcarboxaldehyde for 4-nitrobenzaldehyde in Example 12B. MS (ESI(+)) m/z 399 (M+H)+;
*H NMR (300 MHz, CDCI3) δ 7.77-7.70 (m, 2H), 7.47 (d, IH), 7.38-7.27 (m, 4H), 7.20 (d, IH), 6.88 (s, IH), 4.91 (s, IH), 3.65 (s, 3H), 2.47-2.36 (m, 2H), 2.17 (s, 3H), 1.80-1.62 (m, 4H), 1.52-1.38 (m, IH), 1.30-1.05 (m, 4H), 1.00-0.82 (m, 2H).
Example 25 5-(((4-cyanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l,r-biphenyl)-2- carbonitrile The desired product was prepared by substituting 4-formylbenzonitrile for 4-nitrobenzaldehyde in Example 12B. MS (ESI(+)) m/z 418 (M+H)+;
*H NMR (300 MHz, CDCI3) δ 7.77 (d, IH), 7.63 (d, 2H), 7.47-7.28 (m, 8H), 7.19 (d, IH), 6.86 (s, IH), 4.93 (s, IH), 3.84 (abq, 2H), 3.52 (s, 3H), 2.17 (s, 3H), 2.00 (s, IH).
Example 26
5-((((6-cyano-2 -methyl(l,r-biphenyl)-3-yl)methyl)amino)(l-methyl-lH-imidazol-5- yl)methyl)-2 -methyl(l, -biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 861 for 4- nitrobenzaldehyde in Example 12B. MS (ESI(+)) m/z 508 (M+H)+;
*H NMR (300 MHz, CDC13) δ 7.77-7.70 (m, 2H), 7.48-7.24 (m, 11H), 7.16 (dd, 2H), 6.85 (s, IH), 4.97 (s, IH), 3.92-3.82 (m, 2H), 3.54 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 2.02 (s, IH).
Example 27 5-((ethyl(4-mtrobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2 -methyl(l, -biphenyl)-
2-carbonitrile dihydrochloride The free base of the desired product was obtained as a byproduct in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 466 (M+H)+; 1H NMR (400 MHz, CDC13) δ 8.17 (d, 2H), 7.74 (d, IH), 7.46-7.43 (m, 4H), 7.38-7.26 (m, 4H), 7.17 (m, IH), 6.99 (s, IH), 5.06 (s, IH), 3.80 (abq, 2H), 3.47 (s, 3H), 2.77-2.68 (m, IH), 2.64-2.55 (m, IH), 2.16 (s, 3H), 1.08 (t, 3H).
Example 28 5-(((4-cyanobenzyl)(ethyl)amino)(l -methyl- lH-imidazol-5-yl)methyl)-2 '-methyl ( 1 , 1 - biphenyl)-2-carbonitrile dihydrochloride The free base of the desired product was obtained as a byproduct in Example 25. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 446 (M+H)+;
!H NMR (400 MHz, CDC13) δ 8.17 (d, 2H), 7.74 (d, IH), 7.46-7.27 (m, 8H), 7.17 (d, IH), 6.99 (s, IH), 5.06 (s, IH), 3.80 (abq, 2H), 3.47 (s, 3H), 2.77-2.68 (m, IH), 2.64-2.55 (m, IH), 2.16 (s, 3H), 1.08 (t, 3H).
Example 29
4-(((4-cyanobenzyl)(methyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyDbenzonitrile A solution of Example 13B (42 mg, 0.09 mmol) in formic acid (5 mL) was treated with 37% aqueous formaldehyde(3 mL), heated to 95 °C for 4 hours, cooled to room temperature, and extracted with ethyl acetate. The extract was washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m z 468 (M+H)+; *H NMR (300 MHz, CDC13) δ 7.97 (d, IH), 7.96-7.93 (m, IH), 7.85 (d, IH), 7.66-7.35 (m, 12H), 7.05 (d, IH), 4.89 (d, IH), 3.66 (d, 2H), 3.62 (d, 3H), 2.20 (d, 3H).
Example 30 4-((butyl(4-cvanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyDbenzonitrile dihydrochloride
The desired product was prepared by substituting butyraldehyde and Example 13B for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 510 (M+H)+; lR NMR (400 MHz, CDC13) δ 7.98-7.93 (m, 2H), 7.82 (dd, IH), 7.61-7.35 (m, 12H), 7.02 (d, IH), 5.06 (s, IH), 3.85-3.70 (m, 2H), 3.44 (d, 3H), 2.69-2.62 (m, IH), 2.58-2.50 (m, IH), 1.50-1.41 (m, 2H), 1.26-1.16 (m, 2H), 0.80 (t, 3H).
Example 31 4-((l-methyl-lH-imidazol-5-yl)(phenethylamino)methyl -2-(l-naphthyl)benzonitrile (31-A) and
4-(((2-hydroxy-2-phenylethyl)(2-phenylethyl)amino)(l-methyl-lH-imidazol-5- yl)methyl)-2-(l-naphthyl)benzonitrile (31-B)
The desired product was prepared by substituting a 9:1 mixture of phenylacetaldehyde/styrene oxide and Example 13A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B to provide a 9:1 mixture of Example 31-A and Example 31-B. 31-A: MS (ESI(+)) m/z 443 (M+H)+;
!H NMR (400 MHz, CDCI3) δ 7.94 (dd, 2H), 7.78, (d, IH), 7.58-7.08 (m, 13H), 6.74 (d, IH), 4.93 (d, IH), 3.47 (d, 3H), 2.90-2.86 (m, 2H), 2.82-2.78 (m, 2H); 31-B: MS (ESI(+)) m/z 563 (M+H)+;
*H NMR (400 MHz, CDCI3) δ 6.69-6.66 (m, IH), 4.86 (dd, IH), 4.20-4.12 (m, IH), 3.38 (d, 3H), 3.23-3.14 (m, IH), 3.09-3.02 (m, 2H), 2.73-2.69 (m, IH), 2.69-2.51 (m, 2H).
Example 32 5-((benzyl((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2 -methyl(l,r-biphenyl)-2- carbonitrile dihydrochloride
Example 32A (l-methyl-2-sulfanyl-lH-imidazol-5-yl methanol A solution of 1,3-dihydroxyacetone dimer (25 g, 0.28 mol) in n-butanol (115 mL) at room temperature was treated with acetic acid (56 mL), potassium thiocyanate (80.75 g, 0.83 mol) and methylamine hydrochloride (41.15 g. 0.61 mol), stirred at room temperature for 3 days, treated with a 1:1 mixture of diethyl etheπhexanes (100 mL), washed with water, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
*H NMR (400 MHz, DMSO-d6) δ 12.0 (s, IH), 6.81 (s, IH), 5.21 (t, IH), 4.32 (d, 2H), 3.45 (s, 3H).
Example 32B ( 1-methyl- lH-imidazol-5-yl)methanol A solution of Example 32A (50 g, 0.35 mol) in ethanol (500 mL) was treated with Raney® nickel (500 g), heated to reflux for 1 hour, cooled to room temperature, filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 113 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, IH), 6.75 (s, IH), 5.01 (s, IH), 4.41 (s, 2H), 3.59
(s, 3H).
Example 32C l-methyl-lH-imidazole-5-carbaldehyde A solution of Example 32B (2.3 g, 20 mmol) in dioxane (100 mL), was treated with manganese dioxide (17.3 g, 200 mmol), heated to reflux for 16 hours, cooled to room temperature, filtered through a pad of diatomaceous earth (Celite®), and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. *H NMR (300 MHz, CDCI3) δ 9.77 (d, IH), 7.79 (s, IH), 7.62 (s, IH), 3.95 (d, 3H).
Example 32D
5-((benzylamino)methyl)-2 -methyld , 1 -biphenyl)-2-carbonitrile The desired product was prepared by substituting Example 861 and benzylamine for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. 1H NMR (300 MHz, CDC13) δ 7.75-7.68 (m, 2H), 7.47-7.14 (m, 10H), 3.90 (s, 2H), 3.83 (s, 2H), 2.19 (s, 3H), 1.65, (s, lH).
Example 32E 5-((benzyl((l-methyl-lH-imidazol-5-yl)methyl amino)methyl)-2 -methyl(l,r-biphenyl -2- carbonitrile dihydrochloride The desired product was prepared by substituting Example 32C and Example 32D for nitrobenzaldehyde and Example 12 A, respectively, in Example 12B. MS (ESI(+)) m/z 407 (M+H)+; !H NMR (300 MHz, CDC13) δ 7.69 (d, IH), 7.40-7.27 (m, 11H), 7.18 (d, IH), 6.97 (s, IH), 3.63 (s, 2H), 3.57 (s, 2H), 3.54 (s, 2H), 3.47 (s, 3H), 2.18 (s, 3H).
Example 33 4-(((3-bromo-4-cyanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyPbenzonitrile dihydrochloride
Example 33A 4-amino-3-bromobenzaldehyde A solution of 4-aminobenzaldehyde (3.0 g, 25 mmol) in methanol (50 mL), acetone
(100 mL), and water (30 mL) was treated with p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol), heated to reflux for 8 hours, cooled to 0 °C, treated with N-bromosuccinimide (4.4 g, 25 mmol), stirred for 30 minutes, and concentrated. The concentrate was treated with ethyl acetate, washed sequentially with saturated Na2CO3, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
*H NMR (300 MHz, CDCI3) δ 9.72 (s, IH), 7.95 (d, IH), 7.64 (dd, IH), 6.80 (d, IH), 4.72 (s, 2H).
Example 33B
2-bromo-4-formylbenzonitrile A solution of Example 33 A (1.0 g, 5 mmol) in acetone (5 mL) at 0 °C was added to 4.5M HCl (8 mL). The mixture was treated with 40% sodium nitrite (1 mL), warmed to room temperature, and stirred for 1 hour. The mixture was added to a 0°C solution of copper(I) cyanide (0.45 g, 5 mmol) and potassium cyanide (0.65 g, 10 mmol) in water (20 mL) and toluene (50 mL), warmed to room temperature, stirred for 16 hours, and concentrated. The concentrate was extracted with ethyl acetate, washed sequentially with saturated Na2CO3, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. *H NMR (300 MHz, CDC13) δ 10.04 (s, IH), 8.18 (d, IH), 7.93 (dd, IH), 7.85 (d, IH).
Example 33C 4-(((3-bromo-4-cyanobenzyl)amino)(l-methyl-lH-imidazol-5-yl)methyl)-2-(l- naphthyPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 33B and Example 13 A for
4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2/dichloromethane:methanol. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 534 (M+2H)+;
XH NMR (300 MHz, CDC13) δ 7.97 (t, 2H), 7.87 (d, IH), 7.67 (s, IH), 7.61-7.43 (m, 9H), 7.36 (d, IH), 6.91 (d, IH), 4.98 (s, IH), 3.91-3.82 (m, 2H), 3.56 (d, 3H).
Example 34 4-(((4-cyanobenzyl)(( 1 -methyl- lH-imidazol-5-yl)methyl)amino)methyl)-2-( 1 - naphthyDbenzonitrile
Example 34A 4-(aminomethyl)benzonitrile A solution of 4-(bromomethyl)benzonitrile (27.5 g, 0.14 mol) in DMF (125 mL) was treated with potassium phthalimide (27.8 g, 0.15 mol), heated to 130 °C for 2.5 hours, cooled to room temperature, poured over ice, filtered, rinsed with water and a 1 : 1 mixture of hexanes: diethyl ether, and dried for 16 hours in a vacuum oven at 50 °C. The compound was treated with ethanol (200 mL) and 35% aqueous hydrazine (8 mL), heated to reflux for 3 hours, cooled to room temperature, filtered, and concentrated. The concentrate was purified by vacuum distillation to provide the desired product. XH NMR (300 MHz, CDC13) δ 7.63 (d, 2H), 7.45 (d, 2H), 3.96 (s, 2H), 1.48 (s, 2H).
Example 34B 4-(((4-cvanobenzyl)amino)methyl)-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 89C and Example 34A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. MS (ESI(+)) m/z 374 (M+H)+.
Example 34C 4-(((4-cyanobenzyl)((l-methyl-lH-imidazol-5-yl)methyl)amino)methyl)-2-(l- naphthyDbenzonitrile
The desired product was prepared by substituting Example 32C and Example 34B for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. *H NMR (300 MHz, CDC13) δ 7.92-7.88 (m, 2H), 7.74-7.71 (m, IH), 7.54-7.29 (m, 12H), 6.90 (s, IH), 3.68-3.39 (m, 6H), 3.37 (s, 3H).
Example 35 4-(((3-chloro-4-cyanobenzyDamino)(l-methyl-lH-imidazol-5-vDmethyD-2-(l- naphthvDbenzonitrile dihydrochloride
Example 35A 2-chloro-4-iodobenzonitrile
The desired product was prepared by substituting 4-amino-2-chlorobenzonitrile for 5- aminoquinoline in Example 43A. XH NMR (300 MHz, CDC13) δ 7.92 (d, IH), 7.74 (dd, IH), 7.36 (d, IH).
Example 35B methyl 3-chloro-4-cyanobenzoate A solution of Example 35A (39.9 g, 0.15 mol) in methanol (1 L) was treated with (1,1 -bis(diphenylphosphino)ferrocene)dichloropalladium(H) complex with dichloromethane (1:1) (1.25 g, 1.53 mmol) and triethylamine (24 mL), heated to 97 °C under 500 psi CO pressure for 20 hours, cooled to room temperature, filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. 1H NMR (300 MHz, CDCI3) δ 8.17 (d, IH), 8.02 (dd, IH), 7.77 (d, IH), 3.97 (s, 3H).
Example 35C 2-chloro-4-(hydroxymethyDbenzonitrile
The desired product was prepared by substituting Example 35B for Example 5 A in Example 5B.
Example 35D 2-chloro-4-formylbenzonitrile
A solution of Example 35C (5.49 g, 32.76 mmol) in dichloromethane (100 mL) at room temperature was treated with Dess-Martin periodinane (25 g, 58.9 mmol), stirred for 20 minutes, treated with saturated NaHCO3 and saturated Na2S2O3, stirred for 5 minutes, concentrated, and extracted with diethyl ether. The extracts were washed with brine, dried (Na SO4), filtered, and concentrated to provide the desired product. MS (DCI(+)) m/z 183 (M+NH4)+; 1H NMR (300 MHz, CDCI3) δ 10.06 (s, IH), 8.03-8.02 (m, IH), 7.88 (d, 2H).
Example 35E 4-(((3-chloro-4-cvanobenzyDamino)(l-methyl-lH-imidazol-5-yDmethyD-2-(l- naphthvDbenzonitrile dihydrochloride The desired product was prepared by substituting Example 35D and Example 13 A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 488 (M+H)+;
XH NMR (400 MHz, CDC13) δ 7.96 (t, 2H), 7.86 (d, IH) 7.62-7.42 (m, 10H), 7.31 (d, IH), 6.91 (d, IH), 4.98 (s, IH), 3.90 -3.81 (m, 2H), 3.55 (d, 3H).
Example 36 4-((( 1 -(4-cyanophenyDethvDamino) ( 1 -methyl- 1 H-imidazol-5-yDmethyl)-2-( 1 - naphthyDbenzonitrile dihydrochloride The desired product was prepared by substituting 4-acetylbenzonitrile and Example 13A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 468 (M+H)+;
XH NMR (300 MHz, CDC13) δ 7.98-7.35 (m, 15H), 7.00-6.72 (m, IH), 4.81-4.58 (m, IH), 3.93-3.70 (m, IH), 3.56-3.47 (m, 3H), 1.41-1.36 (m, 3H).
Example 37
4-(((4-cyano-3-iodobenzyDamino)(l-methyl-lH-imidazol-5-vDmethyl)-2-(l- naphthvDbenzonitrile dihydrochloride
Example 37A 4-(hydroxymethvD-2-iodobenzonitrile
A suspension of Example 63 A (296 mg, 1.0 mmol) in water (10 mL) was treated with diatomaceous earth (Celite®) (296 mg), heated to reflux for 2 hours, cooled to room temperature, and filtered. The filtrate was extracted with ethyl acetate, dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
MS (DCI/NH3) m/z 277 (M+NH-t)+;
XH NMR (300 MHz, CDC13) δ 7.96 (s, IH), 7.60 (d, IH), 7.44 (dt, IH), 4.75 (d, 2H), 1.86 (t,
IH).
Example 37B
4-formyl-2-iodobenzonitrile A solution of Example 37 A (70 mg, 0.27 mmol) in DMSO (2 mL) and triethylamine (190 μL, 1.35 mmol) at room temperature was treated with small portions of pyridine sulfur trioxide (107 mg, 0.68 mmol), stirred for 16 hours, treated with ethyl acetate, washed sequentially with IM HCl, water, and brine, dried (Na2SO4), and filtered. The filtrate was treated with activated charcoal, stirred for 45 minutes, filtered through a pad of diatomaceous earth (Celite®) with 9:l/dichloromethane:methanol, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 257 (M)+; XH NMR (300 MHz, CDC13) δ 10.01 (s, IH), 8.41 (s, IH), 7.96 (d, IH), 7.80 (d, IH).
Example 37C 4-(((4-cvano-3-iodobenzyDamino)(l-methyl-lH-imidazol-5-yDmethyD-2-(l- naphthyPbenzonitrile dihydrochloride A solution of 13 A (32 mg, 0.09 mmol) and molecular sieves (100 mg) in 1,2- dichloroethane (2 mL) at room temperature was treated with Example 37B (34 mg, 0.57 mmol) and acetic acid, stirred for 30 minutes, treated with sodium triacetoxyborohydride (60 mg, 0.28 mmol), and stirred for 16 hours. The mixture was treated with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in dichloromethane (5 mL), treated with 4M HCl in dioxane (1 mL), stirred for 30 minutes, and concentrated. The concentrate was dissolved in ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2/dichloromethane:methanol. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 580 (M+H)+;
1H NMR (400 MHz, CDCI3) δ 7.87 (t, 2H), 7.81-7.76 (m, 2H) 7.52-7.29 (m, 10H), 6.81 (d, IH), 4.87 (s, IH), 3.78-3.69 (m, 2H), 3.47 (d, 3H), 1.97 (s, IH).
Example 38 methyl 4-((((4-cyano-3-( 1 -naphthyl)phenyp( 1 -methyl- lH-imidazol-5- vDmethvDamino)methvPbenzoate The desired product was prepared by substituting methyl 4-formylbenzoate for Example 37B in Example 37C. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m/z 487 (M+H)+; 1H NMR (300 MHz, CDC13) δ 8.01-7.89 (m, 5H), 7.62-7.32 (m, 10H), 7.10-7.00 (m, IH), 5.00-4.93 (m, IH), 3.92 (s, 3H), 3.90-3.64 (m, 2H), 3.75-3.60 (m, 3H).
Example 39 lithium 4-((((4-cvano-3-(l-naphthyPphenyP(l-methyl-lH-imidazol-5- yPmethyPamino)methyPbenzoate A solution of Example 38 (55 mg, 0.113 mmol) in methanol (2 mL) and water (0.5 mL) at room temperature was treated with lithium hydroxide monohydrate (4.7 mg, 0.112 mmol), stirred for 16 hours, treated with a second portion of lithium hydroxide monohydrate (2.4 mg, 0.057 mmol), stirred for 8 hours, and concentrated. The concentrate was treated with THF (1 mL) and water (1.0 mL), stirred for 16 hours, treated with a third portion of lithium hydroxide monohydrate (3.0 mg, 0.07 mmol), stirred for 16 hours, and concentrated. The concentrate was dissolved in water (3 mL), washed with diethyl ether, and lyophilized to provide the desired product. MS (ESIC+)) m z 473 (M+H)+;
!H NMR (300 MHz, CDCI3) δ 8.08-8.01 (m, 3H), 7.76-7.42 (m, 10H), 7.16 (d, 2H), 6.53 (d, IH), 4.98 (s, IH), 3.72-3.60 (m, 2H), 3.54 (d, 3H).
Example 40 4-(((4-chlorobenzvP(( 1 -methyl- lH-imidazol-5-ypmethypamino)methyD-2-( 1 - naphthyDbenzonitrile dihydrochloride
Example 40A 4-(((4-chlorobenzypamino methyP-2-(l-naphthyPbenzonitrile The desired product was prepared by substituting Example 89C and (4- chlorophenyl)methylamine for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B.
MS (ESI(+)) m z 383 (M+H)+;
!H NMR (400 MHz, CDCI3) δ 7.94 (dd, 2H), 7.79 (d, IH), 7.58-7.42 (m, 8H), 7.30-7.24 (m, 3H), 3.91 (s, 2H), 3.81 (s, 2H).
Example 40B 4-(((4-chlorobenzyp((l-methyl-lH-imidazol-5-yPmethyPamino)methyl)-2-(l- naphthyPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 32C and Example 40A for
4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 479 (M+2H)+;
1H NMR (300 MHz, CDC13) δ 7.96 (dd, 2H), 7.80-7.77 (m, IH), 7.58-7.19 (m, 12H), 7.10- 7.00 (m, IH), 3.70-3.48 (m, 6H), 1.90 (m, 3H).
Example 41 4-(((( 1-methyl- lH-imidazol-5-yDmethvD(4-(trifluoromethoxy)benzvDamino)methyD-2-( 1 - naphthyDbenzonitrile dihydrochloride
Example 41 A 4-(((4-trifluoromethoxybenzyDamino)methvD-2-(l-naphthvDbenzonitrile The desired product was prepared by substituting Example 89C and 4- trifluoromethoxybenzylamine for 4-nitrobenzaldehyde and Example 12 A, respectively, in Example 12B.
MS (ESI(+)) m/z 433 (M+H)+;
*H NMR (400 MHz, CDC13) δ 7.94 (dd, 2H), 7.82-7.78 (m, IH), 7.58-7.34 (m, 9H), 7.16 (d,
2H), 3.93 (s, 2H), 3.84 (s, 2H).
Example 4 IB
4-(((( 1 -methyl- lH-irnidazol-5-yDmethyD(4-(trifluoromethoxy)benzyDamino)methvD-2-( 1 - naphthyDbenzonitrile dihydrochloride The desired product was prepared by substituting Example 32C and Example 41 A for 4-nitrobenzaldehyde and Example 12 A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 527 (M+H)+;
*H NMR (400 MHz, CDC13) δ 7.97-7.94 (m, 2H), 7.77 (d, IH), 7.60-7.28 (m, 10H), 7.14 (d, 2H), 6.96 (s, IH), 3.74-3.49 (m, 6H), 3.43 (s, 3H).
Example 42 4-(((4-chlorobenzyDamino)( 1 -methyl- lH-imidazol-5-vDmethvD-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting 4-chlorobenzaldehyde and Example 13A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. MS (ESI(+)) m/z 463 (M+H)+;
1H NMR (400 MHz, CDC13) δ 7.97-7.92 (m, 2H), 7.84 (d, IH), 7.60-7.39 (m, 8H), 7.29-7.20 (m, 4H), 6.85 (d, IH), 4.94 (d, IH), 3.82-3.70 (m, 2H), 3.43 (d, 3H). Example 43 4-(((4-cvanobenzyPoxy (l-methyl-lH-imidazol-5-yPmethyp-2-(5-quinolinyPbenzonitrile dihydrochloride
Example 43 A 5-iodoquinoline A solution of 5-aminoquinoline (5.5 g, 38.1 mmol) in 3M HCl (100 mL) at 0 °C was treated dropwise with a solution of sodium nitrite (3.65 g, 52.9 mmol) in water (25 mL), then with a solution of potassium iodide (13.0 g, 78.3 mmol) in water (25 mL) with periodic treatment with acetone to prevent foaming. The reaction was warmed to room temperature, stirred for 16 hours, treated with saturated sodium thiosulfate, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 8:1 to 4:l/hexanes:ethyl acetate to provide the desired product.
XH NMR (400 MHz, CDC1 ) δ 8.89 (d, IH), 8.39 (d, IH), 8.14-8.10 (m, 2H), 7.51-7.41 (m, 2H).
Example 43B 5-quinolinylboronic acid
A solution of 1.6M n-butyllithium in diethyl ether (15.6 mL, 25 mmol) in diethyl ether (40mL) at -78 °C was treated with a solution of Example 43 A (2.55 g, 10 mmol) in diethyl ether (30 mL), stirred for 40 minutes, treated with a solution of tributyl borate (6.9 g, 17.4 mmol) in diethyl ether (10 mL), warmed to room temperature, and stirred for 16 hours. The mixture was cooled to 0 °C, and adjusted to pH 2 with IM HCl. The aqueous layer was cooled to 0 °C, adjusted to pH 7 with saturated NaHCU3, and the resulting precipitate was filtered and dried to provide the desired product of sufficient purity for subsequent use without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.88-8.82 (m, IH), 8.46 (s, IH), 8.04-8.00 (dd, IH), 7.88 (dd, IH), 7.72 (dd, IH), 7.51 (dd, IH).
Example 43C 4-(((4-cyanobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethvP-2-(5-quinolinyPbenzonitrile dihydrochloride A solution of Example 60C (45 mg, 0.1 mmol) in toluene (1 mL) and ethanol (1 mL) was treated with Example 43B (35 mg, 0.2 mmol), 2M Na2CO3 (0.15 mL, 0.3 mmol), lithium chloride (13 mg, 0.3 mmol), and Pd(PPh3)4 (5.8 mg, 0.005 mmol), heated to reflux for 16 hours, and cooled to room temperature. The mixture was treated with ethyl acetate, washed with water and brine, dried (Na2SU4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 99:1 to 90:10/dichloromethane/methanol. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 456 (M+H)+;
!H NMR (400 MHz, CDC13) δ 8.98-8.97 (m, IH), 8.24 (d, IH), 7.90-7.78 (m, 3H), 7.66-7.40 (m, 9H), 6.98-6.97 (m, IH), 5.70-5.69 (m, IH), 4.69-4.58 (m, 2H), 3.49-3.44 (m, 3H).
Example 44
4-(((4-cyanobenzyPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(5-isoquinolinvPbenzonitrile
Example 44A 5-iodoisoquinoline The desired product was prepared by substituting 5-aminoisoquinoline for 5- aminoquinoline in Example 43A.
1H NMR (300 MHz, CDCI3) δ 9.15 (s, IH), 8.64 (d, IH), 8.28 (d, IH), 7.99 (d, IH), 7.85 (d, IH), 7.37 (t, IH).
Example 44B
5-isoquinolinylboronic acid The desired product was prepared by substituting Example 44A for Example 43 A in Example 43B.
Example 44C
4-(((4-cvanobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyP-2-(5-isoquinolinvPbenzonitrile
The desired product was prepared by substituting Example 44B for Example 43B in Example 43C. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 99:1 to 90:10/dichloromethane:methanol to provide the desired product.
MS (ESI(+)) m z 456 (M+H)+;
!H NMR (400 MHz, CDCI3) δ 9.36 (s, IH), 8.50 (dd, IH), 8.12-8.08 (m, IH), 7.89 (d, IH),
7.73-7.41 (m, 9H), 7.27 (dd, IH), 6.98 (d, IH), 5.70 (d, IH), 5.69-4.59 (m, 2H), 3.47 (s, 3H).
Example 45
4-(((4-cvanobenzvP(lH-imidazol-5-ylmethyPamino)methyP-2-(l-naphthvPbenzonitrile dihydrochloride A solution of Example 34B (25 mg, 0.067 mmol) in 1,2-dichloroethane (1 mL) at room temperature was treated with lH-imidazole-5-carbaldehyde (9.6 mg, 0.1 mmol) and acetic acid (2 mL, 35 mmol), stirred for 30 minutes, treated with sodium triacetoxyborohydride (140 mg, 0.66 mmol), stirred for 72 hours, treated with additional 1H- imidazole-5-carbaldehyde (20 mg, 0.21 mmol), and stirred for 2 days. The mixture was treated with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in dichloromethane (5 mL), treated with 4M HCl in dioxane (1 mL), stirred for 30 minutes, and concentrated. The concentrate was dissolved in ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2 to 95:5/dichloromethane/methanol. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 454 (M+H)+;
!H NMR (400 MHz, CDC13) δ 7.92 (dd, 2H), 7.75 (d, IH), 7.64 (s, IH), 7.57-7.32 (m, 12H), 6.89 (s, IH), 3.79-3.61 (m, 6H).
Example 46 4-(((4-cyanobenzyDoxy)(lH-imidazol-5-yDmethyD-2-(l-naphthyl)benzonitrile hydrochloride A solution of Example 49C (50 mg, 0.07 mmol) in 80% aqueous acetic acid (5 mL), at room temperature was stirred for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:l/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m/z 441 (M+H)+;
XH NMR (500 MHz, CDCI3) δ 7.94-7.91 (m, 2H), 7.82 (dd, IH), 7.68-7.36 (m, 13H), 6.93 (d, IH), 5.66 (d, IH), 4.68 (abq, 2H).
Example 47 4-(((3,4-dichlorobenzyDamino)(l-methyl-lH-imidazol-5-yDmethyD-2-(l- naphthvDbenzonitrile The desired product was prepared by substituting 3,4-dichlorobenzaldehyde and Example 13 A for 4-nitrobenzaldehyde and Example 12 A, respectively, in Example 12B. MS (ESI(+)) m/z 497 (M)+; *H NMR (300 MHz, CDC13) δ 7.98-7.93 (m, 2H), 7.86 (d, IH), 7.61-7.36 (m, lOH), 7.12 (d, IH), 6.87 (s, IH), 4.94 (s, IH), 3.82-3.69 (m, 2H), 3.56 (d, 3H). Example 48 4-((((4-cyano-3-(l-naphthyDphenyD(l-methyl-lH-imidazol-5-yDmethyDamino)methvD-N- methylbenzamide dihydrochloride A solution of Example 39 (20 mg, 0.04 mmol) in DMF (1 mL) at room temperature was treated with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mg, 0.06 mmol), 1-hydroxybenzotriazole (8.5 mg, 0.06 mmol), methylamine hydrochloride (28.4 mg, 0.42 mmol), and 4-methylmorpholine (46 μL, 0.42 mmol), stirred for 16 hours, treated with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSU4), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 98:2 to 95:5/dichloromethane:methanol. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 486 (M+H)+;
XH NMR (400 MHz, CDC13) δ 7.96-7.92 (m, 2H), 7.83 (d, IH), 7.71 (d, 2H), 7.59-7.33 (m, lOH), 6.86 (d, IH), 6.14 (m, IH), 4.94 (d, IH), 3.89-3.67 (m, 2H), 3.53 (d, 3H), 3.00 (d, 3H).
Example 49 4-(((4-cyanobenzyDoxy)(l-trityl-lH-imidazol-4-vPmethyP-2-(l-naphthyl)benzonitrile
Example 49 A
4-iodo- 1 -trityl- lH-imidazole A suspension of 4-iodoimidazole (3.38 g, 17.4 mmol) and triphenylmethyl chloride (5.56 g, 19.9 mmol) in DMF (15 mL) at 0 °C was treated with triethylamine (1.5 mL, 10.8 mmol), warmed to room temperature, stirred for 16 hours, poured into ice water, filtered, and dried in a vacuum oven at 50 °C to provide the desired product of sufficient purity for subsequent use without further purification.
Example 49B 4-(hydroxy( 1 -trityl- lH-imidazol-4-yPmethyP-2-( 1 -naphthyDbenzonitrile A solution of Example 49A (873 mg, 2.0 mmol) in dichloromethane (8 mL) at room temperature was treated with 3M ethyl magnesium bromide in diethyl ether (0.73 mL, 2.2 mmol), stirred for 30 minutes, and cooled to -20 °C. The mixture was treated with a solution of Example 89C (514 mg, 2 mmol) in dichloromethane (2 mL), warmed to room temperature, stirred for 16 hours, treated with saturated ammonium chloride, and concentrated. The concentrate was extracted with ethyl acetate, the extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. 1H NMR (300 MHz, CDC13) δ 7.94 (dd, 2H), 7.79 (dd, IH), 7.68-7.23 (m, 17H), 7.08-7.05 (m, 6H), 6.64-6.62 (m, IH), 5.87 (d, IH).
Example 49C 4-(((4-cyanobenzvDoxy)(l-trityl-lH-imidazoI-4-vDmethyD-2-(l-naphthyDbenzonitrile
A solution of Example 49B (113 mg, 0.2 mmol) in dichloromethane (1 mL) at room temperature was treated with 4-(bromomethyl)benzonitrile (50 mg, 0.25 mmol) and silver (I) oxide (140 mg, 0.6 mmol), and stirred for 72 hours. The mixture was purified by flash column chromatography on silica gel with 6:1 to 4:l/hexanes:ethyl acetate to provide the desired product.
MS (ESI(+)) mz 382 (M)+;
2H NMR (400 MHz, CDC13) δ 7.94 (dd, 2H), 7.80 (dd, IH), 7.65 (dq, IH), 7.58-7.23 (m,
20H), 7.09-7.06 (m, 6H), 6.73 (dd, IH), 5.56 (s, IH), 4.69-4.60 (m, 2H).
Example 50 ethyl 4-(((4-cyano-3-(l-naphthyDphenvD(l-methyl-lH-imidazol-5-yDmethvDamino)-l- piperidinecarboxylate dihydrochloride The desired product was prepared by substituting ethyl 4-oxo-l -piperidinecarboxylate and Example 13A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 494 (M+H)+;
*H NMR (300 MHz, CDC13) δ 7.96 (dd, 2H), 7.85 (d, IH), 7.61-7.42 (m, 8H), 6.74 (d, IH), 5.15 (s, IH), 4.16-4.00 (m, 2H), 4.11 (q, 2H), 3.62 (d, 3H), 2.87-2.78 (m, 2H), 2.70-2.61 (m, IH), 1.97-1.73 (m, 2H), 1.40-1.20 (m, 5H).
Example 51 6-((((4-cyano-3-(l-naphthyDphenyD(l-methyl-lH-imidazol-5- yDmethvDamino)methyDnicotinonitrile trihydrochloride
Example 51 A 6-formylnicotinonitrile A solution of 6-methylnicotinonitrile (590 mg, 5.0 mmol) in dioxane (10 mL) and water (0.5mL) was treated with selenium dioxide (555 mg, 5.0 mmol), heated to reflux for 16 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes then 9.T/hexanes:ethyl acetate to provide the desired product. XH NMR (300 MHz, CDC13) δ 10.13-10.12 (m, IH), 9.06-9.05 (m, IH), 8.19-8.16 (m, IH), 8.09-8.05 (m, IH).
Example51B 6-((((4-cyano-3-(l-naphthyDphenyD(l-methyl-lH-imidazol-5- yDmethyl)amino)methyDnicotinonitrile trihydrochloride The desired product was prepared by substituting Example 51 A and Example 13 A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 99:1 to 98:2/dichloromethane:methanol. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 455 (M+H)+;
*H NMR (300 MHz, CDCI3) δ 8.80 (s, IH), 7.97-7.82 (m, 4H), 7.59-7.36 (m, 9H), 6.94 (s, IH), 5.07 (s, IH), 3.99 (s, 2H), 3.56 (d, 3H), 2.67 (s, IH).
Example 52 methyl 6-((((4-cvano-3-(l-naphthyDphenyD(l-methyl-lH-imidazol-5- yDmethyDamino)methyDnicotinate trihydrochloride
Example 52A methyl 6-(hydroxymethyDnicotinate The desired product was prepared by substituting dimethyl 2,5-pyridinedicarboxylate for Example 5 A in Example 5B.
Example 52B methyl 6-formylnicotinate The desired product was prepared by substituting Example 52A for Example 37A in Example 37B.
Example 52C methyl 6-((((4-cvano-3-(l-naphthyDphenyl)(l-methyl-lH-imidazol-5- yDmethvDamino methyDnicotmate trihydrochlori.de The desired product was prepared by substituting Example 52B and Example 13 A for 4-nitrobenzaldehyde and Example 12 A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESIC+)) m z 488 (M+H)+; 1H NMR (300 MHz, CDC13) δ 9.14 (s, IH), 8.23 (dd, IH), 7.97-7.92 (m, 2H), 7.83 (d, IH), 7.61-7.40 Cm, 7H), 7.32-7.24 (m, 2H), 6.93 (s, IH), 5.05 (s, IH), 3.98-3.92 (m, 5H), 3.56 (s, 3H), 2.71 (s, IH).
Example 53
N-(4-((((4-cyano-3-(l-naphthyDphenyD(l-methyl-lH-imidazol-5- yDmethyDamino)methyl)phenyDacetamide dihydrochloride The desired product was prepared by substituting N-(4-formylphenyl)acetamide and Example 13 A for 4-nitrobenzaldehyde and Example 12 A, respectively, in Example 12B. The purified concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS CESIC+)) m/z 486 (M+H)+;
XH NMR (400 MHz, CDCI3) δ 7.93 (dd, 2H), 7.82 (d, IH), 7.58-7.38 (m, 10H), 7.21 (d, 2H), 6.84 (d, IH), 4.94 (s, IH), 3.79-3.67 (m, 2H), 3.52 (d, 3H), 2.13 (s, 3H).
Example 54 benzyl 4-(((4-cvano-3-(l-naphthvDphenyD(l-methyl-lH-imidazol-5-yDmethvDamino)-l- piperidinecarboxylate dihydrochloride The desired product was prepared by substituting benzyl-4-oxo-l- piperidinecarboxylate and Example 13A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 556 (M+H)+;
*H NMR (400 MHz, CDCI3) δ 7.94 (dd, 2H), 7.83 (d, IH), 7.59-7.28 (m, 13H), 6.74 (d, IH), 5.13-5.11 (m, 3H), 4.07 (m, 2H), 3.60 (d, 3H), 2.90-2.83 (m, 2H), 2.69-2.61 (m, IH), 1.95- 1.72 (m, 2H), 1.36-1.30 (m, 2H).
Example 55 4-((( 1 -benzyl-4-piperidinvDamino) ( 1 -methyl- 1 H-imidazol-5- yl)methyl)-2-( 1 - naphthyDbenzonitrile trihydrochloride
The desired product was prepared by substituting 1 -benzyl -4-piperidinone and Example 13A for 4-nitrobenzaldehyde and Example 12A, respectively, in Example 12B. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m z 512 (M+H)+; 1H NMR (400 MHz, CDC13) 6 7.96-7.91 (m, 2H), 7.82 (d, IH), 7.59-7.22 (m, 13H), 6.71 (d, IH), 5.12 Cs, IH), 3.60 Cd, 3H), 3.51-3.45 Cm, 2H), 2.82-2.74 (m, 2H), 2.52-2.43 Cm, IH), 2.05-1.43 (m, 6H).
Example 56 tert-butyl 4-(((4-cyano-3-(l-naphthyDphenyD(l-methyl-lH-irmdazol-5-yDmethvDamino)-l- piperidinecarboxylate A solution of Example 13 A (20 mg, 0.06 mmol) in 1,2-dichloroethane (1 mL) at room temperature was treated with tert-butyl 4-oxo-l -piperidinecarboxylate (11.8 mg, 0.06 mmol) and acetic acid (21 mg, 0.35 mmol), stined for 30 minutes, treated with sodium triacetoxyborohydride (37.5 mg, 0.18 mmol), stined for 16 hours, treated with ethyl acetate, washed sequentially with saturated NaHCU3, water, and brine, dried (MgSU4), filtered, and concentrated. The concentratewas dissolved in methanol (3 mL), heated to 60 °C for 1 hour, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 99:1 to 97:3/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m/z 522 (M+H)+;
XH NMR (500 MHz, CDC13) δ 7.96-7.92 (m, 2H), 7.83 (d, IH), 7.59-7.39 (m, 8H), 6.71 (d, IH), 5.14 (s, IH), 3.99-3.98 (m, 2H), 3.61 Cd, 3H), 2.80-2.75 (m, 2H), 2.67-2.60 Cm, IH), 1.88-1.60 Cm, 3H), 1.45 (s, 9H), 1.33-1.25 (m, 2H).
Example 57 4-(((l-benzoyl-4-piperidinyDamino (l-methyl-lH-imidazol-5-ypmethyD-2-(l- naphthyPbenzon trile dihydrochloride The desired product was prepared by substituting l-benzoyl-4-piperidinone for tert- butyl 4-oxo-l-piperidinecarboxylate in Example 56. MS (ESI(+)) m/z 526 (M+H)+;
XH NMR (300 MHz, CDC13) δ 7.98-7.93 (m, 2H), 7.85 (d, IH), 7.61-7.36 (m, 13H), 6.76 Cd, IH), 5.15 (s, IH), 4.56 (s, IH), 3.73-3.59 (m, IH), 3.62 (d, 3H), 2.95-2.72 (m, 3H), 2.10-0.80 (m, 5H).
Example 58
4-((((4-cyano-3-(l-naphthyPphenvP(l-methyl-lH-imidazol-5- yl)methyPamino)methyPbenzamide dihydrochloride A solution of Example 39 (20 mg, 0.04 mmol) in DMF (0.5 mL) at room temperature was treated sequentially with PyBOP (33 mg, 0.06 mmol), 0.5M ammonia in dioxane l mL,
0.5 mmol), and HOBt, stined for 16 hours, treated with ammonia, stined for 16 hours, treated with ethyl acetate, washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane then 95:5 to
90:10/dichloromethane:methanol. The concentrate was dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 472 (M+H)+;
XH NMR (500 MHz, CDC13) δ 8.39 (d, IH), 8.00-7.96 (m, 3H), 7.82 (dd, 2H), 7.75-7.72 (m, IH), 7.68-7.42 (m, 8H), 7.11 (s, IH), 5.17 (d, IH), 3.92-3.82 (m, 2H), 3.77 (d,'3H).
Example 59
4-((l-methyl-lH-imidazol-5-vP((4-nitrobenzypoxy)methvP-2-(l-naphthyPbenzonitriIe hydrochloride The desired product was prepared by substituting Example 89D and 4-nitrobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS CDCI NH3) m/z 475 CM+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.09 Cs, IH), 8.22-8.02 (m, 6H), 7.79 Cm, IH), 7.69-7.43 (m, 9H), 6.19 (s, IH), 4.8 (m, 2H), 3.79 (d, 3H).
Example 60 4-(((4-cyanobenzyPoxy)(l-methyl-lH-imidazol-5-vPmethyP-2-iodobenzonitrile hydrochloride
Example 60A 4-(hydroxymethyP-2-iodobenzonitrile The desired product was prepared by substituting Example 93C for Example 5A in
Example 5B.
Example 60B 4-formyl-2-iodobenzonitrile The desired product was prepared by substituting Example 60A for Example 5B in
Example 5C.
Example 60C 4-(hvdroxy(l-methyl-lH-imidazol-5-yPmethyp-2-iodobenzonitrile The desired product was prepared by substituting Example 60B for Example 1 A in
Example IB. 1H NMR (300 MHz, DMSO-d6) δ 8.04 Cs, IH), 7.85 Cd, IH), 7.58 Cm, 2H), 6.39 (s, IH), 6.22 (d, IH), 5.88 (d, IH), 3.55 (s, 3H).
Example 60D 4-(((4-cvanobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyP-2-iodobenzonitrile hydrochloride The desired product was prepared by substituting Example 60C and 4-cyanobenzyl bromide for Example 5D and (bromomethyPbenzene, respectively, in Example 5E. MS (DCI NH3) m/z 455 (M+H)+; XH NMR (300 MHz, CDC13) δ 9.1 (s, IH), 8.0 (m, IH), 7.7 (m, 4H), 7.5 (m, 3H), 5.68 (br s, IH), 4.63 (m, 2H), 3.8 (br s, 3H).
Example 61 4-(((3-chloro-4-cvanobenzvPoxy)(l-methyl-lH-imidazol-5-yPmethvP-2-(l- naphthyDbenzonitrile hydrochloride
Example 61 A 2-chloro-4-(hvdroxymethvDbenzonitrile The desired product was prepared by substituting Example 35B for Example 5A in Example 5B.
MS (DCI NH3) m/z 185 (M+NH4)+;
!H NMR (300 MHz, CDCI3) δ 7.67 (d, IH), 7.57 (s, IH), 7.37 (d, IH), 4.69 (d, 2H), 1.90 (t,
IH).
Example 61B
4-(bromomethyl)-2-chlorobenzonitrile A solution of Example 61 A (0.22 g, 1.31 mmol) and LiBr (0.13 g, 1.44 mmol) in DMF (2 mL) at 0 °C was treated with PBr3 (0.38 g, 1.39 mmol), stined for 30 minutes, treated with water, and extracted with diethyl ether. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity to be used in subsequent steps without further purification. 1H NMR (300 MHz, CDCI3) δ 7.67 (d, IH), 7.57 (d, IH), 7.40 (dd, IH), 4.44 (s, 2H).
Example 61C 4-(((3-chloro-4-cy anobenzvDoxyX 1 -methyl- lH-imidazol-5-vDmethyD-2-( 1 - naphthyDbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and Example 6 IB for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 489 (M+H)+;
!H NMR C300 MHz, DMSO-d6) δ 8.08 Cm, 3H), 7.94 Cm, IH), 7.6 (m, 11H), 6.62 Cm, IH), 5.98 Cs, IH), 4.65 Cm, 2H), 4.05 Cs, 3H).
Example 62 4-(( ( 4-c yanobenzyPsulf anylX 1 -methyl- lH-imidazol-5-vPmethyl)-2-( 1 -naphthyDbenzonitrile hydrochloride
Example 62A 4-(sulfanylmethyl)benzonitrile A mixture of 4-cyanobenzyl bromide (10 g, 50 mmol) and thiourea (9.8 g, 100 mmol) in ethanol (70 mL) was refluxed for 1 hour, cooled, and concentrated. The concentrate was washed with ethyl acetate, treated with 1.6M NaOH (100 mL), stined for 22 hours, adjusted to pH 4 with concentrated HCl, and extracted with diethyl ether. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity to be used in subsequent steps without further purification.
Example 62B
4-(chloro(l-methyl-lH-imidazol-5-yDmethyD-2-(l-naphthvPbenzonitrile A solution of Example 89D (100 mg, 0.29 mmol) in dichloromethane (10 mL) at 0 °C was treated with thionyl chloride (70 mg, 0.59 mmol), stined for 15 minutes, warmed to room temperature, stined for 2 hours, and concentrated to provide the desired product of sufficient purity to be used in subsequent steps without further purification.
Example 62C
4-(((4-cyanobenzyPsulfanyp(l-methyl-lH-iιi-idazol-5-ypmethyP-2-(l-naphthyl)benzonitrile hydrochloride A solution of Example 62B in dichloromethane (5 mL) at room temperature was treated with Example 62 A (53 mg, 0.35 mmol) and diisopropylethylamine (5 mL, 0.71 mmol), stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/chloroform:methanol, treated with IM HCl in diethyl ether, and filtered to provide the desired product. MS CDCI/NH3) m z 471 CM+H)+;
*H NMR (300 MHz, DMSO-d6) δ 9.3 (br s, IH), 7.9 (m, 4H), 7.5 (m, 13H), 4.9 (br s, 2H),
4.2 (br s, IH), 3.8 (br s, 3H). Example 63 4-(((4-cyano-3-iodobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethyP-2-(l- naphthyPbenzonitrile hydrochloride
Example 63A 2-iodo-4-methylbenzonitrile The desired product was prepared by substituting 2-iodo-4-methylaniline for Example 87A in Examples 87B and 87C.
Example 63B 4-(bromomethvD-2-iodobenzonitrile A mixture of Example 63A (11.6 g, 47.2 mmol), N-bromosuccinimide (9.2 g, 51.9 mmol), and benzoyl peroxide (57 mg, 0.24 mmol) in carbon tetrachloride (150 mL) was heated to reflux for 18 hours, cooled to room temperature, washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:l/hexanes:ethyl acetate to provide the desired product. MS (DCI/NH3) m/z 339 and 341 (M+NH-t)+;
XH NMR (300 MHz, CDC13) δ 7.95 (d, IH), 7.59 (d, IH), 7.48 (dd, IH), 4.40 (s, 2H).
Example 63C 4-(((4-cvano-3-iodobenzyPoxy)(l-methyl-lH-imidazol-5-vPmethyl)-2-(l- naphthvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and Example 63B for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI NH3) m/z 581 (M+H)+;
2H NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 8.1 (m, 4H), 7.8 (m, 2H), 7.6 (m, 9H), 6.13 (s, IH), 4.7 (m, 2H), 3.79 (d, 3H).
Example 64 methyl 4-(((4-cvano-3-( 1 -naphthvDphenylX 1 -methyl- lH-imidazol-5- ypmethoxy)methvPbenzoate hydrochloride The desired product was prepared by substituting Example 89D and 4- (bromomethyl)-benzoate for Example 5D and (bromomethyl)benzene, respectively, in Example 5E.
MS (DCI/NH3) m/z 488 (M+H)+; 1HNMR (300 MHz, DMSO-d6) δ 9.02 (s, IH), 8.17 (m, IH), 8.09 (m, 2H), 7.93 (m, 2H), 7.79 (m, IH), 7.55 (m, 9H), 6.12 (s, IH), 4.7 (m, 2H), 3.85 (s, 3H), 3.79 (d, 3H).
Example 65 4-((l-methyl-lH-imidazol-5-vD((4-(trifluoromethvDbenzyDoxy)methyD-2-(l- naphthyPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and 4-(trifluoromethyl)benzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 498 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.09 (m, IH), 8.17 (m, IH), 8.08 (m, 2H), 7.79 (d, IH), 7.6 (m, 12H), 6.18 (s, IH), 4.75 (m, 2H), 3.80 (d, 3H).
Example 66 4-(((4-chlorobenzvPoxy)(l-methyl-lH-imidazol-5-ypmethvP-2-(l-naphthyPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and 4-chlorobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 464 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.03 (s, IH), 8.17 (m, IH), 8.09 (m, 2H), 7.78 (m, 2H), 7.62 (m, 5H), 7.51 (m, 2H), 7.41 (m, 4H), 6.10 (s, IH), 4.6 (m, 2H), 3.78 (d, 3H).
Example 67 4-((l-methyl-lH-imidazol-5-vP((4-(trifluoromethoxy)benzvPoxy)methyP-2-(l- naphthvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and 4-(trifluoromethoxy)benzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 514 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.94 Cs, IH), 8.16 Cm, IH), 8.09 (m, 2H), 7.78 (m, IH), 7.61 (m, 4H), 7.50 (m, 5H), 7.35 (m, 3H), 6.11 (s, IH), 4.65 (m, 2H), 3.77 (d, 3H).
Example 68 4-((l-methyl-lH-imidazol-5-yl)((3-(trifluoromethyPbenzvPoxy)methyP-2-(l- naphthvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and 3-(trifluoromethyl)benzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E.
MS (DCI/NH3) m/z 498 (M+H)+;
XH NMR C300 MHz, DMSO-d6) δ 8.98 (s, IH), 8.17 (m, IH), 8.09 (m, 2H), 7.79 (m, IH), 7.6 (m, 11H), 7.40 (m, IH), 6.13 (s, IH), 4.7 (m, 2H), 3.78 (d, 3H).
Example 69 lithium 4-(((4-cvano-3-(l-naphthvPphenvP(l-methyl-lH-imidazol-5- yPmethoxy)methypbenzoate A solution of Example 64 (98 mg, 0.20 mmol) in methanol (2 mL) at room temperature was treated with IM LiOH (0.21 mL, 0.21 mmol), stined for 48 hours, and concentrated. The concentrate was treated with water, washed with diethyl ether, and lyophilized to provide the desired product of sufficient purity to be used in subsequent steps without further purification. MS (DCI/NH3) m/z 474 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.09 (m, 3H), 7.78 (m, 3H), 7.6 (m, 7H), 7.20 (m, 2H), 6.55 (d, IH), 5.89 (d, IH), 4.51 (m, 2H), 3.54 (d, 3H).
Example 70 4-(((4-cvano-3-(l-naphthyl)phenvP(l-methyl-lH-imidazol-5-vPmethoxy)methyP-N,N- dimethylbenzamide hydrochloride A solution of Example 69 (50 mg, 0.10 mmol) and oxalyl chloride (0.10 mmol) in dichloromethane (2 mL) was treated with DMF (1 drop), stined for 1 hour, and concentrated. The concentrate was treated with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/chloroform:methanol, treated with HCl, and concentrated to provide the desired product.
MS (DCI/NH3) m/z 501 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.61 (m, IH), 8.1 (m, 3H), 7.78 (m, IH), 7.5 (m, 11H), 7.17 (m, IH), 6.08 (m, IH), 4.65 (m, 2H), 3.71 (d, 3H), 2.97 (s, 3H), 2.88 (s, 3H).
Example 71 4-(((4-cvanobenzyPsulfonyP(l-methyl-lH-imidazol-5-yPmethyp-2-(l-naphthvPbenzonitrile hydrochloride A solution of Example 62C (31 mg, 0.07 mmol) in dichloromethane (2 mL) at room temperature was treated with 70% m-CPBA (100 mg), stined for 48 hours, treated with ethyl acetate, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/chloroform:methanol. The appropriate fractions were treated with HCl and concentrated to provide the desired product. MS (DCI/NH3) m/z 503 (M+H)+.
Example 72 4-(((2,4-dichlorobenzvDoxy)( 1 -methyl- lH-imidazol-5-vDmethvD-2-( 1 -naphthyDbenzonitrile hydrochloride
Example 72A
2,4-dichloro-l-(iodomethvPbenzene A solution of 2,4-dichlorobenzyl chloride (65 mg, 0.33 mmol) and Nal (0.5 g, 3.3 mmol) in acetone (5 mL) was heated to 50 °C, stirred for 18 hours, and concentrated. The concentrate was treated with dichloromethane (1.5 mL) and filtered to provide the desired product of sufficient purity for use in subsequent steps without further purification.
Example 72B 4-(((2,4-dichlorobenzyPoxy)(l-methyl-lH-imidazol-5-vPmethyP-2-(l-naphthyPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and Example 72A for
Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 498 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 9.09 (s, IH), 8.16 (m, IH), 8.09 (m, 2H), 7.78 (m, IH), 7.55 (m, 11H), 6.18 (s, IH), 4.7 (m, 2H), 3.79 (d, 3H).
Example 73
4-((l-methyl-lH-imidazol-5-yP((4-(methylsulfonyPbenzyPoxy)methvD-2-(l- naphthypbenzonitrile hydrochloride
Example 73A l-(iodomethyP-4-(methylsulfonvPbenzene The desired product was prepared by substituting 4-(methylsulfonyl)benzyl chloride for 2,4-dichlorobenzyl chloride in Example 72A. MS (DCI/NH3) m/z 314 (M+H)+.
Example 73B 4-((l-methyl-lH-imidazol-5-vP((4-(methylsulfonyl)benzyPoxy)methyl)-2-(l- naphthyPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and Example 73 A for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 508 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.01 (m, IH), 8.17 (m, IH), 8.09 (m, 2H), 7.90 (m, 4H), 7.80 (m, IH), 7.6 (m, 8H), 6.16 (s, IH), 4.75 (m, 2H), 3.79 (d, 3H), 3.20 (s, 3H).
Example 74 4-(((2,6-dichloro-4-pyridinvPmethoxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(l- naphthvPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 89D and 4-(bromomethyl)-2,6-dichloropyridine for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI NH3) m/z 499 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.04 (s, IH), 8.17 (m, IH), 8.08 (m, 2H), 7.81 (m, IH), 7.58 (m, 11H), 6.16 (m, IH), 4.7 (m, 2H), 3.79 (d, 3H).
Example 75 4-(((3-bromo-4-cvanobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyD-2-(l- naphthvPbenzonitrile hydrochloride
Example 75A 2-bromo-4-(hvdroxymethvPbenzonitrile The desired product was prepared by substituting Example 87C for Example 5 A in
Example 5B.
MS (DCI/NH3) m/z 229 and 231 (M+NI i ;
XH NMR (300 MHz, CDCI3) δ 7.74 (s, IH), 7.65 (m, IH), 7.41 Cd, 4.30 (s, 2H), 1.89 (br s, IH).
Example 75B 2-bromo-4-(bromomethypbenzonitrile The desired product was prepared by substituting Example 75A for Example 61 A in Example 6 IB. MS (DCI NH3) m/z 293 (M+NH4)+;
*H NMR (300 MHz, CDC13) δ 7.73 (m, IH), 7.64 (d, IH), 7.44 (dd, IH), 4.42 (s, 2H). Example 75C 4-(((3-bromo-4-cyanobenzypoxy)(l-methyl-lH-iιnidazol-5-yDmethyD-2-(l- naphthypbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and Example 75B for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m z 533 and 535 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 9.07 (s, IH), 8.17 (m, IH), 8.09 (m, 2H), 7.91 (m, 2H), 7.80 (m, IH), 7.55 (m, 9H), 6.15 (s, IH), 4.73 (m, 2H), 3.79 (d, 3H).
Example 76
6-(((4-cvano-3-(l-naphthvDphenyD(l-methyl-lH-imidazol-5- yDmethoxy)methyDnicotinonitrile dihydrochloride
Example 76A 6-(bromomethyDnicotinonitrile
The desired product was prepared by substituting 6-methylnicotinonitrile for Example 63 A in Example 63B. MS (DCI/NH3) m/z 197 (M+H)+;
XH NMR (300 MHz, CDCI3) δ 8.86 (s, IH), 7.99 (dd, IH), 7.60 (d, IH), 4.58 (s, 2H).
Example 76B 6-(((4-cvano-3-(l-naphthyDρhenyD(l-methyl-lH-imidazol-5- yDmethoxy)methvDnicotinonitrile dihydrochloride The desired product was prepared by substituting Example 89D and Example 76A for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 456 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, IH), 8.98 (m, IH), 8.32 (m, IH), 8.11 (m, 3H), 7.80 (m, IH), 7.6 (m, 10H), 6.23 (m, IH), 4.72 (m, 2H), 3.81 (d, 3H).
Example 77
4-(((4-cvano-3-fluorobenzyDoxy)(l-methyl-lH-imidazol-5-yDmethyD-2-(l- naphthyPbenzonitrile hydrochloride
Example 77A 2-fluoro-4-methylbenzonitrile
The desired product was prepared by substituting 2-fluoro-4-methylaniline for Example 87A in Examples 87B and 87C. MS (DCI/NH3) m/z 153 CM+NH4)+;
1H NMR C300 MHz, CDCI3) δ 7.50 (m, IH), 7.16 Cm, 2H), 2.44 (s, 3H).
Example 77B 4-(bromomethyP-2-fluorobenzonitrile
The desired product was prepared by substituting Example 77A for Example 63 A in Example 63B.
Example 77C 4-(((4-cyano-3-fluorobenzyPoxy) ( 1 -methyl- 1 H-imidazol-5- yl)methyl)-2-( 1 - naphthyDbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and Example 77B for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 473 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 8.88 (br s, IH), 8.16 (m, IH), 8.08 (m, 2H), 7.92 (m, IH), 7.79 ( , IH), 7.55 (m, 10H), 6.12 Cm, IH), 4.75 Cm, 2H), 3.75 Cd, 3H).
Example 78 5-((benzyloxy)(l-methyl-lH-1.2.4-triazol-5-vDmethvD-2 -methyl(l,l -biρhenvD-2- carbonitrile hydrochloride
Example 78 A 5-(hydroxy( 1 -methyl-lH-1 ,2,4-triazol-5-yDmethyD-2>-methyl( 1 , 1 -biphenyD-2-carbonitrile A solution of l-methyl-lH-l,2,4-triazole (68 mg, 0.82 mmol) in THF (3 mL) at -78 °C was treated with n-butyllithium (2.5M, 0.33 mL, 0.82 mmol), stined for 1 hour, treated with a solution of 861 (150 mg, 0.68 mmol) in THF (2 mL), stirred for 16 hours while warming to room temperature, and treated with 5.5M ammonium chloride to provide two layers. The aqueous layer was adjusted to a pH greater than 7 with sodium bicarbonate and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:l/ethyl acetate:hexanes to provide the desired product. MS (ESIC+)) m/z 305 CM+H)+;
XH NMR (300 MHz, CDCI3) δ 7.88 (s, IH), 7.77 (d, IH), 7.52 (m, IH), 7.42 (s, IH), 7.38- 7.25 (m, 3H), 7.17 (d, IH), 6.26 (s, IH), 3.81 (s, 3H), 2.15 (s, 3H).
Example 78B 5-((benzyloxyXl-methyl-lH-l,2,4-triazol-5-vDmethvD-2 -methyl(l,l -biphenvD-2- carbonitrile hydrochloride A solution of 78A (126 mg, 0.41 mmol) in dichloromethane (8 mL) at room temperature was treated with silver(I) oxide (115 mg, 0.5 mmol) and benzyl bromide (59 μL, 0.5 mmol), stirred for 48 hours in darkness, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 60:40/hexanes:ethyl acetate. The appropriate fractions were dissolved in acetonitrile, treated with IM HCl, and lyopholized to provide the desired product. MS (ESI(+)) m/z 395 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, IH), 7.91 (s, IH), 7.66 (dd, IH), 7.50 (s, IH), 7.42-7.28 (m, 8H), 7.24 (m, IH), 6.14 (s, IH), 4.57 (s, 2H), 3.84 (s, 3H), 2.11 (s, 3H); Anal, calcd for C25H22N4OΗC1-0.5 H2O: C, 68.25; H, 5.50; N, 12.73; Cl, 8.06. Found: C, 67.89; H, 5.61; N, 12.90; Cl, 8.34.
Example 79
5-((benzyloxy)(l-methyl-lH-pyrazol-5-yDmethyD-2 -methyl(l, -biphenyD-2-carbonitrile hydrochloride
Example 79A 5-(hvdroxy(l-methyl-lH-pyrazol-5-vDmethyD-2'-methyl(l,r-biphenvD-2-carbonitrile
The desired product was prepared by substituting 1 -methyl- lH-pyrazole for 1-methyl- lH-l,2,4-triazole in Example 78A. MS (ESI(+)) m/z 304 (M+H)+;
1H NMR (300 MHz, CDC13) δ 7.78 (d, IH), 7.50 (d, IH), 7.40 (m, 2H), 7.38-7.25 (m, 3H), 7.19 (d, IH), 6.05 (d, IH), 6.04 (s, IH), 3.84 (s, 3H), 2.17 (s, 3H).
Example 79B 5-((benzyloxy)(l-methyl-lH-pyrazol-5-vDmethvD-2 -methyl(l,r-biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 79A for Example 78A in
Example 78B.
MS (DCI/NH3) m z 394 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, IH), 7.64 (dd, IH), 7.46 (d, IH), 7.42-7.27 Cm, 5H), 6.00 (d, IH), 5.98 (s, IH), 4.54 (q, 2H), 3.75 (s, 3H), 2.11 (s, 3H); Anal, calcd for C26H23N3OΗCl: C, 72.63; H, 5.63; N, 9.77. Found: C, 72.61; H, 5.64; N, 9.62. Example 80 5-((benzyloxyX3-thienvDmethyP-2 -methyld , 1 -biphenvP-2-carbonitrile
Example 80A 5-(hydroxy(3-thienyPmethyP-2 -methyld,! -biphenyP-2-carbonitrile
A solution of 3-bromothiophene (70 μL, 0.75 mmol) in hexanes (3 mL) at -40 °C was treated with n-butyllithium (2.5M, 0.33 mL, 0.82 mmol), stirred for 20 minutes, added to a solution of 861 (150 mg, 0.68 mmol) in THF (3 mL) at -78 °C, stined for 16 hours while warming to room temperature, treated with 5.5M ammonium chloride, and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:1 to 4:l/hexanes:ethyl acetate to provide the desired product. MS (ESI(+)) m/z 323 (M+NH4)+;
XH NMR (300 MHz, CDC13) δ 7.66 (d, IH), 7.44 (dd, IH), 7.36 (s, IH), 7.29-7.11 (m, 6H), 6.92 (d, IH), 5.91 (s, IH), 2.10 (s, 3H).
Example 80B 5-((benzyloxy)(3-thienvPmethyP-2'-methyl(l, -biphenvP-2-carbonitrile The desired product was prepared by substituting Example 80A for Example 78A in Example 78B.
XH NMR (300 MHz, CDC13) δ 7.72 (d, IH), 7.49 (dd, IH), 7.40-7.12 (m, 12H), 6.98 (m, IH),
5.56 (s, IH), 4.55 (m, 2H), 2.16 (s, 3H);
HRMS (FAB) calcd m/z for C26H22NO5: 396.1422 (M+H)+. Found: 396.1419.
Example 81
5-((benzyloχy)(l-methyl-lH-l,2.3-triazol-5-vPmethvP-2 -methyld.1 -biphenyl)-2- carbonitrile hydrochloride
Example 81 A 5-(hvdroxy(l-methyl-lH- 2,3-triazol-5-yPmethvP-2 -methyld.1 -biphenvP-2-carbonitrile The desired product was prepared by substituting l-methyl-lH-l,2,3-triazole for 1- methyl-lH-l,2,4-triazole in Example 78A. MS (ESI(+)) m/z 305 (M+H)+.
Example 8 IB
5-((benzyloxy)(l-methyl-lH- 2,3-triazol-5-vPmethvP-2 -methyl(l.l -biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting Example 81 A for Example 78 A in Example 78B.
MS (ESI(+)) m/z 395 (M+H)+;
*H NMR (300 MHz, CD3OD) δ 7.93 (d, IH), 7.72 (s, IH), 7.64 (dd, IH), 7.51 (d, IH), 7.37- 7.29 (m, 8H), 7.22 (m, IH), 6.02 (s, IH), 4.64 (s, 2H), 4.04 (s, 3H), 2.16 (s, 3H);
Anal, calcd for C25H22N4OΗCl: C, 69.68; H, 5.38; N, 13.00. Found: C, 70.01; H, 5.37; N, 13.08.
Example 82 5-(((2-cyclohexylethvP((l -methyl- lH-imidazol-5-vPmethyPamino)methvP-2 -methyld , 1 - biphenvD-2-carbonitrile hydrochloride
Example 82A 5-(((2-cvclohexylethyDamino)methyD-2 -methyl(l,r-biphenyD-2-carbonitrile A solution of 861 and 2-(cyclohexyl)ethylamine (153 mg, 1.21 mmol) in dichloromethane (15 mL) at room temperature was treated with acetic acid (3 drops), stined for 1 hour, treated with sodium triacetoxyborohydride (384 mg, 1.81 mmol), stined for three hours, treated with ethyl acetate, washed with saturated NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 0.2% concentrated ammonium hydroxide/ethyl acetate to provide the desired product.
MS (ESI(+)) m/z 333 (M+H)+;
1H NMR (300 MHz, CDC13) δ 7.70 (d, IH), 7.46 (m, IH), 7.35 (m, IH), 7.31 (m, 2H), 7.26 (m, IH), 7.20 (d, IH), 3.89 (s, 2H), 2.66 (dd, 2H), 2.19 (s, 3H), 1.67 (m, 5H), 1.43 (m, 2H), 1.32-1.10 (m, 4H), 0.95-0.83 (m, 2H).
Example 82B 5-(((2-cyclohexylethvD(( 1 -methyl- lH-imidazol-5-vDmethyDamino)methvD-2 -methyl ( 1 , 1 - biphenvD-2-carbonitrile hydrochloride The free base of the desired product was prepared by substituting Example 82A and
Example 32C for 2-(cyclohexyl)ethylamine and Example 861, respectively, in Example 82A. The purified concentrate was dissolved in acetonitrile, treated with IM HCl, and lyopholized to provide the desired product. MS (ESI(+)) m/z 427 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 9.04 (s, IH), 7.96 (m, 2H), 7.84 (m, IH), 7.74 (m, IH), 7.37 (m, 2H), 7.35-7.28 (m, IH), 7.22 (m, IH), 4.56 (br s, 4H), 3.94 (s, 3H), 3.18 (m, 2H), 2.19 (s, 3H), 1.73-1.64 (m, 7H), 1.31-1.14 (m, 4H), 1.01-0.89 (m, 2H); Anal, calcd for C28H34N4-3.01 HC1 .48 H2O: C, 61.71; H, 7.02; N, 10.28. Found: C, 61.77; H, 7.02; N, 9.91.
Example 83 4-(((2-cyclohexylethvD((l-methyl-lH-imidazol-5-yDmethvDamino)methvD-2-(l- naphthyPbenzonitrile dihydrochloride
Example 83A 4-(((2-cyclohexylethyPamino)methyP-2-(l-naphthyPbenzonitrile The desired product was prepared by substituting Example 89C for Example 861 in
Example 82A.
MS (ESI(+)) m/z 369 (M+H)+;
!H NMR (300 MHz, CDC13) δ 7.96 (d, IH), 7.93 (d, IH), 7.79 (d, IH), 7.59-7.41 (m, 7H), 3.92 (s, 2H), 2.66 (t, 2H), 1.67 (m, 5H), 1.51 (s, IH), 1.40 (m, 2H), 1.35-1.06 (m, 4H), 0.96- 0.83 (m, 2H).
Example 83B 4-(((2-cvclohexylethvP((l-methyl-lH-imidazol-5-vPmethyPamino)methyp-2-(l- naphthyPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 83A for Example 82A in
Example 82B.
MS (ESI(+)) m/z 463 (M+H)+;
1H NMR (300 MHz, CD3OD) δ 9.02 (s, IH), 8.02 (m, 3H), 7.94 (m, 2H), 7.84 (m, IH), 7.62 (m, IH), 7.56 (m, IH), 7.49 (m, 3H), 4.55 (br s, 4H), 3.95 (s, 3H), 3.18 (br s, 2H), 1.66 (m, 7H), 1.29-0.91 (m, 6H);
Anal, calcd for C37H34N4-2.18 HCM.58 H2O: C, 65.26; H, 6.95; N, 9.82. Found: C, 65.30; H, 6.95; N, 9.56.
Example 84 4-(((cvclohexylmethvP((l-methyl-lH-imidazol-5-vPmethyPamino)methvP-2-(l- naphthyDbenzonitrile dihydrochloride
Example 84A 4-(((cyclohexylmethvDamino)methyD-2-(l-naphthvDbenzonitrile The desired product was prepared by substituting cyclohexylmethylamine for
2-(cyclohexyl)ethylamine in Example 83A. Example 84B 4-(((cvclohexylmethyD((l-methyl-lH-imidazol-5-yDmethyDamino methvD-2-(l- naphthvDbenzonitrile dihydrochloride The desired product was prepared by substituting Example 84A for Example 83A in Example 83B.
1H NMR (300 MHz, CD3OD) δ 9.01 (s, IH), 8.09-7.75 (m, 6H), 7.64-7.47 (m, 5H), 4.5 (br s, 4H), 3.96 (s, 3H), 3.0 (br s, 2H), 1.85-1.68 (m, 6H), 1.29-1.13 (m, 3H), 0.92-0.88 (m, 2H); HRMS (FAB) calcd m/z for C30H33N4: 449.2705 (M+H)+. Found: 449.2715; Anal, calcd for C3oH32N4-2.31 HC1-2.02 H2O: C, 63.30; H, 6.79; N, 9.84. Found: C, 63.28; H, 6.79; N, 9.94.
Example 85 N-(4-cvano-3-(l-naphthvDbenzyD-N-(2-cvclohexylethyD-2-(lH-imidazol-l-yDacetamide
Example 85A
2-chloro-N-(4-cyano-3-(-l-naphthyDbenzvD-N-(2-cyclohexylethyDacetamide A solution of Example 83 A (103 mg, 0.28 mmol) in dichloromethane (3 mL) and pyridine (0.05 mL) at 0 aC was treated with chloroacetic anhydride (53 mg, 0.31 mmol), stined for 1 hour, poured into IM NaHSO4, and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
Example 85B N-(4-cyano-3-(l-naphthvDbenzyD-N-(2-cyclohexylethvD-2-(lH-imidazol-l-yDacetamide A solution of Example 85A in DMSO (3 mL) at room temperature was treated with imidazole (57 mg, 0.83 mmol), stined for 2 hours, heated to 50 °C, and stirred for 16 hours. The mixture was treated with saturated NaHCO3, extracted with dichloromethane, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98.8:l:0.2/ethyl acetate:methanol:concentrated ammonium hydroxide to provide the desired product. MS (ESI(+)) m/z 477 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.09-7.99 (m, 3H), 7.68-7.41 (m, 8H), 7.03 (m, IH), 6.84 (s, IH), 5.06 (m, 2H), 4.80-4.68 (m, 2H), 3.40-3.25 (m, 2H), 2.54 (s, 2H), 1.63-0.83 (m, 11H).
Example 86 5-(hydroxy(l-methyl-lH-imidazol-5-yDmethyD-2'-methyl(l,r-biphenvD-2-carbonitrile Example 86A dimethyl 2 -methyK 1 , 1 -biphenyD-2,5-dicarboxylate The desired product was prepared by substituting 2-methylphenylboronic acid for 2- chlorophenylboronic acid in Example 10A.
Example 86B 6-(methoxycarbonyl)-2 -methyld, r-biphenvD-3-carboxylic acid The desired product was prepared by substituting Example 86A for Example 10A in Example 10B.
Example 86C methyl 5-(hydroxymethyD-2'-methyl(l, -biphenyD-2-carboxylate The desired product was prepared by substituting Example 86B for Example 10B in Example IOC.
MS (DCI/NH3) m/z 257 (M+H)+;
XH NMR (300 MHz, CDCI3) δ 7.98 (d, IH), 7.43 (dd, IH), 7.28-7.16 (m, 4H), 7.07 (br d,
IH), 4.77 (s, 2H), 3.62 (s, 3H), 2.05 (s, 3H), 1.78 (br s, IH).
Example 86D
4-(hydroxymethyl)-2-( 1 -naphthyDbenzonitrile A solution of Example 86C (6.0 g, 23.4 mmol) in dichloromethane (25 mL) at room temperature was treated with chloromethyl ethyl ether (4.4 mL, 4.5 g, 47 mmol) and diisopropylethyl amine (8.3 mL, 6.1 g, 47 mmol), stirred for 1.5 hours, treated with water and diethyl ether, and extracted with diethyl ether. The extract was washed with brine, dried
(Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
MS (DCI/NH3) m z 315 CM+H)+;
*H NMR (300 MHz, CDCI3) δ 7.98 (d, IH), 7.40 (dd, IH), 7.28-7.16 (m, 4H), 7.07 (br d, IH), 4.78 (s, 2H), 4.67 (s, 2H), 3.65 (q, 2H), 3.60 (s, 3H), 2.05 (s, 3H), 1.21 (t, 3H).
Example 86E 5-((ethoxymethoxy)methyD-2'-methyl(l,r-biphenyD-2-carboxylic acid The desired product was prepared by substituting Example 86D for Example 10F in Example 10G.
Example 86F 5-((ethoxymethoxy)methvD-2 -methyld, 1 -biphenyP-2-carboxamide The desired product was prepared by substituting Example 86E for Example 10G in Example 10H.
MS CDC1/NH3) m z 300 (M+H)+; XH NMR C300 MHz, DMSO-d6) δ 7.50 Cd, IH), 7.37 (dd, 1H),7.31 (br s, IH), 7.25-7.08 Cm, 6H), 4.72 (s, 2H), 4.59 (s, 2H), 3.55 (q, 2H), 2.05 (s, 3H), 1.21 (t, 3H).
Example 86G 5-(hydroxymethyl)-2 -methyld , 1 -biphenyP-2-carboxamide A solution of Example 86F (0.37 g, 1.2 mmol) in methanol (5 mL) at room temperature was treated with concentrated HCl (0.1 mL), stined for 16 hours, and concentrated. The concentrate was treated with toluene, concentrated, and dried under vacuum with P2O5 to provide the desired product of sufficient purity for subsequent use without further purification.
Example 86H 5-(hydroxymethyP-2 -methyld, -biphenyP-2-carbonitrile The desired product was prepared by substituting Example 86G for Example 10H in Example 101. MS (DCI NH3) m/z 241 (M+N-it)"1"; lH NMR (300 MHz, CDCI3) δ 7.73 (d, IH), 7.45 (m, IH), 7.37 (m, IH), 7.30 (m, 2H), 7.25 (m, IH), 7.18 (br d, IH), 4.80 (br d, 2H), 2.20 (s, 3H), 1.93 (br t, IH).
Example 861 5-formyl-2 -methyld , 1 -biphenyp-2-carbonitrile
The desired product was prepared by substituting Example 86H for Example 5B in Example 5C.
MS (DCI/NH3) m/z 239 (M+NH4)+;
XH NMR C300 MHz, CDCI3) δ 10.12 Cs, IH), 7.95 (m, 2H), 7.89 (s, IH), 7.42-7.30 Cm, 3H), 7.22 (br d, IH), 2.24 (s, 3H).
Example 86J 5-(hydroxy(l-methyl-lH-imidazol-5-yl)methyP-2 -methyld,! -biphenyP-2-carbonitrile The desired product was prepared by substituting Example 861 for Example 1 A in Example IB.
MS (DCI/NH3) m/z 304 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 7.95 (d, IH), 7.60 (br d, IH), 7.55 (s, IH), 7.44 (br s, IH), 7.38 (m, 2H), 7.30 ( , IH), 7.22 (br d, IH), 6.42 (s, IH), 6.18 (d, IH), 5.94 (d, IH), 3.58 (s, 3H), 2.13 (br s, 3H).
Anal, calcd for Cι9Hι7N3O-0.20 H2O: C, 74.34; H, 5.71; N, 13.69. Found: C, 74.26; H, 5.74; N, 13.68.
Example 87 5-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethyl)(l,l -biphenvP-2-carbonitrile hydrochloride
Example 87A ethyl 4-amino-3-bromobenzoate A solution of ethyl 4-aminobenzoate (5.5 g, 33 mmol) in dichloromethane (48 mL), at -12 °C, was treated with pyridine (5.5 mL, 5.4 g, 68 mmol) and a solution of bromine (1.75 mL, 5.4 g, 34 mmol) in dichloromethane (15 mL), warmed to room temperature, stined for 16 hours, and treated with diethyl ether and 0.5M H3PO4 to provide two layers. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 85:15/hexanes:ethyl acetate to provide the desired product. MS (DCI/NH3) m/z 244 and 246 (M+H)+, 261 and 263 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 8.11 (d, IH), 7.80 (dd, IH), 6.72 (d, IH), 4.50 (br s, 2H), 4.33 (q, 2H), 1.38 (t, 3H).
Example 87B 2-bromo-4-(ethoxycarbonvPbenzenediazonium tetrafluoroborate
A solution of Example 87A (1.2 g, 4.8 mmol) in dichloromethane (10 mL) at -8 °C, was treated with a -8 °C solution of BF3-OEt2 (0.9 mL, 1.0 g, 7.3 mmol) and tert-butyl nitrite (0.7 mL, 0.6 g, 5.9 mmol) and warmed to room temperature. The mixture was treated with hexanes and the resulting solid was removed by filtration to provide the desired product.
Example 87C ethyl 3-bromo-4-cyanobenzoate A solution of copper(I) cyanide (520 mg, 5.8 mmol) and sodium cyanide (710 mg, 14.5 mmol) in water (3.5 mL) at 5 ° C was treated with toluene (1.5 mL) and Example 87B, stined for 30 minutes, warmed to room temperature, heated to 60 °C for 25 minutes, cooled to room temperature, and treated with water and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was treated with hexanes (22 mL), heated to 60 °C, decanted, cooled to room temperature, cooled to 4 °C for 16 hours, and filtered to provide the desired product. MS (DCI/NH3) m/z 271 and 273 (M+NH )+; 1H NMR (300 MHz, CDC13) δ 8.33 (d, IH), 8.07 (dd, IH), 7.74 (d, IH), 4.43 (q, 2H), 1.42 (t, 3H).
Example 87D ethyl 6-cyano(l,r-biphenvP-3-carboxylate The desired product was prepared by substituting Example 87C and phenylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A.
MS (DCI/NH3) m z 269 (M+NH^'1";
1H NMR (300 MHz, CDC13) δ 8.19 (d, IH), 8.10 (dd, IH), 7.84 (d, IH), 7.59 (m, 2H), 7.50 (m, 3H), 4.43 (q, 2H), 1.42 (t, 3H).
Example 87E 5-(hydroxymethyl)( 1 , 1 -biphenyp-2-carbonitrile The desired product was prepared by substituting Example 87D for Example 5 A in Example 5B.
MS (DCI/NH3) m/z 227 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 7.77 (d, IH), 7.50 (m, 7H), 4.82 (d, 2H), 1.91 (t, IH).
Example 87F 1 -methyl-2-(triethylsilyP- lH-imidazole
A solution of 1-methylimidazole (23 mL, 23.7 g, 288 mmol) in THF (700 mL) at -73 °C was treated dropwise with 2.5M n-butyllithium in hexanes (125 mL, 312 mmol), warmed to 0 °C, stirred for 30 minutes, cooled to -73 °C, treated with chlorotriethylsilane (50 g, 330 mmol), warmed to room temperature, stirred for 16 hours, and concentrated. The concentrate was treated with ethyl acetate and water, the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by vacuum distillation (0.5-0.6 πrmHg, 98-100 °C) with a 6 inch Nigeraux column to provide the desired product. 1H ΝMR (300 MHz, CDCI3) δ 7.19 (s, IH), 6.96 (s, IH), 3.75 (s, 3H), 1.00 (m, 9H), 0.93 (m, 6H).
Example 87G 5-formyld .1 -biphenvD-2-carbonitrile The desired product was prepared by substituting Example 87E for Example 5B in Example 5C.
MS (DCI/NH3) m/z 225 (M+NH4)+; XH NMR (300 MHz, CDC13) δ 10.12 (s, IH), 8.02 ( , IH), 7.95 (m, 2H), 7.60 (m, 2H), 7.54 (m, 3H).
Example 87H 5 -(hydroxy ( 1 -methyl- lH-imidazol-5-yPmethyp( 1 , 1 -biphenyP-2-carbonitrile The desired product was prepared by substituting Example 87G for Example 1 A in
Example IB.
MS (DCI/NH3) m/z 290 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, IH), 7.63 (s, IH), 7.55 (s, IH), 7.55 (m, 7H), 6.46 (s, IH), 6.18 (d, IH), 5.95 (d, IH), 3.58 (s, 3H).
Example 871 5-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP(l,l -biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 87H for Example 2B in Example 2C.
MS (APCI(+)) m/z 380 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.06 (d, IH), 7.69 (m, 2H), 7.60 (m, 2H),
7.55 (m, 3H), 7.35 (m, 6H), 6.10 (s, IH), 4.65 (dd, IH), 4.55 (dd, IH), 3.78 (s, 3H).
Example 88
(2 -meth yl-5-((l -methyl- lH-imidazol-5-yDcarbonyP( 1 , 1 -biphenyP-2-carbonitrile hydrochloride A solution of Example 86F (50 mg, 0.16 mmol) in dioxane (2 mL), at 85 °C was treated with MnO2 (105 mg, 1.2 mmol), stined for 1 hour, cooled to room temperature, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with chloroform then 98:2/chloroform:methanol to provide the desired product. MS (DCI/NH3) m/z 302 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.93 (br s, IH), 8.17 Cd, IH), 8.08 (br s, IH), 8.00 (dd, IH), 7.82 (d, IH), 7.40 (m, 2H), 7.35 (m, 2H), 4.03 (s, 3H), 2.19 (s, 3H).
Example 89 4-((benzyloxyXl-methyl-lH-imidazol-5-yPmethvP-2-(l-naphthvPbenzonitrile hydrochloride
Example 89A ethyl 4-cyano-3 -(1 -naphthypbenzoate The desired product was prepared by substituting Example 87C and
1-naphthylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1 A. MS (DCI NH3) m/z 319 (M+NH )"1";
XH NMR (300 MHz, CDCI3) δ 8.20 (m, 2H), 7.96 (dd, 2H), 7.90 (d, IH), 7.55 (m, 2H), 7.47 (m, 3H), 4.43 (q, 2H), 1.39 (t, 3H).
Example 89B 4-(hydroxymethyP-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 89A for Example 5A in Example 5B.
MS (DCI/NH3) m/z 277 (M+NfflU ;
XH NMR (300 MHz, CDCI3) δ 7.94 (m, 2H), 7.82 (d, IH), 7.50 (m, 7H), 4.87 (s, 2H).
Example 89C 4-formyl-2-( 1 -naphthyDbenzonitrile
The desired product was prepared by substituting Example 89B for Example 5B in Example 5C.
MS (DCI NH3) m z 275 (M+NH4)+;
XH NMR (300 MHz, CDCI3) δ 10.15 (s, IH), 8.02 (m, 5H), 7.62-7.46 (m, 5H).
Example 89D 4-(hydroxy( 1 -methyl- lH-imidazol-5-vDmethyP-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 89C for Example 1 A in Example IB. !H NMR (300 MHz, CDCI3) δ 7.95 (m, 2H), 7.84 (d, IH), 7.62-7.38 (envelope, 8H), 6.74 and 6.72 (both s, total IH), 6.02 (s, IH), 3.61 and 3.59 (both s, total 3H).
Example 89E 4-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethyP-2-(l-naphthvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D for Example 5D in
Example 5E. MS (APCI(+)) m/z 430 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.16 (m, IH), 8.09 (m, 2H), 7.79 (d, IH), 7.64 (m, 4H), 7.51 (m, 2H), 7.44 (s, IH), 7.35 (m, 5H), 6.11 (s, IH), 4.64 (m, 2H), 3.80 and 3.78 (both s, total 3H);
Anal, calcd for C29H24C1N3O-0.95 H2O: C, 72.10; H, 5.40; N, 8.70. Found: C, 72.17; H, 5.43; N, 8.70.
Example 90 4-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(3-thienypbenzonitrile hydrochloride
Example 90A ethyl 4-cyano-3-(3-thienyPbenzoate The desired product was prepared by substituting Example 87C and 3-thienylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A. MS (DCI/NH3) m/z 275 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 8.23 (m, IH), 8.03 (dd, IH), 7.80 (d, IH), 7.73 (m, IH), 7.47 (m, 3H), 7.46 (m, 2H), 4.43 (q, 2H), 1.42 (t, 3H).
Example 90B 4-(hvdroxymethyp-2-(3-thienyPbenzonitrile
The desired product was prepared by substituting Example 90A for Example 5 A in Example 5B. MS (DCI NH3) m/z 233 (M+NHU .
Example 90C
4-formyl-2-(3-thienvPbenzonitrile The desired product was prepared by substituting Example 90B for Example 5B in Example 5C.
MS (DCI/NH3) m/z 231 (M+NH4)+.
Example 90D 4-(hvdroxy(l-methyl-lH-imidazol-5-vPmethvP-2-(3-thienvPbenzonitrile The desired product was prepared by substituting Example 90C for Example 1 A in Example IB. MS (APCI(+)) m/z 296 (M+H)+.
Example 90E 4-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyp-2-(3-thienyl)benzonitrile hydrochloride
The desired product was prepared by substituting Example 90D for Example 5D in Example 5E.
MS CAPCIC+)) m/z 386 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.02 (d, IH), 7.95 (m, IH), 7.77 (m, 2H), 7.62 (dd, IH), 7.48 (dd, IH), 7.37 (m, 6H), 6.04 (s, IH), 4.58 (dd, 2H), 3.78 (s, 3H).
Example 91 5-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP-3 -methyl(l, -biphenvP-2-carbonitrile hydrochloride
Example 91 A ethyl 6-cyano-3 -methyld , 1 -biphenyP-3-carboxylate The desired product was prepared by substituting Example 87C and 3- methylphenylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1 A. MS (APCIC+)) m/z 283 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 8.18 (d, IH), 8.08 (dd, IH), 7.82 (d, IH), 7.40 (m, 3H), 7.30 (m, IH), 4.43 (q, 2H), 2.45 (s, 3H), 1.42 (t, 3H).
Example 9 IB 5-(hydroxymethyl)-3 -methyld, r-biphenyP-2-carbonitrile The desired product was prepared by substituting Example 91 A for Example 5 A in Example 5B. MS (DCI/NH3) m/z 241 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 7.75 (d, IH), 7.51 (s, IH), 7.43 (d, IH), 7.37 (m, 3H), 7.27 (m, IH), 4.82 (s, 2H), 2.44 (s, 3H).
Example 91C 5-formyl-3 -methyld , 1 '-biphenyP-2-carbonitrile
The desired product was prepared by substituting Example 9 IB for Example 5B in Example 5C.
MS (DCI/NH3) m/z 239 (M+NIΪ4)+;
XH NMR (300 MHz, CDC13) δ 10.12 (s, IH), 8.00 (m, IH), 7.92 (m, 2H), 7.40 (m, 3H), 7.30 (m, IH), 2.46 (s, 3H).
Example 9 ID 5-(hydroxy(l-methyl-lH-imidazol-5-vPmethvP-3'-methyl(l, -biphenyP-2-carbonitril The desired product was prepared by substituting Example 91C for Example 1A in Example IB.
MS (DCI NH3) m/z 304 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 7.94 (d, IH), 7.62 (s, IH), 7.57 (m, 2H), 7.42 (m, IH), 7.38 (m, 2H), 7.30 (m, IH), 6.45 (s, IH), 6.20 (d, IH), 5.95 (d, IH), 3.58 (s, 3H), 2.40 (s, 3H).
Example 9 IE 5-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethyP-3 -methyl(l, -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 9 ID for Example 5D in Example 5E.
MS (APCI(+)) m/z 394 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.07 (m, IH), 7.68 (m, 2H), 7.38 (m, 10H), 6.09 (s, IH), 4.60 (dd, 2H), 3.78 (s, 3H), 2.40 (m, 3H);
Anal, calcd for C26H23ClN3O-H2O: C, 69.71; H, 5.85; N, 9.38. Found: C, 69.75; H, 5.70; N, 9.38.
Example 92
4-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP-2-(2-naphthypbenzonitrile hydrochloride
Example 92A ethyl 4-cyano-3-(2-naphthyl)benzoate The desired product was prepared by substituting Example 87C and 2- naphthylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1 A. MS (DCI/NH3) m/z 319 (M+NE )"1";
1H NMR (300 MHz, CDC13) δ 8.30 (d, IH), 8.13 (dd, IH), 8.07 (d, IH), 8.00 (d, IH), 7.95 (m, 2H), 7.90 (d, IH), 7.70 (dd, IH), 7.58 (m, 2H), 4.44 (q, 2H), 1.43 (t, 3H).
Example 92B 4-(hvdroxymethyl)-2-(2-naphthyPbenzonitrile The desired product was prepared by substituting Example 92A for Example 5 A in Example 5B.
MS (DCI/NH3) m/z 277 (M+NH4)+; XH NMR (300 MHz, CDC13) δ 8.05 (d, IH), 7.96 (d, IH), 7.90 (m, 2H), 7.80 (d, IH), 7.67 (dd, IH), 7.63 (s, IH), 7.53 (m, 2H), 7.47 (dd, IH), 4.85 (d, 2H), 1.88 (t, IH).
Example 92C 4-formyl-2-(2-naphthyPbenzonitrile
The desired product was prepared by substituting Example 92B for Example 5B in Example 5C.
MS (DCI/NH3) m/z 275 (M+NHi ;
*H NMR (300 MHz, CDC13) δ 10.18 (s, IH), 8.14 (s, IH), 8.09 (s, IH), 8.00 (m, 3H), 7.94 (m, 2H), 7.70 (dd, IH), 7.59 (m, 2H).
Example 92D 4-(hydroxy(l-methyl-lH-imidazol-5-yl)methyP-2-(2-naphthyPbenzonitrile The desired product was prepared by substituting Example 92C for Example 1 A in Example IB.
MS (DCI/NH3) m/z 340 (M+H)+;
*H NMR (300 MHz, CDC13) δ 8.13 (s, IH), 8.08 (d, IH), 8.02 (m, 2H), 7.98 (d, IH), 7.77 (s, IH), 7.70 (dd, IH), 7.60 (m, 3H), 7.57 (s, IH), 6.48 (s, IH), 6.21 (d, IH), 5.98 (d, IH), 3.60 (s, 3H).
Example 92E 4-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP-2-(2-naphthyDbenzonitrile hydrochloride
The desired product was prepared by substituting Example 92D for Example 5D in Example 5E. MS (APCI(+)) m/z 430 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.12 (s, IH), 8.15 (m, 2H), 8.11 (m, 2H), 8.03 (m, 2H), 7.81 (s, IH), 7.73 (m, 2H), 7.62 (m, 2H), 7.38 (m, 5H), 6.12 (s, IH), 4.62 (dd, 2H), 3.80 (s, 3H);
Anal, calcd for C29H24CIN3O .OO H2O: C, 71.87; H, 5.41; N,8.68. Found: C, 71.87; H, 5.39; N, 8.65.
Example 93 5-((benzyloxy (l-methyl-lH-imidazol-5-vDmethyD-4 -methyl(l, -biphenyD-2-carbonitrile hydrochloride
Example 93A ethyl 4-amino-3-iodobenzoate A solution of ethyl 4-aminobenzoate (6.0 g, 36 mmol) in dichloromethane (110 mL) and methanol (65 mL) at room temperature was treated with calcium carbonate (10.8 g, 108 mmol) and benzyltrimethylammonium dichloroiodate (25 g, 72 mmol), stined for 16 hours, and filtered. The filtrate was washed with 5% NaHSO3, dried (Na2SO4), filtered, and concentrated to provide a solid. The solid was recrystallized from ethanol and water, treated with diethyl ether, stirred for 30 minutes, and filtered. The filtrate was concentrated to provide the desired product.
MS (DCI NH3) m z 292 (M+H)+ and 309 (M+NH4)+; !H NMR (300 MHz, CDCI3) δ 8.33 (d, IH), 7.82 (dd, IH), 6.70 (d, IH), 4.51 (br s, 2H), 4.42 (q, 2H), 1.38 (t, 3H).
Example 93B 4-(ethoxycarbonyD-2-iodobenzenediazonium tetrafluoroborate The desired product was prepared by substituting Example 93 A for Example 87A in Example 87B.
Example 93C ethyl 4-cyano-3-iodobenzoate The desired product was prepared by substituting Example 93B for Example 87B in Example 87C.
XH NMR (300 MHz, CDCI3) δ 8.56 (d, IH), 8.10 (dd, IH), 6.70 (d, IH), 4.42 (q, 2H), 1.41 (t, 3H).
Example 93D methyl 4-amino-3-iodobenzoate
The desired product was prepared by substituting methyl-4-aminobenzoate for ethyl- 4-aminobenzoate in Example 93 A.
Example 93E 2-iodo-4-(methoxycarbonyDbenzenediazonium tetrafluoroborate
The desired product was prepared by substituting Example 93D for Example 93 A in Example 93B.
Example 93F ethyl 4-cyano-3-iodobenzoate
The desired product was prepared by substituting Example 93E for Example 93B in Example 93C. Example 93 G methyl 6-cy ano-4 -methylC 1 , 1 -biphenvD-3-carboxylate The desired product was prepared by substituting Example 93F and 4-methylphenylboronic for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid in Example 1A.
MS (DCI NH3) m/z 269 CM+NH4)+;
XH NMR (300 MHz, CDC13) δ 8.18 (d, IH), 8.06 (dd, IH), 7.82 (d, IH), 7.49 (d, 2H), 7.32 (d, 2H), 3.98 (s, 3H), 2.4 (s, 3H).
Example 93H 5-(hvdroxymethvP-4 -methyld , 1 -biphenyD-2-carbonitrile The desired product was prepared by substituting Example 93G for Example 5 A in Example 5B. MS (DCI NH3) m z 241 (M+NHi ;
XH NMR (300 MHz, CDC13) δ 7.75 (d, IH), 7.51 (s, IH), 7.49 (d, 2H), 7.43 (d, IH), 7.32 (d, 2H), 4.82 (s, 2H), 2.44 (s, 3H).
Example 931 5-formyl-4 -methyld , 1 -biphenyP-2-carbonitrile
The desired product was prepared by substituting Example 93H for Example 5B in Example 5C.
MS (DCI/NH3) m z 239 (M+NH4)+;
XH NMR (300 MHz, CDC13) δ 10.12 (s, IH), 8.00 (s, IH), 7.92 (s, 2H), 7.49 (d, 2H), 7.33 (d, 2H), 2.44 (s, 3H).
Example 93J 5-(hydroxy(l -methyl- lH-imidazol-5-yPmethyP-4'-methyl( 1 , 1 '-biphenyp-2-carbonitrile The desired product was prepared by substituting Example 931 for Example 1 A in Example IB.
MS (DCI/NH3) m/z 304 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 7.93 (d, IH), 7.62 (s, IH), 7.55 (m, 3H), 7.46 (m, 2H),
7.35 (m, 2H), 6.45 (s, IH), 6.20 (d, IH), 5.95 (d, IH), 3.58 (s, 3H), 2.40 (s, 3H).
Example 93K
5-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP-4 -methyl(l, -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 93 J for Example 5D in Example 5E.
MS (APCIC+)) m/z 394 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.07 (m, IH), 7.65 (m, 2H), 7.50 (d, 2H), 7.38 (m, 8H), 6.09 (s, IH), 4.60 (dd, 2H), 3.78 (s, 3H), 2.40 (m, 3H);
Anal, calcd for C26H23C1N3O-0.80 H2O: C, 70.28; H, 5.81; N, 9.46. Found: C, 70.21; H, 5.82; N, 9.46.
Example 94 5-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP-2,-phenyld, -biphenvP-2-carbonitrile hydrochloride
Example 94A 2-(dihydroxyboryl)-l , 1 -biphenyl The desired product was prepared by substituting 2-bromobiphenyl for 3-bromo- 1,1 - biphenyl in Example 6A. MS (DCI NH3) m/z 216 (M+NH4)+.
Example 94B ethyl 6-cyano-2'-phenyl( 1 , 1 -biphenvD-3-carboxylate
The desired product was prepared by substituting Example 93C and Example 94A for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A.
MS (DCI NH3) m/z 345 (M+NIL ; *H NMR (300 MHz, CDCI3) δ 7.95 (m, 2H), 7.62 (m, IH), 7.55-7.40 (m, 4H), 7.20 (m, 2H), 7.10 (m, 2H), 4.35 (q, 2H), 1.38 (t, 3H).
Example 94C 5-(hydroxymethyp-2 -phenyl(l, -biphenvP-2-carbonitrile The desired product was prepared by substituting Example 94B for Example 5 A in
Example 5B.
MS (DC1VNH3) m/z 303 (M+NH_ι)+;
*H NMR (300 MHz, CDCI3) δ 7.57 (d, IH), 7.50 (in, 2H), 7.43 (m, 2H), 7.30 (m, IH), 7.19 (m, 3H), 7.10 Cm, 3H), 4.63 (s, 2H).
Example 94D 5-f ormyl-2 -phenvK 1 , 1 -biphenvD-2-carbonitriie The desired product was prepared by substituting Example 94C for Example 5B in Example 5C.
MS (DCI/NH3) m/z 301 (M+NH4)+;
!H NMR (300 MHz, CDC13) δ 9.92 (s, IH), 7.82 (m, IH), 7.73 (m, 2H), 7.55-7.40 (m, 4H), 7.20 and 7.10 (both m, total 5H).
Example 94E 5-(hydroxy(l-methyl-lH-imidazol-5-vPmethvP-2 -phenyld,r-biphenyP-2-carbonitrile The desired product was prepared by substituting Example 94D for Example 1 A in Example IB.
MS (DCI NH3) m/z 366 (M+H)+;
^NMR (300 MHz, DMSO-d6) δ 7.76 (d, IH), 7.60-7.40 (m, 5H), 7.40-6.90 (envelope, 7H),
6.30-6.05 (envelope, 2H), 5.80 (d, IH).
Example 94F
5-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethvP-2 -phenyl(l, -biphenvP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 94E for Example 5D in Example 5E. MS (APCI(+)) m/z 456 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 7.96 (d, IH), 7.55 (m, 5H), 7.40-6.90 (envelope, 12H), 5.87 (s, IH), 4.38 (dd, 2H), 3.50 (s, 3H);
Anal, calcd for C3ιH26ClN3O-1.00 H2O: C, 73.00; H, 5.53; N, 8.24. Found: C, 72.97; H, 5.54; N, 8.37.
Example 95 5-((benzyloxy)( 1 -methyl- lH-imidazol-5- yl)methvP-2,,5 -dimethvK 1 , 1 -biphenyl)-2- carbonitrile hydrochloride
Example 95 A
2,5-dimethylphenylboronic acid The desired product was prepared by substituting 2-bromo-p-xylene for 3-bromo-l,l - biphenyl in Example 6A. MS (DCI/NH3) m/z 168 (M+NH-t)"".
Example 95B ethyl 6-cvano-2',5 '-dimethyld , 1 -biphenyP-3-carboxylate The desired product was prepared by substituting Example 93C and Example 95A for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A.
MS (DCI/NH3) m/z 297 (M+NH4)+; *H NMR (300 MHz, CDCI3) δ 8.10 (dd, IH), 8.05 (d, IH), 7.82 (d, IH), 7.20 (m, 2H), 7.02 (s, IH), 4.41 (q, 2H), 2.39 (s, 3H), 2.16 (s, 3H), 1.41 (t, 3H).
Example 95C 5-(hydroxymethyp-2',5 -dimethyld , 1 -biphenvP-2-carbonitrile The desired product was prepared by substituting Example 95B for Example 5 A in
Example 5B.
MS (DCI/NH3) m/z 255 (M+NTL^;
1H NMR (300 MHz, CDC13) δ 7.72 (d, IH), 7.45 (m, IH), 7.36 (s, IH), 7.17 (m, 2H), 7.00 (s, IH), 4.80 (s, 2H), 2.35 (s, 3H), 2.13 (s, 3H).
Example 95D 5-f ormyl-2',5 -dimethyld , 1 '-biphenyp-2-carbonitrile The desired product was prepared by substituting Example 95C for Example 5B in Example 5C. MS (DCI/NH3) m/z 253 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 10.11 (s, IH), 7.95 (dd, IH), 7.91 (d, IH), 7.86 (m, IH), 7.20 (m, 2H), 7.00 (s, IH), 2.38 (s, 3H), 2.14 (s, 3H).
Example 95E 5-(hydroxy( 1 -methyl- lH-imidazol-5-yPmethyP-2 ',5 -dimethyK 1 , 1 -biphenvP-2-carbonitrile The desired product was prepared by substituting Example 95D for Example 1 A in Example IB.
MS (DCI/NH3) m/z 318 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 7.93 (d, IH), 7.58 (m, 2H), 7.42 (br s, IH), 7.20 (m, 2H), 7.02 (br s, IH), 6.40 (s, IH), 6.18 (d, IH), 5.93 (d, IH), 3.58 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H).
Example 95F 5-((benzyloxy)d-methyl-lH-imidazol-5-yPmethyP-2',5 -dimethyld,r-biphenvP-2- carbonitrile hydrochloride
The desired product was prepared by substituting Example 95E for Example 5D in Example 5E. MS CAPCIC+)) m z 408 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.09 (s, IH), 8.04 (d, IH), 7.67 (dd, IH), 7.49 (d, 1H),7.38 (m, 6H), 7.22 (m, 2H), 7.07 (br s, IH), 6.07 (s, IH), 4.60 (dd, 2H), 3.76 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H); Anal, calcd for C27H26C1N3O-0.70 H2O: C, 71.03; H, 6.05; N, 9.20. Found: C, 71.03; H, 6.20; N, 9.26.
Example 96 4-(((4-c vanobenzvpoxyX 1 -methyl- lH-imidazol-5-yPmethyp-2-( 1 -naphthyDbenzonitrile hydrochloride
The desired product was prepared by substituting Example 89D and 4-cyanobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively in Example 5E. MS CAPCIC+)) m/z 455 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, IH), 8.15 (dd, IH), 8.09 (m, 2H), 7.80 (m, 3H), 7.65 (m, 2H), 7.58 (m, 5H), 7.45 (m, 2H), 6.15 (s, IH), 4.73 (m, 2H), 3.79 and 3.77 (both s, total 3H);
Anal, calcd for C30H23ClN.tO-l.OO H2O: C, 70.79; H, 4.95; N, 11.01. Found: C, 70.99; H, 4.99; N, 10.93.
Example 97
4-(((2-methoxy-5-nitrobenzyDoxy)(l-methyl-lH-imidazol-5-yDmethyD-2-(l- naphthvDbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and 2-methoxy-5- nitrobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E.
MS (APCI(+)) m/z 505 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 9.08 (s, IH), 8.25 (m, 2H), 8.15 (dd, IH), 8.09 (m, 2H), 7.76 (d, IH), 7.70-7.50 (m, 5H), 7.46 (d, IH), 7.40 (d, IH), 7.20 (m, IH), 6.18 and 6.17 (both s, total IH), 4.70 (m, 2H), 3.82 and 3.80 (both s, total 6H); Anal, calcd for C30H25C1N4O4-0.85 H2O: C, 64.77; H, 4.84; N, 10.07. Found: C, 64.74; H, 4.81; N, 10.01.
Example 98 5-((benzyloxy)(l-methyl-lH-imidazol-5-yDmethvD-2-ethyl(l, -biphenvD-2-carbonitrile hydrochloride
Example 98 A 2-ethylphenylboronic acid The desired product was prepared by substituting 2-bromoethylbenzene for 3-bromo- 1,1 -biphenyl in Example 6 A. MS (DCI/NH3) m/z 168 (M+NH4)+.
Example 98B ethyl 6-cyano-2 -ethyl(l, -biphenyD-3-carboxylate The desired product was prepared by substituting Example 93C and Example 98A for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A.
MS (DCI/NH3) m/z 297 (M+NIL ;
1H NMR (300 MHz, CDCI3) δ 8.12 (d, IH), 8.06 (s, IH), 7.82 (d, IH), 7.40 (m, 2H), 7.30
(m, IH), 7.17 (d, IH), 4.40 (q, 2H), 2.50 (m, 2H), 1.40 (t, 3H), 1.19 (t, 3H).
Example 98C
2'-ethyl-5-(hydroxymethvD(l , 1 -biphenyD-2-carbonitrile The desired product was prepared by substituting Example 98B for Example 5A in Example 5B.
MS (DCI/NH3) m/z 255 (M+NH4)+; *H NMR (300 MHz, CDC13) δ 7.72 (d, IH), 7.46 (m, IH), 7.38 (m, 3H), 7.17 (m, 2H), 4.82 (s, 2H), 2.50 (m, 2H), 1.09 (t, 3H).
Example 98D 2 -ethyl-5-formyl(l, -biphenyD-2-carbonitrile The desired product was prepared by substituting Example 98C for Example 5B in
Example 5C.
MS (DCI/NH3) m/z 253 (M+NH4)+;
1H NMR (300 MHz, CDCI3) δ 10.11 (s, IH), 7.97 (dd, IH), 7.92 (d, IH), 7.89 (m, IH), 7.40 (m, 2H), 7.30 (m, IH), 7.18 (d, IH), 2.50 (m, 2H), 1.10 (t, 3H).
Example 98E 2-ethyl-5-(hydroxy(l-methyl-lH-imidazol-5-yDmethvD(l, -biphenyD-2-carbonitrile The desired product was prepared by substituting Example 98D for Example 1A in Example IB. MS (DCI NH3) m z 318 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.93 (d, IH), 7.57 (m, 2H), 7.40 (m, 3H), 7.30 (m, IH), 7.20 (m, IH), 6.40 (m, IH), 6.19 (m, IH), 5.93 (d, IH), 3.55 (s, 3H), 2.40 (m, 2H), 1.00 (m, 3H).
Example 98F
5 -((benzyloxyX 1 -methyl- lH-imidazol-5-vPmethyD-2'-ethyl( 1 , 1 '-biphenvP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 98E for Example 5D in Example 5E. MS (APCI(+)) m/z 408 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.12 (s, IH), 8.07 (d, IH), 7.70 (d, IH), 7.51 (s, IH), 7.40 (m, 3H), 7.35 (m, 7H), 6.09 (s, IH), 4.60 (m, 2H), 3.76 (s, 3H), 2.40 (m, 2H), 1.00 (m, 3H); Anal, calcd for C27H26C1N3O-0.90 H2O: C, 70.47; H, 6.09; N, 9.130. Found: C, 70.68; H, 5.85; N, 9.24.
Example 99 5-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethvP-2,,3 -dimethyld, l -biphenvP-2- carbonitrile hydrochloride
Example 99 A
2,3-dimethylphenylboronic acid The desired product was prepared by substituting 3-bromoOxylene for 3-bromo-l,l - biphenyl in Example 6A. MS (DCI NH3) m/z 168 (M+NH4)+.
Example 99B methyl 6-cyano-2',3 '-dimethyld , 1 -biphenyp-3-carboxylate The desired product was prepared by substituting Example 93F and Example 99A for 3-bromo-4-fmorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A.
MS (DCI/NH3) m/z 283 (M+NH4)+;
XH NMR (300 MHz, CDC13) δ 8.10 (dd, IH), 8.04 (m, IH), 7.30 (d, IH), 7.27 (d, IH), 7.20
(dd, IH), 7.04 (d, IH), 3.96 (s, 3H), 2.09 (s, 3H).
Example 99C
5-(hydroxymethyl)-2',3 -dimethyld , 1 -biphenyP-2-carbonitrile The desired product was prepared by substituting Example 99B for Example 5 A in Example 5B.
MS (DCI/NH3) m/z 255 (M+NH4);
1H NMR (300 MHz, CDC13) δ 7.72 (d, IH), 7.45 (m, IH), 7.36 (s, IH), 7.23 (d, IH), 7.17 (dd, IH), 7.03 (d, IH), 4.81 (d, 2H), 2.35 (s, 3H), 2.09 (s, 3H), 1.85 (t, IH).
Example 99D 5-f ormyl-2',3 -dimethvK 1 , 1 -biphenyP-2-carbonitrile The desired product was prepared by substituting Example 99C for Example 5B in Example 5C. MS (DCI/NH3) m/z 253 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 10.11 (s, IH), 7.95 (dd, IH), 7.91 (d, IH), 7.87 (s, IH), 7.27 (d, IH), 7.20 (d, IH), 7.05 (d, IH), 2.38 (s, 3H), 2.10 (s, 3H).
Example 99E 5-(hy(iroxy(l-methyl-lH-imidazol-5-vDmethyD-2',3 -dimethyl(l, -biphenyD-2-carbonitrile The desired product was prepared by substituting Example 99D for Example 1 A in Example IB.
MS (DCI/NH3) m/z 318 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.93 (dd, IH), 7.56 (m, 2H), 7.40 (d, IH), 7.27 (d, IH), 7.20 (m, IH), 7.06 (m, IH), 6.41 and 6.40 (both s, total IH), 6.18 (m, IH), 5.93 (d, IH), 3.58 and 3.56 (both s, total 3H), 2.32 and 2.30 (both s, total 3H), 2.03 and 1.97 (both s, total 3H).
Example 99F 5-((benzyloxy d-methyl-lH-imidazol-5-vDmethvD-2,,3,-dimethyld,l -biphenvD-2- carbonitrile hydrochloride
The desired product was prepared by substituting Example 99E for Example 5D in Example 5E.
MS (APCI(+)) 408 m/z (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.09 (s, IH), 8.04 (m, IH), 7.67 (m, IH), 7.48 (s, IH), 7.37 (m, 7H), 7.20 (m, IH), 7.14 and 7.05 (both d, total IH), 6.07 (s, IH), 4.60 (m, 2H), 3.76 (s, 3H), 2.32 and 2.30 (both s, total 3H), 2.03 and 1.97 (both s, total 3H); Anal, calcd for C27H26C1N3O-0.90 H2O: C, 70.47; H, 6.09; N, 9.13. Found: C, 70.54; H, 5.88; N, 8.86.
Example 100
4-((benzyloxy)( 1 -methyl- lH-imidazol-5-yPmethyP-2-cyclohexylbenzonitrile hydrochloride Example 100 A methyl 4-cyano-3-cyclohexylbenzoate A mixture of 93F (400 mg, 1.4 mmol) and Pd(PPh3)4 (247 mg, 0.2 mmol) was treated with 0.33M cyclohexylzinc bromide in THF (5.5 mL, 1.8 mmol), heated to reflux, stined for 1 hour, cooled to room temperature, treated with water, diethyl ether, and 2M HCl (3 drops), washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95 :5/hexanes: ethyl acetate to provide the desired product.
MS (DCI/NH3) m/z 261 (M+NHi)*; 1H NMR (300 MHz, CDCI3) δ 8.04 (d, IH), 7.92 (dd, IH), 7.69 (d, IH), 3.96 (s, 3H), 3.01 (m, IH), 1.90 (m, 4H), 1.80 (m, IH), 1.50 (m, 4H), 1.30 (m, IH).
Example 100B 2-cyclohexyl-4-(hydroxymethyPbenzonitrile The desired product was prepared by substituting Example 100A for Example 5A in
Example 5B.
MS (DCI/NH3) m/z 233 (M+NTLt ;
*H NMR (300 MHz, CDC13) δ 7.60 (d, IH), 7.36 (s, IH), 7.27 (m, IH), 4.77 (d, 2H), 3.00 (m, IH), 1.90 (m, 5H), 1.80 (m, IH), 1.50 (m, 4H), 1.30 (m, IH).
Example 100C 2-cyclohexyl-4-formylbenzonitrile The desired product was prepared by substituting Example 100B for Example 5B in Example 5C. MS (DCI/NH3) m/z 231 (M+NH4)+;
1H NMR (300 MHz, CDC13) δ 10.08 (s, IH), 7.88 (s, IH), 7.78 (s, 2H), 3.00 (m, IH), 1.90 (m, 4H), 1.80 (m, IH), 1.50 (m, 4H), 1.30 (m, IH).
Example 100D 2-cvclohexyl-4-(hydroxy(l-methyl-lH-imidazol-5-yPmethyPbenzonitrile
The desired product was prepared by substituting Example 100C for Example 1 A in Example IB.
MS (DCI/NH3) m/z 296 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 7.75 (d, IH), 7.55 (m, 2H), 7.39 (d, IH), 6.33 (s, IH), 6.11 (d, IH), 5.87 (d, IH), 3.58 (s, 3H), 2.86 (m, IH), 1.80 (m, 5H), 1.40 (m, 5H).
Example 100E 4-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethyP-2-cyclohexylbenzonitrile hydrochloride
The desired product was prepared by substituting Example 100D for Example 5D in Example 5E.
MS CAPCIC+)) m/z 386 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 7.90 (d, IH), 7.59 (s, IH), 7.48 (dd, IH), 7.37 (m, 5H), 7.27 (s, IH), 6.00 (s, IH), 4.62 (d, IH), 4.46 (d, IH), 3.76 (s, 3H), 2.90 (m, IH), 1.85 (m, 4H), 1.74 (m, IH), 1.45 (m, 4H), 1.25 (m, IH);
Anal, calcd for C25H28C1N3O-0.65 H2O: C, 69.24; H, 6.81; N, 9.69. Found: C, 69.29; H, 6.79; N, 9.79._
Example 101
4-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP-2-(5,6,7,8-tetrahydro-l- naphthalenvPbenzonitrile hydrochloride
Example 101A
5 -bromo- 1,2,3 ,4-tetrah vdronaphthalene A solution of copper(H) bromide (10.4 g, 46.7 mmol) and tert-butyl nitrite (7.0 mL, 6.1 g, 58.5 mmol) in acetonitrile(150 rnL) at 65 °C, was treated dropwise with a solution of 1- amino-5,6,7,8-tetrahydronaphthalene (6.1 mL, 6.5 g, 44 mmol) in acetonitrile (10 mL), stirred for 10 minutes, cooled to room temperature, treated with 3M HCl, and extracted with diethyl ether. The extract was washed with 3M HCl and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was distilled under vacuum (0.3 mm Hg, 77-86 °C) and purified by flash column chromatography on silica gel with hexanes to provide the desired product. *H NMR (300 MHz, CDC13) δ 7.38 (d, IH), 7.01 (d, IH), 6.95 (dd, IH), 2.75 (m, 4H), 1.80 (m, 4H).
Example 101B 5,6,7,8-tetrahydro-l-naphthalenylboronic acid The desired product was prepared by substituting Example 101A for 3-bromo-l,l - biphenyl in Example 6A. MS (DCI/NH3) m/z 194 (M+NIL,)"1".
Example 101 C ethyl 4-cyano-3 -(5.6 ,8-tetrahydro- 1 -naphthalenvPbenzoate
The desired product was prepared by substituting Example 93C and Example 101B for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A.
MS (DCI NH3) m/z 323 (M+NE-4)+;
!H NMR (300 MHz, CDC13) δ 8.10 (dd, IH), 8.03 (d, IH), 7.80 (d, IH), 7.20 (m, 2H), 7.00 (m, IH), 4.41 (q, 2H), 2.86 (m, 2H), 2.42 (m, 2H), 1.80 (m, 4H), 1.40 (t, 3H).
Example 101D 4-(hvdroxymethvP-2-(5,6,7,8-tetrahvdro-l-naphthalenypbenzonitrile The desired product was prepared by substituting Example 10 IC for Example 5 A in Example 5B. MS (DCI NH3) m/z 281 (M+NELt)"";
*H NMR (300 MHz, CDC13) δ 7.73 Cd, IH), 7.44 Cd, IH), 7.38 (s, IH), 7.16 Cm, 2H), 7.00 (m, IH), 4.81 (d, 2H), 2.88 (m, 2H), 2.45 (m, 2H), 1.80 (m, 5H).
Example 101E 4-f ormyl-2-(5 ,6 ,7 , 8-tetrahydro- 1 -naphthalen vPbenzonitrile
The desired product was prepared by substituting Example 101D for Example 5B in Example 5C.
MS (DCI/NH3) m z 279 (M+NH4)+;
!H NMR (300 MHz, CDC13) δ 10.11 (s, IH), 7.95 (dd, IH), 7.91 (d, IH), 7.87 (s, IH), 7.20 (m, 2H), 7.00 (m, IH), 2.88 (m, 2H), 2.45 (m, 2H), 1.80 (m, 4H).
Example 101F 4-(hvdroxy(l-methyl-lH-iιnidazol-5-vDmethvD-2-(5,6,7,8-tetrahvdro-l- naphthalenvPbenzonitrile The desired product was prepared by substituting Example 101E for Example 1 A in
Example IB.
MS (DCI/NH3) m/z 344 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.90 (dd, IH), 7.55 (m, 2H), 7.40 (d, IH), 7.20 (m, 2H), 7.00 (m, IH), 6.42 and 6.38 (both s, total IH), 6.14 (m, IH), 5.92 (d, IH), 3.57 and 3.55 (both s, total 3H), 2.80 ( , 2H), 2.35 (m, 2H), 1.70 (m, 4H).
Example 101G 4-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(5,6,7,8-tetrahvdro-l- naphthalenvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 101F for Example 5D in
Example 5E. MS (APCI(+)) m/z 434 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.05 (dd, IH), 7.65 (dd, IH), 7.48 (s, IH), 7.37 (m, 6H), 7.20 (m, 2H), 7.10 and 7.00 (both m, total IH), 6.06 (s, IH), 4.60 (m, 2H), 3.76 and 3.74 (both s, total 3H), 2.81 (m, 2H), 2.37 (m, 2H), 1.70Cm, 4H); Anal, calcd for C29H28C1N3O-1.20 H2O: C, 70.85; H, 6.23; N, 8.55. Found: C, 70.90; H,
6.17; N, 8.55.
Example 102 4-((benzyloxy)( 1 -methyl- lH-imidazol-5-ypmethyP-2-(2-methyl- 1 -naphthyDbenzonitrile hydrochloride
Example 102 A 2-methyl-l-naphthylboronic acid A sluny of Rieke® magnesium (0.5 g, 21 mmol) in THF (10 mL) at room temperature was treated with l-bromo-2-methylnaphthalene (3.0 mL, 4.2 g, 19 mmol), stined for 30 minutes, treated with a solution of trimethyl borate (10 mL, 9.1 g, 88 mmol) in diethyl ether (20 mL), stirred for 1 hour, treated sequentially with NaOH and concentrated HCl, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was triturated with hexanes, and purified by flash column chromatography on silica gel with 4:l/hexanes:ethyl acetate to provide the desired product. MS (DCI/NH3) m/z 218 (M+NILD .
Example 102B ethyl 4-cyano-3-(2-methyl-l-naphthyPbenzoate The desired product was prepared by the method described in Synlett., 1992, page 207 using Examples 93C and 102A.
MS (DCI NH3) m/z 333 (M+NH-i)+.
Example 102C 4-(hydroxymethyl)-2- ( methyl- 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 102B for Example 5 A in
Example 5B.
Example 102D 4-formyl-2-(2-methyl- 1 -naphthyDbenzonitrile A solution of Example 102C (45 mg, 0.16 mmol) in dichloromethane (1.7 mL) at room temperature was treated with Dess-Martin periodinane (87 mg, 0.2 mmol), stined for 45 minutes, washed with saturated. NaHCO3, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 88:12/hexanes:ethyl acetate to provide the desired product. MS (DCI/NH3) m z 289 (M+Nat)"1".
Example 102E 4-(hvdroxy(l-methyl-lH-imidazol-5-vDmethyD-2-(2-methyl-l-naphthvDbenzonitrile The desired product was prepared by substituting Example 102D for Example 1 A in Example IB. MS (DCI/NH3) m/z 354 (M+H)+.
Example 102F 4-((benzyloxy)(l-methyl-lH-imidazol-5-yDmethyl)-2-(2-methyl-l-naphthvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 102E for example 5D in Example 5E.
MS (APCI(+)) m/z 444 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 9.09 Cs, IH), 8.20 Cd, IH), 7.98 (d, 2H), 7.80 (m, IH), 7.50 (m, 3H), 7.36 (m, 7H), 7.20 and 7.13 (both d, total IH), 6.10 (s, IH), 4.62 (m, 2H), 3.76 and 3.74 (both s, total 3H), 2.22 and 2.15 (both s, total 3H); Anal, calcd for C3oH26ClN3O-1.50 H2O: C, 71.07; H, 5.76; N, 8.29. Found: C, 71.09; H, 5.57; N, 8.35.
Example 103 2-(l -anthryl)-4-((benz yloxyX 1 -methyl- lH-imidazol-5-vPmethvPbenzonitrile hydrochloride
Example 103 A 1 -iodoanthracene A solution of 1-aminoanthracene (5.0 g, 26 mmol) in acetone (500 mL) was treated with 2M HCl (50 mL), cooled to 3 °C, treated dropwise with a solution of sodium nitrite (2.0 g, 29 mmol) in water (25 mL), stirred for 1 hour, treated with urea (10.6 g, 10 mmol) and a solution of KI (7.5 g, 45 mmol) in water (25 mL), stined forl5 minutes, warmed to room temperature, stirred for 16 hours, heated to 60 °C, stined for 20 minutes, cooled to room temperature, and treated with 2M Na2SO3 to provide a precipitate. The precipitate was collected by filtration and dried under vacuum with P2Os. The filtrate was partially concentrated and extracted with diethyl ether. The extract was dried (Na2SO4), filtered, concentrated, and combined with the precipitate. The mixture was purified by flash column chromatography on silica gel with hexanes to provide the desired product. MS (DCI/NH3) m/z 305 (M+H)+.
Example 103B 1-anthrylboronic acid The desired product was prepared by substituting Example 103 A for 3-bromo-l,l - biphenyl in Example 6A. MS (DCI NH3) m/z 240 (M+NHj .
Example 103C ethyl 3-( 1 -anthrvP-4-cyanobenzoate
The desired product was prepared by substituting Example 93 C and Example 103B for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1A.
MS (DCI NH3) m/z 369 (M+NHi ; XH NMR (300 MHz, CDC13) δ 8.54 (s, IH), 8.37 (m, 2H), 8.14 (d, IH), 8.04 (d, IH), 7.96 (m, 2H), 7.83 (d, IH), 7.56 (m, IH), 7.45 (m, 3H), 4.43 and 4.42 (both q, total 2H), 1.39 (t, 3H).
Example 103D 2-(l-anthryP-4-(hydroxymethvPbenzonitrile
The desired product was prepared by substituting Example 103C for Example 5A in Example 5B.
MS (DCI/NH3) m/z 327 (M+NH4)+;
1H NMR (300 MHz, CDCI3) δ 8.51 (s, IH), 8.10 (d, IH), 8.03 (m, 2H), 7.85 (m, 2H), 7.60 (m, 2H), 7.55 (m, 2H), 7.45 (m, 2H), 4.89 (s, 2H).
Example 103E 2-(l-anthrvP-4-formylbenzonitrile The desired product was prepared by substituting Example 103D for Example 102C in Example 102D.
MS (DCI/NH3) m/z 325 (M+NH4)+;
1H NMR (300 MHz, CDCI3) δ 10.18 (s, IH), 8.55 (s, IH), 8.18-7.97 (m, 5H), 7.83 (d, IH),
7.57 (m, IH), 7.47 (m, 3H).
Example 103F
2-(l-antl rvP-4-(hydroxy(l-methyl-lH-imidazol-5-vPmethvPbenzonitrile The desired product was prepared by substituting Example 103E for Example 1 A in Example IB.
MS (DCI NH3) m/z 390 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, IH), 8.24 (d, IH), 8.10 (m, 3H), 7.95 (m, IH), 7.73 and 7.63 (both m, total 3H), 7.52 (m, 4H), 6.57 (s, IH), 6.22 (m, IH), 6.03 (d, IH), 3.54 and 3.52 (both s, total 3H).
Example 103G 2-( 1 -anthryP-4-((benzyloxy)(l -methyl- lH-imidazol-5-vPmethyPbenzonitrile hydrochloride The desired product was prepared by substituting Example 103F for Example 5D in Example 5E.
MS CAPCIC+)) m/z 480 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, IH), 8.73 (s, IH), 8.23 and 8.15 (both m, total 4H), 8.02 and 7.92 (both d, total IH), 7.83 (m IH), 7.73 (m, IH), 7.64 and 7.53 (both m, total 5H), 7.37 and 7.30 (both m, total 5H), 6.14 (s, IH), 4.65 (m, 2H), 3.61 and 3.59 (both s, total 3H);
Anal, calcd for C33H26C1N3O-1.30 H2O: C, 73.47; H, 5.34; N, 7.79. Found: C, 73.53; H, 5.47; N, 7.79
Example 104 4-((benzyloxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(4-isoquinolinypbenzonitrile dihydrochloride
Example 104A 4-(diethylboryPisoquinoline The desired product was prepared by the method described in Heterocycles 1984,
Vol.22, p.2471. MS (DCI NH3) m/z 198 (M+H)+.
Example 104B methyl 4-cyano-3-(4-isoquinolinyPbenzoate
The desired product was prepared by substituting Example 93 G, Example 104 A, and DMF for Example 3B, 2-methylphenylboronic acid, and DME, respectively, in Example 3C. MS (DCI NH3) m z 289 (M+H)+;
XH NMR (300 MHz, CDC13) δ 9.39 (br s, IH), 8.53 (br s, IH), 8.26 (m, IH), 8.22 (s, IH), 8.12 (m, IH), 7.96 (d, IH), 7.71 (m, 2H), 7.52 (m, IH), 3.98 (s, 3H).
Example 104C 4-(hvdroxymethvP-2-(4-isoquinolinvPbenzonitrile The desired product was prepared by substituting Example 104B for Example 5A in Example 5B, and by adjusting the aqueous layer to pH >7 with saturated NaHCOs prior to extraction with diethyl ether. MS (DCI/NH3) m/z 261 (M+H)+.
Example 104D 4-formyl-2-(4-isoquinolinvPbenzonitrile The desired product was prepared by substituting Example 104C for Example 102C in Example 102D.
MS (DCI NH3) m/z 259 (M+H)+.
Example 104E 4-(hydroxy(l-methyl-lH-imidazol-5-yPmethyl)-2-(4-isoquinolinvPbenzonitrile The desired product was prepared by substituting Example 104D for Example 1 A in
Example IB. MS (DCI/NH3) m/z 341 (M+H)+.
Example 104F 4-((benzyloxy)(l-methyl-lH-imidazol-5-yPmethyP-2-(4-isoquinolinvPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 104E for Example 5D in Example 5E.
MS (APCI(+)) 431 m/z (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.17 and 9.13 (both s, total IH), 9.14 (s, IH), 8.18 and 8.10 (both s, total IH), 8.40 (m, IH), 8.23 (m IH), 7.90 (m, 3H), 7.70 (m, 2H), 7.46 (s, IH), 7.37 (m, 5H), 6.13 (s, IH), 4.63 (m, 2H), 3.81 and 3.79 (both s, total 3H).
Example 105 4-((benzyloxy)(l-(ethoxymethvP-lH-imidazol-5-vPmethvP-2-d-naphthvPbenzonitrile hydrochloride
Example 105 A 1 -(ethoxymethv - lH-imidazole A solution of imidazole (13 g, 191 mmol) in THF (200 mL) at room temperature was treated with small portions of 60% NaH (7.6 g, 190 mmol), stirred for 30 minutes, treated with THF (100 mL) and chloromethyl ethyl ether (17.5 mL, 17.8 g, 189 mmol), and stirred for 16 hours, filtered through a pad of diatomaceous earth (Celite®) and concentrated. The concentrate was purified by vacuum distillation (5-5.5 mmHg, 96-98 °C) to provide the desired product.
XH NMR (300 MHz, CDC13) δ 7.62 (s, IH), 7.11 (s, IH), 7.06 (s, IH), 5.30 (s, 2H), 3.45 (q, 2H), 1.19 (t, 3H).
Example 105B l-(ethoxymethyP-2-(triethylsilyP-lH-imidazole The desired product was prepared substituting Example 105 A for 1-methylimidazole in Example 87F.
!H NMR (300 MHz, CDC13) δ 7.22 (s, IH), 7.12 (s, IH), 5.31 (s, 2H), 3.45 (q, 2H), 1.19 (t, 3H), 0.95 (m, 15H).
Example 105C 4-((l-(ethoxymethvP-lH-imidazol-5-vP(hvdroxy)methyP-2-(l-naphthvPbenzonitrile
The desired product was prepared by substituting Example 105B and Example 89C for Example 87F and Example 1 A, respectively, in Example IB. MS (DCI/NΗ3) m/z 384 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.06 (m, 3H), 7.77 (s, IH), 7.70-7.40 (m, 7H), 6.51 and 6.50 (both s, total IH), 6.28 (d, IH), 6.00 (d, IH), 5.40 (m, 2H), 3.35 (m, 2H), 1.08 and 0.93 (both m, total 3H).
Example 105D 4-((benzyloxy)(l-(ethoxymethyP-lH-imidazol-5-yPmethvP-2-(l-naphthyPbenzonitrile hydrochloride
The desired product was prepared by substituting Example 105C for Example 5D in Example 5E.
MS (APCI(+)) m/z 474 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.11 (br s, IH), 8.10 (m, 3H), 7.75 (d, IH), 7.70-7.45 (m, 7H), 7,34 (m, 5H), 6.07 (s, IH), 5.55 (m, 2H), 4.60 (m, 2H), 3.35 (m, 2H), 0.94 (m, 3H); Anal, calcd for C3ιH28ClN3O2-0.75 H2O: C, 71.12; H, 5.68; N, 8.03. Found: C, 71.16; H, 5.69; N, 8.08.
Example 106 4-(((4-cvanobenzvPoxy)(l-(ethoxymethyP-lH-imidazol-5-vPmethyP-2-(l- naphthvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 105C and 4-cyanobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E.
MS (APCI(+)) m/z 499 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 9.10 (br s, IH), 8.10 (m, 3H), 7.86 (m, IH), 7.79 (m, 2H), 7.75-7.45 (m, 9H), 6.10 (s, IH), 5.55 (m, 2H), 4.67 (m, 2H), 3.35 (m, 2H), 0.94 (m, 3H); Anal, calcd for C32H27C1N4O2-0.90 H2O: C, 69.72; H, 5.27; N, 10.16. Found: C, 69.78; H, 5.28; N, 10.01.
Example 107 4-(((4-c yanobenzyPoxy) ( 1 -methyl- 1 H-imidazol-5- vPmeth vP-
2 -phenvKl,! -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 94E and 4-cyanobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (APCI(+)) m/z 481 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 8.95 (br s, IH), 7.95 (d, IH), 7.82 (d, 2H), 7.50 (m, 7H), 7.30-6.90 (br m, 7H), 5.90 (s, IH), 4.48 (m, 2H), 3.50 (s, 3H);
Anal, calcd for C32H25C1N4O-1.30 H2O: C, 71.12; H, 5.15; N, 10.37. Found: C, 71.13; H, 4.90; N, 10.35.
Example 108
4-(((4-cvanobenzypoxy)(l-(3-hydroxypropyP-lH-imidazol-5-yPmethvP-2-(l- naphthvPbenzonitrile hydrochloride
Example 108 A l-(3-((tert-butyl(dimethyPsilvPoxy)propyP-lH-imidazole
The desired product was prepared by substituting (3-chloropropoxy)-tert- butyldimethylsilane for chloromethyl ethyl ether in Example 105 A, and purified by flash column chromatography on silica gel with ethyl actate then 98:2:l/ethyl acetate:ethanol:concentrated ammonium hydroxide. MS (DCI NH3) m/z 241 (M+H)+;
!H NMR (300 MHz, CDCI3) δ 7.47 (s, IH), 7.05 (s, IH), 6.91 (s, IH), 4.07 (t, 2H), 3.56 (t, 2H), 1.94 (m, 2H), 0.91 (s, 9H), 0.05 (s, 6H).
Example 108B l-(3-((tert-butyl(dimethyPsilyPoxy)propyP-2-(triethylsilyP-lH-imidazole
The desired product was prepared by substituting Example 108 A for imidazole in Example 87F. Example 108C 4-((l-(3-((tert-butyl(Q^methyPsilyPoxy)propyP-lH-imidazol-5-vP(hvdroxy)methvP-2-(l- naphthyDbenzonitrile The desired product was prepared by substituting Example 89C and Example 108B for Example 1A and Example 87F, respectively, and by eliminating TBAF in Example IB. MS (APCI(+)) m/z 498 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.06 (m, 3H), 7.71-7.37 (m, 8H), 6.51 and 6.52 (both s, total IH), 6.25 (m, IH), 5.97 (d, IH), 4.00 (m, 2H), 3.52 (m, 2H), 1.82 (m, 2H), 0.83 and 0.81 (both s, total 9H), 0.05 (m, 6H).
Example 108D 4-((l-(3-((tert-butyl(dimethvDsilvDoxy)propyD-lH-imidazol-5-vD((4- cyanobenzvDoxy)methvD-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 108C and
4-cyanobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in
Example 5E.
MS (APCIC+)) m/z 613 (M+H)+.
Example 108E
4-(((4-cyanobenzyl)oxy)( 1 -(3-hydroxypropyD- lH-imidazol-5-vDmethvD-2-( 1 - naphthyDbenzonitrile hydrochloride A solution of Example 108C (32 mg, 0.05 mmol) in THF (0.25 mL) at room temperature was treated with IM tetrabutylammonium fluoride in 95 :5/THF: water (0.1 mL), stined for 2.5 hours, and treated with half-saturated NH-tCl and ethyl acetate to provide two layers. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography using 97:3:1/ to 96:4:l/ethyl acetate:ethanol:concentrated ammonium hydroxide. The appropriate fractions were concentrated and converted to the HCl salt to provide the desired product. MS (APCI(+)) m/z 499 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.15 (m, IH), 8.08 (m, 2H), 7.70 (m, 3H), 7.70-7.40 (m, 9H), 6.15 (s, IH), 4.73 (m, 2H), 4.20 (m, 2H), 3.50 (m, 2H), 1.86 (m, 2H).
Example 109 5-(l-hydroxy- 1 -( 1 -methyl- lH-imidazol-5-vD-3-phenyl-2-propynyD-2 -methyK 1 , 1 -biphenvD-
2-carbonitrile Example 109 A 5-(l-oxo-l-(l-methyl-lH-imidazol-5-vD-2 -methyl(l, -biphenvD-2-carbonitrile A solution of Example 4A (400 mg, 1.32 mmol) in dioxane (8 mL) at 45 °C was treated with manganese dioxide (400 mg, 4.6 mmol), refluxed for 5 hours, cooled to room temperature, filtered through a pad of diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10:0.6:0.1/ethyl acetate:methanol:concentrated ammonium hydroxide to provide the desired product. MS (DCI/NH3) m/z 302 (M+H)+ and 319 (M+NILt ;
1H NMR (300 MHz, CD3OD) δ 8.02-7.95 (m, 3H), 7.80 (d, IH), 7.61 (d, IH), 7.42-7.25 (m, 4H), 4.03 (s, 3H), 2.21 (s, 3H).
Example 109B 5-( 1 -hydroxy- 1-( 1 -methyl- lH-imidazol-5-vP-3-phenyl-2-propynyP-2'-methyl(l , 1 '-biphenyp-
2-carbonitrile A solution of phenylacetylene (37 μL, 0.34 mmol) in THF (1 mL) at -78 °C was treated with 1.5M tert-butyllithium in pentane (0.27 mL, 0.34 mmol), stined for 1 hour, treated with Example 109A (50 mg, 0.17 mmol) in THF (1 mL), stirred for 16 hours while warming to room temperature, treated with water, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10:0.6:0.1/ethyl acetate:methanol:concentrated ammonium hydroxide to provide the desired product. MS (DCI/NH3) m/z 404 (M+H)+;
XH NMR (300 MHz, CDC13) δ 7.81-7.68 (m, 3H), 7.46-7.21 (m, 10H), 6.96 (br s, IH), 3.60 (s, 3H), 2.17 (s,.3H).
Example 110 5-(l -hydroxy- 1 -( 1 -methyl- lH-imidazol-5-vP-3-phenylpropyP-2'-methyl( 1 , 1 '-biphenvP-2- carbonitrile A mixture of Example 109B (25 mg, 0.062 mmol), palladium on barium sulfate (20 mg), and potassium hydroxide (20 mg) in methanol (2 mL) was stined under hydrogen (1 atm) for 16 hours, filtered through a pad of diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10:0.6:0.1/ethyl acetate:methanol:concentrated ammonium hydroxide to provide the desired product. MS CAPCIC+)) m/z 408 (M+H)+;
XH NMR (300 MHz, CDC13) δ 7.74 (d, IH), 7.48-7.11 (m, 13H), 3.30 (s, 3H), 2.84 (m, IH), 2.58-2.52 (m, 2H), 2.35 (m, IH), 2.13 (s, 3H). Example 111 4-(l-hvdroxy-l-(l-methyl-lH-imidazol-5-vP-3-phenyl-2-propynyP-2-(l- naphthvPbenzonitrile
Example 111A 4-(l -oxo-1 -( 1 -methyl- lH-imidazol-5-vP)-2-d -naphthyDbenzonitrile The desired product was prepared by substituting Example 89D for Example 4A in Example 109A. MS (DCI NΗ3) m/z 338 (M+H)+ and 355 (M+NH4)+;
XH NMR (300 MHz, CDC13) δ 8.00-7.95 (m, 4H), 7.77-7.46 (m, 8H), 4.13 (s, 3H).
Example 11 IB 4-( 1 -hydroxy- 1 -( 1 -methyl- lH-imidazol-5-yl)-3 -phenyl-2-propynyl)-2-( 1 - naphthyDbenzonitrile
The desired product was prepared by substituting Example 111 A for Example 109 A in Example 109B. MS (DCI/NH3) m/z 440 (M+H)+;
XH NMR (300 MHz, CDCI3) δ 7.98-7.80 (m, 3H), 7.71-7.26 (m, 13H), 6.98 (d, IH), 3.64 (d, 3H).
Example 112 4-(((4-fluoro-3-d-naphthvPphenvPd-methyl-lH-imidazol-5- yPmethoxy)methyl)benzonitrile para-toluenesulfonic acid salt
Example 112A 4-fluoro-3 - (1 -naphthypbenzaldehyde The desired product was prepared by substituting 2-naphthylboronic acid and tetrakis(triphenylphosphine)palladium(0) for 2-methylphenylboronic acid and palladium(II) acetate, respectively in Example 1A. MS (DCI/NH3) m/z 250 (M+H)+; XH NMR (300 MHz, CDCI3) δ 10.04 (s, IH), 8.06-7.9 (m, 4H), 7.59-7.32 (m, 6H).
Example 112B
(4-fluoro-3-(l-naphthyPphenyP(l-methyl-lH-imidazol-5-yPmethanol The desired product was prepared by substituting Example 112A for Example 1 A in Example IB and chromatographed on silica gel with 10:0.6:0.1/ethyl acetate:methanol:concentrated ammonium hydroxide to provide the desired product. MS (DCI NH3) m z 333 (M+H)+; XH NMR (300 MHz, CD3OD) δ 7.93 (d, 2H), 7.59-7.39 (m, 7H), 7.28 (dd, IH), 7.00 (dt, IH), 6.61 (s, IH), 5.96 (s, IH), 3.69 (s, 3H).
Example 112C 4-(((4-fluoro-3-(l-naphthyPphenyP(l-methyl-lH-imidazol-5- yl)methoxy)methyPbenzonitrile para-toluenesulfonic acid salt
The desired product was prepared by substituting Example 112B and 4-(bromomethyl)benzonitrile for Example 5D and (bromomethyl)benzene, respectively, in Example 5E, and chromatographed on silica gel with 10:0.6:0.1/ethyl acetate:methanol:concentrated ammonium hydroxide. The appropriate fractions were concentrated, and the free base was dissolved in ethanol, treated with para-toluenesulfonic acid, and concentrated to provide the desired product. MS (DCI/NH3) m/z 448 (M+H)+;
XH NMR (300 MHz, CD3OD) δ 8.89 (s, IH), 7.94 (d, 2H), 7.70-7.62 (m, 4H), 7.60-7.46 (m, 6H), 7.39 (t, 2H), 7.27 (m, IH), 7.17 (d, 2H), 5.95 (s, IH), 4.77 (s, 2H), 4.73 (m, IH), 3.86 (s, 3H), 2.33 (s, 3H);
Anal, calcd. for C29H22N3FO-(CH3)C6H4SO3H-H2O: C, 67.80; H, 5.06; N, 6.59. Found: C, 67.97; H, 5.09; N, 6.47.
Example 113 5-(((3-cyanobenzvPoxy)(l-methyl-lH-imidazol-5-yPmethyP-2 -methyl(l, -biphenyl)-2- carbonitrile hydrochloride A suspension of silver(I) oxide (45 mg, 0.196 mmol) in dichloromethane(2 mL) at room temperature was treated with Example 86J (20 mg, 0.066 mmol) and 3-(bromomethyl)benzonitrile (15 mg, 0.076 mmol), and stirred for 16 hours, treated with methanol (2 mL), centrifuged, decanted, and concentrated. The concentrate was dissolved in l:l/DMSO:methanol (1 mL) and purified by preparative HPLC. The concentrate was dissolved in dichloromethane (1 mL), treated with IM HCl in diethyl ether (1 mL), and concentrated to provide the desired product. MS (APCI(+)) m/z 419 (M+H)+; MS (APCI(-)) m/z 453 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 9.04 (s, IH), 8.05 (d, IH), 7.85 (s, IH), 7.79 (dt, IH), 7.71 (dt, IH), 7.68 (dd, IH), 7.57 (t, IH), 7.52 (d, IH), 7.42 (s, IH), 7.40-7.37 (m, 2H), 7.32 (m, IH), 7.26 (br s, IH), 6.09 (s, IH), 4.71 (d, IH), 4.61 (d, IH), 3.75 (s, 3H), 2.12 (s, 3H).
Example 114
4-(((4-cyanobenzvP((l-methyl-lH-imidazol-5-yPmethvPamino)methvP-2-(8- quinolinyPbenzonitrile
Example 114A 4-formyl-2-(8-quinolinyl)benzonitrile
The desired product can be prepared by substituting Example 200A and 8-quinolinylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively in Example 1 A.
Example 114B 4-(((4-cyanobenzyPamino)methvP-2-(8-quinolinvPbenzonitrile
The desired product can be prepared by substituting Example 114A for Example 89C in Example 34B.
Example 114C 4-(((4-cyanobenzyP((l-methyl-lH-imidazol-5-yPmethyPamino)methyP-2-(8- quinolinyPbenzonitrile The desired product can be prepared by substituting Example 114B for Example 34B in Example 34C.
Example 115
5-(((4-(tert-butvPbenzyl)oxy)(l-methyl-lH-imidazol-5-yPmethvP-2'-methyl(l,l -biphenyl)-
2-carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-4-tert- butylbenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCIC+)) m/z 450 (M+H)+; MS (APCI(-)) m/z 484 (M+Cl)";
!H NMR (500 MHz, DMSO-d6) δ 9.10 (s, IH), 8.04 (d, IH), 7.65 (dd, IH), 7.50 (d, IH), 7.40-7.26 (m, 5H), 7.36 (d, 2H), 7.28 (d, 2H), 6.06 (s, IH), 4.61 (d, IH), 4.51 (d, IH), 2.13 (s, 3H), 1.26 (s, 9H).
Example 116 5-(((4-cvanobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2 -methyld, l -biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting 4-(bromomethyl)benzonitrile for 3- (bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 419 (M+H)+; MS (APCI(-)) m/z 453 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 9.07 (s, IH), 8.05 (d, IH), 7.82 (d, 2H), 7.68 (dd, IH), 7.57 (d, 2H), 7.52 (d, IH), 7.44 (s, IH), 7.42-7.25 (m, 4H), 6.11 (s, IH), 4.75 (d, IH), 4.65 (d, IH), 3.75 (s, 3H), 2.12 (s, 3H).
Example 117 5-(((3-iodobenzyl)oxy)(l-methyl-lH-imidazol-5-yDmethyl)-2 -methyld, l -biphenyD-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3-iodobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 520 (M+H)+; MS (APCI(-)) m/z 554 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, IH), 8.05 (d, IH), 7.73 (t, IH), 7.69-7.66 (m, 2H), 7.51 (d, IH), 7.42 (s, IH), 7.40-7.26 (m, 5H), 7.16 (t, IH), 6.08 (s, IH), 4.63 (d, IH), 4.53 (d, IH), 3.76 (s, 3H), 2.13 (s, 3H).
Example 118 5-(((4-fluorobenzyDoxy)(l-methyl-lH-imidazol-5-yl)methyD-2 -methyld, -biphenyl)-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-4-fluorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m z 412 (M+H)+; MS (APCI(-)) m/z 446 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, IH), 8.05 (d, IH), 7.67 (dd, IH), 7.50 (d, IH), 7.43-7.26 (m, 7H), 7.18 (t, 2H), 6.06 (s, IH), 4.63 (d, IH), 4.54 (d, IH), 3.75 (s, 3H), 2.13 (s, 3H).
Example 119 5-(((4-bromobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2 -methyl(l, -biρhenvP-2- carbonitrile hydrochloride
The desired product was prepared by substituting l-bromo-4-(bromomethyl)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCI(+)) m/z 474 (M+H)+; MS (APCI(-)) m/z 508 (M+Cl)";
!H NMR (500 MHz, DMSO-d6) δ 9.05 (s, IH), 8.05 (d, IH), 7.66 (dd, IH), 7.55 (d, 2H), 7.50 (d, IH), 7.41-7.26 (m, 5H), 7.33 (d, 2H), 6.06 (s, IH), 4.62 (d, IH), 4.52 (d, IH), 3.74 (s, 3H), 2.12 (s, 3H).
Example 120 5-(((3-chlorobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2 -methyld, r-biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3-chlorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 428 (M+H)+; MS (APCI(-)) m/z 462 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 9.13 (s, IH), 8.05 (d, IH), 7.68 (dd, IH), 7.52 (d, IH), 7.43 (br s, 2H), 7.40-7.26 (m, 7H), 6.10 (s, IH), 4.67 (d, IH), 4.56 (d, IH), 3.76 (s, 3H), 2.13 (s, 3H).
Example 121 (2 -methyl-5-((l-methyl-lH-imidazol-5-yl)((4-nitrobenzvPoxy)methvPd, -biphenyP-2- carbonitrile hydrochloride
The desired product was prepared by substituting l-(bromomethyl)-4-nitrobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 439 (M+H)+; MS (APCI(-)) m/z 473 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, IH), 8.21 (d, 2H), 8.06 (d, IH), 7.70 (dd, IH),
7.66 (d, 2H), 7.53 (d, IH), 7.47 (s, IH), 7.42-7.25 (m, 4H), 6.15 (s, IH), 4.82 (d, IH), 4.71 (d, IH), 3.77 (s, 3H), 2.12 (s, 3H).
Example 122 5-(((2-methoxy-5-nitrobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyP-2'-methyld, - biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 2-(bromomethyl)-l-methoxy-4- nitrobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 469 (M+H)+; MS (APCI(-)) m/z 503 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, IH), 8.26-8.24 (m, 2H), 8.06 (d, IH), 7.66 (dd, IH), 7.55 (d, IH), 7.42-7.20 (m, 6H), 6.14 (s, IH), 4.72 (d, IH), 4.63 (d, IH), 3.86 (s, 3H), 3.79 (s, 3H), 2.13 (s, 3H).
Example 123
(2-methyl-5-((l-methyl-lH-imidazol-5-vP((3-(trifluoromethvPbenzyPoxy)methvP(l,l - biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3- (trifluoromethyl)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 462 (M+H)+; MS (APCI(-)) m/z 496 (M+Cl)";
JH NMR (500 MHz, DMSO-d6) δ 8.93 (s, IH), 8.05 (d, IH), 7.70-7.66 (m, 4H), 7.60 (t, IH), 7.51 (d, IH), 7.42-7.25 (m, 5H), 6.09 (s, IH), 4.76 (d, IH), 4.66 (d, IH), 3.74 (s, 3H), 2.12 (s, 3H).
Example 124 5-(((2,6-dichlorobenzvPoxy)d-methyl-lH-imidazol-5-vPmethvP-2 -methyld. l -biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting 2-(bromomethyl)-l,3- dichlorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 462 (M+H)+; MS (APCI(-)) m/z 496 CM+C1)";
*H NMR (500 MHz, DMSO-d6) δ 9.00 (s, IH), 8.06 (d, IH), 7.69 (dd, IH), 7.56 (br s, IH), 7.50 (d, IH), 7.49-7.25 (m, 7H), 6.14 (s, IH), 4.85 (d, IH), 4.73 (d, IH), 3.81 (s, 3H), 2.14 (s, 3H).
Example 125
5-(((3,4-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-yPmethvP-2'-methyl(l, -biphenyP-2- carbonitrile hydrochloride The desired product was prepared by substituting 4-(bromomethyl)-l,2- dichlorobenzene for 3-(bromomethyl)benzonitrile in Example 113.
MS (APCI(+)) m/z 462 (M+H)+;
MS (APCI(-)) m/z 469 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, IH), 8.05 (d, IH), 7.65 (dd, IH), 7.62-7.60 (m, 3H), 7.48 (d, IH), 7.42-7.25 (m, 5H), 6.03 (s, IH), 4.64 (d, IH), 4.55 (d, IH), 3.70 (s, 3H),
2.12 (s, 3H). Example 126 5-(((2-cvanobenzyl)oxy)d-methyl-lH-imidazol-5-yl)methyl)-2 -methyld,! -biphenyl)-2- carbonitrile hydrochloride The desired product was prepared by substituting 2-(bromomethyl)benzonitrile for 3- (bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 419 (M+H)+; MS (APCI(-)) m/z 453 (M+Cl)';
*H NMR (500 MHz, DMSO-d6) δ 8.87 (s, IH), 8.04 (d, IH), 7.85 (dd, IH), 7.72 (td, IH), 7.68-7.65 Cm, 2H), 7.55 (td, IH), 7.52 (d, IH), 7.42-7.25 (m, 5H), 6.13 (s, IH), 4.81 (d, IH), 4.71 (d, IH), 3.72 (s, 3H), 2.12 (s, 3H).
Example 127 (2 -methyl-5-C((4-methylbenzyPoxy)(l-methyl-lH-imidazol-5-vPmethvP(l, -biphenyP-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-4-methylbenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 408 (M+H)+; MS (APCI(-)) m/z 442 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, IH), 8.04 (d, IH), 7.65 (dd, IH), 7.48 (d, IH), 7.40-7.20 (m, 5H), 7.23 Cd, 2H), 7.16 (d, 2H), 6.00 Cs, IH), 4.57 (d, IH), 4.49 (d, IH), 3.71 (s, 3H), 2.29 Cs, 3H), 2.12 (s, 3H).
Example 128 (2 -methyl-5-(((3-methylbenzypoxy)(l-methyl-lH-imidazol-5-vPmethyP(l,r-biphenyl)-2- carbonitrile hydrochloride
The desired product was prepared by substituting l-(bromomethyl)-3-methylbenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCIC+)) m/z 408 (M+H)+; MS (APCI(-)) m/z 442 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 8.91 (s, IH), 8.10 (d, IH), 7.72 (dd, IH), 7.55 (d, IH),
7.45-7.17 (m, 9H), 6.07 (s, IH), 4.64 (d, IH), 4.55 (d, IH), 3.77 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H).
Example 129 5-(((2,5-difluorobenzypoxy)d-methyl-lH-imidazol-5-vPmethvP-2 -methyl(l,l'-biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting 2-(bromomethyl)-l,4- difluorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 430 (M+H)+; MS (APCI(-)) m/z 464 (M+Cl)"; JH NMR (500 MHz, DMSO-d6) δ 8.83 (s, IH), 8.04 (d, IH), 7.65 (dd, IH), 7.50 (d, IH), 7.40-7.21 (m, 8H), 6.07 (s, IH), 4.67 (d, IH), 4.59 (d, IH), 3.72 (s, 3H), 2.12 (s, 3H).
Example 130 methyl 4-(((6-cyano-2 -methyl(l,l -biphenyl)-3-yP(l-methyl-lH-imidazol-5- vPmethoxy)methyl)benzoate hydrochloride
The desired product was prepared by substituting methyl 4-(bromomethyl)benzoate for 3-(bromomethyl)benzonitrile in Example 113. MS (APCIC+)) m/z 452 (M+H)+; MS (APCI(-)) m/z 486 (M+Cl)'; 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, IH), 8.04 (d, IH), 7.94 (d, 2H), 7.67 (dd, IH),
7.51 (d, 2H), 7.50 (d, IH), 7.41-7.28 (m, 4H), 7.25 (s, IH), 6.06 (s, IH), 4.73 (d, IH), 4.63 (d, IH), 3.85 (s, 3H), 3.71 (s, 3H), 2.12 (s, 3H).
Example 131 5-(((3,5-difluorobenzyl)oxy)d-methyl-lH-imidazol-5-vPmethvP-2 -methyld, 1 -biphenyl)-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3,5- difluorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCIC+)) m/z 430 (M+H)+; MS (APCI(-)) m/z 464 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 9.04 (s, IH), 8.18 (d, IH), 7.81 (dd, IH), 7.65 (d, IH), 7.54-7.22 (m, 8H), 6.20 (s, IH), 4.81 (d, IH), 4.71 (d, IH), 3.86 (s, 3H), 2.26 (s, 3H).
Example 132 5-(((2-chlorobenzyl)oxy)(l-methyl-lH-imidazol-5-vPmethvP-2 -methyld,! -biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-2-chlorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 428 (M+H)+; MS (APCI(-)) m z 462 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, IH), 8.15 (d, IH), 7.78 (dd, IH), 7.67-7.34 (m, 10H), 6.21 (s, IH), 4.83 (d, IH), 4.73 (d, IH), 3.83 (s, 3H), 2.23 (s, 3H). Example 133 5-(((4-chlorobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2 -methyld, l -biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-4-chlorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m z 428 (M+H)+; MS (APCI(-)) m/z 462 (M+Cl)";
*H NMR (500 MHz, DMSO-d6) δ 8.78 (s, IH), 8.04 (d, IH), 7.65 (dd, IH), 7.48 (d, IH), 7.44-7.22 (m, 9H), 6.02 (s, IH), 4.62 (d, IH), 4.53 (d, IH), 3.70 (s, 3H), 2.12 (s, 3H).
Example 134 5-(((3-methoxybenzvDoxy)(l-methyl-lH-imidazol-5-yl)methvD-2 -methyld, l -biphenyD-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3- methoxybenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m z 424 (M+H)+; MS (APCI(-)) m/z 458 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, IH), 8.05 (d, IH), 7.67 (dd, IH), 7.51 (d, IH), 7.40-7.22 (m, 5H), 6.94-6.85 (m, 4H), 6.05 (s, IH), 4.61 (d, IH), 4.52 (d, IH), 3.75 (s, 3H), 3.72 (s, 3H), 2.13 (s, 3H).
Example 135 (2 -methyl-5-(((2-methylbenzvDoxy)d-methyl-lH-imidazol-5-vDmethvD(l,r-biphenvD-2- carbonitrile hydrochloride
The desired product was prepared by substituting l-(bromomethyl)-2-methylbenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 408 (M+H)+; MS (APCI(-)) m/z 442 (M+Cl)"; !H NMR (500 MHz, DMSO-d6) δ 8.98 (s, IH), 8.05 (d, IH), 7.66 (dd, IH), 7.51 (d, IH), 7.42-7.15 (m, 9H), 6.06 (s, IH), 4.64 (d, IH), 4.56 (d, IH), 3.71 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H).
Example 136 5-(((3-fluorobenzvDoxy)(l-methyl-lH-imidazol-5-vDmethvD-2 -methyld, l -biphenvD-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3-fluorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 412 (M+H)+; MS (APCI(-)) m/z 446 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, IH), 8.05 (d, IH), 7.67 (dd, IH), 7.51 (d, IH), 7.42-7.12 (m, 9H), 6.05 (s, IH), 4.66 (d, IH), 4.56 (d, IH), 3.72 (s, 3H), 2.12 (s, 3H).
Example 137 5-(((2,6-dichloro-4-pyridinyDmethoxyX 1 -methyl- lH-imidazol-5-vPmethvP-2 -methyl ( 1 , 1 - biphenyP-2-carbonitrile hydrochloride
The desired product was prepared by substituting 4-(bromomethyl)-2,6- dichloropyridine for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 463 (M+H)+; MS (APCI(-)) m/z 497 (M+Cl)"; !H NMR (500 MHz, DMSO-d6) δ 8.94 (s, IH), 8.05 (d, IH), 7.69 (dd, IH), 7.57-7.54 (m, 3H), 7.42-7.25 (m, 5H), 6.10 (s, IH), 4.74 (d, IH), 4.63 (d, IH), 3.73 (s, 3H), 2.12 (s, 3H).
Example 138 5-(((2-fluorobenzvPoχy)d-methyl-lH-imidazol-5-vPmethvP-2 -methyld, l -biρhenvP-2- carbonitrile hydrochloride
The desired product was prepared by substituting l-(bromomethyl)-2-fluorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 412 (M+H)+; MS (APCI(-)) m/z 446 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 8.85 (s, IH), 8.04 (d, IH), 7.71-7.49 (m, 9H), 7.65 (dd, IH), 7.50 (d, IH), 6.06 (s, IH), 4.68 (d, IH), 4.60 (d, IH), 3.72 (s, 3H), 2.13 (s, 3H).
Example 139 (2 -methyl-5-((l-methyl-lH-imidazol-5-vP((4-(trifluoromethvPbenzyPoxy)methyP(l,r- biphenyP-2-carbonitrile hydrochloride
The desired product was prepared by substituting l-(bromomethyl)-4- (trifluoromethyl)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 462 (M+H)+; MS (APCI(-)) m/z 496 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, IH), 8.05 (d, IH), 7.72 (d, 2H), 7.67 (dd, IH), 7.59 (d, 2H), 7.51 (d, IH), 7.41-7.25 (m, 5H), 6.08 (s, IH), 4.75 (d, IH), 4.64 (d, IH), 3.73 (s, 3H), 2.12 (s, 3H).
Example 140
5-(((3,5-dimethylbenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyp-2 -methyl(l,l -biphenyl)-
2-carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3,5- dimethylbenzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 422 (M+H)+; MS (APCI(-)) m/z 456 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.86 (s, IH), 8.05 (d, IH), 7.65 (dd, IH), 7.49 (d, IH), 7.41-7.25 (m, 5H), 6.93 (s, 3H), 6.00 (s, IH), 4.55 (d, IH), 4.45 (d, IH), 3.72 (s, 3H), 2.24 (s, 6H), 2.13 (s, 3H).
Example 141 5-(((4-fluoro-2-(trifluoromethyl)benzvPoxy)(l-methyl-lH-imidazol-5-ypmethyP-2 - methyld , 1 -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-4-fluoro-2- (trifluoromethyl)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 480 (M+H)+; MS (APCI(-)) m/z 514 (M+Cl)"; lH NMR (500 MHz, DMSO-d6) δ 8.73 (s, IH), 7.86 (d, IH), 7.59-7.42 (m, IH), 7.47-7.28 (m, 4H), 7.22-7.03 (m, 5H), 5.97 (s, IH), 4.59 (d, IH), 4.47 (d, IH), 3.53 (s, 3H), 1.91 (s, 3H).
Example 142 (2 -methyl-5-((l-methyl-lH-imidazol-5-vP((2-nitrobenzvPoxy)methvPd,l'-biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-2-nitrobenzene for
3-(bromomethyl)benzonitrile in Example 113. MS (APCIC+)) m/z 439 (M+H)+; MS (APCI(-)) m/z 473 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.12 (dd, IH), 8.10 (d, IH), 8.01 (s, IH), 7.86 (dd, IH), 7.83 (td, IH), 7.71 (dd, IH), 7.67 (td, IH), 7.57 (d, IH), 7.48 (s, IH), 7.46-7.31 (m, 4H), 6.22 (s, IH), 4.95 (d, IH), 4.07 (d, IH), 3.76 (s, 3H), 2.18 (s, 3H). Example 143 (2,-methyl-5-((l-methyl-lH-imidazol-5-vP((3-(trifluoromethoxy)benzvPoxy)methyl)(l, - biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-3- (trifluoromethoxy)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m z 478 (M+H)+; MS (APCI(-)) m/z 512 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.99 (s, IH), 8.05 (d, IH), 7.67 (dd, IH), 7.52 (d, IH), 7.50 (t, IH), 7.41-7.25 (m, 8H), 6.08 (s, IH), 4.71 (d, IH), 4.61 (d, IH), 3.74 (s, 3H), 2.12 (s, 3H).
Example 144
4-(((6-cyano-2 -methyld, r-biphenyP-3-vP(l-methyl-lH-imidazol-5-vPmethoxy)methyP-6- methylisophthalonitrile hydrochloride The desired product was prepared by substituting 4-(bromomethyl)-6- methylisophthalonitrile for 3-(bromomethyl)benzonitrile in Example 113.
MS (APCI(+)) m z 458 (M+H)+;
MS (APCI(-)) m/z 492 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, IH), 8.40 (s, IH), 8.05 (d, IH), 7.75 (s, IH), 7.67 (dd, IH), 7.52 (d, IH), 7.41-7.25 (m, 5H), 6.16 (s, IH), 4.86 (d, IH), 4.74 (d, IH), 3.72 (s,
3H), 2.55 (s, 3H), 2.12 (s, 3H).
Example 145 5-(((2 -cyanod, -biphenyl)-4-vPmethoxy)(l-methyl-lH-imidazol-5-vPmethvP-2 - methyld,! -biphenvP-2-carbonitrile hydrochloride
The desired product was prepared by substituting 4'-(bromomethyl)(l,l -biphenyl)-2- carbonitrile for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 495 (M+H)+; MS (APCI(-)) m z 529 (M+Cl)"; *H NMR (500 MHz, DMSO-d6) δ 8.99 (s, IH), 8.07 (d, IH), 7.95 (dd, IH), 7.80 (td, IH), 7.72 (dd, IH), 7.62-7.53 (m, 7H), 7.41-7.25 (m, 5H), 6.12 (s, IH), 4.73 (d, IH), 4.64 (d, IH), 3.77 (s, 3H), 2.14 (s, 3H).
Example 146 methyl 3-(((6-cvano-2 -methyld,! -biphenvP-3-viXl-methyl-!H-imidazol-5- yPmethoxy)methvPbenzoate hydrochloride The desired product was prepared by substituting methyl 3-(bromomethyl)benzoate for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 452 (M+H)+; MS (APCI(-)) m/z 486 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, IH), 8.09 (d, IH), 7.96-7.94 (m, 2H), 7.71-7.69 (m, 2H), 7.58-7.50 (m, 2H), 7.41-7.25 (m, 5H), 6.12 (s, IH), 4.78 (d, IH), 4.68 (d, IH), 3.89 (s, 3H), 3.78 (s, 3H), 2.17 (s, 3H).
Example 147 5-(((3,4-difluorobenzvPoxy)d-methyl-lH-imidazol-5-yl)methvP-2 -methyld,! -biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting 4-(bromomethyl)-l,2- difluorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 430 (M+H)+; MS (APCI(-)) m/z 464 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.95 (s, IH), 8.05 (d, IH), 7.67 (dd, IH), 7.50 (d, IH), 7.48-7.22 (m, 8H), 6.05 (s, IH), 4.62 (d, IH), 4.54 (d, IH), 3.73 (s, 3H), 2.12 (s, 3H).
Example 148 (2 -methyl-5-((l-methyl-lH-imidazol-5-vP((3,4,5-trimethoxybenzyl)oxy)methvDd.l - biphenvP-2-carbonitrile hydrochloride A solution of 5-(chloromethyl)-l,2,3-trimethoxybenzene (20 mg, 0.092 mmol) in acetone (3 mL) at 60 °C was treated with KI (166 mg, lmmol), stined for 16 hours, centrifuged, decanted, and concentrated. The concentrate was dissolved in dichloromethane (2 mL), treated with Example 86J (20 mg, 0.066 mmol) and silver(I) oxide (140 mg, 0.604 mmol), stirred for 16 hours, treated with methanol, centrifuged, decanted, and concentrated.
The concentrate was treated with l:l/:methanol/DMSO, purified by preparative HPLC, dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (APCI(+)) m/z 484 (M+H)+;
MS (APCI(-)) m/z 518 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.94 (s, IH), 8.04 (d, IH), 7.65 (dd, IH), 7.51 (d, IH),
7.41-7.25 (m, 5H), 6.64 (s, 2H), 6.02 (s, IH), 4.56 (d, IH), 4.49 (d, IH), 3.74 (s, 3H), 3.72 (s,
6H), 3.63 (s, 3H), 2.13 (s, 3H).
Example 149 (2-methyl-5-((l-methyl-lH-imidazol-5-yP(8-quinolinylmethoxy)methyP(l,r-biphenyP-2- carbonitrile hydrochloride The desired product was prepared by substituting 8-(chloromethyl)quinoline for 5- (chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 445 (M+H)+; MS (APCI(-)) m/z 479 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.38 (d, IH), 8.04 (dd, IH), 7.98 (d, IH), 7.93 (d, IH), 7.76 (td, IH), 7.71 (br d, IH), 7.64 (d, IH), 7.61 (t, IH), 7.56 (br s, IH), 7.41-7.22 (m, 6H), 6.31 (br s, IH), 4.90 (br d, IH), 4.82 (br d, IH), 3.76 (br s, 3H), 2.11 (s, 3H).
Example 150 5-(((3,5-dimethoxybenzvDoxy)d-methyl-lH-imidazol-5-yDmethyD-2 -methyld,! - biphenyD-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(chloromethyl)-3,5- dimethoxybenzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 454 (M+H)+; MS (APCI(-)) m/z 488 (M+Cl)';
1H NMR (500 MHz, DMSO-d6) δ 8.94 (br s, IH), 8.04 (d, IH), 7.65 (d, IH), 7.50 (s, IH), 7.39-7.25 (m, 5H), 6.51-6.40 (m, 3H), 6.02 (br s, IH), 4.56 (d, IH), 4.47 (d, IH), 3.73 (s, 3H), 3.70 (s, 6H), 2.12 (s, 3H).
Example 151 (2 -methyl-5-((l-methyl-lH-imidazol-5-yD((4-(methylsulfonvDbenzvDoxy)methvD(l, - biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(chloromethyl)-4-
(methylsulfonyl)benzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 472 (M+H)+; MS (APCI(-)) m/z 506 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 9.09 (s, IH), 8.06 (d, IH), 7.91 (d, 2H), 7.68 (dd, IH), 7.64 (d, 2H), 7.53 (d, IH), 7.45 (s, IH), 7.41-7.25 (m, 4H), 6.13 (s, IH), 4.78 (d, IH), 4.67 (d, IH), 3.76 (s, 3H), 3.19 (s, 3H), 2.13 (br s, 3H).
Example 152 5-(((6-chloro-l,3-benzodioxol-5-yl)methoxy)(l-methyl-lH-imidazol-5-vDmethvD-2 - methyld , 1 -biphenvD-2-carbonitrile hydrochloride
The desired product was prepared by substituting 5-chloro-6-(chloromethyl)-l,3- benzodioxole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS CAPCIC+)) m/z 472 (M+H)+; MS (APCI(-)) m/z 506 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.85 (br s, IH), 8.04 (d, IH), 7.67 (br d, IH), 7.50 (br s, IH), 7.41-7.25 (m, 5H), 7.10 (s, IH), 7.08 (s, IH), 6.06 (s, 3H), 4.58 (d, IH), 4.51 (d, IH), 3.72 (s, 3H), 2.12 (s, 3H).
Example 153
5-(((4-isopropylbenzyDoxy)(l-methyl-lH-imidazol-5-vDmethvD-2 -methyld,! -biphenyl)-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(chloromethyl)-4- isopropylbenzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148.
MS (APCI(+)) m/z 436 (M+H)+;
MS (APCI(-)) m/z 470 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 9.03 (s, IH), 8.04 (d, IH), 7.65 (br d, IH), 7.50 (br s, IH), 7.41-7.25 (m, 5H), 7.27 (d, 2H), 7.21 (d, 2H), 6.05 (s, IH), 4.59 (d, IH), 4.50 (d, IH), 3.74 (s,
3H), 2.87 (heplet, IH), 2.13 (s, 3H), 1.18 (d, 6H).
Example 154 5-(((3,4-dimethylbenzvDoxy)d-methyl-lH-imidazol-5-yl)methvD-2 -methyld,! -biphenvD- 2-carbonitrile hydrochloride
The desired product was prepared by substituting 4-(chloromethyl)-l,2- dimethylbenzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCIC+)) m/z 422 (M+H)+; MS (APCI(-)) m/z 456 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 8.60 (br s, IH), 8.03 (d, IH), 7.63 (d, IH), 7.46 (s, IH), 7.41-7.25 (m, 5H), 7.15-7.02 (m, 3H), 6.00 (br s, IH), 4.52 (d, IH), 4.44 (d, IH), 3.66 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H).
Example 155 5-(((4-(benzyloxy)benzvDoxy)d-methyl-lH-imidazol-5-vDmethvD-2 -methyld,! -biphenyl)-
2-carbonitrile hydrochloride The desired product was prepared by substituting l-(benzyloxy)-4- (chloromethyl)benzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 500 (M+H)+; MS (APCI(-)) m/z 534 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 8.93 (br s, IH), 8.04 (d, IH), 7.64 (dd, IH), 7.48 (d, IH), 7.41-7.24 (m, 10H), 7.28 (d, 2H), 6.98 (d, 2H), 6.00 (s, IH), 5.10 (s, 2H), 4.54 (d, IH), 4.46 (d, IH), 3.71 (s, 3H), 2.12 (s, 3H).
Example 156
5-(((6-fluoro-4H-l,3-benzodioxin-8-yDmethoxy)(l-methyl-lH-imidazol-5-vDmethyD-2 - methyld , 1 -biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting 8-(chloromethyl)-6-fluoro-4H-l,3- benzodioxine for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 470 CM+H)+; MS (APCIC-)) m/z 504 CM+C1)";
XH NMR C500 MHz, DMSO-d6) δ 8.95 (br s, IH), 8.05 (d, IH), 7.66 (d, IH), 7.53 (s, IH), 7.41-7.25 (m, 5H), 7.20 (dd, IH), 6.95 ( dd, IH), 6.08 (br s, IH), 5.17 (d, IH), 5.15 (d, IH), 4.85 (s, 2H), 4.58 (d, IH), 4.49 (d, IH), 3.75 (s, 3H), 2.12 Cs, 3H).
Example 157 5-(((2,4-dichlorobenzyl)oxy)(l-methyl-lH-imidazol-5-vDmethvD-2 -methyld.l -biphenvD-2- carbonitrile hydrochloride The desired product was prepared by substituting 2,4-dichloro-l- (chloromethyl)benzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 462 (M+H)+; MS (APCI(-)) m/z 496 CM+C1)";
XH NMR C500 MHz, DMSO-d6) δ 8.84 (br s, IH), 8.04 (d, IH), 7.65 (dd, IH), 7.62 (d, IH), 7.57 (d, IH), 7.50 (d, IH), 7.44 Cdd, IH), 7.41-7.25 (m, 5H), 6.10 (s, IH), 4.70 Cd, IH), 4.60 (d, IH), 3.72 (s, 3H), 2.12 (s, 3H).
Example 158
5-(((3,5-dimethylbenzyDoxy)(l-methyl-lH-imidazol-5-vDmethvD-2'-methyl(l,l -biphenyD-
2-carbonitrile hydrochloride The desired product was prepared by substituting l,3-dichloro-5-
(chloromethyl)benzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148.
MS (APCI(+)) m/z 462 (M+H)+;
MS (APCI(-)) m/z 496 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.45 (br s, IH), 8.02 (d, IH), 7.64 (d, IH), 7.53 (t, IH), 7.47 (s, IH), 7.41 (d, 2H), 7.39-7.25 (m, 5H), 6.02 (br s, IH), 4.64 (d, IH), 4.54 (d, IH), 3.65
(s, 3H), 2.12 (s, 3H). Example 159 5-(((5-(tert-butyD- 1 ,2,4-oxadiazol-3-yDmethoxy)( 1 -methyl-lH-imidazol-5-yl)methyP-2 - methyK 1 , 1 -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 5-tert-butyl-3-(chloromethyl)-l,2,4- oxadiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m z 442 (M+H)+; MS (APCI(-)) m/z 476 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.00 (d, IH), 7.59 (br d, IH), 7.48 (br s, IH), 7.41-7.25 (m, 4H), 7.24 (s, IH), 7.14 (s, IH), 7.03 (s, IH), 4.68 (s, 2H), 3.63 (s, 3H), 2.13 (s, 3H), 1.34 (s, 9H).
Example 160 5-(((4-iodobenzyl)oxy)(l-methyl-lH-imidazol-5-yPmethyP-2 -methyld,! -biphenyl)-2- carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-4-iodobenzene for
3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 520 (M+H)+; MS (APCI(-)) m/z 554 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.78 (br s, IH), 8.03 (d, IH), 7.71 (d, 2H), 7.65 (dd, IH), 7.47 (d, IH), 7.41-7.25 ( , 5H), 7.17 (d, 2H), 6.01 (s, IH), 4.58 (d, IH), 4.49 (d, IH), 3.70 (s, 3H), 2.12 (s, 3H).
Example 161 5-((d,l -biρhenyl)-4-ylmethoxy)d-methyl-lH-imidazol-5-yl)methvP-2 -methyl(l,l - biphenyP-2-carbonitrile hydrochloride
The desired product was prepared by substituting 4-(chloromethyl)-l,l -biphenyl for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 470 (M+H)+; MS (APCI(-)) m/z 504 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 8.99 (s, IH), 8.06 (d, IH), 7.69 (dd, IH), 7.66 (s, 2H), 7.64 (s, 2H), 7.52 Cd, IH), 7.49-7.25 (m, 10H), 6.09 Cs, IH), 4.69 Cd, IH), 4.59 Cd, IH), 3.76 (s, 3H), 2.13 (s, 3H).
Example 162 5-(((2-(4-chlorophenvP-l,3-thiazol-4-vPmethoxyXl-methyl-lH-imidazol-5-yl)methvP-2 - methvK 1 , 1 -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 4-(chloromethyl)-2-(4- chlorophenyl)-l,3-thiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 511 (M+H)+; MS (APCI(-)) m/z 545 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 9.12 (s, IH), 8.04 (d, IH), 7.89 (d, 2H), 7.78 (s, IH), 7.67 (dd, IH), 7.58 Cd, IH), 7.55 (d, 2H), 7.41-7.25 (m, 5H), 6.17 (s, IH), 4.78 (d, IH), 4.73 (d, IH), 3.81 (s, 3H), 2.12 (s, 3H).
Example 163 5-(((5-(2-methoxyphenyP-l,2,4-oxadiazol-3-yPmethoxy)(l-methyl-lH-imidazol-5- yPmethyP-2'-methyl( 1 , 1 '-biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-(chloromethyl)-5-(2- methoxyphenyl)-l,2,4-oxadiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 492 (M+H)+; MS (APCI(-)) m/z 526 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.01 (dd, IH), 7.90 (dd, IH), 7.67 (td, IH), 7.63 (d, IH), 7.51 (br s, IH), 7.41-7.25 (m, 6H), 7.30 (d, IH), 7.14 (td, IH), 6.08 (br s, IH), 4.78 (br s, 2H), 3.68 (br s, 3H), 2.11 (s, 3H).
Example 164 5-(((4-chloro-2-nitrobenzyDoxy)( 1 -methyl-lH-imidazol-5-yPmethyP-2 -methyl ( 1,1 - biphenyp-2-carbonitrile hydrochloride The desired product was prepared by substituting 4-chloro-l-(chloromethyl)-2- nitrobenzene for 5-(chloromethyl)-l ,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 473 CM+H)+; MS (APCI(-)) m/z 509 CM+C1)";
XH NMR (500 MHz, DMSO-d6) δ 8.89 (br s, IH), 8.15 (d, IH), 8.04 (d, IH), 7.85 (dd, IH), 7.81 (d, IH), 7.63 (d, IH), 7.49 (s, IH), 7.41-7.25 (m, 5H), 6.17 (s, IH), 4.97 (d, IH), 4.85 (d, IH), 3.69 (s, 3H), 2.11 (s, 3H).
Example 165 methyl 5-(((6-cyano-2,-methyl(l, r-biphenvP-3-yl)d-methyl-lH-imidazol-5- yPmethoxy)methyP-2-furoate hydrochloride The desired product was prepared by substituting methyl 5-(chloromethyl)-2-furoate for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 442 (M+H)+; MS (APCI(-)) m/z 476 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.88 (br s, IH), 8.03 (d, IH), 7.61 (dd, IH), 7.50 (d, IH),
7.46 (s, IH), 7.41-7.25 (m, 5H), 7.23 (d, IH), 6.66 (d, IH), 6.04 (s, IH), 4.67 (s, 2H), 3.79 (s,
3H), 3.72 (s, 3H), 2.13 (s, 3H).
Example 166
2-methyl-5-((l-methyl-lH-imidazol-5-yP((5-(4-(trifluoromethyPphenyl)-l,2,4-oxadiazol-3- yl)methoxy)methyl)( 1 , 1 -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-(chloromethyl)-5-(4- (trifluoromethyl)phenyl)- 1 ,2,4-oxadiazole for 5-(chloromethyl)- 1 ,2,3-trimethoxybenzene in
Example 148.
MS (APCI(+)) m/z 530 (M+H)+;
MS (APCI(-)) m z 564 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.98 (br s, IH), 8.27 (d, 2H), 8.06 (d, IH), 8.01 (d, 2H), 7.66 (dd, IH), 7.57 (s, IH), 7.41-7.25 (m, 5H), 6.22 (s, IH), 4.87 (d, IH), 4.70 (d, IH), 3.81
(s, 3H), 2.13 (s, 3H).
Example 167 methyl 8-(((6-cvano-2 -methyld, l -biphenvP-3-vP(l-methyl-lH-imidazol-5- yl)methoxy)methyl)-4H- 1 ,3-benzodioxine-6-carboxylate hydrochloride
The desired product was prepared by substituting methyl 8-(chloromethyl)-4H-l,3- benzodioxine-6-carboxylate for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 510 (M+H)+; MS (APCI(-)) m/z 544 (M+Cl)"; *H NMR (500 MHz, DMSO-d6) δ 8.93 (br s, IH), 8.05 (d, IH), 7.82 (d, IH), 7.69 (d, IH), 7.64 (d, IH), 7.53 (s, IH), 7.41-7.25 (m, 5H), 6.08 (s, IH), 5.28 (d, IH), 5.26 (d, IH), 4.92 (s, 3H), 4.65 (d, IH), 4.57 (d, IH), 3.80 (s, 3H), 3.76 (s, 3H), 2.13 (s, 3H).
Example 168 (2 -methyl-5-(( 1 -methyl- lH-imidazol-5-vP((6-nitro-4H- 1 ,3-benzodioxin-8- yPmethoxy)methvP(l, -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 8-(chloromethyl)-6-nitro-4H-l,3- benzodioxine for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 497 (M+H)+; MS (APCI(-)) m z 531 (M+Cl)"; *H NMR (500 MHz, DMSO-d6) δ 9.01 (s, IH), 8.15 (d, IH), 8.07 (d, IH), 8.06 (d, IH), 7.66 (dd, IH), 7.54 (d, IH), 7.41-7.25 (m, 5H), 6.13 (s, IH), 5.35 (d, IH), 5.33 Cd, IH), 4.98 (s, 2H), 4.70 (d, IH), 4.61 (d, IH), 3.77 (s, 3H), 2.13 Cs, 3H).
Example 169
2-methyl-5-((l-methyl-lH-imidazol-5-vP((5-(3-(trifluoromethyPphenvP-l,2,4-oxadiazol-3- vPmethoxy)methyP(l, -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-(chloromethyl)-5-(3- (trifluoromethyl)phenyl)-l,2,4-oxadiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148.
MS (APCI(+)) m/z 530 (M+H)+; MS (APCI(-)) m/z 564 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 9.05 (s, IH), 8.36 (d, IH), 8.30 (s, IH), 8.12 (d, IH), 8.05 (d, IH), 7.91 (t, IH), 7.67 (dd, IH), 7.56 (d, IH), 7.41-7.25 (m, 5H), 6.23 (s, IH), 4.92 (d, IH), 4.87 (d, IH), 3.83 (s, 3H), 2.12 (s, 3H).
Example 170 5-(((5-acetyl-2-methoxybenzvPoxy)d-methyl-lH-imidazol-5-vPmethvP-2 -methyld, 1 - biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(3-(chloromethyl)-4- methoxyphenypethanone for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 466 (M+H)+; MS (APCI(-)) m/z 500 (M+Cl)";
*H NMR (500 MHz, DMSO-d6) δ 8.96 (s, IH), 8.05 (d, IH), 7.97 (d, IH), 7.93 (s, IH), 7.65 (d, IH), 7.54 (s, IH), 7.41-7.25 (m, 5H), 7.11(dd, IH), 6.08 (s, IH), 4.66 (d, IH), 4.59 (d, IH), 3.80 (s, 3H), 3.76 (s, 3H), 2.50 (s, 3H), 2.13 (s, 3H).
Example 171 2 -methyl-5-(d-methyl-lH-imidazol-5-vP((5-phenyl-l,2,4-oxadiazol-3- vPmethoxyXnethyl l , 1 -biphenyP-2-carbonitrile hydrochloride
The desired product was prepared by substituting 3-(chloromethyl)-5-phenyl-l,2,4- oxadiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 462 (M+H)+; MS (APCI(-)) m/z 497 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, IH), 8.07-8.04 (m, 3H), 7.73 (tt, IH), 7.67-7.63 (m, 3H), 7.58 (d, IH), 7.41-7.25 (m, 5H), 6.20 (s, IH), 4.88 (d, IH), 4.84 (d, IH), 3.81 (s, 3H), 2.13 (s, 3H). Example 172 5-(((5-(4-methoxyphenyP-l,2,4-oxadiazol-3-ypmethoxy)(l-methyl-lH-imidazol-5- vPmethvD-2 -methyl , 1 -biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-(chloromethyl)-5-(4- methoxyphenyl)-l,2,4-oxadiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148.
MS (APCIC+)) m/z 492 (M+H)+; MS (APCI(-)) m/z 526 (M+Cl)"; !H NMR (500 MHz, DMSO-d6) δ 9.00 (s, IH), 8.05 (d, IH), 8.00 (d, 2H), 7.66 (dd, IH),
7.57 (d, IH), 7.41-7.25 (m, 5H), 7.16 (d, 2H), 6.20 (s, IH), 4.85 (d, IH), 4.81 (d, IH), 3.88 (s, 3H), 3.82 (s, 3H), 2.13 (s, 3H).
Example 173 5-(((5-(3-methoxyphenyP-l,2,4-oxadiazol-3-vPmethoxy)(l-methyl-lH-imidazol-5- yl)methyP-2 -methyld, -biphenvP-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-(chloromethyl)-5-(3- methoxyphenyl)-l,2,4-oxadiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 492 (M+H)+; MS (APCI(-)) m/z 526 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, IH), 8.05 (d, IH), 7.68-7.63 (m, 2H), 7.58-7.53 (m, 3H), 7.41-7.25 (m, 6H), 6.22 (s, IH), 4.89 (d, IH), 4.86 (d, IH), 3.86 (s, 3H), 3.83 (s, 3H), 2.13 (s, 3H).
Example 175 2 -methyl-5-((l-methyl-lH-imidazol-5-vP((2-(4-(trifluoromethvPphenvP-l,3-thiazol-4- yl)methoxy)methyP(l , 1 -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 4-(chloromethyl)-2-(4- (trifluoromethyl)phenyl)-l,3-thiazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148.
MS CAPCIC+)) m/z 545 (M+H)+; MS (APCI(-)) m/z 579 (M+Cl)";
*H NMR (500 MHz, DMSO-d6) δ 9.03 (s, IH), 8.09 (d, 2H), 8.04 (d, IH), 7.87 (s, IH), 7.84 (d, 2H), 7.67 (dd, IH), 7.57 (d, IH), 7.41-7.25 (m, 5H), 6.16 (s, IH), 4.81 (d, IH), 4.76 (d, IH), 3.80 (s, 3H), 2.12 (s, 3H). Example 176
4-(( 1 -methyl- 1 H-imidazol-5- yl) ((( 1 -methyl-2-oxo- 1 ,2-dihvdro-4- pyridinyl)methyDamino)methyD-2-(l-naphthyDbenzonitrile
Example 176A
4-(methoxycarbonvD- 1 -methylpyridinium iodide A solution of 4-carbomethoxypyridine (5.6 g, 40 mmol) in toluene (20 mL) at 40 °C was treated dropwise with methyl iodide (2.5 mL, 5.7 g, 40 mmol), cooled to room temperature, stined for 1.5 hours, heated to 80 °C, stined for 1 hour, treated with toluene (30 mL), and filtered to provide a solid was of sufficient purity for subsequent use without further purification.
Example 176B 1 -methyl-2-oxo- 1 ,2-dihydro-4-pyridinecarboxylic acid A solution of Example 176A (4.0 g, 18 mmol) in water (20 mL) at room temperature was treated alternatively, at 45-minute intervals, with 2 mL and 3 mL portions of K3Fe(CN)6 (9.6 g, 29 mmol) in water (16 mL) at 50 °C and NaOH (3.5 g, 87 mmol) in water (6 mL) at room temperature. After the fourth addition (of the NaOH solution), the mixture was treated four times with 3 mL of K3Fe(CN>6 solution at 45 minute intervals, heated to 55 °C, stined for 1 hour, cooled to room temperature, adjusted to pH 3 with NaOH, and filtered to provide the desired product of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 154 (M+H)+ and 171 (M+NH4)+; 1H NMR (300 MHz, CD3OD) δ 7.73 (d, IH), 7.10 (d, IH), 6.79 (dd, IH), 3.60 (s, 3H).
Example 176C
4-(hvdroxymethvD- 1 -methyl-2( lHVpyridinone A solution of Example 176B (612 mg, 4.0 mmol) in THF (40 mL), at -8 °C, was treated with isobutylchloroformate (0.57 mL, 0.60 g, 4.4 mmol) and N-methylmorpholine (0.48 mL, 0.44 g, 4.4 mmol), stined for 1 hour, treated with sodium borohydride (930 mg, 24.6 mmol) and MeOH (12 mL), stined for 2 hours, treated with concentrated HCl (2 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 85:15/hexanes:ethyl acetate to provide the desired product. MS (DCI NH3) m/z 140 (M+H)+ and 157 (M+NH4)+; !H NMR (300 MHz, CDCI3) δ 7.23 (d, IH), 6.57 (d, IH), 6.18 (dd, IH), 4.53 (s, 2H), 3.53 (s, 3H), 2.97 (br s, IH).
Example 176D 1 -methyl-2-oxo- 1 ,2-dihydro-4-pyridinecarbaldehyde The desired product was prepared by substituting Example 176C for Example 102C in Example 102D.
MS (DCI/NH3) m/z 138 (M+H)+ and 155 (M+NH4)+;
!H NMR (300 MHz, CDCI3) δ 9.89 (s, IH), 7.42 (d, IH), 7.00 (d, IH), 6.56 (dd, IH), 3.60 (s, 3H).
Example 176E 4-(( 1 -methyl- lH-imidazol-5-ylX(( 1 -methyl-2-oxo- 1 ,2-dihydro-4- pyridinvDmethyDamino)methyD-2-(l-naphthvDbenzonitrile
The desired product was prepared by substituting Example 13A and Example 176D for Example 12A and 4-nitrobenzaldehyde, respectively, in Example 12B. MS CAPCIC+)) m/z 460 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 7.95 (m 2H), 7.84 (d, IH), 7.54 (m, 4H), 7.45 (m, 4H), 7.21 (d, IH), 6.89 (d, IH), 6.52 (s, IH), 6.12 (dd, IH), 5.00 (d, IH), 3.62 (d, 2H), 3.47 and 3.48 (both s, total 3H), 3.53 (s, 3H);
Anal, calcd for C29H27C12N5O-0.65 H2O: C, 64.01; H, 5.24; N, 12.87. Found: C, 64.11; H, 5.60; N, 12.50.
Example 177
2 -methyl-5-((l-methyl-lH-imidazol-5-yD((5-methyl-3-isoxazolyDmethoxy)methyD(l, - biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-(chloromethyl)-5-methylisoxazole for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS CAPCIC+)) m/z 399 (M+H)+; MS (APCI(-)) m/z 433 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 9.01 (s, IH), 8.05 (d, IH), 7.64 (dd, IH), 7.49 (d, IH), 7.41-7.25 (m, 5H), 6.31 (s, IH), 6.08 (s, IH), 4.65 (d, IH), 4.59 (d, IH), 3.74 (s, 3H), 2.38 (s, 3H), 2.13 (s, 3H).
Example 178 (2 -meth yl-5-((l -methyl- lH-imidazol-5-vD((2-methyl- 1 -naphthvDmethoxy)methvD( 1 , 1 - biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(chloromethyl)-2- methymaphthalene for 5-(chloromethyl)- 1 ,2,3-trimethoxybenzene in Example 148. MS CAPCIC+)) m/z 458 (M+H)+; MS (APCI(-)) m/z 492 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 8.96 (s, IH), 8.06 Cd, IH), 8.05 Cd, IH), 7.88 (dd, IH), 7.82 (d, IH), 7.67 (dd, IH), 7.54 (s, IH), 7.49-7.22 (m, 8H), 6.20 (s, IH), 5.12 (d, IH), 4.99 (d, IH), 3.68 (s, 3H), 2.43 (s, 3H), 2.13 (s, 3H).
Example 179
(2 -methyl-5-((l -methyl- lH-imidazol-5-vD((2.3.5 ,6-tetramethylbenzvDoχy)methvD(l , 1 - biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-(chloromethyl)-l,2,4,5- tetramethylbenzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 450 (M+H)+; MS (APCI(-)) m/z 484 (M+Cl)";
*H NMR (500 MHz, DMSO-d6) δ 8.98 (s, IH), 8.06 (d, IH), 7.67 (dd, IH), 7.51 (s, IH), 7.41-7.25 (m, 5H), 6.94 (s, IH), 6.08 (s, IH), 4.67 (d, IH), 4.55 (d, IH), 3.71 (s, 3H), 2.15 (s, 6H), 2.13 (s, 3H), 2.10 (s, 6H).
Example 180 (2 -methyl-5-((l-methyl-lH-imidazol-5-vP((4-(trifluoromethoxy)benzyPoxy)methyP(l, - biphenvP-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(chloromethyl)-4- (trifluoromethoxy)benzene for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 478 (M+H)+; MS (APCI(-)) m/z 512 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, IH), 8.04 (d, IH), 7.67 (dd, IH), 7.51 (s, IH), 7.50 (d, 2H), 7.41-7.25 (m, 5H), 7.34 (d, 2H), 6.08 (s, IH), 4.68 (d, IH), 4.58 (d, IH), 3.74 (s, 3H), 2.12 (s, 3H).
Example 181 5-(((5 ,6-dichloro-3-pyridinvDmethoxy)(l -methyl- lH-imidazol-5-yDmethyD-2-methyl( 1,1 - biphenvD-2-carbonitrile hydrochloride The desired product was prepared by substituting 2,3-dichloro-5-
(chloromethyl)pyridine for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS (APCI(+)) m/z 463 (M+H)+; MS (APCI(-)) m/z 497 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, IH), 8.41 (d, IH), 8.16 (d, IH), 8.04 (d, IH), 7.67 (dd, IH), 7.52 (d, IH), 7.41-7.25 (m, 5H), 6.10 (s, IH), 4.72 (d, IH), 4.63 (d, IH), 3.74 (s, 3H), 2.12 (s, 3H). Example 182 5-(((3-chloro-5-(trifluoromethyD-2-pyridinyDmethoxy)(l-methyl-lH-imidazol-5-vDmethyD- 2 -methyld , 1 '-biphenyD-2-carbonitrile hydrochloride The desired product was prepared by substituting 3-chloro-2-(chloromethyl)-5- (trifluoromethyl)pyridine for 5-(chloromethyl)-l,2,3-trimethoxybenzene in Example 148. MS CAPCIC+)) m/z 497 (M+H)+; MS (APCI(-)) m/z 531 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, IH), 8.92 (d, IH), 8.48 (d, IH), 8.03 (d, IH), 7.65 (dd, IH), 7.52 (d, IH), 7.41-7.25 (m, 5H), 6.18 (s, IH), 4.92 (d, IH), 4.85 (d, IH), 3.80 (s, 3H), 2.13 (s, 3H).
Example 183 2 -methyl-5-(( 1 -methyl- lH-imidazol-5-vP(2-naphthylmethoxy)methvP( 1 , 1 -biphenvD-2- carbonitrile hydrochloride The desired product was prepared by substituting 2-(bromomethyl)naphthalene for 3-
(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 444 (M+H)+; MS (APCI(-)) m/z 480 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, IH), 8.05 (d, IH), 7.92-7.87 (m, 4H), 7.71 (dd, IH), 7.53-7.51 (m, 4H), 7.41-7.25 (m, 5H), 6.10 (s, IH), 4.72 (d, IH), 4.68 (d, IH), 3.76 (s, 3H), 2.12 (s, 3H).
Example 184 5-(((3-bromobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyP-2 -methyl(l,r-biphenyP-2- carbonitrile hydrochloride
The desired product was prepared by substituting l-bromo-3-(bromomethyl)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m z 474 (M+H)+; MS (APCI(-)) m/z 508 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 8.94 (s, IH), 8.05 (d, IH), 7.66 (dd, IH), 7.55 (t, IH), 7.50 (d, IH), 7.41-7.25 (m, 8H), 6.06 (s, IH), 4.65 (d, IH), 4.55 (d, IH), 3.73 (s, 3H), 2.13 (s, 3H).
Example 185 5-(((2-bromobenzvPoxy)(l-methyl-lH-imidazol-5-yl)methyP-2 -methyld, l -biphenyl)-2- carbonitrile hydrochloride
The desired product was prepared by substituting l-bromo-2-(bromomethyl)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 473 (M+H)+; MS (APCI(-)) m/z 508 (M+Cl)";
XH NMR (500 MHz, DMSO-d6) δ 8.97 (s, IH), 8.04 (d, IH), 7.68 (dd, IH), 7.62 (dd, IH), 7.55 (dd, IH), 7.54 (d, IH), 7.41-7.25 (m, 7H), 6.13 (s, IH), 4.70 (d, IH), 4.60 (d, IH), 3.75 (s, 3H), 2.12 (s, 3H).
Example 186 5-(((2,6-difluorobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2 -methyl(l,l -biphenvP-2- carbonitrile hydrochloride The desired product was prepared by substituting 2-(bromomethyl)-l,3- difluorobenzene for 3-(bromomethyl)benzonitrile in Example 113. MS CAPCIC+)) m/z 430 (M+H)+;
1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, IH), 8.06 (d, IH), 7.64 (dd, IH), 7.50 (d, IH), 7.48-7.15 (m, 7H), 7.12 (t, IH), 6.10 (s, IH), 4.70 (d, IH), 4.61 (d, IH), 3.77 (s, 3H), 2.14 (s, 3H).
Example 187 5-(((2-fluoro-4-(trifluoromethyPbenzyPoχy)(l-methyl-lH-imidazol-5-yPmethvP-2 - methyl , 1 '-biphenyl)-2-carbonitrile hydrochloride The desired product was prepared by substituting l-(bromomethyl)-2-fluoro-4-
(trifluoromethyl)benzene for 3-(bromomethyl)benzonitrile in Example 113. MS (APCI(+)) m/z 480 (M+H)+; MS (APCI(-)) m/z 514 (M+Cl)";
1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, IH), 8.04 (d, IH), 7.74-7.65 (m, 3H), 7.60 (d, IH), 7.51 (d, IH), 7.41-7.25 (m, 5H), 6.13 (s, IH), 4.79 (d, IH), 4.69 (d, IH), 3.75 (s, 3H), 2.12 (s, 3H).
Example 188 4-(((6-cvano-2 -methyld,! -biphenvD-3-vDd-methyl-lH-imidazol-5- vDmethoxy)methvDbenzamide
A solution of Example 272 (12 mg, 0.028 mmol) in dichloromethane (1 mL) at room temperature was treated with PyBop (17.5 mg, 0.033 mmol, 1.2 eq) and 2M ammonia in methanol (100 μL), stirred for 16 hours, and concentrated. The concentrate was dissolved in l:l/DMSO:methanol (1 mL) and purified by preparative HPLC to provide the desired product.
MS (APCI(+)) m/z 437 (M+H)+; MS (APCI(-)) m/z 471 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 8.55 (br s, IH), 8.04 (d, IH), 7.93 (br s, IH), 7.85 (d, 2H), 7.66 (dd, IH), 7.49 (d, IH), 7.42 (d, 2H), 7.41-7.25 (m, 5H), 7.11 (br s, IH), 6.01 (s, IH), 4.66 (d, IH), 4.58 (d, IH), 3.67 (s, 3H), 2.12 (s, 3H).
Example 189
4-(((6-cvano-2 -methyl(l,r-biphenvD-3-vD(l-methyl-lH-imidazol-5-yl)methoxy)methvD-N- methylbenzamide A solution of Example 272 (12 mg, 0.028 mmol) in dichloromethane (1 mL) at room temperature was treated with PyBop (17.5 mg, 0.033 mmol, 1.2 eq) and 2M methylamine in methanol (100 μL), stirred for 16 hours, and concentrated. The concentrate was dissolved in l:l/DMSO:methanol (1 mL) and purified by preparative HPLC to provide the desired product.
MS (APCI(+)) m/z 451 (M+H)+;
MS (APCI(-)) m/z 485 (M+Cl)"; 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, IH), 8.39 (q, IH), 8.05 (d, IH), 7.81 (d, 2H), 7.67
(dd, IH), 7.51 (d, IH), 7.43 (d, 2H), 7.41-7.25 (m, 5H), 6.06 (s, IH), 4.68 (d, IH), 4.59 (d,
IH), 3.73 (s, 3H), 2.78 (d, 3H), 2.12 (s, 3H).
Example 190 4-(((6-cvano-2'-methyl(l, -biphenyl)-3-yD(l-methyl-lH-imidazol-5-vDmethoxy)methvD-
N,N-dimethylbenzamide A solution of Example 272 (12 mg, 0.028 mmol) in dichloromethane (1 mL) at room temperature was treated with PyBop (17.5 mg, 0.033 mmol, 1.2 eq) and 2M dimethylamine in THF (100 μL), stined for 16 hours, and concentrated. The concentrate was dissolved in 1 : l/DMSO:methanol (1 mL) and purified by preparative HPLC to provide the desired product.
MS (APCI(+)) m/z 465 (M+H)+; MS (APCI(-)) m/z 499 (M+Cl)";
!H NMR (500 MHz, DMSO-d6) δ 8.92 (s, IH), 8.05 (d, IH), 7.67 (dd, IH), 7.51 (d, IH), 7.41-7.25 (m, 9H), 6.06 (s, IH), 4.68 (d, IH), 4.58 (d, IH), 3.74 (s, 3H), 2.97 (s, 3H), 2.88 (s, 3H), 2.13 (s, 3H).
Example 191
4-cyano-N-(4-cyanobenzyl)-N-(d -methyl- lH-imidazol-5-yDmethyl)-3-d- naphthvDbenzamide Example 191A 4-((((l-methyl-lH-imidazol-5-yDmethvDamino)methyDbenzonitrile The desired product was prepared by substituting 34A for 192C in Example 192D. MS CAPCIC+)) m/z 227 (M+H)+;
1H NMR (500 MHz, CDC13) δ 7.61 (d, IH), 7.44 (d, IH), 7.41 (s, IH), 6.91 (s, IH), 3.86 (s, 2H), 3.76 (s, 2H), 3.66 (s, 3H).
Example 191B 4-carboxy-2-(l -naphthyDbenzonitrile
A solution of Example 89 A (0.20 g, 0.70 mmol) in THF (5.0 mL) and water (2.0 mL) at room temperature was treated with lithium hydroxide (0.040 g, 1.67 mmol), stined for 2 hours, and concentrated. The concentrate was dissolved in water (10 mL) and adjusted to pH 3 with 10% HCl to provide a precipitate. The precipitate was filtered and washed with cold water to provide the desired product of sufficient purity for subsequent use without further purification.
MS (APCI(+)) m/z 291 (M+NH-t)+;
1H NMR (500 MHz, DMSO-d6) δ 8.18 (s, 2H), 8.11 (d, IH), 8.08 (d, IH), 8.02 (s, IH), 7.69- 7.51 (m, 4H), 7.45 (d, lH).
Example 19 IC 4-cyano-N-(4-cvanobenzyD-N-(( 1 -methyl- lH-imidazol-5-yl)methyD-3-(l - naphthyPbenzamide The desired product was prepared by substituting Example 191A and Example 191B for Example 192D and 4-cyanobenzoic acid, respectively, in Example 196. MS (APCIC+)) m/z 482 (M+H)+; lH NMR (500 MHz, DMSO-d6) δ 8.61 (s, IH), 8.06-8.01 (m, 3H), 7.74 (d, IH), 7.70 (d, 2H), 7.62-7.59 (m, 2H), 7.55 (t, IH), 7.44-7.37 (m, 5H), 7.29 (d, IH), 4.75-4.69 (br s, 4H), 3.70 (s, 3H).
Example 192 4-((((l -methyl- lH-imidazol-5-vPmethyP(4-trifluoromethylbenzyPamino)methyP-2-( 1 - naphthyDbenzonitrile dihydrochloride
Example 192 A
4-(bromomethyD-2-(l-naphthvDbenzonitrile A solution of Example 89B (1.90 g, 7.34 mmol) in dioxane (35 mL) at room temperature was treated with N-bromosuccinimide (1.44 g, 8.09 mmol) and triphenylphosphine (2.12 g, 8.08 mmol), heated to 80 °C for 10 minutes, cooled to room temperature, and concentrated. The concentrate was treated with ethyl acetate (100 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:l/hexanes:ethyl acetate to provide the desired product.
MS (DCI/NH3) m/z 339, 340, 341 and 342 (M+NH4)+; 1H NMR (500 MHz, CDC13) δ 7.92-7.8 (m, 2H), 7.83-7.80 (m, IH), 7.60-7.44 (m, 7H), 4.53 (s, 2H).
Example 192B 4-(azidomethvD-2-( 1 -naphthyDbenzonitrile A solution of Example 192A (1.71 g, 5.31 mmol) in DMF (25 mL) at room temperature was treated with sodium azide (3.46 g, 53.1 mmol) and sodium iodide (80 mg, 0.53 mmol), stined for 10 minutes, treated with ethyl acetate (100 mL), washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 302 (M+NILD ; *H NMR (500 MHz, CDC13) δ 7.96 (d, IH), 7.94 (d, IH), 7.85 (d, IH), 7.59-7.44 Cm, 7H), 4.51 (s, 2H).
Example 192C 4-(aminomethvP-2-(l-naphthvPbenzonitrile hydrochloride A solution of Example 192B in THF (20 mL) at room temperature was treated with triphenylphosphine (1.39 g, 5.31 mmol), stined for 30 minutes, treated with water (5 mL), heated to 60 °C for 30 minutes, and concentrated. The concentrate was treated with ethyl acetate (100 mL) and extracted with 2M HCl (100 mL). The aqueous extract was adjusted to pH 12 with sodium carbonate and extracted with diethyl ether (100 mL). The extract was dried (MgSO4), filtered, and treated with IM HCl in diethyl ether (10 mL) to provide a solid. The solid was collected by filtration and washed with diethyl ether to provide the desired product of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 259 (M+H)+ and 276 (M+NH4)+; XH NMR (500 MHz, DMSO-d6) δ 8.46 (br s, 2H), 8.13-8.07 (m, 3H), 7.79 (d, IH), 7.75 (s, IH), 7.70-7.52 (m, 4H), 7.50 (s, IH), 4.22 (s, 2H).
Example 192D 4-(((( 1 -methyl- lH-imidazol-5-yPmethyPamino)methyP-2-( 1 -naphthyDbenzonitrile dihydrochloride A solution of Example 252A (0.68 g, 2.93 mmol) and Example 192C (0.82 g, 2.78 mmol) in 5% acetic acid/DMF (25 mL) at room temperature was treated with 4A molecular sieves, stined for 1 hour, treated with sodium cyanoborohydride (0.26 g, 4.17 mmol), stirred for 16 hours, treated with ethyl acetate (100 mL), washed with saturated sodium carbonate and brine, dried (MgSO4), filtered, and concentrated. The concentrate was treated with l:l/methanol:lM HCl (100 mL), stirred for 16 hours, and concentrated. The concentrate was adjusted to pH 12 with sodium carbonate and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. MS (APCI(+)) m/z 353 (M+H)+;
1H NMR (500 MHz, CDC13) δ 7.96-7.92 (m, 2H), 7.79 (d, IH), 7.73 (s, IH), 7.58-7.42 (m, 7H), 7.03 (s, IH), 3.96 (s, 2H), 3.85 (s, 2H), 3.71 (s, 3H).
Example 192E 4-((((l -methyl- lH-imidazol-5-yDmethyD(4-(trifluoromethvDbenzyDamino)methyD-2-( 1 - naphthyDbenzonitrile dihydrochloride A solution of Example 192D in 5% acetic acid/DMF (1.0 mL) at room temperature was treated with 4-(trifluoromethyl)benzaldehyde (35 mg, 2.0 mmol) and anhydrous Na2SO4, stined for 2 hours, treated with sodium cyanoborohydride (13 mg, 2.0 mmol), stined for 16 hours, treated with ethyl acetate (1.0 mL), washed with saturated sodium carbonate and brine, filtered through a Chem Elut® CE1000M tube (Alltech, Northbrook, IL), and concentrated. The concentrate was treated with l:l/methanol:2M HCl (1.0 mL), stirred for 16 hours, and concentrated. The concentrate was adjusted to pH 12 with sodium carbonate and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by preparative HPLC, and the appropriate fractions were treated with dichloromethane (0.5 mL) and IM HCl in diethyl ether (0.5 mL) and concentrated to provide the desired product. MS (ESI(+)) m/z 511 and 512 (M+H)+;
XH NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H).8.08 (d, IH), 8.06 (d, IH), 7.94 (d, IH), 7.67- 7.46 (m, 9H), 7.50 (s, IH), 7.46 (dd, IH), 7.39 (d, IH), 3.84-3.74 (m, 6H), 3.72 (s, 3H).
Example 193 4-(((4-cvano-3-(l-naphthyDbenzyD((l-methyl-lH-imidazol-5- yPmethyPammo)methyPbenzoic acid dihydrochloride The desired product was prepared by substituting 4-formylbenzoic acid for 4- (trifluoromethyl)benzaldehyde in Example 192E. MS CESIC+)) m/z 487 (M+H)+;
*H NMR (500 MHz, DMSO-d6) δ 8.94 (s, IH), 8.08 (d, IH), 8.06 (d, IH), 7.95 (d, IH), 7.85 (d, 2H), 7.66-7.58 (m, 3H), 7.53 (s, IH), 7.50-7.46 (m, 3H), 7.43 (d, 2H), 7.39 (dd, IH), 3.82- 3.70 (m, 6H), 3.68 (s, 3H).
Example 194 N-(4-(((4-cyano-3-(l-naphthvPbenzyP((l-methyl-lH-imidazol-5- vPmethyPamino)methyl)phenvPacetamide dihydrochloride The desired product was prepared by substituting N-(4-formylphenyl)acetamide for 4-
(trifluoromethyl)benzaldehyde in Example 192E. MS (ESI(+)) m/z 500 (M+H)+;
*H NMR (500 MHz, DMSO-d6) δ 9.93 (s, IH), 8.94 (s, IH), 8.08 (d, IH), 8.06 (d, IH), 7.95 (d, IH), 7.66-7.47 (m, 9H), 7.40 (d, IH), 7.23 (d, 2H), 3.78-3.57 (m, 6H), 3.68 (s, 3H).
Example 195 4-(((( 1 -methyl- lH-imidazol-5-yPmethyP(4-(methylsulfonyl)benzypamino)methvP-2-( 1 - naphthyDbenzonitrile dihydrochloride The desired product was prepared by substituting 4-(methylsulfonyl)benzaldehyde for 4-(trifluoromethyl)benzaldehyde in Example 192E. MS (ESI(+)) m/z 521 (M+H)+;
*H NMR (500 MHz, DMSO-d6) δ 8.80 (s, IH), 8.09 (d, IH), 8.06 (d, IH), 7.95 (d, IH), 7.83 (d, 2H), 7.67-7.47 (m, 9H), 7.40 (d, IH), 3.84-3.76 (m, 6H), 3.69 (s, 3H), 3.17 (s, 3H).
Example 196
4-cyano-N-(4-cvano-3-(l-naphthyDbenzyD-N-((l-methyl-lH-imidazol-5- ypmethypbenzamide A solution of Example 192D (35 mg, 0.10 mmol) in dichloromethane (0.5 mL) at room temperature was treated with a solution of 4-cyanobenzoic acid (15 mg, 1.0 mmol), PyBop (47 mg, 0.10 mmol), and N,N-diisopropylethylamine (39 mg, 0.30 mmol) in dichloromethane (0.5 mL), stined for 72 hours, washed with brine, filtered through a Chem Elut® CEIOOOM tube, and concentrated. The concentrate was purified by preparative HPLC (CH3CN/O.OIOM NH4OAC) to provide the desired product. MS (APCI(+)) m/z 482 (M+H)+; !H NMR (500 MHz, DMSO-d6) δ 8.03 (d, IH), 8.02 (d, IH), 7.89 (d, IH), 7.83 (d, 2H), 7.62 (t, IH), 7.59-7.55 (m, 3H), 7.51 (dt, IH), 7.46-7.42 (m, 3H), 7.38 (d, IH), 7.27 (s, IH), 6.80 (s, IH), 4.65 (s, 4H), 3.43 (s, 3H). Example 197 3,4-dichloro-N-(4-cvano-3-(l-naphthyl)benzvP-N-((l-methyl-lH-imidazol-5- yPmethyPbenzamide The desired product was prepared by substituting 3,4-dichlorobenzoic acid for 4- cyanobenzoic acid in Example 196. MS CAPCIC+)) m/z 525, 526, 527 and 528 (M+H)+;
*H NMR (500 MHz, DMSO-d6) δ 8.03 (d, IH), 8.02 (d, IH), 7.89 (d, IH), 7.64-7.60 (m, 3H), 7.57 (dt, IH), 7.51 (dt, IH), 7.45-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.28 (s, IH), 6.80 (s, IH), 4.66 (s, 4H), 3.44 (s, 3H).
Example 198 4-chloro-N-(4-cyano-3-(l -naphthvPbenzvP-3-fluoro-N-(( 1 -methyl- lH-imidazol-5- yPmethvPbenzamide The desired product was prepared by substituting 4-chloro-3-fluorobenzoic acid, for
4-cyanobenzoic acid in Example 196. MS CAPCI(+)) m/z 509, 510, 511 and 512 (M+H)+;
*H NMR (500 MHz, DMSO-d6) δ 8.03 (d, IH), 8.02 (d, IH), 7.89 (d, IH), 7.63-7.55 (m, 3H), 7.50 (dt, IH), 7.46-7.42 (m, 4H), 7.39 (d, IH), 7.28 (s, IH), 7.25 (dd, IH), 6.80 (s, IH), 4.66 (s, 2H), 4.65 (s, 2H), 3.44 (s, 3H).
Example 199 5,6-dichloro-N-(4-cyano-3-( 1 -naphthypbenzyl)-N-(( 1 -methyl- lH-imidazol-5- yPmethvPnicotinamide The desired product was prepared by substituting 5,6-dichloronicotinic acid for 4- cyanobenzoic acid in Example 196. MS (APCI(+)) m z 526, 527, 528 and 529 (M+H)+;
1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, IH), 8.14 (d, IH), 8.03 (d, IH), 8.02 (d, IH), 7.89 (d, IH), 7.62 (dt, IH), 7.57 (dt, IH), 7.49 (dt, IH), 7.47-7.44 (m, 3H), 7.39 (d, IH), 7.31 (s, IH), 6.82 (s, IH), 4.70 (s, 4H), 3.45 (s, 3H).
Example 200 5-(((4-cvanobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethyl)-2 -formyl(l,r-biphenyP-2- carbonitrile hydrochloride
Example 200A 2-bromo-4-formylbenzonitrile A solution of compound 87C (5.1 g, 20.0 mmol) in dichloromethane (150 mL) at -100 °C was treated dropwise with IM DIBAL-H in toluene (26.0 mL, 26.0 mmol), stirred for 30 minutes, treated with methanol (20 mL), stirred for 10 minutes, treated with saturated potassium sodium tartrate, warmed to room temperature, extracted with ethyl acetate, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:l/hexanes:ethyl acetate to provide the desired product. 1H NMR (300 MHz, CDC13) δ 10.04 (s, IH), 8.17 (d, IH), 7.93 (dd, IH), 7.86 (d, IH).
Example 200B 2-bromo-4-(hydroxy(l-methyl-lH-imidazol-5-yPmethvPbenzonitrile
A solution of Example 87F (2.59 g, 13.2 mmol) in THF (40 mL) at-78 °C was treated dropwise with 1.7M tert-butyllithium in pentane (7.06 mL, 12.0 mmol), stirred for 30 minutes, treated with a solution of Example 200A (2.1 g, 10.0 mmol) in THF (10 mL), stined for 1 hour, treated with methanol (10 mL), stirred for 20 minutes, treated with saturated ammonium chloride (100 mL), warmed to room temperature, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 92:5:3/ethyl acetate:methanol: triethylamine to provide the desired product. MS CAPCIC+)) m/z 292 and 294 (M+H)+; 1H NMR (300 MHz, CDCI3) δ 7.94 (d, IH), 7.86 (s, IH), 7.57 (dd, 2H), 6.41 (s, IH), 6.25 (d, IH), 5.91 (d, IH), 3.56 (s, 3H).
Example 200C 2-bromo-4-(((4-cvanobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyPbenzonitrile A solution of Example 200B (2.48 g, 8.5 mmol) and 4-cyanobenzyl bromide (2.50 g,
12.8 mmol) in dichloromethane (60 mL) at room temperature was treated with silver(I) oxide (7.8 g, 34 mmol), stined for 16 hours in darkness, filtered through a pad of diatomaceous earth (Celite®) with methanol and concentrated. The concentrate was purified by flash column chromatography on silica gel with 92:5:3/ethyl acetate:methanol:triethylamine to provide the desired product.
MS CAPCIC+)) m/z 407 and 409 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 7.76 (s, IH), 7.72-7.67 (m, 4H), 7.45-7.41 (m, 3H), 7.03 (br s,
IH), 5.61 (s, IH), 4.65 (d, IH), 4.57 (d, IH), 3.44 (s, 3H).
Example 200D
5-(((4-c yanobenzvPoxyX 1 -methyl- lH-imidazol-5-yl)methvP-2'-formyl( 1 , 1 '-biphenyl)-2- carbonitrile hydrochloride A solution of Example 200C (30 mg, 0.074 mmol) and 2-formyTphenylboronic acid (13 mg, 0.085 mmol) in n-propanol (0.5 mL) was treated with Pd(OAc)2 (1.5 mg), triphenylphosphine (4.5 mg), 2.0M Na2CO3 (0.044 mL), and water (0.25 mL), heated to 100 °C, stined for 3 hours, and extracted with ethyl acetate. The extract was concentrated and the concentrate was purified by preparative HPLC to provide the desired product. MS (APCI(+)) m/z 433 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9. SI (d, IH), 9.08 (s, IH), 8.10-8.03 (m, 2H), 7.86-7.75 (m, 3H), 7.75-7.73 (m, 2H), 7.60-7.50 (m, 4H), 7.41 (br s, IH), 6.12 (s, IH), 4.75 (d, IH), 4.66 (d, IH), 3.76 (s, 3H).
Example 201 5-(((4-cyanobenzvDoxyX 1 -methyl- lH-imidazol-5-vPmethvP-2'-(trifluoromethyP( 1 , 1 '- biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting 2-trifluoromethylphenylboronic acid for 2-formylphenylboronic acid in Example 200D. MS (APCIC+)) m/z 473 (M+H)+;
XH NMR (300 MHz, DMSO-d6) (rotamers) δ 9.07 and 9.05 (2s, IH each), 8.08 (t, IH), 7.92 (t, IH), 7.84-7.82 (m, 2H), 7.77-7.40 (m, 2H), 7.60-7.50 (m, 4H), 7.38 (d, IH), 6.13 (s, IH), 4.74 (dd, IH), 4.63 and 4.60 (2d, IH each), 3.72 and 3.70 (2s, 3H each).
Example 202 2\4'-dichloro-5-(((4-cvanobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyP(l,r-biphenyP-2- carbonitrile hydrochloride The desired product was prepared by substituting with 2,4-dichlorophenylboronic acid for 2-formylphenylboronic acid in Example 200D. MS (APCIC+)) m/z 473 (M+H)+;
XH NMR (300 MHz, DMSO-d6) (rotamers) δ 9.05 (s, IH), 8.09 (d, IH), 7.85-7.75 (m, 3H), 7.74 (dd, IH), 7.65-7.45 (m, 5H), 7.41 (s, IH), 6.13 (s, IH), 4.75 (d, IH), 4.65 and 4.61 (2d, IH each), 3.73 (s, 3H).
Example 203 2-(l-benzothien-2-yP-4-(((4-cvanobenzvPoxy)d-methyl-lH-imidazol-5- yPmethvPbenzonitrile hydrochloride The desired product was prepared by substituting benzothiophene-2-boronic acid for 2-formylphenylboronic acid in Example 200D. MS (APCIC+)) m/z 461 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 9.06 (s, IH), 8.12 (d, IH), 8.07 (t, IH), 8.00 (d, IH), 7.96 (s, IH), 7.87 (s, IH), 7.85 (d, 2H), 7.70 (d, IH), 7.60 (d, 2H), 7.49-7.45 (m, 2H), 7.43 (s, IH), 6.16 (s, IH), 4.78 (d, IH), 4.66 (d, IH), 3.74 (s, 3H).
Example 204
5-(((4-cyanobenzyPoxy)(l-methyl-lH-imidazol-5-vPmethyP-2'-(hvdroxymethvP(l, - biphenvP-2-carbonitrile A solution of Example 200D (55 mg) in THF (1 mL) at room temperature was treated with a solution of CaCl2 (30 mg) in ethanol (1 mL) and NaBEL (19 mg), stirred for 3 hours, and filtered. The filtrate was purified by preparative HPLC to provide the desired product. MS (DCI/NH3) m/z 435 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, 2H), 7.83 (d, 3H), 7.60-7.20 (m, 8H), 6.59 (s, IH), 5.91 (s, 2H), 4.65 (d, IH), 4.57 (d, IH), 3.74 (s, 3H).
Example 205
2"-cyano-5'-(((4-cyanobenzyPoxy)(l-methyl-lH-imidazol-5-vPmethvP(l, -biphenyP-2- carboxylic acid A solution of Example 200D (50 mg) in acetone (2 mL) at room temperature was titrated with 2M CJ.O3 in concentrated H2SO (Jones' reagent) until the orange endpoint, stined for 16 hours, and concentrated. The concentrate was purified by preparative HPLC and lyophilized to provide the desired product. MS (DCI/NH3) m/z 449 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.88-7.79 (m, 5H), 7.60-7.27 (m, 8H), 6.16 (s, IH), 4.61 (d, IH), 4.55 (d, IH), 3.74 (s, 3H).
Example 206 4-cvano-N-(4-cyanobenzvP-N-((l-methyl-lH-imidazol-5-vPmethyP-3-(8- quinolinypbenzamide
Example 206A
3-bromo-4-cyanobenzoic acid A solution of Example 87C (150 mg) in methanol (3 mL) and water (1 mL) was treated with LiOH (80 mg) and stirred for 2 hours. The solution was adjusted to pH 2 with IM HCl, then extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m z 243 and 245 (M+NH4)+; *H NMR (300 MHz, CDC13) δ 8.40 (d, IH), 8.13 (dd, IH), 7.79 (d, IH).
Example 206B 3-bromo-4-cyano-N-(4-cvanobenzyl)-N-((l-methyl-lH-imidazol-5-vPmethyPbenzamide A solution of Example 206 A (27 mg) and Example 191 A (25 mg) in dichloromethane
(1 mL) at room temperature was treated with diisopropylethylamine (63 mL) and bromotris(pyrrolidino)phosphonium hexafluorophosphate (53.5 mg) and stined for 16 hours. The mixture was purified by preparative HPLC and lyophilized to provide the desired product. MS (APCI(+)) m/z 434 and 436 (M+H)+.
Example 206C 4-cyano-N-(4-cyanobenzvP-N-((l-methyl-lH-imidazol-5-yPmethyP-3-(8- quinolinvPbenz amide A solution of Example 206B (10 mg) and 8-quinolinylboronic acid (8.0 mg) in n-propanol (0.8 mL) and water (0.4 mL) was treated with Pd(OAc)2 (1.0 mg), triphenylphosphine (3.0 mg), and 2M Na2CO3 (15 mL), heated to 90 °C, and stined for 2 hours. The mixture was purified by preparative HPLC and lyophilized to provide the desired product. MS (APCI(-)) m/z 517 (M+Cl)";
XH NMR (300 MHz, DMSO-d6, at 90 °C) δ 8.92 (s, IH), 8.79 (dd, IH), 8.45 (dd, IH), 8.12 (dd, IH), 7.96 (d, IH), 7.71-7.39 (m, 10H), 4.77 (s, 2H), 4.74 (s, 2H), 3.74 (s, 3H).
Example 210 5-( 1 -(benzyloxy)-2-( lH-imidazol- 1 -vDethvP-2'-methyl(l , 1 '-biρhenvP-2-carbonitrile hydrochloride
Example 210A 2'-methyl-5-(2-oxiranyP(l , 1 '-biphenvD-2-carbonitrile A solution of Example 861 (0.5 g, 2.26 mmol) in acetonitrile/water (30:1) was treated with trimethylsulfonium iodide (0.48 g, 2.32 mmol) and potassium hydroxide (0.226 g, 4.52 mmol), heated to 60 °C, stined for 4 hours, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:l/hexanes:ethyl acetate to provide the desired product.
Example 210B 5-( 1 -hydroxy-2-( lH-imidazol- 1 -yPethvP-2'-methyl(l , 1 '-biphenvP-2-carbonitrile A solution of Example 210A (0.39 g, 1.65 mmol) in ethanol (15 mL) was treated with imidazole (0.121 g, 1.82 mmol) and catalytic pyridine, heated to reflux for 12 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/dichloromethane:methanol to provide the desired product.
Example 210C 5-(l-(benzyloxy)-2-(lH-imidazol-l-vPethyP-2'-methyl(l,r-biphenvP-2-carbonitrile hydrochloride The free base of the desired product was prepared by substituting Example 21 OB for Example 5D in Example 5E. The purified concentrate was treated with IM HCl in diethyl ether and concentrated to provide the desired product. MS (ESI(+)) m/z 394 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 9.0 (s, IH), 8.05 (d, IH), 7.63 (s, 2H), 7.43 (s, IH), 7.4-7.2 (m, 9H), 7.2-7.1 (m, 2H), 5.1-5.0 (m, IH), 4.6-4.5 (m, 2H), 4.49 (d, IH), 4.43 (m, IH), 2.15 (s, 3H).
Example 211 5-(h vdroxy(3-pyridinvPmethvP-2 -methyld , 1 -biphenyP-2-carbonitrile The desired product was prepared by substituting 3-bromopyridine for Example 87F in Example IB.
MS (ESI(+)) m/z 301 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, IH), 8.45 (dd, IH), 7.90 (d, IH), 7.77 (dd, IH), 7.61 (dd, IH), 7.52 (s, IH), 7.40-7.25 (m, 4H), 7.21 (d, IH), 6.35 (d, IH), 5.93 (d, IH), 2.08 (s, 3H); Anal, calcd for C20Hι6N2O-0.2 H2O: C, 79.03; H, 5.44; N, 9.22. Found: C, 79.15; H, 5.55; N, 8.99.
Example 212 2'-methyl-5-((3-pyridinylamino)methvP(l, -biphenyP-2-carbonitrile The desired product was prepared by substituting 3-aminopyridine for picolylamine in
Example 215A.
MS (ESI(+)) m/z 300 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.97 (d, IH), 7.91 (d, IH), 7.76 (dd, IH), 7.43 (s, IH),
7.40-7.25 (m, 3H), 7.20 (d, IH), 7.04 (dd, IH), 6.9-6.8 (m, IH), 6.64 (t, IH), 4.45 (d, 2H), 2.04 (s, 3H);
Anal, calcd for C20Hι7N3-0.3 H2O): C, 78.82; H, 5.82; N, 13.79. Found: C, 79.19; H, 5.96;
N, 13.41. Example 213 5-((benzyloxy)d,3-thiazol-5-vPmethyP-2 -methyl(l, -biphenvP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 214 for Example 5D in Example 5E.
MS (ESI(+)) m/z 397 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, IH), 8.0-7.9 (m, 2H), 7.66 (dd, IH), 7.50 (s, IH), 7.5-7.2 (m, 9H), 6.15 (s, IH), 4.57 (s, 2H), 2.09 (s, 3H).
Example 214 5-(hvdroxy(l,3-thiazol-5-yPmethyP-2'-methyl(l,l -biphenyP-2-carbonitrile The desired product was prepared by substituting 2-trimethylsilylthiazole for Example 87F in Example IB. MS (ESI(+)) m/z 307 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, IH), 7.94 (d, IH), 7.79 (s, IH), 7.63 (dd, IH), 7.50 (s, IH), 7.40-7.25 (m, 3H), 7.22 (d, IH), 6.69 (d, IH), 6.23 (d, IH), 2.10 (s, 3H); Anal, calcd for C18Hι4N2SO-0.2 H2O: C, 69.74; H, 4.68; N, 9.04. Found: C, 69.78; H, 4.79; N, 8.82.
Example 215 5-((benzyl(3-pyridinylmethvPamino)methvP-2'-methyl(l, -biphenvP-2-carbonitrile hydrochloride
Example 215 A
5-((3-pyridinylmethyPamino)methyl-2'-methyl(l,r-biphenvP-2-carbonitrile A solution of Example 861 (0.2 g, 0.9mmol) in 1,2-dichloroethane (10 mL) at room temperature was treated with picolylamine (0.12 g, l.Ommol), acetic acid (3.6mmol), and sodium (triacetoxy)borohydride, stined for 16 hours, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was washed with water and brine, dried filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 97:3/dichloromethane:methanol to provide the desired product.
Example 215B 5-((benzyl(3-pyridinylmethvPamino)methyP-2'-methyl(l, -biphenvP-2-carbonitrile hydrochloride The free base of the desired product was prepared by substituting benzaldehyde and Example 215 A for Example 861 and picolylamine, respectively, in Example 215 A. The purified concentrate was treated with IM HCl in diethyl ether and concentrated to provide the desired product. MS CESIC+)) m/z 404 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.9 (br s, IH), 8.80 (d, IH), 8.57 (d, IH), 7.90 (d, 2H), 7.4- 7.3 (m, 8H), 7.17 (d, IH), 3.7-3.5 (m, 6H), 2.10 (s, 3H).
Example 216 2 -methyl-5 -((3 -pyridinylmethyPamino) (1,1 '-biphenyp-2-carbonitrile
The desired product was prepared by substituting 3-pyridinecarboxaldehyde and Example 225B for Example 861 and picolylamine, respectively, in Example 215 A. MS (ESI(-)) m/z 298 (M-H)"; MS (ESI(+)) m/z 300 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, IH), 8.47 (d, IH), 7.73 (d, IH), 7.52 (d, IH), 7.4- 7.2 (m, 5H), 7:12 (d, IH), 6.61 (d, IH), 6.5 (s, IH), 4.43 (d, 2H), 2.05 (s, 3H).
Example 217 5-(benzyl(3-pyridinylmethvPamino)-2 -methyld , 1 '-biphenvD-2-carbonitrile A solution of Example 216 (206 mg, 0.69 mmol) in THF at 0 °C was treated dropwise with IM potassium tert-butoxide in THF (750 μL, 0.75 mmol), stined for 30 minutes, treated with benzyl bromide (132 mg, 0.75 mmol), warmed to room temperature, stined for 16 hours, treated with water, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m/z 390 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.5-8. 4 (m, 2H), 7.65-7.55 (m, 2H), 7.4-7.2 (m, 8H), 7.08 (d, IH), 6.83 (d, IH), 6.55 (s, IH), 4.9-4.8 (br m, 4H), 2.89 (s, 3H).
Example 218 4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methvPbenzonitrile hydrochloride
Example 218 A 4-(hydroxyd-methyl-lH-imidazol-5-yPmethyl)benzonitrile
The desired product was prepared by substituting 4-cyanobenzaldehyde for Example 1A in Example IB. Example 218B 4-((benzyloxy)(l-methyl-lH-imidazol-5-yl)methvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 218 A for Example 21 OB in Example 210C .
MS (ESI(+)) m/z 304 (M+H)+;
!H NMR C300 MHz, DMSO-d6) δ 9.15 (s, IH), 7.97 (d, 2H), 7.67 (d, 2H), 7.4-7.3 (m, 6H), 6.05 (s, IH), 4.55 (m, 2H), 3.74 (s, 3H);
Anal, calcd for C19H17N3O-O.8 H2O: C, 64.42; H, 5.58; N, 11.86. Found: C, 64.44; H, 5.62; N, 11.01.
Example 219 4-((( 1 -methyl- lH-imidazol-5-yP(phenyPmethoxy)methyPbenzonitrile hydrochloride
Example 219A d-methyl-lH-imidazol-5-ylXphenyDmethanol The desired product was prepared by substituting benzaldehyde for Example 1 A in Example IB.
Example 219B
4-((( 1 -methyl- lH-imidazol-5-vP(ρhenyPmethoxy)methyPbenzonitrile hydrochloride The desired product was prepared by substituting Example 219 A and 4-cyanobenzyl bromide for Example 210B and benzyl bromide, respectively, in Example 210C. MS (ESI(+)) m/z 304 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, IH), 7.84 (d, 2H), 7.57 (d, 2H), 7.5-7.4 (m, 5H), 7.34 (s, IH), 5.95 (s, IH), 4.63 (m, 2H), 3.74 (s, 3H);
Anal, calcd for Cι9Hι7N3O-1.0 H2O: C, 63.77; H, 5.63; N, 11.74. Found: C, 63.99; H, 5.60; N, 10.68.
Example 220
5-d-(benzyloxy)-2-(l-methyl-lH-imidazol-2-vPethvP-2 -methyld, l -biphenvP-2- carbonitrile hydrochloride
Example 220A 5 -(hydroxy( 1 -methyl- lH-imidazol-5 -yl)methyP-2 -methyK 1 , 1 '-biphenyP-2-carbonitrile
The desired product was prepared by substituting 1,2-dimethylimidazole for Example 87F in Example IB. Example 220B 5-(l -( benzyloxy)-2-( 1 -methyl- lH-imidazol-2-vPethvP-2 -methvK 1 , 1 -biρhenyl)-2- carbonitrile hydrochloride The desired product was prepared by substituting Example 220A for Example 210B in Example 2 IOC. MS (ESI(+)) m/z 408 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.05 (d, IH), 7.7-7.1 (m, 14H), 5.05-4.95 (m, IH), 4.38 (m, 2H), 3.71 (s, 3H), 2.13 (s, 3H), 14.43 (br s, IH); Anal, calcd for C27H26N3OCl-1.25 H2O: C, 69.51; H, 6.15; N, 9.00. Found: C, 69.61; H, 5.96; N, 8.23.
Example 221 5-((benzyloxyX 1 -methyl- lH-imidazol-2-yl)methvP-2 VmethyK 1 , 1 -biphenyP-2-carbonitrile hydrochloride
Example 221A 5-(hyc3joxy(l-methyl-lH-imidazol-2-yPmethyP-2 -methyl(l, -biphenyP-2-carbonitrile The desired product was prepared by substituting 1-methylimidazole for Example 87F in Example IB.
Example 22 IB 5-((benzyloxy)( 1 -methyl- lH-imidazol-2-yPmethvP-2'-methyl( 1 , 1 -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 221 A for Example 210B in Example 2 IOC. MS (ESI(+)) m/z 394 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.06 (d, IH), 7.7-7.5 (m, 4H), 7.4-7.2 (m, 9H), 6.41 (s, IH), 4.69 (s, 2H), 3.77 (s, 3H), 2.11 (s, 3H).
Example 222 5-( lH-imidazol- 1 - ylmethyp-2 -methvK 1 , 1 '-biphenyP-2-carbonitrile hydrochloride A suspension of Example 20A (200 mg, 0.7 mmol) in DMF (5 mL) was treated with imidazole (57 mg, 0.84 mmol) and K2CO3 (193 mg, 1.4 mmol), heated to 50 °C, stined for 2 hours, treated with ethyl acetate, washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/dichloromethane:methanol, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 274 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.35 (s, IH), 8.02 (d, IH), 7.86 (t, IH), 7.73 (t, IH), 7.65- 7.55 (m, 2H), 7.5-7.3 (m, 3H), 7.23 (d, IH), 5.59 (s, 2H), 2.11 (s, 3H);
Anal, calcd for d8Hι6N3Cl-0.9 H2O: C, 66.32; H, 5.50; N, 12.89. Found: C, 66.45; H, 5.67; N, 11.74.
Example 223 4-((( 1 -methyl- lH-imidazol-5-yP(3-(l -naphthyPphenvPmethoxy)methyl)benzonitrile
The desired product was prepared by substituting 4-(bromomethyl)benzonitrile for benzyl bromide in Example 224C. MS (ESI(+)) m/z 430 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.0-7.9 (m, 2H), 7.9-7.7 (m, 3H), 7.6-7.4 (m, 11H), 6.61 (s, IH), 5.87 (s, IH), 4.65 (m, 2H), 3.57 (s, 3H);
Anal, calcd for C29H23N3O-0.25 H2O: C, 80.25; H, 5.45; N, 9.68. Found: C, 80.02; H, 5.56; N, 9.56.
Example 224 benzyl (l-methyl-lH-imidazol-5-vP(3-d-naphthyPphenypmethyl ether hydrochloride
Example 224A 3-d -naphthyPbenzaldehyde The desired product was prepared by substituting 3-bromobenzaldehyde and 1- naphthylboronic acid for 3-bromo-4-fluorobenzaldehyde and 2-methylphenylboronic acid, respectively, in Example 1 A.
Example 224B (l-methyl-lH-imidazol-5-yl)(3-(l-naphthyPphenyPmethanol The desired product was prepared by substituting Example 224A for Example 1 in
Example IB.
Example 224C benzyl (l-methyl-lH-imidazol-5-yP(3-(l-naphthvPphenyPmethyl ether hydrochloride The desired product was prepared by substituting Example 224B for Example 5D in
Example 5E. MS (ESI(+)) m/z 405 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, IH), 7.97 (d, IH), 7.79 (d, IH), 7.6-7.4 (m, 9H), 7.40-7.25 (m, 5H), 6.56 (s, IH), 5.81 (s, IH), 4.54 (m, 2H), 3.56 (s, 3H); Anal, calcd for C28H24N2O-0.5 H2O: C, 81.15; H, 5.89; N, 6.56. Found: C, 81.32; H, 6.09; N, 6.77.
Example 225 2 -methyl-5-(((l-methyl-lH-imidazol-5-yPmethvPamino)(l, -biphenvP-2-carbonitrile
Example 225A 6-cyano-2'-methyl(l,r-biphenvD-3-carboxyιic acid
A solution of Example 86H (2.0 g, 8.9 mmol) in acetone (25 mL) at 0 °C was titrated with Jones' reagent, stined for 30 minutes, treated with iso-propanol and concentrated to 1/3 its original volume treated with water (200 mL) while stirring vigorously, then filtered and dried in a vacuum oven to provide the desired product.
Example 225B 3-((tert-butoxycarbonyl)amino-6-cvano-2 -methyl-1 , 1 -biphenyl A solution of Example 225A (2.16 g, 9.11 mmol) in tert-butanol (30 mL) was treated with diphenylphosphoryl azide (1.96 mL, 9.11 mmol) and triethylamine (1.3 mL, 9.11 mmol), heated to reflux, stined for 21 hours, cooled to room temperature, and concentrated. The concentrate was treated with ethyl acetate (50 mL), washed sequentially with water, 5% citric acid , water, 5% NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 85:15/hexanes:ethyl acetate, to provide the desired product.
Example 225C 5-amino-2 -methyld, r-biphenvp-2-carbonitrile A solution of Example 225B in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL), stirred for 45 minutes, and concentrated under a nitrogen atmosphere. The concentrate was treated with ethyl acetate, washed with saturated NaHCO3 and brine; dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 60:40/hexanes:ethyl acetate to provide the desired product.
Example 225D l-methyl-2-triethylsilylimidazole-5-carboxaldehyde A solution of Example 87F (1 g, 5.10 mmol) in THF (20 mL) at -78 °C was treated dropwise with 1.7M tert-butyllithium in hexanes (3 mL, 5.10 mmol), stined for 10 minutes, treated slowly with N-formylmorpholine, stined for 1 hour, treated with saturated NaHCO3 and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
Example 225E 2'-methyl-5-(((l-methyl-lH-irmdazol-5-yPmethyPamino)(l, -biphenvP-2-carbonitrile A solution of Example 225C (100 mg, 0.48 mmol) in 1,2-dichloroethane (5 mL) at room temperature was treated with Example 225D (215 mg, 0.96 mmol), (triacetoxy)borohydride (283 mg, 1.33 mmol), and acetic acid (136 μL, 2.38 mmol), stined for 16 hours, treated with saturated NaHCO3 and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m/z 303 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 7.6-7.5 (m, 2H), 7.4-7.2 (m, 3H), 7.16 (d, IH), 7.06 (t, IH), 6.85 (d, IH), 6.76 (dd, IH), 6.58 (d, IH), 4.32 (d, 2H), 3.60 (s, 3H), 2.13 (s, 3H); Anal, calcd for d9H18N4-0.75 H2O: C, 72.24; H, 6.22; N, 17.73. Found: C, 72.50; H, 5.97; N, 17.17.
Example 226 5-(benzyl((l-methyl-lH-imidazol-5-yPmethyPamino)-2'-methyl(l, -biphenvP-2-carbonitrile A solution of Example 225E (100 mg, 0.33 mmol) in THF (2 mL) at room temperature was treated dropwise with IM potassium tert-butoxide in THF (500 μL, 0.50 mmol) and benzyl bromide (50 mL, 0.42 mmol), sealed in a screw-cap vial, heated to 50 °C, stined for 3 hours, cooled to room temperature, treated with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 96:4/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m/z 393 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.60 (d, IH), 7.55 (d, IH), 7.40-7.15 (m, 8H), 7.11 (d, IH), 6.89 (dd, IH), 6.7-6.6 (m, 2H), 4.9-4.7 (m, 4H), 3.56 (s, 3H), 1.94 (s, 3H); Anal, calcd for C26H 4N4-0.25 H2O: C, 78.65; H, 6.22; N, 14.11. Found: C, 78.71; H, 6.24; N, 13.88. Example 227 4-(methyl(d -methyl- 1 H-imidazol-5 -yPmeth vPamino)-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting methyl iodide for benzyl bromide in Example 232. MS (ESI(+)) m/z 353 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.02 (d, 2H), 7.72 (d, IH), 7.6-7.4 (m, 6H), 7.01 (dd, IH), 6.88 (d, IH), 6.66 (s, IH), 4.67 (m, 2H), 3.54 (s, 3H), 3.02 (s, 3H);
Anal, calcd for C23H20N4-1.0 H2O: C, 74.57; H, 5.98; N, 15.12. Found: C, 74.55; H, 5.85; N, 13.83.
Example 228 4-(allyl((l-methyl-lH-imidazol-5-vDmethvDamino)-2-(l-naphthyl)benzonitrile The desired product was prepared by substituting allyl bromide for benzyl bromide in Example 232. MS (ESI(+)) m/z 379 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, 2H), 7.70 (d, IH), 7.6-7.4 (m, 6H), 7.00 (dd, IH), 6.85 (d, IH), 6.69 (s, IH), 5.85-5.75 (m, IH), 5.2-5.1 (m, 2H), 4.66 (m, 2H), 4.07 (dd, 2H), 3.54 (s, 3H);
Anal, calcd for C25H22N4-0.5 H2O: C, 77.49; H, 5.98; N, 14.45. Found: C, 77.50; H, 6.00; N, 14.14.
Example 229 5-((4-cyanobenzyl)(( 1 -methyl- lH-imidazol-5-vDmethvDamino)-2 -methvK 1 , 1 -biphenyP-2- carbonitrile The desired product was prepared by substituting 4-(bromomethyl)benzonitrile for benzyl bromide in Example 226. MS (ESI(+)) m/z 418 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.81 (d, 2H), 7.63 (d, IH), 7.55 (s, IH), 7.38 (d, 2H), 7.35- 7.20 (m, 3H), 7.12 (d, IH), 6.88 (dd, IH), 6.7-6.6 (m, 2H), 4.82 (br s, 4H), 3.55 (s, 3H), 1.94 (s, 3H);
Anal, calcd for C27H23N5-O.4 H2O: C, 76.36; H, 5.65; N, 16.49. Found: C, 76.40; H, 5.58; N, 16.17.
Example 230 4-(((l-methyl-lH-imidazol-5-vPmethyp(3-phenylpropyPamino)-2-(l-naphthvPbenzonitrile The desired product was prepared by substituting l-bromo-3-phenylpropane for benzyl bromide in Example 232. MS (ESI(+)) m/z 457 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.02 (d, 2H), 7.7-7.4 (m, 7H), 7.2-7.0 (m, 5H), 6.94 (dd, IH), 6,72 (d, IH), 6.61 (s, IH), 4.64 (m, 2H), 3.52 (s, 3H), 3.5-3.3 (m, 2H), 2.6-2.5 (m, 2H), 1.75-1.90 (m, 2H).
Example 231 4-((4-cyanobenzvP(( 1 -methyl- lH-imidazol-5-yDmethyl)amino)-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting 4-(bromomethyl)benzonitrile for benzyl bromide in Example 232. MS (ESI(+)) m/z 454 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 7.99 (d, 2H), 7.81 (d, 2H), 7.72 (d, IH), 7.6-7.5 (m, 3H), 7.5-7.3 (m, 5H), 6.99 (dd, IH), 6.80 (d, IH), 6.71 (s, IH), 5.0-4.7 (m, 4H), 3.54 (s, 3H); Anal, calcd for C30H23N5-0.75 H2O: C, 77.14; H, 5.28; N, 14.99. Found: C, 77.32; H, 5.31; N, 14.66.
Example 232 4-(benzyl((l -methyl- lH-imidazol-5-yDmethyDamino)-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 234 for Example 225E in Example 226. MS (ESI(+)) m/z 429 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, 2H), 7.70 (d, IH), 7.6-7.2 (m, 1 IH), 7.00 (dd, IH), 6.84 (d, IH), 6.71 (s, IH), 4.83 (m, 2H), 4.74 (m, 2H), 3.54 (s, 3H);
Anal, calcd for C29H24N4-0.5 H2O: C, 79.60; H, 5.75; N, 12.80. Found: C, 79.80; H, 5.79; N, 12.68.
Example 233 4-(hexyl((l-methyl-lH-imidazol-5-yDmethyDamino)-2-(l-naphthvDbenzonitrile The desired product was prepared by substituting hexyl iodide for benzyl bromide in Example 232. MS (ESI(+)) m/z 423 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.01 (d, 2H), 7.7-7.4 (m, 7H), 6.96 (dd, IH), 6.81 (d, IH), 6.64 (s, IH), 4.63 (m, 2H), 3.53 (s, 3H), 3.5-3.3 (m, 2H), 1.6-1.4 (m, 2H), 1.3-1.2 (m, 6H), 0.9-0.7 (m, 3H);
HRMS calcd m/z for C28H3ιN4: 423.2549 (M+H)+. Found: 423.2551.
Example 234 4-((( 1 -methyl- lH-imidazol-5-yPmethyPamino)-2-( 1 -naphthyDbenzonitrile Example 234A tert-butyl 4-cyano-3-(l-naphthvPphenylcarbamate The desired product was prepared by substituting Example 191B for Example 225A in Example 225B.
Example 234B 4-amino-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 234A for Example 225B in Example 225C.
Example 234C 4-((( 1 -methyl- lH-imidazol-5-yDmethyDamino)-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 234B for Example 225C in Example 225E.
MS (ESI(+)) m/z 339 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.01 (d, 2H), 7.7-7.4 (m, 6H), 7.12 (t, IH), 6.9-6.8 (m, 2H), 6.74 (d, IH), 4.34 (d, 2H), 3.60 (s, 3H);
Anal, calcd for C20Hι8N4O2-1.25 H2O: C, 73.21; H, 5.72; N, 15.52. Found: C, 73.07; H, 5.43; N, 14.84.
Example 235 N-(4-cvano-3-(l-naphthvPphenvP-N-((l-methyl-lH-imidazol-5-vPmethyPbenz amide The desired product was prepared by substituting benzoyl chloride for benzyl bromide in Example 232.
MS (ESI(+)) m/z 443 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.00 (dd, 2H), 7.95 (d, IH), 7.6-7.3 (m, 10H), 7.24 (d, IH), 7.13 (d, IH), 6.72 (s, IH), 6.64 (d, IH), 5.24 (s, 2H), 3.59 (s, 3H);
Anal, calcd for C29H22N4O-0.75 H2O: C, 76.38; H, 5.19; N, 12.28. Found: C, 76.58; H, 5.23; N, 12.08.
Example 236 N-(6-cvano-2'-methyl(l,l'-biphenvP-3-vP-N-((l-methyl-lH-imidazol-5- yPmethyPbenzamide The desired product was prepared by substituting benzoyl chloride for benzyl bromide in Example 226. MS (ESI(+)) m/z 407 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 7.82 (d, IH), 7.51 (s, IH), 7.4-7.2 (m, 9H), 7.05 (d, IH), 6.92 (d, IH), 6.68 (s, IH), 5.21 (s, 2H), 3.58 (s, 3H), 1.73 (s, 3H);
Anal, calcd for C20Hι8N4O2-0.5 H2O: C, 75.16; H, 5.57; N, 13.48. Found: C, 75.40; H, 5.63; N, 13.40.
Example 237 5-((3-cyanobenzyP(( 1 -methyl- lH-imidazol-5-yPmethyPamino)-2'-methyl( 1 , 1 -biphenyP-2- carbonitrile The desired product was prepared by substituting 3-(bromomethyl)benzonitrile for benzyl bromide in Example 226. MS (ESI(+)) m/z 418 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 7.8-7.5 (m, 6H), 7.35-7.20 (m, 3H), 7.12 (d, IH), 6.90 (dd, IH), 6.7-6.6 (m, 2H), 4.9-4.7 (m, 4H), 3.85 (s, 3H), 1.94 (s, 3H);
Anal, calcd for C27H23N5-0.75 H2O: C, 75.23; H, 5.72; N, 16.24. Found: C, 75.38; H, 5.56; N, 16.33.
Example 238 4-((l-methyl-lH-imidazol-5-yPcarbonyP-2-(8-quinolinyPbenzonitrile
Example 238 A
2-bromo-4-((l -methyl- lH-imidazol-5-vPcarbonyPbenzonitrile A solution of Example 200B (250 mg) in dichloromethane(5.0 mL) at room temperature was treated with silver(I) oxide (0.79 g), stined for 16 hours, filtered through a pad of diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/ethyl acetate:methanol to provide the desired product. MS (APCIC+)) m/z 290 and 292 (M+H)+.
Example 238B 4-(d-methyl-lH-imidazol-5-vPcarbonyP-2-(8-quinolinvPbenzonitrile
The desired product was prepared by substituting Example 238 A and 8-quinolinylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (APCIC+)) m/z 338 (M+H)+.
Example 240 4-(((3,4-dichlorobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(8- quinolinyPbenzonitrile dihydrochloride
Example 240A 2-bromo-4-(((3,4-dichlorobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvPbenzonitrile
The desired product was prepared by substituting 3, 4-dichlorobenzyl bromide for 4- cyanobenzyl bromide in Example 200C. MS CAPCIC+)) m/z 450 and 452 (M+H)+.
Example 240B
4-(((3,4-dichlorobenzvPoxy)(l-methyl-lH-imidazol-5-vPmethyl)-2-(8- quinolinvPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 240 A for Example 238 A in Example 238B. MS (APCI(-)) m/z 533, 535, and 537 (M+35 37Cl)";
XH NMR (300 MHz, DMSO-d6) (rotamers) δ 9.13 and 9.11 (2s, IH each), 8.96 (d, IH), 8.54 and 8.51 (2d, IH each), 8.16 and 8.07 (2d, IH each), 7.94-7.36 (m, 8H), 7.09 (d, IH), 6.77 (br s, 0.5H), 6.36 (dd, 0.5H), 6.24 and 6.11 (2s, IH each), 4.75-4.57 (m, 2H), 3.82 and 3.80 (2s, 3H each).
Example 241 4-(((3-fluoro-4-(trifluoromethvPbenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(8- quinolinvPbenzonitrile dihydrochloride
Example 241A
2-bromo-4-(((3-fluoro-4-(trifluoromethyPbenzvPoxy)(l-methyl-lH-imidazol-5- vPmethvPbenzonitrile The desired product was prepared by substituting 4-trifluoromethyl-3-fluoro-benzyl bromide for 4-cyanobenzyl bromide in Example 200C. MS CAPCIC+)) m/z 468 and 470 (M+H)+.
Example 241B 4-(((3-fluoro-4-(trifluoromethyPbenzyPoxy)(l-methyl-lH-imidazol-5-yPmethvP-2-(8- quinolinvPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 241A and 8- quinolinylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (APCI(+)) m/z 517 (M+H)+; MS (APCI(-)) m/z 551 (M+Cl)";
*H NMR (300 MHz, DMSO-d6) (rotamers) δ 9.13 and 9.11 (2s, IH each), 8.96 and 8.94 (2d, IH each), 8.54 and 8.51 (2d, IH each), 8.16 and 8.07 (2d, IH each), 7.96-7.38 (m, 8H), 7.09 (d, IH), 6.77 (br s, 0.5H), 6.36 (dd, 0.5H), 6.25 and 6.12 (2s, IH each), 4.75-4.57 (m, 2H), 3.82 and 3.80 (2s, 3H each).
Example 242 4-(((4-fluoro-3-(1rifluoromethyPbenzvPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2-(8- quinolinvPbenzonitrile dihydrochlori.de
Example 242A 2-bromo-4-(((4-fluoro-3-(trifluoromethyPbenzyPoxy)(l-methyl-lH-imidazol-5- vPmethvPbenzonitrile The desired product was prepared by substituting 3-trifluoromethyl-4-fluoro-benzyl bromide for 4-cyanobenzyl bromide in Example 200C. MS (APCI(+)) m/z 468 and 470 (M+H)+.
Example 242B 4-(((4-fluoro-3-(trifluoromethyPbenzyPoxy)d-methyl-lH-imidazol-5-ypmethvP-2-(8- quinolinvPbenzonitrile dihydrochloride The desired product was prepared by substituting Example 242A and 8- quinolinylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (APCI(+)) m/z 517 (M+H)+; MS (APCI(-)) m/z 551 (M+Cl)";
XH NMR (300 MHz, DMSO-d6) (rotamers) δ 9.16 and 9.11 (2s, IH each), 8.96 and 8.94 (2d, IH each), 8.56 and 8.51 (2d, IH each), 8.16 and 8.07 (2d, IH each), 7.95-7.20 (m, 8H), 7.09 (m, IH), 6.79 (br s, 0.5H), 6.35 (dd, 0.5H), 6.28 and 6.15 (2s, IH each), 4.82-4.64 (m, 2H), 3.83 and 3.81 (2s, 3H each).
Example 243 4-(((4-cvano-3-(8-quinolinvPphenvP(l-methyl-lH-imidazol-5-yPmethoxy)methyl)benzoic acid dihydrochloride
Example 243A methyl 4-(((3-bromo-4-cvanophenvP(l-methyl-lH-imidazol-5-yPmethoxy)methyl)benzoate The desired product was prepared by substituting methyl 4-(bromomethyl)benzoate for 4-cyanobenzyl bromide in Example 200C. MS (APCI(+)) m/z 440 and 442 (M+H)+.
Example 243B
4-(((4-cvano-3-(8-quinolinyPphenyP(l-methyl-lH-imidazol-5-yPmethoxy)methypbenzoic acid dihydrochloride The desired product was prepared by substituting Example 243A and 8- quinolinylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D.
MS (APCIC+)) m/z 475 (M+H)+;
1H NMR (300 MHz, DMSO-d6) (rotamers) δ 9.12 and 9.10 (2s, IH each), 9.00-8.85 (m, IH), 8.51 and 8.49 (2d, IH each), 8.32 (d, IH), 8.11 (d, IH), 7.97-7.48 (m, 8H), 7.09 (m, IH), 6.80 (br s, 0.5H), 6.38 (dd, 0.5H), 6.26 and 6.13 (2s, IH each), 4.82-4.65 (m, 2H), 3.81 and 3.80 (2s, 3H each).
Example 244 6-(((4-cvano-3-(8-quinolinvPphenvPd-methyl-lH-imidazol-5- yPmethoxy)methyl)nicotinamide trihydrochloride
Example 244A 6-(((3-bromo-4-cyanophenvP(l-methyl-lH-imidazol-5-yPmethoxy)methyPnicotinonitrile The desired product was prepared by substituting 6-bromomethyl nicotinonitrile for 4- cyanobenzyl bromide in Example 200C. MS (APCI(+)) m/z 408 and 410 (M+H)+.
Example 244B 6-(((4-cvano-3-(8-quinolinvPphenyl)d -methyl- lH-imidazol-5- yPmethoxy)methvPnicotinamide trihydrochloride The desired product was prepared by substituting Example 244A and
8-quinolinylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D.
MS CAPCI(+)) m/z 475 (M+H)+; MS (APCI(-)) m/z 509 (M+Cl)"; XH NMR (300 MHz, DMSO-d6) (rotamers) δ 9.12 (2s, IH), 9.02-8.74 (m, 2H), 8.59 and 8.50 (2d, IH each), 8.29-7.48 (m, 10H), 6.38 and 6.35 (2s, IH each), 4.88-4.70 (m, 2H), 3.86 and 3.83 (2s, 3H each). Example 245 6-(((4-cyano-3-(8-quinolinyPphenvP(l-methyl-lH-imidazol-5-yl)methoxy)methvPnicotinic acid trihydrochloride
Example 245A methyl 6-(((3-bromo-4-cvanophenyPd-methyl-lH-imidazol-5-yPmethoxy)methyPnicotinate
The desired product was prepared by substituting methyl 6-bromomethyl-nicotinate for 4-cyanobenzyl bromide in Example 200C. MS CAPCIC+)) m/z 441 (M+H)+.
Example 245B 6-(((4-cyano-3-(8-quinolinyPphenvP(l-methyl-lH-imidazol-5-vPmethoxy)methvPnicotinic acid trihydrochloride The desired product was prepared by substituting Example 245A and
8-quinolinylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D.
MS (APCI(+)) m/z 476 (M+H)+; MS (APCI(-)) m/z 510 (M+Cl)"; XH NMR (300 MHz, DMSO-d6) (rotamers) δ 9.12 and 9.11 (2s, IH each), 9.04-8.88 (m, 2H), 8.58 and 8.50 (2d, IH each), 8.31 and 8.25 (2d, IH each), 8.15 and 8.06 (2d, IH each), 7.98- 7.88 (m, IH), 7.78-7.48 (m, 5H), 7.13-7.08 (m, IH), 6.35 (s, IH), 4.91-4.74 (m, 2H), 3.85 and 3.83 (2s, 3H each).
Example 247
6-(((4-cyano-3-(8-quinolinyPphenvPd-methyl-lH-imidazol-5- yPmethoxy)methypnicotinonitrile trihydrochloride A solution of Example 244A (34 mg, 0.084 mmol) and 8-quinolinylboronic acid (23 mg, 0.13 mmol) in 1,2-dimethoxyethane (1.5 mL) was treated with cesium fluoride (32 mg, 0.2 mmol) and Pd(Ph3P)4 (4 mg), purged with argon, heated to 100 °C, stirred for 16 hours, and filtered. The filtrate was purified by HPLC on a Cι8 reverse phase column with acetonitrile/10 mM ammonium acetate, concentrated, lyophilized, dissolved in dichloromethane, treated with IM HCl in diethyl ether, and concentrated to provide the desired product. MS (ESI(+)) m/z 457 (M+H)+ and 489 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, IH), 8.97 (dd, IH), 8.87 (dd, IH), 8.50 (dd, IH), 8.31 (dd, IH), 8.16 (dd, IH), 8.06 (d, IH), 7.87 (dd, IH), 7.79-7.70 (m, 4H), 7.62 (dd, IH), 7.56 (s, IH), 6.22 (s, IH), 4.80 (q, 2H), 3.80 (s, 3H).
Example 248
5-(((3,4-dichlorobenzyPoxy)(l-methyl-lH-imidazol-5-vPmethvP-2'-(trifluoromethyP(l, - biphenyP-2-c arbonitrile hydrochloride The desired product was prepared by substituting Example 240A and 2-(trifluoromethyl)phenylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D.
MS (APCI(-)) m/z 550, 552, and 554 (M+35/37Cl)";
1H NMR (300 MHz, DMSO-d6) (rotamers) δ 8.82 (2s, IH), 8.08 (dd, IH), 7.92 (t, IH), 7.88- 7.80 (m, IH), 7.76-7.67 (m, 2H), 7.63-7.50 (m, 4H), 7.40-7.25 (m, IH), 6.07 (s, IH), 4.66- 4.49 (m, 2H), 3.69 and 3.68 (2s, 3H each)
Example 249 5-(((3-fluoro-4-(trifluoromethvPbenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyp-2'- (trifluoromethvPd,! -biphenyP-2-carbonitrile hydrochloride The desired product was prepared by substituting Example 241 A and 2-(trifluoromethyl)phenylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (APCI(-)) m/z 568 (M+Cl)"; MS CAPCIC+)) m/z 534 (M+H)+;
1H NMR (300 MHz, DMSO-d6) (rotamers) δ 9.03 and 9.01 (2s, IH each), 8.08 (dd, IH), 7.92 (t, IH), 7.84-7.71 (m, 4H), 7.60-7.49 (m, 3H), 7.40-7.36 (m, 2H), 6.14 (s, IH), 4.76 (d, IH), 4.67 and 4.60 (2d, IH each), 3.72 and 3.70 (2s, 3H each).
Example 250 5-(((4-fluoro-3-( fluoromethvPbenzypoxy)(l-methyl-lH-imidazol-5-vPmethvP-2'- (trifluoromethyl)d,l -biphenyP-2-carbonitrile hydrochloride
The desired product was prepared by substituting Example 242A and 2-(trifluoromethyl)phenylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (APCI(-)) m/z 568 (M+Cl)"; MS CAPCIC+)) m/z 534 (M+H)+; 1H NMR (300 MHz, DMSO-d6) (rotamers) δ 9.03 and 9.01 (2s, IH each), 8.08 (dd, IH), 7.94-7.68 (m, 6H), 7.60-7.49 (m, 3H), 7.34 (d, IH), 6.11 (s, IH), 4.78-4.60 (m, 2H), 3.72 and 3.70 (2s, 3H each).
Example 251
6-(((6-cvano-2'-(trifluoromethvD( 1 , 1 -biphenvP-3-vPd -methyl- lH-imidazol-5- yPmethoxy)methyPnicotinonitrile dihydrochloride The desired product was prepared by substituting Example 244A and 2-(trifluoromethyl)phenylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (APCI(-)) m/z 508 (M+Cl)"; MS (APCI(+)) m/z 474 (M+H)+;
!H NMR (300 MHz, DMSO-d6) (rotamers) δ 9.09 and 9.08 (2s, IH each), 8.97 (dd, IH), 8.34-8.31 (m, IH), 8.08 (dd, IH), 7.92 (t, IH), 7.84-7.68 (m, 4H), 7.60-7.59 (m, IH), 7.55- 7.52 (m, IH), 7.43 (d, IH), 6.21 (s, IH), 4.84-4.68 (m, 2H), 3.74 and 3.72 (2s, 3H each).
Example 252 4-(2-((4-cvanobenzyPoxy)-2-(l-methyl-lH-imidazol-5-yPethyP-2-(l-naphthvPbenzonitrile hydrochloride
Example 252A l-methyl-2-(triethylsilvP-lH-imidazole-5-carbaldehyde A solution of Example 87F (10 g, 51 mmol) in THF (150 mL) at -74 °C, was treated dropwise with 1.7M tert-butyllithium in pentane (32 mL, 54 mmol), stined for 20 minutes, treated with 4-formylmorpholine (5.5 mL, 6.3 g, 5.5 mmol), stined for 1 hour, warmed to room temperature, and treated with ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. MS (DCI/NH3) m/z 225 (M+H)+; 1H NMR (300 MHz, CDC13) δ 9.76 (s, IH), 7.89 (s, IH), 4.00 (s, 3H), 1.00 (m, 15H).
Example 252B 4-(bromomethyP-2-(l-naphthyl)benzonitrile A solution of Example 89B (1.3 g, 5.0 mmol) in DMF (10 mL) at 0 °C was treated with LiBr (0.44 g, 5.1 mmol) and PBr3 (0.47 mL, 1.35 g, 5.0 mmol), warmed to room temperature, poured over ice and extracted with diethyl ether. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
1H NMR (300 MHz, CDC13) δ 7.96 (m, 3H), 7.82 (m, IH), 7.55 (m, 7H), 4.56 (s, 2H).
Example 252C 4-(2-hydroxy-2-( 1 -methyl- lH-imidazol-5-yl)ethvD-2-( 1 -naphthyDbenzonitrile
The desired product was prepared by the method described in J. Org. Chem. 1988, Vol.53, page 5789 using Example 252A and Example 252B, then purified by flash column chromatography on silica gel with 95:4:1 to 90:9: 1/ethyl acetate:ethanol:concentrated ammonium hydroxide. MS (DCI NΗ3) m z 354 (M+H)+.
Example 252D 4-(2-((4-cvanobenzyDoxy)-2-(l-methyl-lH-imidazol-5-yl)ethvD-2-(l-naphthvDbenzonitrile hydrochloride The desired product was prepared by substituting Example 252C and 4-cyanobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E.- MS CAPCIC+)) m/z 469 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, IH), 8.06 (m, 2H), 8.00 (d, IH), 7.75-7.22 (envelope, 12H), 5.20 (m IH), 4.62 (m, IH), 4.50 (m, IH), 3.88 (s, 3H), 3.50 (m, 2H); Anal, calcd for C31H25C1N4O-3.00 H2O: C, 66.60; H, 5.59; N, 10.02. Found: C, 66.19; H, 5.46; N, 10.50.
Example 253 4-(((4-cyanophenyl)( 1 -methyl- lH-imidazol-5-yl)methoxy)methvD-2-( 1 -naphthyDbenzonitrile hydrochloride
Example 253A 4-(hydroxy( 1 -methyl- lH-imidazol-5-vDmethyDbenzonitrile Example 252A and 4-cyanophenylzinc iodide were processed as described in J. Org. Chem. 1988, Vol.53, page 5789, treated with NaBFL)., and purified to provide the desired product.
MS (DCI NH3) m/z 214 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.84 (m, 2H), 7.60 (s, IH), 7.55 (m, 2H), 6.38 (s, IH), 6.18 (d, IH), 5.90 (d, IH), 3.57 (s, 3H).
Example 253B 4-(((4-cvanophenyl)(l-methyl-lH-imidazol-5-yDmethoxy)methyl)-2-(l-naphthvDbenzonitrile hydrochloride The desired product was prepared by substituting Example 253 A and Example 252B for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS CAPCIC+)) m/z 455 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.07 (d, IH), 8.06 (m, 3H), 7.93 (m, 2H), 7.66 (m, 4H),
7.60 (m, 2H), 7.50 (m, 2H), 7.43 (d, IH), 7.35 (s, IH), 6.12 (s, IH), 4.82, (m, IH), 4,68 (m,
IH), 3.75 and 3.74 (both s, total 3H);
Anal, calcd for C3oH23ClN4O-1.75 H2O: C, 68.96; H, 5.11; N, 10.72. Found: C, 68.65; H, 4.92; N, 11.17.
Example 254 4-((2-(4-c vanophenyp- 1 -( 1 -methyl- lH-imidazol-5-ypethoxy)methvD-2-( 1 - naphthyDbenzonitrile hydrochloride
Example 254A 4-(2-hydroxy-2-(l-methyl-lH-imidazol-5-yDethvDbenzonitrile Example 252A and 4-cyanobenzylzinc bromide were processed as described in J. Org. Chem. 1988, Vol.53, page 5789, treated with NaBILj, and purified to provide the desired product.
MS (DCI NH3) m/z 228 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 7.73 (m, 2H), 7.59 (m, 2H), 7.55 (s, IH), 6.80 (s, IH), 5.30
(d, IH), 4.81(m, IH), 3.60 (s, 3H), 3.15 (m, 2H).
Example 254B
4-((2-(4-cyanophenyl)- 1 -(1 -methyl- lH-imidazol-5-yl)ethoxy)methyD-2-( 1 - naphthyDbenzonitrile hydrochloride The desired product was prepared by substituting Example 254A and Example 252B for Example 5D and (bromomethyl)benzene, respectively, in Example 5E, and by substituting 4:1 dichloromethane/DMF for dichloromethane. - MS (APCIC+)) m/z 469 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.10 (s, IH), 8.07 (m, 2H), 7.96 (d, IH), 7.88 and 7.78 (both m, total IH), 7.70-7.35 (m, 11H), 5.13 and 5.00 (both m, total IH), 4.67 (m, IH), 4.55 (m, IH), 3.86 (s, 3H), 3.30 (m, 2H).
Example 255 4-((l -(1 -methyl- lH-imidazol-5-yD-3-phenylpropoxy)methyl)-2-( 1 -naphthyDbenzonitrile hydrochloride
Example 255 A l-(l-methyl-lH-imidazol-5-yD-3-phenyl-l-propanol
The desired product was prepared by substituting phenethylmagnesium chloride for phenylmagnesium bromide in Example 256A. MS (DCI NH3) m/z 217 (M+H)+;
*H NMR (300 MHz, CDC13) δ 7.43 (s, IH), 7.30 (m, 2H), 7.20 (m, 3H), 6.94 (s, IH), 4.63 (t, IH), 3.69 (s, 3H), 2.80 (m, 2H), 2.23 (m, 2H).
Example 255B 4-(( 1 -( 1 -methyl- lH-imidazol-5-vD-3-phenylpropoxy)methyD-2-(l -naphthyDbenzonitrile hydrochloride The desired product was prepared by substituting Example 255 A and Example 252B for Example 5D and (bromomethylbenzene), respectively, in Example 5E. - MS CAPCIC+)) m/z 458 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 8.08 (m, 3H), 7.75 (m, IH), 7.65 (m, 3H), 7.54 (m, 3H), 7.43 (m, IH), 7.20 (m, SH), 4.80 (m, IH), 4.60 (m, 2H), 3.82 and 3.80 (both s, total 3H), 2.70 (m, 2H), 2.30 (m, IH), 2.13 (m, IH);
Anal, calcd for C3ιH28ClN3O-2.40 H2O: C, 69.30; H, 6.15; N, 7.83. Found: C, 69.15; H, 5.59; N, 7.83.
Example 256 4-((( 1 -methyl- lH-imidazol-5-vD(phenvDmethoxy)methvD-2-( 1 -naphthyDbenzonitrile hydrochloride
Example 256A d-methyl-lH-imidazol-5-ylXphenyl)methanol A solution of Example 252A (1.2 g, 5.4 mmol) in THF (11 mL) at - 10 °C, was treated with phenylmagnesium bromide (3.M, 1.8 mL, 5.4 mmol), stined for 1 hour, treated with methanol, warmed to room temperature, stined for 16 hours, concentrated, and treated with ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
MS (DCI/NH3) m z 189 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 7.51 (s, IH), 7.38 (m, 4H), 7.29 (m, IH), 6.38 (s, IH), 5.91 (d, IH), 5.77 (d, IH), 3.55 (s, 3H).
Example 256B 4-((( 1 -methyl- lH-imidazol-5-vD(phenyDmethoxy)methyD-2-d -naphthyDbenzonitrile hydrochloride The desired product was prepared by substituting Example 256A and Example 252B for Example 5A and (bromomethyl)benzene, respectively, in Example 5E, and by substituting 4:l/dichloromethane:DMF for dichloromethane - MS (APCI(+)) m/z 430 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, IH), 8.05 (m, 3H), 7.65 (m, 5H), 7.50 (m, 7H), 7.30 (s, IH), 5.99 (s, IH), 4.80 (m, IH), 4.66 (m, IH), 3.75 and 3.74 (both s, total 3H); Anal, calcd for C29H24C1N3O-1.70 H2O: C, 70.14; H, 5.56; N, 8.46. Found: C, 70.14; H, 5.49; N, 8.49.
Example 257 4-((((l-methyl-lH-imidazol-5-vD(phenvDmethyDamino)methvD-2-(l-naphthvDbenzonitrile dihydrochloride
Example 257A
( 1 -methyl- 1 H-imidazol-5 - yl) (phen vDmethanamine hydrochloride The desired product was prepared by substituting Example 256 A for Example 89D in Example 13 A.
MS (DCI/NH3) m/z 188 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 7.45 (s, IH), 7.35 (m, 5H), 6.55 (s, IH), 5.09 (s, IH), 3.50 (s, 3H), 2.26 (br s, 2H).
Example 257B 4-((((l-methyl-lH-iιmdazol-5-yl)(phenyl)methvDamino)methvD-2-(l-naphthyl)benzonitrile dihydrochloride
Example 89C and Example 257 A were processed as described in Example 12B, substituting dichloromethane for 1,2-dichloroethane. The mixture was treated with methanol and stined for 4 hours prior to treatment with ethyl acetate to provide the desired product. MS (APCI(+)) m/z 429 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 8.05 (m, 3H), 7.82, 7.72, and 7.60 (envelope, 6H), 7.45 (m, 7H), 5.75 (br s, IH), 4.15 (br m, 2H), 3.81 and 3.79 (both s, total 3H); Anal, calcd for C29H26C12N4-1.65 H2O: C, 65.57; H, 5.56; N, 10.55. Found: C, 65.61; H, 5.54; N, 10.49.
Example 258 4-(( 1 -( 1 -methyl- lH-imidazol-5-yl)-2-phenylethoxy)methyP-2-( 1 -naphthyDbenzonitrile hydrochloride
Example 258 A l-(l-methyl-lH-imidazol-5-vD-2-phenylethanol The desired product was prepared by substituting benzylmagnesium chloride for phenylmagnesium bromide in Example 256A. MS (DCI/NH3) m/z 203 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 7.46 (s, IH), 7.24 (m, 5H), 6.80 (s, IH), 5.23 (d, IH), 4.77 (m, IH), 3.55 (s, 3H), 3.05 (m, 2H).
Example 258B 4-((l-(l-methyl-lH-imidazol-5-vD-2-phenylethoxy)methyD-2-(l-naphthvPbenzonitrile hydrochloride The desired product was prepared by substituting Example 257A and Example 252B for Example 5D and (bromomethyl)benzene, respectively, in Example 5E, and substituting 4:1 dichloromethane/DMF for dichloromethane.- MS (APCI(+)) m/z 444 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 8.09 (m, 2H), 7.95 (d, IH), 7.70-7.00 (envelope, 13H), 5.07 (m, IH), 4.70 (m, IH), 4.55 (m, IH), 3.80 (m, 3H), 3.12 (m, 2H); Anal, calcd for C3oH26ClN3O-2.70 H2O: C, 68.16; H, 5.99; N, 7.95. Found: C, 68.14; H, 5.89; N, 7.99.
Example 259 4-(((l-(l-methyl-lH-imidazol-5-vP-2-phenylethyPamino)methyP-2-(l-naphthypbenzonitrile dihydrochloride
Example 259A 1 -(- 1 -methyl- lH-imidazol-5-yP-2-phenylethanediazonium chloride A solution of Example 258A (0.4 g, 2.0 mmol) in dichloromethane at 0 °C was treated with thionyl chloride, stirred for 30 minutes, warmed to room temperature, stined for 1.5 hours, and concentrated. The concentrate'was treated with DMF (5 mL) and sodium azide (0.54 g, 8.2 mmol), heated to 55 °C, stirred for 3.5 hours, and treated with ethyl acetate and 0.5M N-1HCO3. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent reaction without further purification.
Example 259B
1 -(1 -methyl- lH-imidazol-5-vD-2-phenylethylamine A solution of Example 259A in THF (5 mL) was treated with triphenylphosphine
(0.75 g, 2.8 mmol), heated to reflux, stirred for 1 hour, cooled to room temperature, treated with water (0.5 mL), stined for 16 hours, concentrated, and treated with 2M HCl and ethyl acetate. The aqueous layer was adjusted to pH 10 with 2M Na2CO3 and extracted with
3:l/chloroform:isopropanol. The extract was dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
MS (DCI NH3) m/z 202 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 7.42 (s, IH), 7.24 (m, 2H), 7.18 (m, 3H), 6.78 (s, IH), 4.05
(m, IH), 3.52 (s, 3H), 2.94 (m, 2H).
Example 259C
4-((( 1 -( 1 -methyl-lH-imidazol-5-yD-2-phenylethvDamino)methvD-2-( 1 -naphthyDbenzonitrile dihydrochloride
The desired product was prepared by substituting Example 259 A for Example 257 A in Example 257B.
MS (APCI(+)) m/z 443 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, IH), 8.20 (s, IH), 8.10 (m, 3H), 7.95 (br d, IH), 7.86 (br d, IH), 7.66 (m, IH), 7.60 (m, IH), 7.53 (m, 3H), 7.25 (m, 3H), 7.14 (m, 2H), 4.91
(br s, IH), 4.40 (br m, 2H), 3.80 (br m, IH), 3.59 (s, 3H), 3.30 (m, IH);
Anal, calcd for C30H28C12N4-1.40 H2O: C, 66.64; H, 5.74; N, 10.36. Found: C, 66.92; H,
5.83; N, 9.92.
Example 260
4-((( 1 -( 1 -methyl- lH-inιidazol-5-yD-3-phenylpropyDamino)methyD-2-( 1 - naphthyDbenzonitrile dihydrochloride
Example 260A 1 -d -methyl- lH-imidazol-5-vD-3-phenylpropyldiazonium chloride
The desired product was prepared by substituting Example 255 A for Example 258 A in Example 259A. Example 260B 1 -( 1 -methyl- 1 H-imidazol-5- yl)-3 -phenylpropylamine The desired product was prepared by substituting Example 260A for Example 259A in Example 259B.
MS (DCIVNH3) m/z 216 (M+H)+.
Example260C 4-(((l-(l-methyl-lH-imidazol-5-yD-3-phenylpropyDamino)methyD-2-(l- naphthyDbenzonitrile dihydrochloride
The desired product was prepared by substituting Example 260B for Example 257A in Example 257B. MS CAPCIC+)) m/z 457 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.05 (br s, IH), 8.10 (m, 2H), 8.00 (br s, IH), 7.90 (br m, IH), 7.81 (s, IH), 7.60 (m, 4H), 7.50 (m, 2H), 7.25 (m, 2H), 7.16 (m, 3H), 4.50, 4.35, and 4.20 (envelope, 3H), 3.79 and 3.75 (both s, total 3H), 2.60 (m, 2H), 2.40 and 2.20 (both br m, total 2H).
Example 261 4-(((2-(4-cyanophenyl)-l-(l-methyl-lH-imidazol-5-yl)ethvPamino)methyP-2-(l- naphthyPbenzonitrile ditrifluoroacetic acid salt
Example 261 A 2-(4-cyanophenyP-l-(l-methyl-lH-imidazol-5-yPethanediazonium chloride The desired product was prepared by substituting Example 254A for Example 258A in Example 259A.
Example 26 IB 4-(2-amino-2-( 1 -methyl- 1 H-imidazol-5 -vPethyPbenzonitrile The desired product was prepared by substituting Example 261 A for Example 259A in Example 259B. MS (DCI NH3) m/z 227 (M+H)+.
Example 26 IC 4-(((2-(4-cvanophenyP-l-(l-methyl-lH-imidazol-5-vPethyPamino)methyP-2-(l- naphthyPbenzonitrile ditrifluoroacetic acid The desired product was prepared by substituting Example 26 IB for Example 257 A in Example 257B, and purified by preparative HPLC with 0-70% acetonitrile/0.1% trifluoroacetic acid. MS (APCI(+)) m/z 468 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 8.86 (s, IH), 8.10 (m, 3H), 7.77-7.56 (envelope, 7H), 7.55- 7.35 (envelope, 5H), 4.60 (br s, IH), 4.13 (br s, 2H), 3.25 (br m, 2H); Anal, calcd for C35H27F6N5O4-1.70 H2O: C, 57.89; H, 4.22; N, 9.64. Found: C, 57.85; H, 4.11; N, 9.71.
Example 262
4-(((3 -c yanobenzyPox y) ( 1 -methyl- 1 H-imidazol-5-yPmethyP-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting Example 89D and 3-(bromoethyl)benzonitrile for Example IB and (bromomethyl)benzene, respectively, in Example IC. MS (ESI(+)) m/z 455 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.15 (s, IH), 8.15 (dd, IH), 8.1 (t, 2H), 7.9-7.45 (m, 11H), 6.15 (s, IH), 4.7 (q, 2H), 3.8 (d, 3H), 3.6 (s, IH);
Anal, calcd for C3oH23ClN4O-1.6H2O: C, 69.32; H, 5.08; N, 10.78. Found: C, 69.40; H, 5.16; N, 10.21.
Example 263 4-(((4-bromobenzyPoxy)(l-methyl-lH-imidazol-5-yPmethyP-2-d-naphthvPbenzonitrile The desired product was prepared by substituting Example 89D and l-bromo-4-(bromomethyl)benzene for Example IB and (bromomethypbenzene, respectively, in Example IC.
MS (ESI(+)) m/z 508 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 9.1 (s, IH), 8.15 (dd, IH), 8.05 (t, 2H), 7.8 (d, IH), 7.7-7.4 (m, 8H), 7.35 (dd, 2H), 6.6 (s, IH), 4.6 (q, 2H), 3.8 (d, 3H);
Anal, calcd for C29H23BrClN3O-0.9H2O: C, 62.08; H, 4.46; N, 7.49. Found: C, 62.13; H, 4.50; N, 7.43.
Example 264 4-((3-chlorobenzyP(d -methyl- lH-imidazol-5-yPmethyl)amino)-2-(l -naphthyDbenzonitrile The desired product was prepared by substituting 3-(bromomethyl)-l-chlorobenzene for benzyl bromide in Example 232. MS (ESI(+)) m/z 463 (M+H)+; ]H NMR (300 MHz, DMSO-d6) δ 7.99 (d, 2H), 7.72 (d, IH), 7.6-7.3 (m, 8H), 7.25-7.20 (m, IH), 7.2-7.1 (m, IH), 7.00 (dd, IH), 6.83 (d, IH), 6.70 (s, IH), 4.84 (m, 2H), 4.75 (m, 2H), 3.55 (s, 3H);
Anal, calcd for C29H23N4CI-O.5 H2O: C, 73.79; H, 5.12; N, 11.87. Found: C, 73.74; H, 5.03; N, 11.72.
Example 265 4-(benzyl(lH-imidazol-5-ylmethyDamino)-2-( 1 -naphthyDbenzonitrile
Example 265A
4-((lH-imidazol-5-ylmethvDamino)-2-(l-naphthyDbenzonitrile The desired product was prepared by substituting Example 270A for Example 234B in Example 234C.
Example 265B
4-(benzyl(lH-imidazol-5-ylmethyl)amino)-2-(l-naphthyl)benzonitrile The desired product was prepared by substituting Example 265A for Example 234C in Example 234D. MS (ESI(+)) m/z 415 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.96 (br s, IH), 7.98 (d, 2H), 7.7-7.5 (m, 4H), 7.5-7.2 (m, 8H), 7.1-7.0 (m, 2H), 6.83 (d, IH), 4.9-4.7 (m, 2H), 4.59 (m, 2H);
Anal, calcd for C28H22N4-0.75 H2O: C, 78.57; H, 5.53; N, 13.08. Found: C, 78.33; H, 5.21; N, 12.93.
Example 266
4-((3-cyanobenzyP(( 1 -methyl- lH-imidazol-5-yDmethyl)amino)-2-( 1 -naphthyDbenzonitrile The desired product was prepared by substituting 3-(bromomethyl)benzonitrile for benzyl bromide in Example 232. MS (ESI(+)) m/z 454 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, 2H), 7.8-7.3 (m, 11H), 7.01 (dd, IH, IH), 6.82 (d, IH), 6.71 (s, IH), 5.0-4.7 (m, 4H), 3.54 (s, 3H);
Anal, calcd for C3oH23N5-1.0 H2O: C, 76.41; H, 5.34; N, 14.85. Found: C, 76.47; H, 5.14; N, 14.46.
Example 267
N-(4-cvano-3-(l-naphthvDphenvD-N-((l-methyl-lH-imidazol-5- vDmethvDbenzenesulfonamide The desired product was prepared by substituting benzenesulfonyl chloride for benzyl bromide in Example 232. MS (ESI(+)) m/z 479 (M+H)+;
2H NMR (300 MHz, DMSO-d6) δ 8.1-8.0 (m, 2H), 7.97 (d, IH), 7.80-7.45 (m, 10H), 7.38 (dd, IH), 7.27 (d, IH), 7.09 (d, IH), 6.59 (s, IH), 4.93 (m, 2H), 3.66 (s, 3H);
Anal, calcd for C28H22N4O2S-0.75 H2O: C, 68.34; H, 4.81; N, 11.38. Found: C, 68.30; H, 4.73; N, 10.93.
Example 268 methyl 4-((4-cyano(( 1 -methyl- lH-imidazol-5-yl)methyP-3-d - naphthypanilino)methyl)benzoate The desired product was prepared by substituting methyl 4-(bromomethyl)-benzoate for benzyl bromide in Example 232. MS (ESI(+)) m/z 487 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, 2H), 7.92 (d, 2H), 7.70 (d, IH), 7.6-7.5 (m, 3H), 7.40 (dd, IH), 7.4-7.3 (m, 4H), 7.00 (dd, IH), 6.81 (d, IH), 6.72 (s, IH), 5.0-4.7 (m, 4H), 3.85 (s, 3H), 3.54 (s, 3H);
Anal, calcd for C20H18N4O2-1.0 H2O: C, 73.79; H, 5.59; N, 11.10. Found: C, 73.87; H, 5.40; N, 10.60.
Example 269 4-((4-c vano(( 1 -methyl- 1 H-imidazol-5- ypmethyP-3 -( 1 -naphth vPanilino)methvPbenzoic acid
The desired product was prepared by substituting Example 268 for Example 10F in Example 10G. MS (ESI(+)) m/z 473 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 12.90 (br s, IH), 7.97 (dd, 2H), 7.90 (d, 2H), 7.71 (d, IH), 7.6-7.3 (m, 8H), 6.82 (d, IH), 6.73 (s, IH), 5.0-4.7 (m, 4H), 3.55 (s, 3H); HRMS calcd m/z for C3oH25N4O2: 473.1978 (M+H)+. Found: 473.1984.
Example 270
5-(benzyl(lH-imidazol-5-ylmethyPamino)-2'-methyl(l, -biphenyP-2-carbonitrile
Example 270A l-(triphenylmethvPimidazole-4-carboxaldehvde The desired product was prepared as described in J. Med. Chem., 1996, Vol.39, page
353. Example 270B 2 -methyl-5-(((l-trityl-lH-imidazol-4-yPmethvPamino)(l, -biphenyP-2-carbonitrile The desired product was prepared by substituting Example 270Afor Example 225D In Example 225E.
Example 270C 5-(benzyl((l -trityl- lH-imidazol-4-vPmethyPamino)-2 -niethyK 1 , 1 '-biphenvD-2-carbonitrile The desired product was prepared by substituting Example 270B for Example 225E in Example 226.
Example 270D 5-(benzyl(lH-imidazol-5-ylmethyPamino)-2'-methyl(l, -biphenvP-2-carbonitrile A solution of Example 270C (380 mg, 0.61 mmol) in dichloromethane (10 mL) at room temperature was treated with trifluoroacetic acid (3 mL) and triethylsilane (1.5 mL), stined for 2 hours, and concentrated under a nitrogen atmosphere. The concentrate was treated with ethyl acetate, washed with saturated NaHCO3 and brine; dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/dichloromethane:methanol to provide the desired product. MS CESI(+)) m/z 379 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 11.90 (br s, IH), 7.6-7.5 (m, 2H), 7.4-7.1 (m, 9H), 7.1-7.0 (m, 2H), 6.95 (dd, IH), 6.64 (d, IH), 4.78 (br s, 2H), 4.57 (br s, 2H), 1.96 (s, 3H); Anal, calcd for C25H22N4-0.5 H2O: C, 77.49; H, 5.98; N, 14.45. Found: C, 77.20; H, 6.08; N, 13.96.
Example 271 methyl 3-((4-cyano(d-methyl-lH-imidazol-5-yPmethyP-3-(l- naphthvPanilino)methyPbenzoate The desired product was prepared by substituting methyl 3-(bromomethyl)benzoate for benzyl bromide in Example 232. MS (ESI(+)) m/z 487 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 8.0-7.9 (m, 2H), 7.9-7.8 (m, IH), 7.77 (s, IH), 7.71 (d, IH), 7.60-7.45 (m, 5H), 7.41 (dd, IH), 7.31 (d, 2H), 7.03 (dd, IH), 6.85 (d, IH), 6.72 (s, IH), 5.0-4.7 (m, 4H), 3.83 (s, 3H), 3.56 (s, 3H);
Anal, calcd for C31H26N4O2-0.75 H2O: C, 74.45; H, 5.54; N, 11.20. Found: C, 74.58; H, 5.31; N, 10.83.
Example 272 4-(((6-cyano-2'-methyld,l -biphenvP-3-yPd-methyl-lH-imidazol-5- ypmethoxy)methyPbenzoic acid A solution of Example 130 in THF (10 mL) and water (5 mL) at room temperature was treated with LiOH (100 mg ), stined for 16 hours, adjusted to pH 7 with saturated ammonium chloride (20 mL) and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification. MS (APCIC+)) m/z 438 (M+H)+; MS (APCI(-)) m/z 472 (M+Cl)"; XH NMR (500 MHz, DMSO-d6) δ 8.95 (br s, IH), 8.06 (d, IH), 7.93 (d, 2H), 7.68 (dd, IH), 7.52 (s, IH), 7.48 (d, 2H), 7.41-7.25 (m, 5H), 6.08 (s, IH), 4.66 (d, IH), 4.64 (d, IH), 3.74 (s, 3H), 2.13 (s, 3H).
Example 273 4-((l-methyl-lH-imidazol-5-vP((3-chlorobenzvPoxy)methvP-2-(l-naphthyPbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and 3-chlorobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 464 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 9.05 (s, IH), 8.17 (m, IH), 8.09 (m, 2H), 7.78 (m, IH), 7.5 (m, 11H), 7.40 (m, IH), 6.12 (s, IH), 4.65 (m, 2H), 3.79 (d, 3H).
Example 274 5-(((4-cyano-3-( 1 -naphthyPphenylX 1 -methyl- lH-imidazol-5-vPmethoxy)methyP-2- pyridinecarbonitrile dihydrochloride
Example 274A methyl 6-cyanonicotinate A solution of 6-cyanonicotinic acid (5 g) in methanol (100 mL) was titrated to a yellow endpoint with 2M trimethylsilyldiazomethane in hexanes and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3.T/hexanes:ethyl acetate to provide the desired product.
Example 274B 5-(hvdroxymethvP-2-pyridinecarbonitrile
The desired product was prepared by substituting Example 274A for Example 5A in Example 5B. MS (DCI NH3) m/z 136 (M+H)+;
XH NMR (300 MHz, CDC13) δ 8.71 (m, IH), 7.88 (m, IH), 7.71 (m, IH), 4.86 (d, 2H).
Example 274C 5-(bromomethvP-2-pyridinecarbonitrile The desired product was prepared by substituting Example 274B for Example 61 A in Example 6 IB.
MS (DCIJNH3) m/z 197 and 199 (M+H)+; XH NMR (300 MHz, CDCI3) δ 8.73 (d, IH), 7.89 (dd, IH), 7.70 (d, IH), 4.50 (s, 2H).
Example 274D 5-(((4-cyano-3-(l-naphthyPphenvP(l-methyl-lH-imidazol-5-ypmethoxy)methyP-2- pyridinecarbonitrile dihydrochloride The desired product was prepared by substituting Example 89D and Example 274C for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI NH3) m/z 456 (M+H)+;
XH NMR (300 MHz, CDC13) δ 8.69 (s, IH), 7.99 (t, 2H), 7.89 (d, IH), 7.79 (m, 2H), 7.68 (m, IH), 7.5 (m, 7H), 7.08 (d, IH), 5.75 (d, IH), 4.70 (s, 2H), 3.55 (d, 3H).
Example 275
5-(((4-cyanobenzvPoxy)(l-methyl-lH-imidazol-5-ypmethyP-3-(l-naphthvP-2- pyridinecarbonitrile dihydrochloride
Example 275A methyl 5,6-dichloronicotinate
A solution of 5,6-dichloronicotinic acid (19.2 g, 100 mmol) in methanol (150 mL) at 0 °C was treated with thionyl chloride (10.9 mL, 150 mmol), warmed to room temperature over 18 hours, treated with ethyl acetate, washed sequentially with half-saturated NaHCO3, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
Example 275B methyl 5-chloro-6-cyanonicotinate A mixture of Example 275A (2.0 g, 10 mmol), potassium iodide (830 mg, 5 mmol), K2CO3 (6.91 g, 50 mmol), and potassium cyanide (3.26 g, 50 mmol) in DMSO (20 mL) at 80 °C was stined for 6 hours, cooled, treated with ethyl acetate, washed with water and brine, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:l/hexanes:ethyl acetate to provide the desired product.
Example 275C methyl 6-cyano-5-d -naphthyPnicotinate
A mixture of Example 275B (800 mg, 4 mmol), 1-naphthaleneboronic acid (1.5 g, 8.7 mmol), palladium(H) acetate (11 mg, 0.08 mmol), 2-dimethylamino-2 - dicyclohexylphosphino-biphenyl (44 mg, 0.11 mmol), and CsF C2 g, 13 mmol) in dioxane C20 mL) at room temperature was stined for 48 hours, treated with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:l/hexanes:ethyl acetate to provide the desired product.
Example 275D 5-(hydroxymethyP-3-(l-naphthvD-2-pyridinecarbonitrile
The desired product was prepared by substituting Example 275C for Example 5A in Example 5B.
Example 275E 5-f ormyl-3-(l -naphthvD-2-pyridinecarbonitrile
The desired product was prepared by substituting Example 275D for Example 35C in Example 35D.
*HNMR (300 MHz, CDC13) δ 10.28 (s, IH), 9.25 (d, IH), 8.36 (d, IH), 8.02 (m, 2H), 7.57 (m, 4H), 7.42 (m, IH), 4.50 (s, 2H).
Example 275F 5-(hydroχy(l-methyl-lH-imidazol-5-yPmethyP-3-(l-naρhthvP-2-ρyridinecarbonitrile The desired product was prepared by substituting Example 275E for Example 1 A in Example IB. MS (DCI NH3) m/z 341 (M+H)+;
2H NMR (300 MHz, CDC13) δ 8.81 (dd, IH), 7.98 (m, 3H), 7.5 (m, 4H), 6.78 (s, IH), 6.11 (s, IH), 4.10 (m, 2H), 3.65 (d, 3H).
Example 275G 5-(((4-cvanobenzvPoxy)(l-methyl-lH-imidazol-5-yPmethyP-3-(l-naphthyP-2- pyridinecarbonitrile dihydrochloride The desired product was prepared by substituting Example 275F and 4-cyanobenzyl bromide for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 456 (M+H)+;
1H NMR (300 MHz, CDCI3) δ 8.82 (dd, IH), 7.98 (m, 3H), 7.5 (m, 4H), 7.09 (d, IH), 5.80 (s, IH), 4.66 (m, 2H), 3.54 (s, 3H).
Example 276 4-((l-methyl-lH-imidazol-5-vD((4-azidobenzvDoxy)methyD-2-(l-naphthyDbenzonitrile hydrochloride
Example 276A 4-(hydroxymethvDbenzenediazonium tetrafluoroborate The desired product was prepared by substituting 4-aminobenzyl alcohol for Example 87A in Example 87B.
Example 276B (4-azidophenvDmethanol The desired product was prepared by substituting Example 276 A and sodium azide for Example 87B and CuCN/NaCN, respectively, in Example 87C. 1H NMR (300 MHz, CDCI3) δ 7.48 (d, 2H), 7.02 (d, 2H), 4.69 (s, 2H).
Example 276C 1 -azido-4-(bromomethvDbenzene The desired product was prepared by substituting Example 276B for Example 61 A in Example 6 IB.
Example 276D 4-((l-methyl-lH-imidazol-5-yD((4-azidobenzvDoxy)methvD-2-(l-naphthyDbenzonitrile hydrochloride The desired product was prepared by substituting Example 89D and Example 276C for Example 5D and (bromomethyl)benzene, respectively, in Example 5E. MS (DCI/NH3) m/z 471 (M+H)+; XH NMR (300 MHz, CDCI3) δ 7.96 (m, 2H), 7.87 (d, IH), 7.70 (s, IH), 7.50 (m, 7H), 7.29
(m, 2H), 6.99 (m, 3H), 5.63 (s, IH), 4.54 (s, 2H), 3.52 (d, 3H).
Example 277 methyl 6-(((6-cyano-2'-(trifluoromethvD( 1 , 1 -biphenyl)-3-yD( 1 -methyl- lH-imidazol-5- yl)methoxy)methvDnicotinate dihydrochloride The desired product was prepared by substituting Example 245 A and 2- (trifluoromethyl)phenylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (APCI(-)) m/z 541 (M+Cl)"; MS (APCI(+)) m/z 507 (M+H)+;
XH NMR (300 MHz, DMSO-d6) (rotamers) δ 9.13 and 9.12 (2s, IH each), 9.02 (dd, IH), 8.32-8.28 (m, IH), 8.09 (dd, IH), 7.92 (t, IH), 7.83-7.51 (m, 6H), 7.60-7.49 (m, IH), 7.41 (dd, IH), 6.22 (s, IH), 4.82 (d, IH), 4.72 (dd, IH), 3.76 and 3.74 (2s, 3H each).
Example 278
5-(((4-cvanobenzyDoxy)(l-methyl-lH-imidazol-5-yDmethyD-2',3'-dimethyl(l, -biphenyl)-2- carbonitrile hydrochloride The desired product was prepared by substituting 2,3-dimethylphenylboronic acid for
2-formylphenylboronic acid in Example 200D.
MS (APCI(-)) m z 467 (M+Cl)";
MS (APCI(+)) m z 433 (M+H)+;
1H NMR (300 MHz, DMSO-d6) (rotamers) δ 8.99 (s, IH), 8.04 (dd, IH), 7.82 (d, 2H), 7.68- 7.66 (m, IH), 7.57 (d, 2H), 7.47 (d, IH), 7.40 (d, IH), 7.28 (d, IH), 7.21 (q, IH), 7.13-7.02
(m, IH), 6.09 (s, IH), 4.76-4.62 (m, 2H), 3.73 (s, 3H), 2.32 (d, 3H), 2.03 and 1.97 (2s, 3H each).
Example 279 2',3 -dichloro-5-(((4-cvanobenzyDoxy)(l-methyl-lH-imidazol-5-vDmethyD(l, -biρhenyD-2- carbonitrile hydrochloride The desired product was prepared by substituting 2,3-dichlorophenylboronic acid for 2-formylphenylboronic acid in Example 200D. MS (APCI(-)) m/z 507 and 509 (M+Cl)"; MS (APCI(+)) m/z 473 and 475 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.99 (s, IH), 8.04 (dd, IH), 7.82 (d, 2H), 7.68-7.66 (m, IH), 7.57 (d, 2H), 7.47 (d, IH), 7.39 (d, IH), 7.28 (d, IH), 7.21 (q, IH), 7.13-7.02 (m, IH), 6.09 (s, IH), 4.76-4.62 (m, 2H), 3.73 (s, 3H).
Example 280
6-(((2'.3'-dichloro-6-cvanod,l'-biphenvD-3-yl)d-methyl-lH-imidazol-5- yPmethoxy)methvPnicotinonitrile dihydrochloride The desired product was prepared by substituting Example 244A and 2,3-dichlorophenylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (ESI(+)) m/z 474 and 476 (M+H)+; XH NMR (300 MHz, DMSO-d6) δ 9.08 (s, IH), 8.98 (dd, IH), 8.33 (dd, IH), 8.10 (d, IH), 7.82-7.46 (m, 7H), 6.21 (s, IH), 4.85-4.71 (m, 2H), 3.76 (s, 3H).
Example 281 6-(((6-cvano-2',3 -dimethvK 1 , 1 -biρhenyl)-3-yp( 1 -methyl- lH-imidazol-5- yPmethoxy)methyPnicotinonitrile dihydrochloride
The desired product was prepared by substituting Example 244A and 2,3-dimethylphenylboronic acid for Example 200C and 2-formylphenylboronic acid, respectively, in Example 200D. MS (ESI(+)) m/z 434 (M+H)+ and 456 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) (rotamers) δ 9.11 (s, IH), 8.33 (dd, IH), 8.04 (d, IH), 7.72- 7.50 (m, 6H), 7.29 (d, IH), 7.21 (dd, IH), 7.12 (d, IH), 6.19 (s, IH), 4.85-4.70 (m, 2H), 3.78 (s, 3H), 2.32 (d, 3H), 2.03 and 1.97 (2s, 3H each).
Example 282 4-cvano-N-((4-cyano-3-(l-naphthyPphenyPd -methyl- lH-imidazol-5- yPmethvPbenzenesulfonamide A solution of Example 13A (50 mg, 0.148 mmol) in dichloromethane (1 mL) at room temperature was treated with 4-cyanobenzenesulfonyl chloride (35 mg, 0.174 mmol), triethylamine (150 μL), and catalytic DMAP, stined for 14 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5: 1/ethyl acetate: ethanol concentrated ammonium hydroxide to provide the desired product. MS (DCI NH3) m/z 504 (M+H)+;
XH NMR (300 MHz, DMSO-d6) δ 9.13 (br s, IH), 8.06 (m, 2H), 7.89 (m, 3H), 7.72-7.45 (m, 9H), 7.22-7.10 (m, IH), 6.31-6.26 (two s, IH), 5.96 (br. IH), 3.63-3.60 (two s, 3H);
Example 283 4-((4-cvanoanilino)(l-methyl-lH-imidazol-5-vPmethyP-2-(l-naphthyPbenzonitrile
Example 283A 4-(hydroxy(l-methyl-lH-imidazol-5-yPmethvP-2-d-naphthvPbenzonitrile
A solution of Example 89D (1.13 g, 3.33 mmol) in dichloromethane (20 mL) at 0 °C was treated dropwise with thionyl chloride (1.4 mL, 19.2 mmol), warmed to room temperature, stined for 2 hours, concentrated, treated with toluene, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
Example 283B 4-((4-cvanoanilino)(l-methyl-lH-imidazol-5-yPmethyP-2-(l-naphthypbenzonitrile A solution of Example 283A (100 mg, 0.280 mmol) in DMF (2 mL) at room temperature was treated with 4-cyanoaniline (165 mg, 1.40 mmol) and diisopropylethylamine (100 μL, 0.574 mmol), stirred for 72 hours, treated with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/dichloromethane:methanol to provide the desired product.
MS (DCI/NH3) m/z 440 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.08 (m, 3H), 7.5-7.20 (m, 10H), 6.78 (m, 2H), 6.40-6.36
(two s, IH), 6.15-6.11 (two s, IH), 3.61-3.59 (two s, 3H);
Example 284 4-((3-cyanoanilino)d -methyl- lH-imidazol-5- ypmethvP-2-d -naphthyDbenzonitrile The desired product was prepared by substituting 3-cyanoaniline for 4-cyanoaniline in
Example 283B.
MS (DCI NH3) m/z 440 (M+H)+;
XH NMR (300 MHz, CDCI3) δ 7.90 (m, 3H), 7.52 (m, 7H), 7.25 (m, 2H), 7.07 (m. IH), 6.80 (m, 2H), 6.62 (m, IH), 5.68 (m, IH), 4.72 (m, IH), 3.69-3.67 (two s, 3H);
Example 285 tert-butyl 1 -((4-cyano-3-(l -naphthyPphenylX 1 -methyl- lH-imidazol-5-vPmethvP-4- piperidinylcarbamate A solution of Example 283A (30 mg, 0.0838 mmol) in DMF (1 mL) at room temperature was treated with tert-butyl 4-piperidinylcarbamate (90 mg, 0.449 mmol) and diisopropylethylamine (80 μL, 0.46 mmol), stirred for 72 hours, heated to 60 °C, stirred for 16 hours, treated with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/dichloromethane:methanol to provide the desired product. MS (ESI(+)) m/z 522 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.05 (m, IH), 7.94 (s, IH), 7.50 (m, 7H), 6.89 (m, IH), 6.75 (m, IH), 4.02 (m, 2H), 3.60-3.50 (m, 3H), 3.31 Cs, 3H), 3.05 (m, IH), 2.70 (m, 2H), 1.72 (m, 2H), 1.38 (s, 9H).
Example 286
4-((4-cvanophenoxy)(l-methyl-lH-imidazol-5-yPmethvP-2-(l-naphthvPbenzonitrile A solution of Example 89D in THF (2 mL) at room temperature was treated with DEAD (60 μL, 0.38 mmol), 4-hydroxybenzonitrile (42 mg, 0.353 mmol), and triphenylphosphine (93 mg, 0.355 mmol), stined for 16 hours, treated with diethyl ether, washed with IM NaOH, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5: 1/ethyl acetate:ethanol:concentrated ammonium hydroxide to provide the desired product. MS (DCI/NH3) m/z 441 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.08 (m, 3H), 7.80-7.15 (m, 11H), 7.07(s, IH), 6.63-6.60 (two s, IH), 3.62-3.60 (two s, 3H);
Example 287 4-(((4-cyanophenyP(l-methyl-lH-imddazol-5-yPmethvPamino)-2-(l-naphthypbenzonitrile
Example 287A
2-(l-naphthyP-4-nitrobenzonitrile A solution of 1 -naphthylboronic acid (2.58 g, 15.0 mmol) in toluene (20 mL) and dioxane (20 mL) was treated with 2-chloro-4-nitrobenzonitrile (1.83 g, 10.0 mmol), trans- dichloro(bis(tricyclohexylphosphino))palladium (370 mg, 0.50 mmol), and 2M Na2CO3 (20 mL), purged with nitrogen, heated to reflux, stined for 19 hours, treated with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with ethyl acetate/hexanes to provide the desired product. MS (DCI/NH3) m/z 292 (M+NILi ;
1H NMR (300 MHz, CDC13) δ 8.41(m, 2H), 8.00 (m, 3H), 7.53(m, 5H).
Example 287B 4-amino-2-( 1 -naphthyDbenzonitrile A suspension of Example 287A (500 mg, 1.82 mmol) in ethanol (7 mL) at room temperature was treated with concentrated HCl (2 mL) and a solution of SnCl2.2H2θ (1.25 g, 5.54 mmol) in ethanol (4 mL), stined for 3 hours, and concentrated. The concentrate was treated with diethyl ether and 30% NaOH. The aqueous layer was extracted with diethyl ether, and the extract was washed sequentially with IM NaOH, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with hexanes to provide the desired product.
MS (DCI/NΗ3) m/z 262 (M+NKi ;
XH NMR (300 MHz, CDC13) δ 7.91 (m, IH), 7.55 (m, 8H), 6.70 (m, 2H), 4.2 (br s, 2H).
Example 287C
4-(hvdroχy(l-methyl-lH-imidazol-5-vDmethyDbenzonitrile
A solution of Example 87F (3.35 g, 17.08 mmol) in THF (50 mL) at -78 °C was treated dropwise with 1.5M tert-butyllithium in pentane (11.4 mL, 17.1 mmol), stined for 30 minutes, treated with a solution of 4-cyanobenzaldehyde (2.04 g, 15.56 mmol) in THF (10 mL) at -78 °C, stirred for 1 hour, treated with methanol (4 mL), warmed to room temperature, stirred for 1 hour, treated with IM HCl (40 mL), stirred for 1.5 hours, adjusted to pH 12 with
30% NaOH, and extracted with ethyl acetate. The extract was washed with brine, dried
(MgSO4), filtered, and concentrated. The concentrate was triturated with 4:l/hexanes:ethyl acetate to provide the desired product.
MS (DCI/NH3) m/z 214 (M+H)+ and 231 (M+NH4)+;
1H NMR C300 MHz, CDC13) δ 7.67 (d, 2H), 7.52 (d, 2H), 7.40 (s, IH), 6.67 (s, IH), 5.95 (s,
IH), 3.53 (s, 3H).
Example 287D
4-(chloro( 1 -methyl- lH-imidazol-5-vDmethyDbenzonitrile A solution of Example 286 in dichloromethane (40 mL) at 0 °C was treated with thionyl chloride (2.8 mL, 38.4 mmol), warmed to room temperature, stirred for 4 hours, and concentrated. The concentrate was treated with toluene and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
Example 287E 4-(((4-cyanophenvD(l-methyl-lH-imidazol-5-yDmethvDamino)-2-(l-naphthyl)benzonitrile A solution of Example 287D (143 mg, 0.534 mmol) in DMF (4 mL) at room temperature was treated with Example 287B (130 mg, 0.532 mmol) and diisopropylethylamine (470 μL, 2.70 mmol), stined for 72 hours, treated with ethyl acetate, washed with water and brine, dried (MgSO ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/dichloromethane:methanol to provide the desired product. MS (DCI/NH3) m/z 440 (M+H)+;
1H NMR (300 MHz, CDC13) δ 7.90-7.50 (m, 11H), 6.60 (m, 3H), 5.66 (m, IH), 5.05 (m, IH), 3.68-3.62 (two s, 3H). Example 288 6-(((4-c yano-3-d -naphthyPbenzylXd -methyl-lH-imidazol-5- vPmethyPamino)methvPnicotinonitrile A solution of Example 192D (35 mg, 0.10 mmol) in 5% acetic acid DME (1.0 mL) at room temperature was treated with 6-formylnicotinonitrile (30 mg, 3.0 mmol) and 4A molecular sieves, stirred for 1 hour, treated with sodium triacetoxyborohydride (40 mg, 2.0 mmol), stined for 16 hours, treated with ethyl acetate (1.0 mL), washed with saturated sodium bicarbonate and brine, filtered through a Chem Elut® CEIOOOM tube (Alltech, Northbrook, IL), and concentrated. The concentrate was purified by preparative HPLC (CH3CN/O.OIOM NH4OAC) to provide the desired product. MS (APCI(+)) m/z 469 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 9.78 (s, IH), 8.88 (s, IH), 8.17 (dd, IH), 8.07 (d, IH), 8.05 (d, IH), 7.93 (d, IH), 7.66-7.45 (m, 8H), 7.39 (d, IH), 3.83 (s, 2H), 3.80 (s, 2H), 3.69 (s, 2H), 3.50 (s, 3H).
Example 289 6-(((4-cvano-3-(l-naphthypphenyP(3-thienyPmethoxy)methvPnicotinonitrile
Example 289A 4-(hvdroxy(3-thienyPmethvP-2-(l-naphthvPbenzonitrile
The desired product was prepared by substituting Example 89C for Example 861 in Example 80A.
MS (DCI/NH3) m/z 359 (M+NH4)+;
*H NMR (500 MHz, CDCI3) δ 7.92 (m, 2H), 7.80 (dd, IH), 7.60-7.41 (m, 7H), 7.31 (m, IH), 7.23 (m, IH), 7.01 (dd, IH), 5.98 (d, IH), 2.42 (d, IH).
Example 289B 6-(((4-cvano-3-(l-naphthvPphenyP(3-thienvPmethoxy)methyPnicotinonitrile Example 289A (360 mg, 1.06 mmol) and Example 76A (416 mg, 2.11 mmol) were dissolved in THF (5 mL). The solution was purged with nitrogen and cooled to -5 °C. Sodium hydride (30 mg, 1.25 mmol) was added and the reaction was stined for 1.5 hours. Aqueous ammonium chloride was added and the mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO ), filtered, and concentrated. Chromatography of the residue on silica gel with 4:1 hexanes:ethyl acetate provided the desired product.
MS (DCI/NH3) m/z 458 (M+H)+; *H NMR (300 MHz, CDC13) δ 8.79 (dd, IH), 7.94 (m, 3H), 7.83 (m, IH), 7.65-7.44 (m, 8H), 7.35 (m, IH), 7.30 (m, IH), 7.02 (dd, IH), 5.72 (s, IH), 4.75 (d, 2H).
Example 290 4-(((4-cyanobenzyPoxy)(l,3-thiazol-5-ypmethyP-2-d-naphthyPbenzonitrile
Example 290A 4-(hydroxy(l,3-thiazol-5-vPmethyP-2-(l-naphthyPbenzonitrile The desired product was prepared by substituting 2-triethylsilylthiazole and Example 89C for Example 87F and Example 1A, respectively, in Example IB. MS (ESI(+)) m/z 343 (M+H)+;
1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, IH), 8.03 (m, 3H), 7.87 (d, IH), 7.73 (d, IH), 7.63 (m, 2H), 7.57 (m, IH), 7.50 (m, 2H), 7.41 (m, IH), 6.28 (s, IH).
Example 290B
4-(((4-cyanobenzvPoxy)d,3-thiazol-5-yl)methvD-2-d-naphthvDbenzonitrile The desired product was prepared by substituting Example 290A for Example 289A and 4-cyanobenzyl bromide for example 76A in Example 289. MS (ESI(+)) m/z 458 (M+H)+; XH NMR (500 MHz, CH3OD) δ 9.69 (s, IH), 8.14 (d, IH), 7.98 (m, 3H), 7.79 (m, IH), 7.68 (m, 3H), 7.60-7.51 (m, 4H), 7.49-7.41 (m, 3H), 6.20 (d, IH), 4.78 (m, 2H); Anal. Calcd. for C29Hι9N3OS-HCl: C, 70.51; H, 4.08; N, 8.51. Found: C, 70.42; H, 4.20; N, 8.61.
Example 291
6-(((4-cyano-3-(l-naphthyDphenyD(l,3-thiazol-5-yDmethoxy)methyDnicotinonitrile The desired product was prepared by substituting Example 290A for Example 289A in Example 289 and was converted to the trifluoroacetic acid salt. MS (ESI(+)) m/z 459 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, IH), 8.97 (d, IH), 8.32 (m, IH), 8.08 (m, 3H), 7.98 (d, IH), 7.80 (dd, IH), 7.70-7.37 (m, 7H), 6.33 (s, IH), 4.77 (m, 2H); Anal. Calcd. for C28Hι8N4OS-0.95 C2HF3O2: C, 63.35; H, 3.37; N, 9.88. Found: C, 63.34; H, 3.22; N, 9.87.
Example 292
6-(((4-cyano-3-(l-naphthvDphenyD(3-pyridinyDmethoxy)methyDnicotinonitrile Example 292A 4-(hvdroxy(3-pyridinvDmethvD-2-(l-naphthvDbenzonitrile A solution of 3-iodopyridine (588 mg, 2.87 mmol) in THF (10 mL) at -50 °C was slowly treated with 0.8M isopropyl magnesium bromide (3.6 mL, 2.88 mmol). The mixture was stirred at <-25 °C for approximately 1 hour, treated with Example 89C (491 mg, 1.91 mmol), and stined overnight while warming to room temperature. The reaction was quenched with aqueous NH4CI and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. Chromatography of the residue on silica gel eluting with 70 to 80% ethyl acetate/hexanes provided the desired product. MS (ESI(+)) m/z 337 (M+H)+; lH NMR (300 MHz, CDCI3) δ 8.58 (s, IH), 8.49 (d, IH), 7.93 (m, 2H), 7.80 (dd, IH), 7.70 (ddd, IH), 7.59-7.44 (m, 4H), 7.41 (m, 3H), 7.28 (dd, IH), 5.94 (s, IH).
Example 292B 6-(((4-cyano-3-d-naphthyDphenyD(3-pyridinvDmethoxy)methyDnicotinonitrile trifluoroacetate salt
The desired product was prepared by substituting Example 292A for Example 289A in Example 289B and converting the product to the trifluoroacetate salt. MS (ESI(+)) m/z 453 (M+H)+; XH NMR (500 MHz, CDCI3) δ 8.98 (t, IH), 8.93 (s, IH), 8.71 (d, IH), 8.34 (ddd, IH), 8.25 (m, IH), 8.07 (m, 3H), 7.86-7.77 (m, 3H), 7.70 (dd, IH), 7.67-7.37 (m, 5H), 6.11 (d, IH), 4.84-4.76 (m, 2H).
Anal. Calcd. for C30H20N4O-1.49 C2HF3O2-0.25 H2O: C, 63.19; H, 3.54; N, 8.94. Found: C, 63.17; H, 3.49; N, 9.04.
Following the schemes and the examples described above, the following compounds can be prepared:
Example 296
Example 297
Example 298 Example 302
Example 299
Example 303
Example 300 Example 306
Example 304
Example 301 Example 307
Example 308
Example 311 Example 314
Example 309 Example 312
Example 315
Example 313
Example 310 Example 316
Example 320
Example 317 Example 323
Example 321
Example 318 Example 324
Example 322
Example 319 Example 325 Example 329
Example 326 Example 332
Example 330 Example 327 Example 333
Example 328 Example 331
Example 334
Example Y
Example 336
Example 342
Example 339
Example 337 Example 343
Example 340
Example 344 Example 347 Example 350
Example 345
Example 348 Example 351
Example 346 Example 349 Example 352
Example 353 Example 359
Example 356
Example 360
Example 357
Example 362 Example 358
Example 355
Example 367
Example 363
Example 371
Example 364 Example 368
Example 372
Example 365
Example 369
Example 373
Example 366
Example 370
Example 374 Example 377 Example 380
Example 378 Example 381
Example 375
Example 379 Example 382 Example 376
Example 383 Example 390
Example 386
Example 387
Example 384 Example 391
Example 389
Example 385
Example 392
Example 393 Example 396 Example 399
Example 400
Example 394 Exam le 397
Example 398 Example 401
Example 395
Example 405 Example 408
Example 403 Example 406
Example 404
Example 407 Example 410
Example 411 Example 414
Examle 417
Example 412 Example 415 Example 418
Example 413
Example 416 Example 419
Example 426
Example 420 Example 423
Example 427 Example 424
Example 421
Example 425 Example 422 Example 432
Example 429 Example 435
Example 433
Example 436
Example 434
Example 431
Example 437
Example 444
Example 441
Example 438
Example 445 Example 442
Example 439
Example 443 Example 446
Example 440
Example 450
Example 453
Example 454
Example 451
Example 448
Example 455
Example 452
Example 449
Example 462 Example 456 Example 459
Example 460 Example 463
Example 457
Example 461
Example 458
Example 468 Example 471 Example 465
Example 469 Example 472
Example 466
Example 473
Example 470
Example 467
Example 474
Example 475
Example 481
Example 482
Example 476
Example 479
Example 483
Example 477
Example 480 Example 491
Example 495 Example 484
Example 485 Example 496
Example 492
Example 486 Example 497
Example 493
Example 490 Example 498
Example 494
Example 506
Example 500
Example 504 Example 507
Example 501
Example 502 Example 505 Example 508
Example 515
Example 509 Example 512
Example 516
Example 510
Example 517
Example 511 Example 514
Example 518 Example 526
Example 519
Example 523 Example 527
Example 520
Example 524 Example 528
Example 521
Example 529
Example 525
Example 522
Example 530
Example 531
Example 538
Example 535
Example 532
Example 539
Example 536
Example 533
Example 540 Example 537
Example 534
Example 544 Example 547
Example 541
Example 545
Example 548
Example 542
Example 549
Example 543 Example 546
Example 552
Example 553 Example 556 Example 559
Example 554 Example 557 Example 561
Example 558
Example 555
Example 562
Example 563 Example 569 Example 566
Example 570 Example 564
Example 567
Example 565 Example 571
Example 568
Example 578
Example 572 Example 575
Example 579
Example 576 Example 573
Example 580
Example 577
Example 574 Example 587
Example 581 Example 584
Example 588
Example 582 Example 585
Example 586 Example 589
Example 583
Example 5
Example 590
Example 594
Example 591
Example 597
Example 595 Example 598
Example 592
Example 5 Example 602 Example 605
Example 603
Example 600
Example 606
Example 604 Example 601 Example 607
Example 611
Example 608 Example 614
Example 612
Example 609 Example 615
xample 610 Example 616
Example 613
Example 624
Example 620 Example 617
Example 625
Example 621
Example 618
Example 622
Example 626
Example 619
Example 623
Example 627
Example 634 xample 628
Example 635
Example 629 Example 632
Example 636
Example 630 Example 633
Example 637 Example 643
Example 640
Example 645
Example 641
Example 639 Example 646
Example 642
Example 650 Example 653
Example 647
Example 654 Example 651
Example 648
Example 655 Example 652
Example 649
Example 662
Example 657 Example 660
Example 663
Example 658 Example 661 Example 664
Example 668
Example 665 Example 671
Example 669
Example 666 Example 672
Example 670
Example 667
Example 673
Example 674 Example 680
Example 677
Example 675
Example 681 Example 678
Example 676 Example 682
Example 679
Example 686
Example 690
Example 684 Exam le 687
Example 688 Example 691
Example 685
Example 692
Example 695 Example 698
Example 696
Example 693
Example 700
Example 697
Example 694
Example 701 Example 704 Example 707
Example 702 Example 708 Example 705
Example 709
Example 706
Example 710 Example 716
Example 711 Example 717 Example 714
Example 718 Example 712
Example 715
Example 725 Example 719 Example 722
Example 723 Example 720
Example 727 Example 724
Example 721
Example 728
Example 732 Example 735
Example 729
Example 736
Example 730
Example 737
Example 734
Example 731
Example 747 Example 751
Example 738
Example 748
Example 739 Example 752
Example 749
Example 753 Example 740
Example 750
Example 741 •
Example 754
Example 755
Example 759
Example 763
Example 756
Example 760
Example 764 Example 761
Example 757
Example 765
Example 762
Example 766
Example 773 Example 767
Example 774
Example 771 Example 779 Example 783
Example 775
Example 780
Example 776
Example 784
Example 781
Example 777
Example 785
Example 782
Example 778 Example 786
Example 791
Example 787
Example 794
Example 788
Example 792
Example 795
Example 789
Example 793
Example 796
Example 790
Example 803
Example 797 Example 800
Example 804
Example 798 Example 801
Example 802 Example 805
Example 799
Example 806
Example 807
Example 808
It will be evident to one skilled in the art that the invention is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced within.

Claims

WHAT IS CLAIMED IS
1. A compound of formula (I)
(I), or pharmaceutically acceptable salts thereof, wherein
1 1 1 2
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,
1 2 3 hydroxyl, oxo, and -Q -Q -R ; with the proviso that when A is methylene, the methylene is substituted;
1 2 1
L and L are independently absent or alkylene, wherein the alkylenes defining L
2 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;
1 2 with the proviso that at least one of L or L is present;
M is selected from the group consisting of O, N(R ), N(R )SO2, SO2N(R5) , N(R5)C(O), C(O)N(R5), OC(O), C(O)O, C(O), N(R5)C(O)O, OC(O)N(R5), OC(O)O, N(R5)C(O)N(R5), 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
2 2 are attac chheedd ttoo LL ;
1 4 5
Q is absent or selected from the group consisting of O, N(R ), N(R )C(O),
N(R5)SO2, 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, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
A compound according to Claim 1 of formula (II)
(π), or a pharmaceutically acceptable salt thereof, wherein
1 2 1 1
L , L , M , and R are defined above;
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;
W is C(H)=C(H), X is N, and Y and Z are C(H); or
W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X and its right end attached to the carbon substituted with L ; and 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 C(H) or N; with the proviso that R is present when and only when W is N.
A compound according to Claim 2, wherein
M^s.O;
L is optionally substituted alkylene;
2
L is optionally substituted alkylene; W and Y are N; and X and Z are C(H).
A compound according to Claim 2 wherein,
M1 is O;
L is optionally substituted alkylene;
2
L L iiss ooppttiioonnaallllyy ssuubbstituted alkylene;
W is N=C(H); and X,Y,andZareC(H).
A compound according to Claim 2 wherein
M1 is O;
L is optionally substituted alkylene;
L is optionally substituted alkylene;
WisS;
Y is N; and
XandZareCCH).
6. A compound according to Claim 2, wherein M1 is N(R4);
WisN;
Y is N; and XandZareC(H).
7. A compound according to Claim 2, wherein M1 is N(R4);
W is N=C(H); and X, Y and Z are C(H).
8. A compound according to Claim 2 wherein M1 is N(R4);
WisS;
Y is N; and
X and Z are C(H).
9. A compound according to Claim 1 of formula (HI)
or a pharmaceutically acceptable salt thereof, wherein
R ,ι i •s defined above; 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 W is C(H)=C(H), X is N, and Y and Z are C(H); or W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X
2 and its right end attached to the carbon substituted with L ; and 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 C(H) or N; with the proviso that R is present when and only when W is N.
10. A compound according to Claim 9 wherein W is N;
Y is N; and
X and Z are C(H).
11. A compound according to Claim 9 wherein W is S;
Y is N; and X and Z are C(H).
12. A compound according to Claim 9 wherein W is N=C(H); and
X, Y, and Z are C(H).
13. A compound according to Claim 1 of formula (IN)
CIV), or a pharmaceutically acceptable salt thereof, wherein
1 1 3
Q , R , and R are defined above; 2
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
W is C(H)=C(H), X is N, and Y and Z are C(H); or
W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X
2 and its right end attached to the carbon substituted with L ; and 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
C(H) or N; with the proviso that R is present when and only when W is N.
14. A compound according to Claim 13 wherein Q1 is O;
W is N;
Y is N; and X and Z are CCH).
15. A compound according to Claim 13 wherein Q1 is O;
W is N=C(H); and X, Y, and Z are C(H).
16. A compound according to Claim 13 wherein Q1 is O;
W is S;
Y is N; and X and Z are CCH).
17. A compound according to Claim 13 wherein Q1 is N(R4);
W is N;
Y is N; and X and Z are CCH).
18. A compound according to Claim 13 wherein Q1 is N(R4);
W is N=C(H); and X,Y, andZareC(H).
19. A compound according to Claim 13 wherein Q1 is N(R4);
WisS;
Y is N; and X and Z are C(H).
20. A compound according to Claim 13 wherein Q is S(O)t, wherein t is zero, one, or two; WisN;
Y is N; and X and Z are C(H).
21. A compound according to Claim 13 wherein Q is S(O)t, wherein t is zero, one, or two; W is N=C(H); and X,Y,andZareC(H).
22. A compound according to Claim 13 wherein Q is S(O)t, wherein t is zero, one, or two; WisS;
Y is N; and XandZareC(H).
23. A compound according to Claim 13 wherein Q^sNCR^SOa;
WisN;
Y is N; and XandZareC(H).
24. A compound according to Claim 13 wherein Q1 is N(R5)SO2;
W is N=C(H); and X, Y, and Z are C(H).
25. A compound according to Claim 13 wherein Q1 is N(R5)SO2; W is S; Y is N; and X and Z are C(H).
26. A compound according to Claim 13 wherein Q is absent;
W is N;
Y is N; and
X and Z are C(H).
27. A compound according to Claim 13 wherein Q is absent;
W is N=C(H); and X, Y, and Z are C(H).
28. A compound according to Claim 13 wherein Q is absent; W is S; Y is N; and X and Z are C(H).
29. A compound according to Claim 1 of formula (V)
(V), or pharmaceutically acceptable salts thereof, wherein
Q 2 , R 1 , and R 3 are defined above;
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 W is C(H)=C(H), X is N, and Y and Z are C(H); or W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X
2 and its right end attached to the carbon substituted with L ; and X, Y and Z are C(H); or W is N or S, one of X, Y, or Z is CCH), and the remainder are C(H) or N; with the proviso that R is present when and only when W is N.
30. A compound according to Claim 29 wherein W is N;
Y is N; and
X and Z are C(H).
31. A compound according to Claim 29 wherein W is N=C(H); and
X, Y, and Z are CCH).
32. A compound according to Claim 29 wherein W is S;
Y is N; and X and Z are CCH).
33. A compound according to Claim 1 of formula (XIV)
or a pharmaceutically acceptable salt thereof, wherein
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 W is C(H)=C(H), X is N, and Y and Z are C(H); or
W is C(H)=N or N=C(H), wherein each group is drawn with its left end attached to X and its right end attached to the carbon substituted with L ; and 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 C(H)orN; with the proviso that R is present when and only when W is N.
34. A compound according to Claim 33 wherein WisN;
Y is N; and XandZareC(H).
35. A compound according to Claim 33 wherein W is N=C(H); and
X, Y, and Z are CCH).
36. A compound according to Claim 33 wherein WisS; and
X,Y,andZareC(H).
EP01932712A 2000-04-27 2001-04-25 Substituted phenyl farnesyltransferase inhibitors Withdrawn EP1276726A2 (en)

Applications Claiming Priority (5)

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US563256 1983-12-19
US56325600A 2000-04-27 2000-04-27
US82220501A 2001-04-02 2001-04-02
US822205 2001-04-02
PCT/US2001/013678 WO2001081316A2 (en) 2000-04-27 2001-04-25 Substituted phenyl farnesyltransferase inhibitors

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