Substituted alkylamine derivatives and methods of use

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

DESCRIPTION OF THE INVENTION

[0015] A class of compounds useful in treating cancer and angiogenesis is defined by Formula I

• [0016] wherein each of A¹ and A² is independently C, CH or N;
• [0017] wherein ring A is selected from
  • [0018] a) 5- or 6-membered partially saturated heterocyclyl,
    • [0019] preferably dihydropyran, dihydrothienyl, dihydrofuryl, oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl, dihydro-oxazolyl, dihydro-isothiazolyl, dihydro-isoxazolyl, imidazolinyl and pyrazolinyl,
  • [0020] b) 5- or 6-membered heteroaryl,
    • [0021] preferably
      • [0022] I) 5-membered heteroaryl selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl,
        • [0023] even more preferably 5-membered heteroaryl selected from
      • [0024] II) preferably 6-membered heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl,
        • [0025] even more preferably 6-membered heteroaryl selected from
  • [0026] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl
    • [0027] preferably tetrahydroquinolinyl,
  • [0028] d) 9- or 10-membered fused heteroaryl,
    • [0029] preferably
      • [0030] i) fused 9-membered fused heteroaryl selected from benzothienyl, benzothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuryl, indazolyl and isoindolyl, and
      • [0031] ii) fused 10-membered heteroaryl selected from quinolyl, isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl,
  • [0032] e) naphthyl, and
  • [0033] f) 4-, 5- or 6-membered cycloalkenyl,
    • [0034] preferably 5-membered cycloalkenyl,
      • [0035] more preferably cyclopentadienyl or cyclopentenyl;
• [0036] wherein X is selected from
  • [0037] preferably X is selected from
    • [0038] more preferably X is
• [0039] wherein Z is oxygen or sulfur;
• [0040] wherein Y is selected from
  • [0041] preferably Y is selected from
    • [0042] more preferably Y is selected from
      • [0043] even more preferably Y is —NH—CH₂—;
• [0044] wherein R^a and R^b are independently selected from H, halo, cyano and C_1-4-alkyl substituted with R², or wherein R^a and R^b together form C₃–C₄ cycloalkyl,
  • [0045] preferably H, halo, cyano and C_1-2-alkyl substituted with R², or wherein R^a and R^b together form C₃–C₄ cycloalkyl,
    • [0046] more preferably H, halo and C₁–C₂-alkyl,
      • [0047] even more preferably H;
• [0048] wherein R^z is selected from C₁–C₄ alkylenyl, where one of the CH₂ groups may be substituted with an oxygen atom or an —NH—,
  • [0049] preferably C₁–C₂ alkylenyl, where one of the CH₂ groups may be substituted with an oxygen atom or an —NH—
    • [0050] more preferably C₁–C₂ alkylenyl;
• [0051] wherein R^d is cycloalkyl,
  • [0052] preferably C₃–C₆ cycloalkyl;
• [0053] wherein R is selected from
  • [0054] a) substituted or unsubstituted 5–6 membered heterocyclyl,
    • [0055] preferably substituted or unsubstituted 5–6 membered heteroaryl comprising one or more nitrogen atoms,
      • [0056] more preferably 4-pyrazolyl, triazolyl, 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 4-pyridazinyl, or 6-pyridazinyl,
        • [0057] even more preferably 4-pyridyl, 4-pyrimidinyl and 4-pyridazinyl,
        • [0058] even more preferably 4-pyridyl, and
  • [0059] b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl,
    • [0060] preferably substituted or unsubstituted 9–10 membered fused heteroaryl comprising one or more nitrogen atoms,
      • [0061] more preferably indazolyl, quinolinyl, isoquinolinyl, or quinazolinyl,
        • [0062] even more preferably indazolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 4-isoquinolyl, 5-isoquinolyl, and 6-isoquinolyl,
    • [0063] wherein substituted R is substituted with one or more substituents independently selected from halo, —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R², cyano, nitro, lower alkenyl and lower alkynyl;
      • [0064] preferably halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, —NR³C(O)NR³R³, cycloalkyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted phenyl, C_1-2-alkyl, cyano, C_1-2-hydroxyalkyl, nitro and C_1-2-haloalkyl;
• [0065] wherein R¹ is selected from
  • [0066] a) substituted or unsubstituted 6–10 membered aryl,
    • [0067] preferably phenyl, naphthyl, indenyl, or tetrahydronaphthyl,
      • [0068] more preferably phenyl,
  • [0069] b) substituted or unsubstituted 5–6 membered heterocyclyl,
    • [0070] preferably 5–6 membered heteroaryl,
      • [0071] more preferably thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, or pyrrolyl,
  • [0072] c) substituted or unsubstituted 9–10 membered fused heterocyclyl,
    • [0073] preferably 9–10 membered fused heteroaryl,
      • [0074] more preferably indazolyl, indolyl, 2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl, benzodioxanyl, or quinazolinyl,
  • [0075] d) cycloalkyl, and
  • [0076] e) cycloalkenyl
    • [0077] wherein substituted R¹ is substituted with one or more substituents independently selected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁–C₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R², cyano, nitro, lower alkenyl and lower alkynyl,
      • [0078] preferably R¹ is unsubstituted or substituted with one or more substituents independently selected from halo, —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁–C₂ alkylenylR³), —(C₁–C₂ alkylenyl) NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted phenyl, optionally substituted phenyl-C_1-2-alkylenyl, optionally substituted 5–6 membered heterocyclyl-C_1-2-alkylenyl, C_1-2-alkyl, cyano, C_1-2-hydroxyalkyl, nitro and C_1-2-haloalkyl,
        • [0079] more preferably R¹ is unsubstituted or substituted with one or more substituents selected from chloro, fluoro, bromo, methoxy, phenyloxy, benzyl, methylthio, methyl, ethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, hydroxymethyl, cyano, carboxy, aminocarbonyl, methylcarbonyl, amino, methylamino, cyclopropyl, cyclohexyl, piperidinyl, morpholinyl, N-methylpiperazinyl, N-ethylpiperazinyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, methylaminothiocarbonyl, N-methylamino-methylenyl, optionally substituted phenyl, N,N-diethylamino, or N,N-dimethylamino;
• [0080] wherein R² is one or more substituents independently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl,
  • [0081] preferably R² is one or more substituents independently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted phenyl, C_1-2-alkyl, cyano, C_1-2-hydroxyalkyl, C_1-3-carboxyalkyl, nitro, C_2-3-alkenyl, C_2-3-alkynyl and C_1-2-haloalkyl;
• [0082] wherein R³ is selected from H, lower alkyl, phenyl, 5–6 membered heterocyclyl, C₃–C₆ cycloalkyl, and lower haloalkyl,
  • [0083] preferably H, C_1-2-alkyl, phenyl, C₃–C₆ cycloalkyl, and C_1-2-haloalkyl,
    • [0084] more preferably H, methyl, phenyl, cyclopropyl, cyclohexyl, and trifluoromethyl;
• [0085] wherein R⁴ is independently selected from C_2-4-alkylenyl, C_2-4-alkenylenyl and C_2-4-alkynylenyl, where one of the CH₂ groups may be substituted with an oxygen atom or an —NH—,
  • [0086] preferably C_2-3-alkylenyl where one of the CH₂ groups may be substituted with an oxygen atom or an —NH—, more preferably C₂–C₃ alkylenyl;
• [0087] wherein R⁵ is selected from H, lower alkyl, phenyl and lower aralkyl,
  • [0088] preferably H, methyl or ethyl;
• [0089] wherein R⁶ is selected from H or C_1-6-alkyl,
  • [0090] preferably H or C_1-2 alkyl; and
• [0091] wherein R^c is selected from H, methyl and optionally substituted phenyl;
• [0092] wherein R¹⁴ is selected from H, phenyl, 5–6 membered heterocyclyl and C₃–C₆ cycloalkyl;
• [0093] wherein p is 0 to 2, preferably p is 2;
  and pharmaceutically acceptable salts thereof;
• [0094] provided A is not naphthyl when X is —C(O)NH— and when R¹ is phenyl when Y is —NHCH₂— and when R is 4-pyridyl; further provided A is not pyridyl when X is —C(O)NH— and when R¹ is 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is —N(CH₃)— and when R is 4-methylpiperidinyl; further provided A is not pyridyl when X is —C(O)NH— and when Y is —NHCH₂— and when R is 4-pyridylpiperidin-4-yl, 1-tertbutylpiperidin-4-yl, 1-isopropylpiperidin-4-yl or 1-cycloalkylpiperidin-4-yl; further provided A is not pyridyl when X is —C(O)NH— and when R¹ is 4-[3-(3-pyridyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is —NHCH₂— and when R is 4-pyridyl; and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl.

[0095] The invention also relates to compounds of Formula II

• [0096] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0097] preferably H;
• [0098] wherein n is 0–2;
  • [0099] preferably 1–2;
• [0100] wherein R is selected from
  • [0101] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0102] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0103] preferably 4-pyridyl, pyrimidinyl, triazolyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
• [0104] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
  • [0105] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0106] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0107] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0108] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
      • [0109] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0110] wherein R² is one or more substituents independently selected from
  • [0111] H,
  • [0112] halo,
  • [0113] C_1-6-alkyl,
  • [0114] C_1-6-haloalkyl,
  • [0115] C_1-6-alkoxy,
  • [0116] C_1-6-haloalkoxy,
  • [0117] C_1-6-carboxyalkyl,
  • [0118] unsubstituted or substituted aryl and
  • [0119] unsubstituted or substituted 5–6 membered heteroaryl;
• [0120] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected
  • [0121] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0122] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0123] The invention also relates to compounds of Formula III

• [0124] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0125] preferably H;
• [0126] wherein n is 0–2;
  • [0127] preferably 1–2;
• [0128] wherein R is selected from
  • [0129] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0130] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0131] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
• [0132] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
  • [0133] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0134] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0135] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0136] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
      • [0137] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0138] wherein R² is one or more substituents independently selected from
  • [0139] H,
  • [0140] halo,
  • [0141] C_1-6-alkyl,
  • [0142] C_1-6-haloalkyl,
  • [0143] C_1-6-alkoxy,
  • [0144] C_1-6-haloalkoxy,
  • [0145] C_1-6-carboxyalkyl,
  • [0146] unsubstituted or substituted aryl and
  • [0147] unsubstituted or substituted 5–6 membered heteroaryl;
• [0148] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0149] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0150] The invention also relates to compounds of Formula IV

• [0151] wherein A³ is selected from CR² and N;
• [0152] wherein A⁴ is selected from CR² and N; provided one of A³ and A⁴ is not CR²;
• [0153] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0154] preferably H;
• [0155] wherein n is 0–2;
  • [0156] preferably 1–2;
• [0157] wherein R is selected from
  • [0158] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0159] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0160] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0161] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
    • [0162] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0163] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0164] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0165] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0166] wherein R² is one or more substituents independently selected from
  • [0167] H,
  • [0168] halo,
  • [0169] C_1-6-alkyl,
  • [0170] C_1-6-haloalkyl,
  • [0171] C_1-6-alkoxy,
  • [0172] C_1-6-haloalkoxy,
  • [0173] C_1-6-carboxyalkyl,
  • [0174] unsubstituted or substituted aryl and
  • [0175] unsubstituted or substituted 5–6 membered heteroaryl;
  • [0176] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0177] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0178] The invention also relates to compounds of Formula V

• [0179] wherein A⁵ is selected from S, O and NR⁶;
• [0180] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0181] preferably H;
• [0182] wherein n is 0–2;
  • [0183] preferably 1–2;
• [0184] wherein R is selected from
  • [0185] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0186] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0187] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0188] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
    • [0189] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0190] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0191] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0192] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
  • [0193] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0194] wherein R² is one or more substituents independently selected from
  • [0195] H,
  • [0196] halo,
  • [0197] C_1-6-alkyl,
  • [0198] C_1-6-haloalkyl,
  • [0199] C_1-6-alkoxy,
  • [0200] C_1-6-haloalkoxy,
  • [0201] C_1-6-carboxyalkyl,
  • [0202] unsubstituted or substituted aryl and
  • [0203] unsubstituted or substituted 5–6 membered heteroaryl;
  • [0204] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0205] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0206] The invention also relates to compounds of Formula VI

• [0207] wherein A⁵ is selected from S, O and NR⁶;
• [0208] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0209] preferably H;
• [0210] wherein n is 0–2;
  • [0211] preferably 1–2;
• [0212] wherein R is selected from
  • [0213] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0214] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0215] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0216] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
    • [0217] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0218] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0219] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0220] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted he3eroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
  • [0221] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0222] wherein R² is one or more substituents independently selected from
  • [0223] H,
  • [0224] halo,
  • [0225] C_1-6-alkyl,
  • [0226] C_1-6-haloalkyl,
  • [0227] C_1-6-alkoxy,
  • [0228] C_1-6-haloalkoxy,
  • [0229] C_1-6-carboxyalkyl,
  • [0230] unsubstituted or substituted aryl and
  • [0231] unsubstituted or substituted 5–6 membered heteroaryl;
  • [0232] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and

[0234] The invention also relates to compounds of Formula VII

• [0235] wherein A⁵ is selected from S, O and NR⁶;
• [0236] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N (R⁶)₂,
  • [0237] preferably H;
• [0238] wherein n is 0–2;
  • [0239] preferably 1–2;
• [0240] wherein R is selected from
  • [0241] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0242] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0243] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0244] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
    • [0245] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0246] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0247] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0248] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
      • [0249] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0250] wherein R² is one or more substituents independently selected from
  • [0251] H,
  • [0252] halo,
  • [0253] C_1-6-alkyl,
  • [0254] C_1-6-haloalkyl,
  • [0255] C_1-6-alkoxy,
  • [0256] C_1-6-haloalkoxy,
  • [0257] C_1-6-carboxyalkyl,
  • [0258] unsubstituted or substituted aryl and
  • [0259] unsubstituted or substituted 5–6 membered heteroaryl;
  • [0260] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0261] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0262] The invention also relates to compounds of Formula VIII

• [0263] wherein A⁵ is selected from S, O and NR⁶;
• [0264] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0265] preferably H;
• [0266] wherein n is 0–2;
  • [0267] preferably 1–2;
• [0268] wherein R is selected from
  • [0269] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0270] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0271] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0272] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
    • [0273] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0274] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0275] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0276] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
      • [0277] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0278] wherein R² is one or more substituents independently selected from
  • [0279] H,
  • [0280] halo,
  • [0281] C_1-6-alkyl,
  • [0282] C_1-6-haloalkyl,
  • [0283] C_1-6-alkoxy,
  • [0284] C_1-6-haloalkoxy,
  • [0285] C_1-6-carboxyalkyl,
  • [0286] unsubstituted or substituted aryl and
  • [0287] unsubstituted or substituted 5–6 membered heteroaryl;
  • [0288] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0289] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0290] The invention also relates to compounds of Formula IX

• [0291] wherein A⁵ is selected from S, O and NR⁶;
• [0292] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0293] preferably H;
• [0294] wherein n is 0–2;
  • [0295] preferably 1–2;
• [0296] wherein R is selected from
  • [0297] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0298] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0299] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0300] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
    • [0301] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0302] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0303] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0304] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
      • [0305] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0306] wherein R² is one or more substituents independently selected from
  • [0307] H,
  • [0308] halo,
  • [0309] C_1-6-alkyl,
  • [0310] C_1-6-haloalkyl,
  • [0311] C_1-6-alkoxy,
  • [0312] C_1-6-haloalkoxy,
  • [0313] C_1-6-carboxyalkyl,
  • [0314] unsubstituted or substituted aryl and
  • [0315] unsubstituted or substituted 5–6 membered heteroaryl;
  • [0316] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected
  • [0317] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0318] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0319] The invention also relates to compounds of Formula X

• [0320] wherein A⁵ is selected from S, O and NR⁶;
• [0321] wherein A⁶ is selected from N and CR²;
• [0322] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0323] preferably H;
• [0324] wherein n is 0–2;
  • [0325] preferably 1–2;
• [0326] wherein R is selected from
  • [0327] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0328] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0329] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
    • [0330] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
      • [0331] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0332] wherein R¹ is selected from unsubstituted or substituted aryl, 5–6-membered heteroaryl and 9–10 membered fused heteroaryl,
  • [0333] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0334] wherein R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5–6 membered heterocyclyl-C₁–C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
    • [0335] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0336] wherein R² is one or more substituents independently selected from
  • [0337] H,
  • [0338] halo,
  • [0339] C_1-6-alkyl,
  • [0340] C_1-6-haloalkyl,
  • [0341] C_1-6-alkoxy,
  • [0342] C_1-6-haloalkoxy,
  • [0343] C_1-6-carboxyalkyl,
  • [0344] unsubstituted or substituted aryl and
  • [0345] unsubstituted or substituted 5–6 membered heteroaryl;
  • [0346] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected
    • [0347] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0348] wherein

[0350] The invention also relates to compounds of Formula II′

• [0351] wherein R is selected from
  • [0352] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl,
  • [0353] preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl, triazolyl, and pyridazinyl,
    • [0354] more preferably 4-pyridyl, and
  • [0355] b) unsubstituted or substituted 9- or 10-membered fused heterocyclyl
  • [0356] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzotriazolyl, 2,3-dihydrobenzofuryl, 2-oxo-1,2-dihydroquinol-7-yl, naphthyridinyl and quinozalinyl,
  • [0357] where substituted R is substituted with one or more substituents selected from halo, amino, hydroxy, oxo, C_1-6-alkyl, C_1-6-haloalkyl, C_1-6-alkoxy, optionally substituted heterocyclyl-C_1-6-alkoxy, optionally substituted heterocyclyl-C_1-6-alkylamino, optionally substituted heterocyclyl-C_1-6-alkyl, C_1-6-alkylamino-C_1-6--alkynyl, C_1-6-alkylamino-C_1-6-alkoxy, C_1-6-alkylamino-C_1-6-alkoxy-C_1-6-alkoxy, and optionally substituted heterocyclyl-C_2-4-alkynyl,
    • [0358] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0359] wherein R¹ is selected from unsubstituted or substituted
  • [0360] aryl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, and naphthyl,
  • [0361] cycloalkyl, preferably cyclohexyl,
  • [0362] 5–6 membered heteroaryl, preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl, and
  • [0363] 9–10 membered bicyclic and 13–14 membered tricyclic heterocyclyl, preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, benzo[d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
• [0364] wherein substituted R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C₁–C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted 4–6 membered heterocyclyl-C₁–C₄-alkylenyl, optionally substituted 4–6 membered heterocyclyl-C₂–C₄-alkenylenyl, optionally substituted 4–6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4–6 membered heterocyclyloxy, optionally substituted 4–6 membered heterocyclyl-C_1-4-alkyloxy, optionally substituted 4–6 membered heterocyclylsulfonyl, optionally substituted 4–6 membered heterocyclylamino, optionally substituted 4–6 membered heterocyclylcarbonyl, optionally substituted 4–6 membered heterocyclyl-C_1-4-alkylcarbonyl, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, —NHC(O)NH₂, alkylcarbonylamino, hydroxy, oxo, cyano, aminosulfonyl, C_1-2-alkylsulfonyl, halosulfonyl, C_1-4-alkylcarbonyl, C₁₃-alkylamino-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkoxy, C_1-3-alkylamino-C_1-3-alkoxy-C_1-3-alkoxy, C_1-4-alkoxycarbonyl, C_1-4-alkoxycarbonylamino-C_1-4-alkyl, C_1-4-hydroxyalkyl,
• [0365]  and C_1-4-alkoxy,
  • [0366] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, 1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl, 1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl, 1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl, 4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl), imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl, 1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0367] wherein R² is one or more substituents independently selected from
  • [0368] H,
  • [0369] halo,
  • [0370] hydroxy,
  • [0371] amino,
  • [0372] C_1-6-alkyl,
  • [0373] C_1-6-haloalkyl,
  • [0374] C_1-6-alkoxy,
  • [0375] C_1-2-alkylamino,
  • [0376] aminosulfonyl,
  • [0377] C_3-6-cycloalkyl,
  • [0378] cyano,
  • [0379] C_1-2-hydroxyalkyl,
  • [0380] nitro,
  • [0381] C_2-3-alkenyl,
  • [0382] C_2-3-alkynyl,
  • [0383] C_1-6-haloalkoxy,
  • [0384] C_1-6-carboxyalkyl,
  • [0385] 5–6-membered heterocyclyl-C_1-6-alkylamino,
  • [0386] unsubstituted or substituted phenyl and
  • [0387] unsubstituted or substituted 5–6 membered heterocyclyl;
  • [0388] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0389] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0390]  preferably a direct bond, ethyl, butyl, and
• [0391] wherein R^z is selected from C_1-2-alkyl, C_2-6-branched alkyl, C_2-4-branched haloalkyl, amino-C_1-4-alkyl and C_1-2-alkylamino-C_1-2-alkyl,
  • [0392] preferably methylenyl, ethylenyl,
  • [0393]  and aminoethylenyl;
• [0394] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,

[0398] The invention also relates to compounds of Formula XI

• [0399] wherein R is selected from
  • [0400] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl,
    • [0401] preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl, triazolyl, and pyridazinyl, more preferably 4-pyridyl, and
  • [0402] b) unsubstituted or substituted 9- or 10-membered fused heteroaryl
    • [0403] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzotriazolyl, naphthyridinyl and quinozalinyl,
  • [0404] where substituted R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl, C_1-6-alkoxy, optionally substituted heterocyclyl-C_1-6-alkoxy, optionally substituted heterocyclyl-C_1-6-alkylamino, optionally substituted heterocyclyl-C_1-6-alkyl, C_1-6-alkylamino-C_2-4-alkynyl, C_1-6-alkylamino-C_1-6-alkoxy, C_1-6-alkylamino-C_1-6-alkoxy-C_1-6-alkoxy, and optionally substituted heterocyclyl-C_2-4-alkynyl,
    • [0405] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0406] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0407] cycloalkyl,
  • [0408] 5–6 membered heteroaryl and
  • [0409] 9–10 membered bicyclic and 13–14 membered tricyclic heterocyclyl,
  • [0410] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, benzo[d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl and benzthiazolyl,
    • [0411] specifically 4–6 membered saturated or partially un-saturated monocyclic heterocyclyl,
      • [0412] 9–10 membered saturated or partially un-saturated bicyclic heterocyclyl, and
      • [0413] 13–14 membered saturated or partially un-saturated tricyclic heterocyclyl,
      • [0414] more specifically 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1H-indolyl, benzo[d]isothiazolyl, dihydro-benzimidazolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, and tetrahydroquinolinyl,
• [0415] wherein substituted R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C₁–C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted 4–6 membered heterocyclyl-C_1-4-alkyl, optionally substituted 4–6 membered heterocyclyl-C₂–C₄-alkenyl, optionally substituted 4–6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4–6 membered heterocyclyloxy, optionally substituted 4–6 membered heterocyclyl-C₁–C₄-alkoxy, optionally substituted 4–6 membered heterocyclylsulfonyl, optionally substituted 4–6 membered heterocyclylamino, optionally substituted 4–6 membered heterocyclylcarbonyl, optionally substituted 5–6 membered heterocyclyl-C_1-4-alkylcarbonyl, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, C_1-2-alkylsulfonyl, halosulfonyl, C_1-4-alkylcarbonyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkoxy, C_1-3-alkylamino-C_1-3-alkoxy-C_1-3-alkoxy, C_1-4-alkoxycarbonyl, C_1-4-alkoxycarbonylamino-C_1-4-alkyl, C_1-4-hydroxyalkyl,
• [0416]  and C_1-4-alkoxy,
  • [0417] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, 1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl, 1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl, 1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl, 4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl), imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl, 1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0418] wherein R² is one or more substituents independently selected from
  • [0419] H,
  • [0420] halo,
  • [0421] hydroxy,
  • [0422] amino,
  • [0423] C_1-6-alkyl,
  • [0424] C_1-6-haloalkyl,
  • [0425] C_1-6-alkoxy,
  • [0426] C_1-2-alkylamino,
  • [0427] aminosulfonyl,
  • [0428] C_3-6-cycloalkyl,
  • [0429] cyano,
  • [0430] C_1-2-hydroxyalkyl,
  • [0431] nitro,
  • [0432] C_2-3-alkenyl,
  • [0433] C_2-3-alkynyl,
  • [0434] C_1-6-haloalkoxy,
  • [0435] C_1-6-carboxyalkyl,
  • [0436] 5–6-membered heterocyclyl-C_1-6-alkylamino,
  • [0437] unsubstituted or substituted phenyl and
  • [0438] unsubstituted or substituted 5–6 membered heterocyclyl,
  • [0439] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl,
    • [0440] specifically chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl, unsubstituted or substituted phenyl and unsubstituted or substituted
      • [0441] heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0442] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0443]  preferably a direct bond, ethyl, butyl, and
• [0444] wherein R^z is selected from C_1-2-alkyl, C_2-6-branched alkyl, C_2-4-branched haloalkyl, amino-C_1-4-alkyl and C_1-2-alkylamino-C_1-2-alkyl,
  • [0445] preferably methylenyl, ethylenyl,
  • [0446]  and aminoethylenyl;
• [0447] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0448] preferably trifluoromethyl; and
• [0449] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-3-alkyl, optionally substituted 4–6 membered heterocyclyl, optionally substituted 4–6 membered heterocyclyl-C₁–C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl;
• [0450] provided R¹ is substituted with optionally substituted phenyloxy, optionally substituted 4–6 membered heterocyclyloxy, optionally substituted 4–6 membered heterocyclyl-C_1-4-alkoxy, optionally substituted 4–6 membered heterocyclylsulfonyl, optionally substituted 4–6 membered heterocyclylamino, optionally substituted 4–6 membered heterocyclylcarbonyl, optionally substituted 4–6 membered heterocyclyl-C_1-4-alkylcarbonyl, C_1-3-alkylamino-C_1-3-alkoxy, or C_1-3-alkylamino-C_1-3-alkoxy-C_1-3-alkoxy; further provided R is not 3-pyridyl when R⁵ is CH₂;
  and pharmaceutically acceptable isomers and derivatives thereof.

[0451] The invention also relates to compounds of Formula XII

• [0452] wherein R¹ is selected from unsubstituted or substituted
  • [0453] aryl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, and naphthyl,
  • [0454] cycloalkyl, preferably cyclohexyl,
  • [0455] 5–6 membered heteroaryl, preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl, and
  • [0456] 9–10 membered bicyclic and 13–14 membered tricyclic heterocyclyl, preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, benzo [d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo [3,4-a]isoquinolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
• [0457] wherein substituted R¹ is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C₁–C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted 4–6 membered heterocyclyl-C₁–C₄-alkyl, optionally substituted 4–6 membered heterocyclyl-C₂–C₄-alkenyl, optionally substituted 4–6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4–6 membered heterocyclyloxy, optionally substituted 4–6 membered heterocyclyl-C₁–C₄-alkoxy, optionally substituted 4–6 membered heterocyclylsulfonyl, optionally substituted 4–6 membered heterocyclylamino, optionally substituted 4–6 membered heterocyclylcarbonyl, optionally substituted 5–6 membered heterocyclyl-C_1-4-alkylcarbonyl, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, C_1-2-alkylsulfonyl, halosulfonyl, C_1-4-alkylcarbonyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkoxy, C_1-3-alkylamino-C_1-3-alkoxy-C_1-3-alkoxy, C_1-4-alkoxycarbonyl, C_1-4-alkoxycarbonylamino-C_1-4-alkyl, C_1-4-hydroxyalkyl,
• [0458]  and C_1-4-alkoxy,
  • [0459] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, 1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl, 1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl, 1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl, 4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl), imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl, 1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0460] wherein R² is one or more substituents independently selected from
  • [0461] H,
  • [0462] halo,
  • [0463] hydroxy,
  • [0464] amino,
  • [0465] C_1-6-alkyl,
  • [0466] C_1-6-haloalkyl,
  • [0467] C_1-6-alkoxy,
  • [0468] C_1-2-alkylamino,
  • [0469] aminosulfonyl,
  • [0470] C_3-6-cycloalkyl,
  • [0471] cyano,
  • [0472] C_1-2-hydroxyalkyl,
  • [0473] nitro,
  • [0474] C_2-3-alkenyl,
  • [0475] C_2-3-alkynyl,
  • [0476] C_1-6-haloalkoxy,
  • [0477] C_1-6-carboxyalkyl,
  • [0478] 5–6-membered heterocyclyl-C_1-6-alkylamino,
  • [0479] unsubstituted or substituted phenyl and
  • [0480] unsubstituted or substituted 5–6 membered heterocyclyl,
  • [0481] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl, unsubstituted or substituted phenyl and unsubstituted or substituted
    • [0482] heteroaryl selected from thienyl, fury, pyridyl, imidazolyl, and pyrazolyl;
• [0483] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl, preferably trifluoromethyl;
• [0484] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-3-alkyl, optionally substituted 4–6 membered heterocyclyl, optionally substituted 4–6 membered heterocyclyl-C₁–C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl; and
• [0485] wherein R²⁰ is one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl, C_1-6-alkoxy, optionally substituted heterocyclyl-C_1-6-alkoxy, optionally substituted heterocyclyl-C_1-6-alkylamino, optionally substituted heterocyclyl-C_1-6-alkyl, C_1-6-alkylamino-C_2-4-alkynyl, C_1-6-alkylamino-C_1-6-alkoxy, C_1-6-alkylamino-C_1-6-alkoxy-C_1-6-alkoxy, and optionally substituted heterocyclyl-C_2-4-alkynyl,
  • [0486] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
    and pharmaceutically acceptable isomers and derivatives thereof.

INDICATIONS

DEFINITIONS

[0879] The present invention also comprises a method of treating angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically-effective amount of a compound of Formula I

• [0880] wherein each of A¹ and A² is independently C, CH or N;
• [0881] wherein ring A is selected from
  • [0882] a) 5- or 6-membered partially saturated heterocyclyl,
  • [0883] b) 5- or 6-membered heteroaryl,
  • [0884] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl,
  • [0885] d) 9-, 10- or 11-membered fused heteroaryl;
  • [0886] e) naphthyl, and
  • [0887] f) 4-, 5- or 6-membered cycloalkenyl;
• [0888] wherein X is
• [0889] wherein Z is oxygen or sulfur;
• [0890] wherein Y is selected from
• [0891] wherein p is 0 to 2,
• [0892] wherein R^a and R^b are independently selected from H, halo, cyano, —NHR⁶ and C_1-4-alkyl substituted with R², or wherein R^a and R^b together form C₃–C₆ cycloalkyl;
• [0893] wherein R^z is selected from C₂–C₆-alkylenyl, where one of the CH₂ groups may be replaced with an oxygen atom or an —NH—; wherein one of the CH₂ groups may be substituted with one or two radicals selected from halo, cyano, —NHR⁶ and C_1-4-alkyl substituted with R²;
• [0894] wherein R^d is cycloalkyl;
• [0895] wherein R is selected from
  • [0896] a) substituted or unsubstituted 5–6 membered heterocyclyl, b) substituted aryl, and
    • [0897] c) substituted or unsubstituted fused 9–14-membered bicyclic or tricyclic heterocyclyl;
    • [0898] wherein substituted R is substituted with one or more substituents independently selected from halo, —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted phenyl, nitro, alkylaminoalkoxyalkoxy, cyano, alkylaminoalkoxy, lower alkyl substituted with R², lower alkenyl substituted with R², and lower alkynyl substituted with R²;
• [0899] wherein R¹ is selected from
  • [0900] a) substituted or unsubstituted 6–10 membered aryl,
  • [0901] b) substituted or unsubstituted 5–6 membered heterocyclyl,
  • [0902] c) substituted or unsubstituted 9–14 membered bicyclic or tricyclic heterocyclyl,
  • [0903] d) cycloalkyl, and
  • [0904] e) cycloalkenyl,
    • [0905] wherein substituted R¹ is substituted with one or more substituents independently selected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³ R³, —NH(C₁–C₄ alkylenyl R¹⁴), —SO₂R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted phenyl, halosulfonyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, lower alkyl substituted with R², lower alkenyl substituted with R², and lower alkynyl substituted with R²;
• [0906] wherein R² is one or more substituents independently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5–6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl;
• [0907] wherein R³ is selected from H, lower alkyl, phenyl, heterocyclyl, C₃–C₆-cycloalkyl, phenylalkyl, heterocyclylalkyl, C₃–C₆ cycloalkylalkyl, and lower haloalkyl;
• [0908] wherein R⁴ is selected from a direct bond, C_2-4-alkylenyl, C_2-4-alkenylenyl and C_2-4-alkynylenyl, where one of the CH₂ groups may be substituted with an oxygen atom or an —NH—, wherein R⁴ is optionally substituted with hydroxy;
• [0909] wherein R⁵ is selected from H, lower alkyl, phenyl and lower aralkyl;
• [0910] wherein R^5a is selected from H, lower alkyl, phenyl and lower aralkyl;
• [0911] wherein R⁶ is selected from H or C_1-6-alkyl; and
• [0912] wherein R¹⁴ is selected from H, phenyl, 5–6 membered heterocyclyl and C₃–C₆ cycloalkyl;
  and pharmaceutically acceptable derivatives thereof; provided A is not naphthyl when X is —C(O)NH— and when R¹ is phenyl when Y is —NCH₂— and when R is 4-pyridyl; and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is —NHCH₂—.

COMBINATIONS

GENERAL SYNTHETIC PROCEDURES

[0930] The compounds of the invention can be synthesized according to the following procedures of Schemes 1–48, wherein the substituents are as defined for Formulas I–XII, above, except where further noted.

[0931] Cyclic amides can be prepared according to the method set out in Scheme 1. The amino group of compound 1 (where R^o is alkyl, aryl, and the like) is protected, such as with Boc anhydride, followed by treatment, to remove the ester, such as with base, forming the protected amine/free acid 2. Alternatively, other amino protecting groups known in the art can be used. Substituted amines are coupled with the free acid, such as with EDC, to form the protected amine/amide 3. The protected amine moiety is deprotected, such as with acid, and reacted via one step reductive alkylation with carbonyl-containing compounds (where R′ is H, halo, cyano, —NHR⁶ and C_1-4 alkyl) to form the 1-amido-2-substituted amino-compounds 4. Preferably the amination is in an alcohol, such as MeOH, EtOH or propanol, and at a temperature between about 0–50° C., such as RT. Aldehydes or ketones are preferred carbonyl-containing compounds. Alternative carbonyl-containing compounds are, for example, bisulfite adducts or hemiacetals, acetals, hemiketals or ketals of compounds with alcohols, for example lower hydroxyalkyl compounds; or thioacetals or thioketals of compounds with mercaptans, for example lower alkylthio compounds. The reductive alkylation is preferably carried out with hydrogenation in the presence of a catalyst, such as platinum or especially palladium, which is preferably bonded to a carrier material, such as carbon, or a heavy metal catalyst, such as Raney nickel, at normal pressure or at pressures of from 0.1 to 10 MegaPascal (MPa), or with reduction by means of complex hydrides, such as borohydrides, especially alkali metal cyanoborohydrides, for example sodium cyanoborohydride, in the presence of a suitable acid, preferably relatively weak acids, such as lower alkylcarboxylic acids, especially acetic acid, or a sulfonic acid, such as p-toluenesulfonic acid; in customary solvents, for example alcohols, such as MeOH or EtOH, or ethers, for example cyclic ethers, such as THF, in the presence or absence of water.

[0932] Alternatively, compounds 4 can be prepared from mixed acid/amines 5 as shown in Scheme 2. Substituted amines are coupled with the mixed acid/amines 5 such as with a coupling reagent, for example EDC, to form the mixed amine/amide 6. Substituted carbonyl compounds, such as acid halides, anhydrides, carboxylic acids, esters, ketones, aldehydes and the like, are added to the mixed amine/amide 6 followed with reduction to give the substituted amide/substituted amine compounds 4.

[0933] Imino compounds 7 can be formed from the mixed amine/amides 6, such as by reacting with a substituted carbonyl compound.

[0934] Substituted cyclic carboxamides can be prepared from the corresponding imino analogs by the process outlined in Scheme 4. Treatment of the imino compound 7 with a reducing agent yields compound 4. Reagents which can be used to add hydrogen to an imine double bond include borane in THF, LiAlH₄, NaBH₄, sodium in EtOH and hydrogen in the presence of a catalyst, and others.

[0938] The amination is preferably carried out in an inert, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, for example DMF or dimethylacetamide, a cyclic ether, for example THF or dioxane, or a nitrile, for example CH₃CN, or in a mixture thereof, at an appropriate temperature, for example in a temperature range of from about 40° C. to about 180° C., and if necessary under an inert gas atmosphere, for example a nitrogen or argon atmosphere.

[0939] Substituted carboxamides 4 can be prepared from the corresponding halo analogs 8 by the process outlined in Scheme 6. The chloro acid 8 is coupled with an amine, preferably in the presence of a coupling agent such as EDC, to form the corresponding chloro amide 10. Substituted amino-amides 4 are prepared from the corresponding chloro compounds 10 such as by reacting with an amine at a suitable temperature, such as about 80° C. The amination reaction can be run in the presence of an appropriate catalyst such as a palladium catalyst, in the presence of an aprotic base such as sodium t-butoxide or cesium carbonate, or a nickel catalyst, or a copper catalyst.

[0940] Substituted carboxamides 4 can be prepared from the corresponding bromo/chloro analogs 11 by the process outlined in Scheme 7. The bromo/chloro acid 11 is coupled with an amine, preferably in the presence of a coupling agent such as EDC, to form the corresponding bromo substituted amide 12. Suzuki coupling with the bromo amide 12 and suitable boronic acids provides the substituted amide 10. Substituted amino-amides 4 are prepared from the corresponding chloro compounds 10 as described in Scheme 6.

[0941] Substituted thiophenes 16 can be prepared by the method of Scheme 8. The free amino group of a 3-amino-2-thiophenecarboxylic acid ester 13 can be protected such as by the addition of Boc₂O in a suitable solvent such as CH₂Cl₂ and DMAP. The ester is removed such as with base to form the free acid 14. The thiophene amide 15 is formed from the acid 14 such as by coupling with a substituted amine in the presence of DIEA, EDC and HOBt. The 2-protected-amino-thiophene amide 15 is deprotected, such as with 25% TFA/CH₂Cl₂. The free amine is alkylated such as with a substituted carboxaldehyde or similar active carbonyl compound, in the presence of a reducing agent NaCNBH₃ and the like, to form compounds 16.

[0942] Substituted pyridines can be prepared such as by the method found in Scheme 9. 2-Aminonicotinic acid 17 is coupled with a substituted amine at a suitable temperature, nonprotic solvent such as CH₂Cl₂, such as with EDC and HOBt, to form the nicotinamide 18. The nicotinamide 18 is reductively alkylated such as with 4-pyridinecarboxaldehyde and NaBH(OAc)₃, to yield the 2-substituted amino-pyridyl carboxamides 19.

[0944] Alternatively, 2-chloro-nicotinoyl chloride (LG is Cl) is coupled first with R¹—NH₂ such as in the presence of base, e.g., NaHCO₃, in a suitable solvent, such as CH₂Cl₂, to form the amide 20A, then coupling with a pyridylmethylamine to yield the 2-substituted amino-nicotinamide 19.

[0945] Imino-substituted pyridines may be prepared by the method found in Scheme 11. (2-Amino-(4-pyridyl))-carboxamide 23 is reacted with 4-pyridine-carboxaldehyde, such as in the presence of p-toluenesulfonic acid monohydrate to yield the imino compound 24.

[0946] Substituted pyridines alternatively may be prepared by the method found in Scheme 12. The imino compound 24 is reduced, such as with NaBH₄, to form the substituted amine 25.

[0947] Substituted pyridines can be prepared by the process outlined in Scheme 13. A solution of sodium hypobromide is freshly prepared and added to 2-hydroxynicotinic acid 26 and heated, preferably at a temperature at about 50° C. Additional sodium hypobromide may be needed to form the bromo compound 27. The 5-bromo-2-hydroxynicotinic acid 27 is reacted with thionyl chloride, preferably at a temperature >RT, more preferably at about 80° C. to form the 2-chloro-nicotinic acid analog 28. The acid is coupled with an amine, preferably in the presence of EDC, HOBT, and DIEA to form the corresponding substituted amide 29. Suzuki coupling with the bromo amide and suitable boronic acids, provides the substituted nicotinamide 30. 2-Amino-nicotinamides 31 are prepared from the corresponding chloro compounds 30 such as by reacting with substituted amines at a suitable temperature, such as about 80° C.

[0953] Alcoholic solvents, for example EtOH, or aromatic solvents, for example benzene or toluene, may also be used. When alkali metal hydroxides are present as bases, acetone may also be added where appropriate.

[0954] Substituted pyridines can be prepared by the process outlined in Scheme 15. 2-Chloronicotinic acid 33 and substituted amine are coupled under conditions similar to that described in the previous schemes to give the amide 34. 6-Chloro-2-aminopyridines 35 are prepared from the amide 34, such as by reacting with substituted amines at a suitable temperature, such as above about 80° C., preferably above about 100° C., more preferably at about 130° C., neat. 6-Chloro-2-aminopyridines 35 are de-chlorinated such as by hydrogenation, for example by treatment with H₂ in the presence of Pd/C, to yield other compounds of the present invention 36.

[0955] 1,2,3,6-Tetrahydro-pyridyl substituted anilines are prepared such as by the procedure described in Scheme 16 (where R^x is a substituent selected from those available for substituted R¹). Nitrobenzenes 37 are brominated, such as with bromine in the presence of acid, H₂SO₄ for example, or with NBS to yield the 3-bromo derivative 38. Suzuki coupling of the bromo-derivative 38 and a substituted pyridylboronic acid, in an appropriate solvent such as toluene, such as at a temperature above RT, preferably above about 50° C., and more preferably at about 80° C., yields the pyridyl derivative 39. Alkylation of the nitrophenyl-pyridine 39, such as by treatment with iodomethane, preferably above about 50° C., and more preferably at about 80° C., yields the pyridinium compound 40, which upon reduction, such as by NaBH₄, yields the tetrahydyropyridine 41.

[0956] 6-Amino substituted pyridines are prepared such as by the procedure described in Scheme 17. Similar to the method of Scheme 13, chloropyridine 42 and is reacted with an amine, preferably above about 50° C., and more preferably at about 80° C., to yield the 6-aminopyridines 43.

[0959] Sulfonamide substituted anilines can be prepared from nitrobezenesulfonyl chlorides 48. Coupling of nitrobezenesulfonyl chlorides 48 with reactive heterocyclic compounds, such as substituted piperazines, piperidines, and the like, in a protic solvent such as EtOH, such as at a temperature about RT, yields the nitrobezenesulfonamides 48. Reduction of the nitro benzenesulfonamide, such as with iron powder, preferably above about 50° C., and more preferably at about 80° C., yields the aniline 49.

[0961] Reduction of the nitrobenzenes 51, such as with iron powder, at a temperature above about 50° C., and preferably at about 80° C., yields the aniline 52. Hydrogenation, such as with H₂ in the presence of catalyst, such as Pd/C, is also possible.

[0964] Alternatively, piperazinyl substituted anilines 61 can be prepared by the treatment of a fluoro-nitro-substituted aryl compounds 59. The fluoro-nitro-substituted aryl compounds 59 and 1-substituted piperazines are heated, preferably neat, at a temperature above about 50° C., and preferably at about 90° C., to yield the piperazinyl-nitroaryl compounds 60. Hydrogenation, such as with H₂ atmosphere in the presence of a catalyst, such as 10% Pd/C, gives the substituted aniline 61.

[0966] Alternatively, substituted amino-indolines 67 are prepared from the nitroindoline 62. Nitroindoline 62, is reacted with an acid chloride to form an amide. Further treatment with a primary or secondary amine, preferably a secondary amine, such as in the presence of NaI, at a temperature above about 50° C., and preferably at about 70° C. yields the nitroindoline 65. The nitro compound 65 is hydrogenated, such as with H₂ in the presence of a catalyst, such as Pd/C, to yield the amino-indoline 66. The carbonyl is reduced, such as with BH₃-THF yields 1-aminoalkyl-indolines 67.

[0967] Substituted indolines are prepared such as by the procedures described in Scheme 22. Substituted acetamides 69 are prepared from the acylation of halo-5-nitroanilines 68 (where LG is bromo or chloro, preferably chloro) with an acylating agent, such as acetyl chloride or acetic anhydride, under standard coupling chemistry, such as with DIEA, and DMAP, at a temperature of about RT, in a suitable solvent, such as CH₂Cl₂, DMF and/or DMAC. The N-(2-methylprop-2-enyl)acetamide 70 is prepared from the acetamide 69, such as by the treatment of base, such as NaH in anhydrous DMF and a 3-halo-2-methylpropene such as 3-bromo-2-methylpropene or 3-chloro-2-methylpropene, at a temperature between about 0° C. and RT, and preferably at about RT; or with CsCO₃ at a temperature above RT, preferably above about 50° C. and more preferably above about 60° C. Cyclization of the N-(2-methylprop-2-enyl)acetamide 70, such as by the Heck-type reaction (treatment with Pd(OAc)₂ in the presence of base, for example tetraethyl-ammonium chloride, sodium formate, and NaOAc) at a temperature above about 50° C., and preferably at about 80° C., yields the protected (3,3-dimethyl-2,3-dihydro-indol-1-yl)ethanone 71. Deprotection, such as with strong acid such as AcOH on HCl at a temperature above about 50° C., and preferably at about 70–80° C., yields the 3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl 72. Alternatively, the protected dihydro-6-nitro indoline 71 can be reduced, such as with Fe, or with 10% Pd/C in the presence of an excess of NH₄CO₂H, or with H₂ in the presence of a catalyst to form the protected dihydro-6-amino indoline 71a.

[0968] Substituted anilines are prepared such as by the procedures described in Scheme 23. Nitrophenyl esters 74 are formed from the acid 73, such as by treatment with MeOH and acid. Alkylation of the ester 74, such as by treatment with base, followed by alkyl halide, yields the branched alkyl compounds 75. Reduction of the ester 75, such as with BH₃, yields the alcohol 76. The aldehyde 77 is prepared from the alcohol 76, such as by treatment with TPAP in the presence of N-methylmorpholine-N-oxide. Subsequent treatment with methoxymethyltriphenylphosphonium chloride and KHMDS yields 77. Coupling of the aldehyde 77 with morpholine, such as with NaBH(OAc)₃ yields the tertiary amine 78. Reduction of the nitro compound, such as with acid, for example AcOH, and zinc yields the aniline 79.

[0969] Substituted aminomethyl compounds are prepared such as by the procedure described in Scheme 24. A piperidinemethanol 80 is reacted with formaldehyde and NaCNBH₃. Subsequently, base, such as sodium hydride, and a halo substituted cyclic nitrile gives the ether 81. Hydrogenation of 81 under conditions described above, furnishes the aminomethyl compound 82.

[0970] Substituted aniline compounds are prepared such as by the procedure described in Scheme 25 (where R^x is a substituent selected from those available for substituted R¹, preferably haloalkyl or alkyl). Alkynyl-aniline 84, prepared similar to that described in Scheme 46, is hydrogenated such as with H₂ in the presence of a catalyst, such as Pd(OH)₂, to yield the substituted alkyl 85.

[0971] Substituted bromophenyl compounds are prepared such as by the procedure described in Scheme 26. Bromine is added to a optionally substituted nitrobenzene 86, silver(II)sulfate and acid, such as H₂SO₄, to provide the bromo derivative 87.

[0972] Substituted anilines are prepared such as by the procedure described in Scheme 27 (where R^t and R^v are alkyl, or together with the nitrogen atom form a 4–6 membered heterocyclic ring). Acryloyl chloride 88 is reacted with an amine, preferably a secondary amine, such as at a temperature between about 0° C. and about RT, to form the amide 89. A bromo-nitrobenzene 87 is reacted with the amide 89, such as in the presence of base, for example TEA, together with Pd(OAc)₂ and Pd(PPh₃)₄, at a temperature above about 50° C., and preferably at about 120° C., such as in a sealed container, to form the substituted alkene 90. Hydrogenation of the alkene 90, such as with H₂-in the presence of a catalyst, for example Pd/C catalyst yields the substituted aniline 91. Reduction of the amide 91, such as with LiAlH₄, at a temperature above about 50° C., and preferably at about 80° C. yields the aniline 92.

[0973] Substituted indoles are prepared such as by the procedure described in Scheme 28. A nitroindole 93 is coupled with a halo compound, in the presence of base, for example K₂CO₃. Heating at a temperature above about 50° C., and preferably at about reflux yields the substituted-nitro-1H-indole 94. Hydrogenation similar to conditions described above yield the amino derivative 95.

[0974] Substituted pyrimidines are prepared such as by the procedure described in Scheme 29. 2-Methylthio-5-pyrimidyl acids 98 are prepared from the corresponding esters 96 similar to procedures described above. The amides 99 are formed from the acids 98 by coupling with the amine such as in the presence of HATU and base, TEA for example. The methylthio group can be removed, such as with Raney-Ni and heat, preferably at about reflux temperature, to form the pyrimidine 100.

[0975] Substituted aminomethyl compounds are prepared such as by the procedure described in Scheme 30 (where LG is a leaving group, such as Cl). Strong base, such as NaH is added to an alcohol and heated at about 50° C. to form the sodium alkoxide, which is added to a halo compound, such as 2-chloro-4-cyanopyridine and heated at a temperature above about 50° C., and preferably at about 70° C. to form the ether 102. Hydrogenation yields the aminomethyl derivative 103.

[0976] Substituted anilines are prepared such as by the procedure described in Scheme 31. Treatment with the haloalkyl alcohol 104 with an alcohol, such as in the presence of DEAD and PPh₃ yields the ether 105 or 106.

[0977] Functionalized pyridines are prepared such as by the procedure described in Scheme 32. 2-Fluoropyridine 107 is treated with base, such as LDA at a temperature below about 0° C., and preferably at about −78° C., and quenched with a stream of dry CO₂ to form the nicotinic acid 108. Alternatively, solid CO₂ (dry ice) can be used, preferably dried with N₂ prior to use. The acid 108 is converted to the acid halide 109, such as by treatment with thionyl chloride and heating at a temperature above about 50° C., and preferably at about reflux.

[0978] Chloro-substituted pyridines 110 are prepared such as by the procedure described in Scheme 33. 2-Chloronicotinic acid is activated with ethyl chloroformate, in the presence of base, such as TEA, at a temperature of about RT. Reaction with an amine produces amide 110. Alternatively, the amine can be coupled with the acid chloride 111, such as with polymer-supported DIPEA, to form amide 110. Excess acid chloride is removed by treating the reaction mixture with polymer-supported trisamine resin.

[0979] Amino-substituted indoles 110 are prepared such as by the procedure described in Scheme 34. Nitroindoline 112 is reacted with N-methyl-4-piperidone in the presence of NaOMe at a temperature above about 50° C., and preferably at about reflux, to form the 3-substituted indole 113. Hydrogenation as previously discussed yields the amino indole 114.

[0980] Alkylated indazoles can be prepared by the process outlined in Scheme 35. To a solution of 6-nitroindazole 115 in a solvent such as THF is added strong base, such as NaH at a temperature below RT, preferably at about 0° C. Alkylhalides, such as where R″ is methyl, are added and reacted at a temperature about RT to give 1-alkyl-6-nitro-1H-indazole 116. The nitro indazole 116 is hydrogenated, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C to give the 1-substituted-6-amino-1H-indazole 117.

[0981] Brominated indazoles can be prepared by the process outlined in Scheme 36. NBS is slowly added to an acidic solution, such as a mixture of TFA:H₂SO₄ (5:1) and tert-butyl-4-nitrobenzene 118 at a temperature of about RT to yield the brominated compound 119.

[0982] Substituted anilines can be prepared by the process outlined in Scheme 38. A mixture of 1-(substituted)-2-bromo-4-nitrobenzene 120 (where R^x is a substituent selected from those available for substituted R¹) and N-methylpiperazine is heated, such as with or without solvent, preferably without solvent, at a temperature above RT, preferably at a temperature above about 100° C., and more preferably at a temperature at about 130° C. to give the 1-[5-(substituted)-2-nitrophenyl]-4-methylpiperazine 121. The nitro compound 121 is hydrogenated, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C to furnish 4-(substituted)-2-(4-methylpiperazinyl)phenylamine 122.

[0983] Tricyclic heterocycles can be prepared by the process outlined in Scheme 38. 7-Nitro-2,3,4-trihydroisoquinolin-1-one 123 is heated in POCl₃ at a temperature above RT, preferably at a temperature sufficient for reflux, to form the 1-chloro-7-nitro-3,4-dihydroisoquinoline 124. The 1-chloro-7-nitro-3,4-dihydroisoquinoline 124 is dissolved in a solvent, such as THF, and H₂NNH₂ is added. The reaction is evaporated to a residue, then heated with HC(OEt)₃ at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 115° C. to give the nitro-substituted tricyclic. Hydrogenation, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, gives 2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline 125.

[0984] Indazolyl ethers can be prepared by the process outlined in Scheme 39. 6-Nitro-1H-2-hydroindazol-3-one 126 is protected such as with Boc₂O and DMAP in CH₂Cl₂ at a temperature of about RT, to give the protected 6-nitro-2-hydroindazol-3-one. The protected 6-nitro-2-hydroindazol-3-one is reacted with an alcohol (where R^x is an appropriate substituent selected from the possible substituents on R) and Ph₃P in a solvent, such as THF, and DEAD, at a temperature of about RT, to give the protected 6-nitro(indazol-3-yl) ether. The nitro intermediate is hydrogenated, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, to give the protected 6-amino(indazol-3-yl) ether 127. The amine 127 is coupled and 2-chloronicotinic acid in a solvent, such as an alcohol, preferably pentanol, at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 130° C. to give the coupled and deprotected compound 128.

[0985] Indolinyl substituted carboxamides can be prepared from the corresponding nitro indoline 129 by the process outlined in Scheme 40. For example, 3,3-dimethyl-6-nitroindoline 129 is alkylated, such as with N-protected-4-formylpiperidine in the presence of NaHB(OAc)₃ and acid, such as glacial AcOH, and solvent, such as dichloromethane, at a temperature of about RT, to afford the alkylated indane 130. Hydrogenation of the alkylated indane 130, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, in the presence of a solvent, such as an alcohol, preferably MeOH, to give the amino intermediate 131. Alternatively, other hydrogenation methods can be used, such as Fe powder with NH₄Cl. Coupling of the amine 131, such as with 2-chloronicotinic acid and DIEA, HOBt and EDC, in a solvent such as CH₂Cl₂ at a temperature of about RT provides the protected carboxamide 132, which upon deprotection and alkylation yields other compounds of the invention, 133 and 134, respectively. Alternatively, amine 131 is reacted with 2-fluoronicotinoyl chloride to form a 2-fluoronicotinamide, which can be alkylated, such as in Scheme 10.

[0986] Substituted anilines can be prepared by the process outlined in Scheme 41. 1-Methyl-4-piperidinone 135 is added to a solution of strong base such as LIHMDS, in a solvent such as THF, at a temperature below RT, preferably lower than about −50° C., more preferably at about −78° C. Tf₂NPh is reacted with the enolate at a temperature of about RT, to give 1-methyl-4-(1,2,5,6-tetrahydro)pyridyl-(trifluoromethyl)sulfonate. A mixture of the triflate intermediate, bis(pinacolato)diboron, potassium acetate, PdCl₂dppf, and dppf in a solvent such as dioxane is heated at a temperature above RT, preferably at a temperature above about 50° C., and more preferably at a temperature at about 80° C. to give 4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane 136. The substituted aniline 137 is formed from the 1,3,2-dioxaborolane 136 such as with treatment with an amine in the presence of 1,1′-bis(diphenyphosphino)ferrocene-palladium dichloride and base, such as K₂CO₃, in a solvent such as DMF at a temperature above RT, preferably at a temperature above about 50° C., and more preferably at a temperature at about 80° C.

[0987] Substituted anilines can be prepared by the process outlined in Scheme 42. 4-Cyano-4-phenylpiperidine hydrochloride 138 is treated with base, such as KOH, at a temperature above RT, preferably at a temperature above about 100° C., and more preferably at a temperature at about 160° C., to provide the phenyl piperidine 139. Alkylation of the phenyl piperidine 139, such as with formaldehyde and NaCNBH₃ in a solvent such as CH₃CN, with sufficient acid to maintain the reaction pH near 7, to provide the alkylated piperidine 140. Nitration of the phenylpiperidine 140, such as with H₂SO₄ and fuming HNO₃ at a temperature below RT, and preferably at about 0° C., gives the nitro intermediate 141. Hydrogenation of the nitro intermediate 141, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, in the presence of a solvent, such as an alcohol, preferably MeOH, to give the amino intermediate 142.

[0988] Substituted amides can be prepared by the process outlined in Scheme 43. 3-Nitrocinnamic acid 143 is coupled with 1-methylpiperazine in the presence of EDC and a solvent such as CH₂Cl₂, at a temperature of about RT gives the carboxamide 144.

[0989] Substituted benzylamines can be prepared by the process outlined in Scheme 44. A substituted bromobenzylamine 145 where R^1a is a substituent described for R¹ is protected such as with Boc₂O in the presence of base, such as TEA in an appropriate solvent such as CH₂Cl₂. The protected bromobenzylamine 146 is alkylated, such as with 1-dimethylamino-2-propyne in the presence of catalyst, such as PdCl₂(PPh₃)₂, and CuI, in the presence of base, such as TEA, at a temperature above RT, preferably at a temperature above about 50° C., and more preferably at a temperature at about 100° C., such as in a sealed tube, to form the propynylbenzylamine 147. The propynylbenzylamine is hydrogenated such as with H₂ in the presence of Pd(OH)₂ and MeOH to provide the propylbenzylamine 148. Deprotection, such as with strong acid, such as TFA, for removal of a Boc protecting group, yields the propylbenzylamine 149.

[0990] Substituted benzylamines can be prepared by the process outlined in Scheme 45. The protected bromobenzylamine 146 is alkylated, such as with propargyl alcohol in the presence of catalyst, such as PdCl₂(PPh₃), and CuI, in the presence of base, such as TEA, at a temperature above RT, preferably at a temperature above about 50° C., and more preferably at a temperature at about 100° C., such as in a sealed tube, to form the protected hydroxypropynylbenzylamine 150. The protected hydroxypropynylbenzylamine is treated with N-methylmorpholine oxide in the presence of a catalyst, such as tetrapropylammonium perruthenate, to form the aldehyde intermediate. Reductive amination, such as with the addition of morpholine and NaBH(OAc)₃ provides the morpholinyl derivative. Deprotection, such as with strong acid, such as TFA, for removal of a Boc protecting group, yields the propylbenzylamine 151.

[0991] Substituted aminomethyl compounds are prepared such as by the procedure described in Scheme 46. A halo compound 152, is reacted with an alkyne in the presence of PdCl₂(PPh₃)₂ and CuI, with base is heated at a temperature above about 50° C., and preferably at about 100° C., such as in a sealed container, to provide the substituted alkyne 153.

[0993] Alternatively, 2-chloro-nicotinoyl chloride 154 (where LG is Cl) is coupled first with R²—NH₂, such as in the presence of base, e.g., NaHCO₃, in a suitable solvent, such as IpOH or CH₂Cl₂, to form the amide 158, then coupled with an amine 155 to yield the 2-substituted amino-nicotinamide 157. Where A is a pi-electron rich heterocycle, the addition of KF, such as 40% KF on alumina in IpOH, at a temperature over about 100° C., preferably about 160° C., can be used in the formation of 157 from 158.

[1018] The compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below:
The invention expressly includes all tautomeric forms of the compounds described herein.

Preparation I

3-nitro-5-trifluoromethyl-phenol

Preparation II

1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine

Preparation III

1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine

Preparation IV

1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine

Preparation V

1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy)-piperidine

Preparation VI

1-Boc-2-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidine

Preparation VII

2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

Preparation VIII

1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

Preparation IX

4-tert-butyl-3-nitro-phenylamine

Preparation X

N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide

Preparation XI

N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

Preparation XII

3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine

Preparation XIII

3,3-Dimethyl-6-nitro-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indole

Preparation XIV

N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

Preparation XV

3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine

Preparation XVI

1-methyl-4-methylene-piperidine

Preparation XVII

N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamide

Preparation XVIII

3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine

Preparation XIX

2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile

Preparation XX

[2-(1-methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine bis hydrochloride

Preparation XXI

2-(2-morpholin-4-yl-ethoxy)-4-pyridylcarbonitrile

Preparation XXII

2-morpholin-4-yl-propanol

Preparation XXIII

2-(2-morpholin-4-yl-propoxy)-4-pyridylcarbonitrile

Preparation XXIV

2-(1-Methyl-pyrrolidin-2-ylmethoxy)-4-pyridylcarbonitrile

Preparation XXV

2-(3-morpholin-4-yl-propylamino)-4-pyridylcarbonitrile

Preparation XXVI

5-Nitro-2-pentafluoroethylphenol

Preparation XXVII

2-tert-Butyl-5-nitro-aniline

Preparation XXVIII

2-tert-Butyl-5-nitrophenol

Preparation XXIX

1-methylpiperidine-4-carboxylic acid ethyl ester

Preparation XXX

N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide

Preparation XXXI

1-[2-(2-tert-Butyl-5-nitro-phenoxy)-ethyl]-piperidine

Preparation XXXII

1-Boc-Piperidine-4-carboxylic acid ethyl ester

Preparation XXXIII

1-Boc-4-hydroxymethyl-piperidine

Preparation XXXIV

1-Boc-4-Methylsulfonyloxymethyl-piperidine

Preparation XXXIV

1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

Preparation XXXVI

4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

Preparation XXXVII

1-methyl-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

Preparation XXXVIII

1-Isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine

Preparation XXXIX

3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indole

Preparation XL

(S) 2-(5-Nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane

Preparation XLI

(S) 2-Chloro-N-[3-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

Preparation XLII

5-nitro-2-trifluoromethylanisole

Preparation XLIII

1-[2-(5-nitro-2-trifluoromethylphenoxy)ethyl]pyrrolidine

Preparation XLIV

1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine

Preparation XLV

3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine

Preparation XLVI

2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide

Preparation XLVII

(R) Acetic acid 2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethyl ester

Preparation XLVIII

(R) 2-Chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

Preparation XLIX

2-Dimethylamino-1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-ethanone

Preparation L

1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone

Preparation LI

2-Boc-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

Preparation LII

2-Bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide

Preparation LIII

2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide

Preparation LIV

Of 2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

Preparation LV

4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

Preparation LVI

4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

Preparation LVII

2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene

Preparation LVIII

1-Methyl-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine

Preparation LIX

1-Boc-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine.

Preparation LX

(4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone

Preparation LXI

1-Boc-4-(3-nitro-5-trifluoromethyl-benzyl)-piperazine

Preparation LXII

2-Ethyl-4-aminomethyl pyridine

Preparation LXIII

N-Boc-[2-(4-morpholin-4-yl-butyl)-pyrimidin-4-ylmethyl]-amine

Preparation LXIV

2-fluoronicotinic acid

Preparation LXV

4-cyano-2-methoxypyridine

Preparation LXVI

(2-methoxypyridin-4-yl)methylamine

Preparation LXVII

2-(4-Amino-phenyl)-2-methyl-propionic acid methyl ester

Preparation LXVIII

1-(2-tert-Butyl-phenyl)-4-methyl-piperazine

Preparation LXIX

3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

Preparation LXX

3,3-Dimethyl-6-nitro-2,3-dihydro-benzo[d]isothiazole 1,1-dioxide

Preparation LXXI

3-(1-Methyl-1,2,3,4-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

Preparation LXXII

Trifluoromethylsulfonic acid 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester

Preparation LXXIII

3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine

Preparation LXXIV

1-Boc-3-Hydroxymethyl-azetidine

Preparation LXXV

1-Boc-3-(3-nitro-5-trifluoromethyl-phenoxymethyl)-azetidine

Preparation LXXVI

2,2-Dimethyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine

Preparation LXXVII

2,2,4-Trimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

Preparation LXXVIII

2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide

Preparation LXXIX

2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

Preparation LXXX

4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridinium iodide

Preparation LXXXI

4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine

Preparation LXXXII

1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium iodide

Preparation LXXXIII

1-Methyl-4-(4-nitro-benzyl)-1,2,3,6-tetrahydro-pyridine

Preparation LXXXIV

1-Boc-4-formylpiperidine

Preparation LXXXV

2-Chloro-4-cyanopyridine

Preparation LXXXVI

4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol

Preparation LXXXVII

4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal

Preparation LXXXVIII

1-[4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine

Preparation LXXXVIV

N-Boc-(2-chloropyrimidin-4-yl)-methylamine

EXAMPLE 1

[1309]
Step A—Preparation of 3-[(tert-butoxy)carbonylamino]thiophene-2-carboxylic acid

EXAMPLE 2

[1314]

EXAMPLE 3

[1316]
Step A—Preparation of (2-amino(3-pyridyl))-N-(4-chlorophenyl)carboxamide

EXAMPLE 4

[1319]

EXAMPLE 5

[1321]

EXAMPLE 6

[1323]

EXAMPLE 7

[1325]

EXAMPLE 8

[1327]

EXAMPLE 9

[1329]
Step A—Preparation of 6-methyl-2-[(4-pyridylmethyl)amino]pyridine-3-carboxylic acid

EXAMPLE 10

[1332]

EXAMPLE 11

[1334]

EXAMPLE 12

[1336]

EXAMPLE 13

[1338]

EXAMPLE 14

[1340]

EXAMPLE 15

[1342]

EXAMPLE 16

[1344]

EXAMPLE 17

[1346]

EXAMPLE 18

[1348]

EXAMPLE 19

[1350]

EXAMPLE 20

[1352]

EXAMPLE 21

[1354]

EXAMPLE 22

[1356]
Step A—Preparation of 5-bromo-2-hydroxynicotinic acid

EXAMPLE 23

[1362]

EXAMPLE 24

[1364]

EXAMPLE 25

[1366]
Step A: Preparation of (2-chloro-3-pyridyl)-N-(4-isopropylphenyl)carboxamide

[1370]

TABLE 1
#	Y	R1	R2	M + H	calc'd
26	—NH—CH2—		H	347	346.2
27	NH—CH2—		H	356	355.1
28	NH—CH2—		H	471	470.1
29	NH—CH2—		H	352	351.4
30	NH—CH2—		H	365	364.2
31	NH—CH2—		H	368	367.5
32	NH—CH2—		H	369	368.5
33	NH—CH2—		H	377	376.2
34	NH—CH2—		H	366.8	366.8
35	NH—CH2—		5-Br	447.0	445.7
36	NH—CH2—		H	425.0	424.5
37	NH—CH2—		H	363.2	362.4
38	NH—CH2—		H	393.2	392.4
39	NH—CH2—		H	393.2	392.4
40	NH—CH2—		H	350.8	350.4
41	NH—CH2—		H	389.2	388.5
42	NH—CH2—		H	351.0	350.4
43	NH—CH2—		H	367.1	366.8
44	NH—CH2—		H	401.3	400.4
45	NH—CH2—		H	377.2	376.5
46	NH—CH2—		H	361.4	360.4
47	NH—CH2—		H	377.1	376.4
48	NH—CH2—		H	347.1	346.4
49	NH—CH2—		H	349.1	348.4
50	NH—CH2—		H	393.2	392.4
51	NH—CH2—		H	411.2	411.3
52	NH—CH2—		H	403.1	401.3
53	NH—CH2—		H	415.2	414.4
54	NH—CH2—		H	393.2	392.4
55	NH—CH2—		H	403.2	401.3
56	NH—CH2—		H	351.0	350.4
57	NH—CH2—		H	369.1	366.8
58	NH—CH2—		H	412.3	411.5
59	NH—CH2—		H	338.8	338.4
60	NH—CH2—		H	334.1	333.4
61	NH—CH2—		H	333.6	333.4
62	NH—CH2—		H	333.6	333.4
63	NH—CH2—		H	361.1	360.4
64	NH—CH2—		H	379.0	378.4
65	NH—CH2—		H	399	398.9
66	NH—CH2—		H	522.3	521

EXAMPLE 67

[1371]

EXAMPLE 68

[1373]
Step A Preparation of 2-bromo-1-tert-butyl-4-nitrobenzene

EXAMPLE 69

[1379]

EXAMPLE 70

[1381]
Step A Preparation of 4-[(4-nitrophenyl)methyl]morpholine

EXAMPLE 71

[1385]
Step A Preparation of (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]carboxamide

EXAMPLE 72

[1389]

EXAMPLE 73

[1409]

EXAMPLE 74

[1411]

EXAMPLE 75

[1413]

EXAMPLE 76

[1415]

EXAMPLE 77

[1417]
Step A Preparation of 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene

EXAMPLE 78

[1421]
Step A Preparation of 4-(1,1,2,2,2-pentafluoroethyl)phenylamine

EXAMPLE 79

[1424]
Step A Preparation of 4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenylamine

EXAMPLE 80

[1427]
Step A Preparation of 2-(1,2,4-triazolyl)ethylamine

EXAMPLE 81

[1430]
Step A Preparation of 2-(2-pyridylamino)ethylamine

EXAMPLE 82

[1433]
Step A: Preparation of (2-chloro(3-pyridyl))-N-(3-trifluoromethylphenyl)carboxamide

[1437]

TABLE 2
#	Y	R1	R2	M + H	calc'd
83	—NH—CH2—		H	356	355.14
84	—NH—CH2—		H	431	430.12
85	—NH—CH2—		H	359	358.1
86	—NH—CH2—		H	355	354.15
87	—NH—CH2—		H	359	358.18
88	—NH—CH2—		H	349	348.128
89	—NH—CH2—		H	355	354.15
90	—NH—CH2—		H	395	394.18
91	—NH—CH2—		H	339	338.12
92	—NH—CH2—		H	339	338.12
93	—NH—CH2—		H	345	344.16
94	—NH—CH2—		H	361	360.20
95	—NH—CH2—		H	361	360.20
96	—NH—CH2—		H	319	318.5
97	—NH—CH2—		H	389	388.11
98	—NH—CH2—		H	333	332.16
99	—NH—CH2—		H	361	360.2
100	—NH—CH2—		H	431	430
101	—NH—CH2—		H	349	348.16
102	—NH—CH2—		H	333	332.16
103	—NH—CH2—		H	457	456.18
104	—NH—CH2—		H	381	380.16
105	—NH—CH2—		H	395	394.18
106	—NH—CH2—		H	334	333.16
107	—NH—CH2—		H	348	347.17
108	—NH—CH2—		H	362	361.19
109	—NH—CH2—		H	321	320.13
110	—NH—CH2—		H	348	347.17
111	—NH—CH2—		H	441	440.11
112	—NH—CH2—		H	407	406.08
113	—NH—CH2—		H	353	352.11
114	—NH—CH2—		H	383	382.11
115	—NH—CH2—		H	388	387.43
116	—NH—CH2—		H	346	345.00
117	—NH—CH2—		H	344	343.38
118	—NH—CH2—		H	344	343.38
119	—NH—CH2—		H	344	343.38
120	—NH—CH2—		H	351	350.43
121	—NH—CH2—		H	371	370.43

EXAMPLE 122

[1438]

EXAMPLE 123

[1440]

EXAMPLE 124

[1442]
Step A—Preparation of {2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine

EXAMPLE 125

[1446]
Step A—Preparation of 1-[2-(tert-butylphenyl]-4-methylpiperazine

EXAMPLE 126

[1450]
Step A—Preparation of 3-(4-methylpiperazinyl)phenylamine

EXAMPLE 127

[1453]
Step A—Preparation of 4-methyl-1-(4-nitrophenyl)piperazine

EXAMPLE 128

[1457]
Step A—Preparation of 1-(1-methyl(4-piperidyl))-6-nitroindoline

EXAMPLE 129

[1461]

EXAMPLE 130

[1463]
Step A—Preparation of 1-(6-nitroindolinyl)-2-piperidylethan-1-one

EXAMPLE 131

[1467]

EXAMPLE 132

[1469]
Step A—Preparation of N-(2-bromo-5-nitrophenyl)acetamide

EXAMPLE 133

[1477]
Step A—Preparation of 1-acetyl-6-amino-3,3-dimethylindoline

EXAMPLE 134

[1481]
Step A—Preparation of 3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole

EXAMPLE 135

[1485]
Step A—Preparation of methyl 2-methyl-2-(4-nitrophenyl)propionate

EXAMPLE 136

[1493]
Step A—Preparation of 4-hydroxymethyl-1-methylpiperidine

EXAMPLE 137

[1497]

EXAMPLE 138

[1499]

EXAMPLE 139

[1501]

EXAMPLE 140

[1503]
Step A—Preparation of (2-methoxy-4-pyridyl)methylamine

EXAMPLE 141

[1506]
Step A—Preparation of {3-[3-amino-5-(trifluoromethyl)phenyl]propyn-2-yl}dimethylamine

EXAMPLE 142

[1510]
Step A—Preparation of 1-piperidylprop-2-en-1-one

EXAMPLE 143

[1517]

EXAMPLE 144

[1519]

EXAMPLE 145

[1521]

EXAMPLE 146

[1523]
Step A—Preparation of 1-(2-morpholin-4-ylethyl)indole-6-ylamine

EXAMPLE 147

[1526]
Step A—Preparation of pyrimidine-4-yl formaldehyde

EXAMPLE 148

[1529]

EXAMPLE 149

[1531]

EXAMPLE 150

[1533]
Step A—Preparation of ethyl 2-methylthio-4-[benzylamino]pyrimidine-5-carboxylate

EXAMPLE 151

[1537]
Step A—Preparation of 2-{2-[2-(dimethylamino)ethoxy]ethoxy}pyridine-4-carbonitrile

EXAMPLE 152

[1545]
Step A—Preparation of 4-[2,2,2-trifluoro-1-(2-piperidin-1-yl-ethoxy)-1-trifluoromethyl-ethyl]-phenylamine

EXAMPLE 153

[1548]
Step A—Preparation of 2,6-difluoropyridine-3-carbonyl chloride

EXAMPLE 154

[1551]
Step A—Preparation of N-(4-tert-butyl-phenyl)-2,6-difluoro-nicotinamide

EXAMPLE 155

[1555]

EXAMPLE 156

[1557]

EXAMPLE 157

[1559]

EXAMPLE 158

[1561]
Step A—Preparation of (2-chloro(3-pyridyl))-N-(4-phenoxy-phenyl)carboxamide

EXAMPLE 159

[1565]

EXAMPLE 160

[1567]

EXAMPLE 161

[1569]

EXAMPLE 162

[1571]
Step A—Preparation of (2-Chloro(3-pyridyl))-N-(4-imidazolylphenyl)carboxamide

EXAMPLE 163

[1575]

EXAMPLE 164

[1578]

EXAMPLE 165

[1580]

EXAMPLE 166

[1582]

EXAMPLE 167

[1585]

EXAMPLE 168

[1587]

EXAMPLE 169

[1589]

[1592]

TABLE 3
#	R1	R2	n
170.	2-chlorophenyl	H	1
171.	4-benzimidazolyl	H	1
172.	5-benzimidazolyl	H	1
173.	7-benzimidazolyl	H	1
174.	2-chlorophenyl	5-Br	1
175.	3-isoquinolinyl	5-Br	1
176.	2-quinolinyl	5-Br	1
177.	2-benzthiazolyl	5-Br	1
178.	2-benzimidazolyl	5-Br	1
179.	4-benzimidazolyl	5-Br	1
180.	5-benzimidazolyl	5-Br	1
181.	6-benzimidazolyl	5-Br	1
182.	7-benzimidazolyl	5-Br	1
183.	4-chlorophenyl	H	3
184.	4-chlorophenyl	3-pyridyl	1
185.	4-pyridyl	H	1
186.	4-pyridyl	6-CH3	1
187.	4-chlorophenyl-	5-Cl	1
188.	3,4-dichlorophenyl-	5-Br	1
189.	4-fluorophenyl	6-CH3	1
190.	3-chlorophenyl	6-CH3	1
191.	3-fluorophenyl	6-CH3	1
192.	3-fluoro-4-methoxyphenyl	6-CH3	1
193.	3-fluoro-4-methylphenyl	6-Cl	1
194.	4-phenoxyphenyl	H	1
195.	3-phenoxyphenyl	H	1
196.	4-biphenyl	H	1
197.	4-cyclohexylphenyl	H	1
198.	2-quinolyl	H	1
199.	3-isoquinolyl	H	1
200.	3-quinolyl	H	1
201.	1-isoquinolyl	H	1
202.	5-quinolyl	H	1
203.	5-isoquinolyl	H	1
204.	6-quinolyl	H	1
205.	6-isoquinolyl	H	1
206.	7-quinolyl	H	1
207.	7-isoquinolyl	H	1
208.	4-quinolyl	H	1
209.	4-isoquinolyl	H	1
210.	4-pyridyl	H	1
211.	4-pyrimidinyl	H	1
212.	2-pyrimidinyl	H	1
213.	6-pyrimidinyl	H	1
214.	4-pyridazinyl	H	1
215.	5-pyridazinyl	H	1
216.	4-indolyl	H	1
217.	5-isoindolyl	H	1
218.	5-naphthyridinyl	H	1
219.	6-quinozalinyl	H	1
220.	6-isoquinolyl	H	1
221.	4-naphthyridinyl	H	1
222.	5-quinozalinyl	H	1
223.	4-naphthyridinyl	H	1
224.	7-tetrahydroquinolinyl	H	1
225.	6-indazolyl	H	1
226.	6-isoindolyl	H	1
227.	5-indazolyl	H	1
228.	5-isoindolyl	H	1
229.	6-benzothienyl	H	1
230.	6-benzofuryl	H	1
231.	5-benzothienyl	H	1
232.	5-benzofuryl	H	1
233.	2-benzimidazolyl	H	1
234.	2-benzoxazolyl	H	1
235.	2-benzthiazolyl	H	1
236.	6-benzimidazolyl	H	1
237.	6-benzoxazolyl	H	1
238.	6-benzthiazolyl	H	1
239.	2-quinazolinyl	H	1
240.	3-(phenoxy)-6-pyridyl	H	1
241.	4-(phenylcarbonyl)phenyl	H	1
242.	4-(phenylamino)phenyl	H	1
243.	4-cyclohexyloxyphenyl	H	1
244.	4-(3-thienyl)phenyl	H	1
245.	4-(pyrazol-3-yl)phenyl	H	1
246.	4-chlorophenyl	6-F	2
247.	4-pyridyl	6-Cl	1
248.	3-methoxyphenyl	6-F	1
249.	4-hydroxyphenyl	6-Cl	1
250.	3-hydroxyphenyl	H	1
251.	2-hydroxyphenyl	H	1
252.	4-chlorophenyl	6-F	1
253.	4-phenoxyphenyl	6-F	1
254.	4-biphenyl	6-phenyl	1
255.	4-hydroxyphenyl	6-phenyl	1
256.	4-cyclohexylphenyl	6-F	1
257.	3-isoquinolyl	6-phenyl	1
258.	4-piperidinylmethylphenyl	H	1
259.	4-morpholinylmethylphenyl	H	1