Process for preparing 3,3-dimethylindolines

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

DESCRIPTION OF THE INVENTION

[0016]

• [0017] wherein each of A¹ and A² is independently C, CH or N;
• [0018] wherein ring A is selected from
  • [0019] a) 5- or 6-membered partially saturated heterocyclyl,
    • [0020] preferably dihydropyran, dihydrothienyl, dihydrofuryl, oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl, dihydro-oxazolyl, dihydro-isothiazolyl, dihydro-isoxazolyl, imidazolinyl and pyrazolinyl,
  • [0021] b) 5- or 6-membered heteroaryl,
    • [0022] preferably
      • [0023] I) 5-membered heteroaryl selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl,
        • [0024] even more preferably 5-membered heteroaryl selected from

[0025]

• • • • [0026] II) preferably 6-membered heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl,
        • [0027] even more preferably 6-membered heteroaryl selected from

[0028]

• • • • • [0029]  more specifically

[0030]

• • [0031] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl
    • [0032] preferably tetrahydroquinolinyl,
  • [0033] d) 9- or 10-membered fused heteroaryl,
    • [0034] preferably
      • [0035] i) fused 9-membered fused heteroaryl selected from benzothienyl, benzothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuryl, indazolyl and isoindolyl, and
      • [0036] ii) fused 10-membered heteroaryl selected from quinolyl, isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl,
  • [0037] e) naphthyl, and
  • [0038] f) 4-, 5- or 6-membered cycloalkenyl,
    • [0039] preferably 5-membered cycloalkenyl,
      • [0040] more preferably cyclopentadienyl or cyclopentenyl;
• [0041] wherein X is selected from

[0042]

• • [0043] preferably X is selected from

[0044]

• • • [0045] more preferably X is

[0046]

• [0047] wherein Z is oxygen or sulfur;
• [0048] wherein Y is selected from

[0049]

• • [0050] preferably Y is selected from

[0051]

• • • [0052] more preferably Y is selected from

[0053]

• • • • [0054] even more preferably Y is —NH—CH₂—;
• [0055] 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,
  • [0056] preferably H, halo, cyano and C_1-2-alkyl substituted with R², or wherein R^a and R^b together form C₃-C₄ cycloalkyl, more preferably H, halo and C₁-C₂-alkyl, even more preferably H;
• [0057] 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—,
  • [0058] preferably C₁-C₂ alkylenyl, where one of the CH₂ groups may be substituted with an oxygen atom or an —NH— more preferably C₁-C₂ alkylenyl;
• [0059] wherein R^d is cycloalkyl,
  • [0060] preferably C₃-C₆ cycloalkyl;
• [0061] wherein R is selected from
  • [0062] a) substituted or unsubstituted 5-6 membered heterocyclyl,
    • [0063] preferably substituted or unsubstituted 5-6 membered heteroaryl comprising one or more nitrogen atoms,
      • [0064] more preferably 4-pyrazolyl, triazolyl, 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 4-pyridazinyl, or 6-pyridazinyl,
        • [0065] even more preferably 4-pyridyl, 4-pyrimidinyl and 4-pyridazinyl,
        • [0066] even more preferably 4-pyridyl, and
  • [0067] b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl,
    • [0068] preferably substituted or unsubstituted 9-10 membered fused heteroaryl comprising one or more nitrogen atoms,
      • [0069] more preferably indazolyl, quinolinyl, isoquinolinyl, or quinazolinyl,
        • [0070] even more preferably indazolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 4-isoquinolyl, 5-isoquinolyl, and 6-isoquinolyl,
    • [0071] 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;
      • [0072] 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;
• [0073] wherein R¹ is selected from
  • [0074] a) substituted or unsubstituted 6-10 membered aryl,
    • [0075] preferably phenyl, naphthyl, indenyl, or tetrahydronaphthyl,
      • [0076] more preferably phenyl,
  • [0077] b) substituted or unsubstituted 5-6 membered heterocyclyl,
    • [0078] preferably 5-6 membered heteroaryl,
      • [0079] more preferably thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, or pyrrolyl,
  • [0080] c) substituted or unsubstituted 9-10 membered fused heterocyclyl,
    • [0081] preferably 9-10 membered fused heteroaryl,
      • [0082] more preferably indazolyl, indolyl, 2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl, benzodioxanyl, or quinazolinyl,
  • [0083] d) cycloalkyl, and
  • [0084] e) cycloalkenyl
    • [0085] 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,
      • [0086] 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-C₁-C₂-alkylenyl, C_1-2-alkyl, cyano, C_1-2-hydroxyalkyl, nitro and C_1-2-haloalkyl,
        • [0087] 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;
• [0088] 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,
  • [0089] 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;
• [0090] wherein R³ is selected from H, lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆ cycloalkyl, and lower haloalkyl,
  • [0091] preferably H, C_1-2-alkyl, phenyl, C₃-C₆ cycloalkyl, and C_1-2-haloalkyl,
    • [0092] more preferably H, methyl, phenyl, cyclopropyl, cyclohexyl, and trifluoromethyl;
• [0093] 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—,
  • [0094] 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;
• [0095] wherein R⁵ is selected from H, lower alkyl, phenyl and lower aralkyl,
  • [0096] preferably H, methyl or ethyl;
• [0097] wherein R⁶ is selected from H or C_1-6-alkyl,
  • [0098] preferably H or C_1-2 alkyl; and
• [0099] wherein R^c is selected from H, methyl and optionally substituted phenyl;
• [0100] wherein R¹⁴ is selected from H, phenyl, 5-6 membered heterocyclyl and C₃-C₆ cycloalkyl;
• [0101] wherein p is 0 to 2, preferably p is 2;
  and pharmaceutically acceptable salts thereof;
  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.

[0103]

• [0104] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0105] preferably H;
• [0106] wherein n is 0-2;
  • [0107] preferably 1-2;
• [0108] wherein R is selected from
  • [0109] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0110] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0111] preferably 4-pyridyl, pyrimidinyl, triazolyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0112] 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,
    • [0113] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0114] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0115] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0116] 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,
      • [0117] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0118] wherein R² is one or more substituents independently
  • [0119] selected from
    • [0120] H,
    • [0121] halo,
    • [0122] C_1-6-alkyl,
    • [0123] C_1-6-haloalkyl,
    • [0124] C_1-6-alkoxy,
    • [0125] C_1-6-haloalkoxy,
    • [0126] C_1-6-carboxyalkyl,
    • [0127] unsubstituted or substituted aryl and
    • [0128] unsubstituted or substituted 5-6 membered heteroaryl;
• [0129] 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
  • [0130] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0131] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0133]

• [0134] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0135] preferably H;
• [0136] wherein n is 0-2;
  • [0137] preferably 1-2;
• [0138] wherein R is selected from
  • [0139] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0140] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0141] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0142] 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,
    • [0143] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0144] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0145] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0146] 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,
      • [0147] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0148] wherein R² is one or more substituents independently
  • [0149] selected from
    • [0150] H,
    • [0151] halo,
    • [0152] C_1-6-alkyl,
    • [0153] C_1-6-haloalkyl,
    • [0154] C_1-6-alkoxy,
    • [0155] C_1-6-haloalkoxy,
    • [0156] C_1-6-carboxyalkyl,
    • [0157] unsubstituted or substituted aryl and
    • [0158] unsubstituted or substituted 5-6 membered heteroaryl;
  • [0159] 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
• [0160] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0162]

• [0163] wherein A³ is selected from CR² and N;
• [0164] wherein A⁴ is selected from CR² and N; provided one of A³ and A⁴ is not CR²;
• [0165] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0166] preferably H;
• [0167] wherein n is 0-2;
  • [0168] preferably 1-2;
• [0169] wherein R is selected from
  • [0170] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0171] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0172] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0173] 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,
    • [0174] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0175] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0176] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0177] 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,
      • [0178] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0179] wherein R² is one or more substituents independently
  • [0180] selected from
    • [0181] H,
    • [0182] halo,
    • [0183] C_1-6-alkyl,
    • [0184] C_1-6-haloalkyl,
    • [0185] C_1-6-alkoxy,
    • [0186] C_1-6-haloalkoxy,
    • [0187] C_1-6-carboxyalkyl,
    • [0188] unsubstituted or substituted aryl and
    • [0189] unsubstituted or substituted 5-6 membered heteroaryl;
  • [0190] 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
  • [0191] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0192] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0194]

• [0195] wherein A⁵ is selected from S, O and NR⁶;
• [0196] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0197] preferably H;
• [0198] wherein n is 0-2;
  • [0199] preferably 1-2;
• [0200] wherein R is selected from
  • [0201] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0202] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0203] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0204] 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,
    • [0205] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0206] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0207] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0208] 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,
      • [0209] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0210] wherein R² is one or more substituents independently
  • [0211] selected from
    • [0212] H,
    • [0213] halo,
    • [0214] C_1-6-alkyl,
    • [0215] C_1-6-haloalkyl,
    • [0216] C_1-6-alkoxy,
    • [0217] C_1-6-haloalkoxy,
    • [0218] C_1-6-carboxyalkyl,
    • [0219] unsubstituted or substituted aryl and
    • [0220] unsubstituted or substituted 5-6 membered heteroaryl;
  • [0221] 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
• [0222] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0224]

• [0225] wherein A⁵ is selected from S, O and NR⁶;
• [0226] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0227] preferably H;
• [0228] wherein n is 0-2;
  • [0229] preferably 1-2;
• [0230] wherein R is selected from
  • [0231] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0232] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0233] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0234] 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,
    • [0235] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0236] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0237] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0238] 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,
      • [0239] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0240] wherein R² is one or more substituents independently
  • [0241] selected from
    • [0242] H,
    • [0243] halo,
    • [0244] C_1-6-alkyl,
    • [0245] C_1-6-haloalkyl,
    • [0246] C_1-6-alkoxy,
    • [0247] C_1-6-haloalkoxy,
    • [0248] C_1-6-carboxyalkyl,
    • [0249] unsubstituted or substituted aryl and
    • [0250] unsubstituted or substituted 5-6 membered heteroaryl;
  • [0251] 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
    • [0252] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0253] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0255]

• [0256] wherein A⁵ is selected from S, O and NR⁶;
• [0257] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0258] preferably H;
• [0259] wherein n is 0-2;
  • [0260] preferably 1-2;
• [0261] wherein R is selected from
  • [0262] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0263] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0264] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0265] 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, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0266] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0267] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0268] 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,
      • [0269] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0270] wherein R² is one or more substituents independently
  • [0271] selected from
    • [0272] H,
    • [0273] halo,
    • [0274] C_1-6-alkyl,
    • [0275] C_1-6-haloalkyl,
    • [0276] C_1-6-alkoxy,
    • [0277] C_1-6-haloalkoxy,
    • [0278] C_1-6-carboxyalkyl,
    • [0279] unsubstituted or substituted aryl and
    • [0280] unsubstituted or substituted 5-6 membered heteroaryl;
  • [0281] 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
• [0282] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0284]

• [0285] wherein A⁵ is selected from S, O and NR⁶;
• [0286] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0287] preferably H;
• [0288] wherein n is 0-2;
  • [0289] preferably 1-2;
• [0290] wherein R is selected from
  • [0291] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0292] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0293] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0294] 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,
    • [0295] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0296] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0297] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0298] 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,
      • [0299] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0300] wherein R² is one or more substituents independently
  • [0301] selected from
    • [0302] H,
    • [0303] halo,
    • [0304] C_1-6-alkyl,
    • [0305] C_1-6-haloalkyl,
    • [0306] C_1-6-alkoxy,
    • [0307] C_1-6-haloalkoxy,
    • [0308] C_1-6-carboxyalkyl,
    • [0309] unsubstituted or substituted aryl and
    • [0310] unsubstituted or substituted 5-6 membered heteroaryl;
  • [0311] 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
• [0312] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0314]

• [0315] wherein A⁵ is selected from S, O and NR⁶;
• [0316] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0317] preferably H;
• [0318] wherein n is 0-2;
  • [0319] preferably 1-2;
• [0320] wherein R is selected from
  • [0321] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0322] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0323] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0324] 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,
    • [0325] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0326] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0327] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0328] 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,
      • [0329] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0330] wherein R² is one or more substituents independently
  • [0331] selected from
    • [0332] H,
    • [0333] halo,
    • [0334] C_1-6-alkyl,
    • [0335] C_1-6-haloalkyl,
    • [0336] C_1-6-alkoxy,
    • [0337] C_1-6-haloalkoxy,
    • [0338] C_1-6-carboxyalkyl,
    • [0339] unsubstituted or substituted aryl and
    • [0340] unsubstituted or substituted 5-6 membered heteroaryl;
    • [0341] 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
    • [0342] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
• [0343] wherein R⁶ is H or C_1-2-alkyl;
  and pharmaceutically acceptable isomers and salts thereof.

[0345]

• [0346] wherein A⁵ is selected from S, O and NR⁶;
• [0347] wherein A⁶ is selected from N and CR²;
• [0348] wherein R^a and R^b are independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
  • [0349] preferably H;
• [0350] wherein n is 0-2;
  • [0351] preferably 1-2;
• [0352] wherein R is selected from
  • [0353] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
  • [0354] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0355] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
  • [0356] 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,
    • [0357] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
• [0358] wherein R¹ is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
  • [0359] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
    • [0360] 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,
    • [0361] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
• [0362] wherein R² is one or more substituents independently
  • [0363] selected from
    • [0364] H,
    • [0365] halo,
    • [0366] C_1-6-alkyl,
    • [0367] C_1-6-haloalkyl,
    • [0368] C_1-6-alkoxy,
    • [0369] C_1-6-haloalkoxy,
    • [0370] C_1-6-carboxyalkyl,
    • [0371] unsubstituted or substituted aryl and
    • [0372] unsubstituted or substituted 5-6 membered heteroaryl;
    • [0373] 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
      • [0374] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0375] wherein

[0376]
and pharmaceutically acceptable isomers and salts thereof.

[0378]

• [0379] wherein R is selected from
  • [0380] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl,
  • [0381] preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl, triazolyl, and pyridazinyl,
    • [0382] more preferably 4-pyridyl, and
  • [0383] b) unsubstituted or substituted 9- or 10-membered fused heterocyclyl
  • [0384] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzotriazolyl, 2,3-dihydrobenzofuryl, 2-oxo-1,2-dihydroquinol-7-yl, naphthyridinyl and quinozalinyl,
  • [0385] 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_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,
    • [0386] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0387] wherein R¹ is selected from unsubstituted or substituted
  • [0388] aryl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, and naphthyl,
  • [0389] cycloalkyl, preferably cyclohexyl,
  • [0390] 5-6 membered heteroaryl, preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl, and
  • [0391] 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;
• [0392] 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, C₁₄-aminoalkyl, nitro, amino, —NHC(O)NH₂, alkylcarbonylamino, 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,

[0393]

• • [0394]  and C_1-4-alkoxy,
    • [0395] 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;
• [0396] wherein R² is one or more substituents independently
  • [0397] selected from
    • [0398] H,
    • [0399] halo,
    • [0400] hydroxy,
    • [0401] amino,
    • [0402] C_1-6-alkyl,
    • [0403] C_1-6-haloalkyl,
    • [0404] C_1-6-alkoxy,
    • [0405] C_1-2-alkylamino,
    • [0406] aminosulfonyl,
    • [0407] C_3-6-cycloalkyl,
    • [0408] cyano,
    • [0409] C_1-2-hydroxyalkyl,
    • [0410] nitro,
    • [0411] C_2-3-alkenyl,
    • [0412] C_2-3-alkynyl,
    • [0413] C_1-6-haloalkoxy,
    • [0414] C_1-6-carboxyalkyl,
    • [0415] 5-6-membered heterocyclyl-C_1-6-alkylamino,
    • [0416] unsubstituted or substituted phenyl and
    • [0417] unsubstituted or substituted 5-6 membered heterocyclyl;
  • [0418] 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,
    • [0419] furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0420] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and

[0421]

• • [0422] preferably a direct bond, ethyl, butyl, and

[0423]

• [0424] 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,
  • [0425] preferably methylenyl, ethylenyl,

[0426]

• • [0427]  and aminoethylenyl;
• [0428] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0429] preferably trifluoromethyl; and
• [0430] 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-alkylamino-C_1-3-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl;
• [0431] provided R² is not H, or provided R¹ is not heteroaryl or aryl or provided R is substituted with 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, or optionally substituted heterocyclyl-C_2-4-alkynyl, or R¹ is substituted with optionally substituted phenyloxy, optionally substituted 5-6 membered heterocyclyloxy, optionally substituted 5-6 membered heterocyclylsulfonyl, optionally substituted 5-6 membered heterocyclylamino, optionally substituted 5-6 membered heterocyclylcarbonyl, optionally substituted 5-6 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 R^z is CH₂;
  and pharmaceutically acceptable isomers and derivatives thereof.

[0433]

• [0434] wherein R is selected from
  • [0435] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl,
    • [0436] preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl, triazolyl, and pyridazinyl, more preferably 4-pyridyl, and
  • [0437] b) unsubstituted or substituted 9- or 10-membered fused heteroaryl
    • [0438] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzotriazolyl, naphthyridinyl and quinozalinyl,
  • [0439] 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,
    • [0440] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0441] wherein R¹ is selected from unsubstituted or substituted aryl, cycloalkyl, 5-6 membered heteroaryl and 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0442] 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,
    • [0443] specifically 4-6 membered saturated or partially un-saturated monocyclic heterocyclyl,
      • [0444] 9-10 membered saturated or partially un-saturated bicyclic heterocyclyl, and
      • [0445] 13-14 membered saturated or partially un-saturated tricyclic heterocyclyl,
      • [0446] 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,
• [0447] 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, C₁₄-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,

[0448]

• • [0449] and C_1-4-alkoxy,
    • [0450] 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;
• [0451] wherein R² is one or more substituents independently
  • [0452] selected from
    • [0453] H,
    • [0454] halo,
    • [0455] hydroxy,
    • [0456] amino,
    • [0457] C_1-6-alkyl,
    • [0458] C_1-6-haloalkyl,
    • [0459] C_1-6-alkoxy,
    • [0460] C_1-2-alkylamino,
    • [0461] aminosulfonyl,
    • [0462] C_3-6-cycloalkyl,
    • [0463] cyano,
    • [0464] C_1-2-hydroxyalkyl,
    • [0465] nitro,
    • [0466] C_2-3-alkenyl,
    • [0467] C_2-3-alkynyl,
    • [0468] C_1-6-haloalkoxy,
    • [0469] C_1-6-carboxyalkyl,
    • [0470] 5-6-membered heterocyclyl-C_1-6-alkylamino,
    • [0471] unsubstituted or substituted phenyl and
    • [0472] unsubstituted or substituted 5-6 membered heterocyclyl,
  • [0473] 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,
    • [0474] pyridyl, imidazolyl, and pyrazolyl,
  • [0475] 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 heteroaryl selected from thienyl, furanyl,
    • [0476] pyridyl, imidazolyl, and pyrazolyl;
• [0477] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and

[0478]

• [0479] preferably a direct bond, ethyl, butyl, and

[0480]

• [0481] 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,
  • [0482] preferably methylenyl, ethylenyl,

[0483]

• • [0484]  and aminoethylenyl;
• [0485] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0486] preferably trifluoromethyl; and
• [0487] 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;
• [0488] 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.

[0490]

• [0491] wherein R¹ is selected from unsubstituted or substituted
  • [0492] aryl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, and naphthyl,
  • [0493] cycloalkyl, preferably cyclohexyl,
  • [0494] 5-6 membered heteroaryl, preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl, and
  • [0495] 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;
• [0496] 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, C₁₄-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,

[0497]

• • [0498] and C_1-4-alkoxy,
  • [0499] 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;
• [0500] wherein R² is one or more substituents independently
  • [0501] selected from
    • [0502] H,
    • [0503] halo,
    • [0504] hydroxy,
    • [0505] amino,
    • [0506] C_1-6-alkyl,
    • [0507] C_1-6-haloalkyl,
    • [0508] C_1-6-alkoxy,
    • [0509] C_1-2-alkylamino,
    • [0510] aminosulfonyl,
    • [0511] C_3-6-cycloalkyl,
    • [0512] cyano,
    • [0513] C_1-2-hydroxyalkyl,
    • [0514] nitro,
    • [0515] C_2-3-alkenyl,
    • [0516] C_2-3-alkynyl,
    • [0517] C_1-6-haloalkoxy,
    • [0518] C_1-6-carboxyalkyl,
    • [0519] 5-6-membered heterocyclyl-C_1-6-alkylamino,
    • [0520] unsubstituted or substituted phenyl and
    • [0521] unsubstituted or substituted 5-6 membered heterocyclyl,
  • [0522] 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, fury, pyridyl, imidazolyl, and pyrazolyl;
• [0523] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0524] preferably trifluoromethyl;
• [0525] 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
• [0526] 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,
  • [0527] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
    and pharmaceutically acceptable isomers and derivatives thereof.

[0529]

• [0530] wherein R is selected from
  • [0531] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl selected from 4-pyridyl, 2-pyridyl, 4-pyrimidinyl, and tetrahydro-2H-pyran-4-yl, and
  • [0532] b) unsubstituted or substituted 9- or 10-membered fused heteroaryl selected from 4-quinolyl, 6-quinolyl, 2,3-dihydro-5-benzofuryl, 5-benzoxazolyl, 1H-pyrrolo[2,3-b]pyridin-4-yl, and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl,
  • [0533] 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-alkylaminocarbonyl, 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;
  • [0534] preferably 2-methylamino-4-pyrimidinyl, 4-pyrimidinyl, 4-quinolyl, 2-methylamino-4-pyridyl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 4-pyridyl, 2-amino-4-pyridyl, 2-methoxy-4-pyrimidinyl, 6-quinolyl, 2-methoxy-4-pyridyl, 2-morpholino-4-pyridyl, and 2-trifluoromethoxy-4-pyridyl;
    • [0535] more preferably 4-quinolyl, 2-methylamino-4-pyridyl, 4-pyridyl and N-oxides thereof, 4-pyrimidinyl, 2-methoxy-4-pyrimidinyl, 2-methoxy-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl and 2-methylamino-4-pyrimidinyl;
• [0536] wherein R¹ is selected from unsubstituted or substituted
  • [0537] aryl,
  • [0538] cycloalkyl,
  • [0539] 5-6 membered heteroaryl and
  • [0540] 9-10 membered bicyclic and 11-14 membered tricyclic heterocyclyl,
• [0541] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1′,2′-dihydro-spiro[cyclopropane-1,3′-[3H]indol]-6′-yl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, 3,4-dihydro-[1,8]naphthyridinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, quinozalinyl, benzo[d]isothiazolyl, 3,4-dihydro-quinazolinyl, 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, dihydro-benzimidazolyl, benzoxazolyl and benzthiazolyl,
  • [0542] more preferably phenyl, 1,2,3,4-tetrahydroisoquinolyl, 2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, 1′,2′-dihydro-spiro[cyclopropane-1,3′-[3H]indol]-6′-yl, and tetrahydroquinolinyl,
    • [0543] even more preferably
      • [0544] phenyl substituted with one or more substituents selected from chloro, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, 2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, methylsulfonylamino, dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—, 4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl, 3-tetrahydrofuryloxy, 1-methylcarbonyl-pyrrolidin-2-ylmethoxy, 1-methyl-pyrrolindin-2-ylmethoxy, pyrrolindin-1-ylethoxy, 1-isopropyl-pyrrolindin-2-ylmethoxy, 3-tetrahydrofurylmethoxy, azetidin-3-ylmethoxy, and methylsulfonylaminoethoxy;
      • [0545] 4,4-dimethyl-3,4-dihydro-2-oxo-1H-quinolinyl;
      • [0546] 4,4-dimethyl-1,2,3,4-tetrahydro-1H-quinolinyl;
      • [0547] 4,4-dimethyl-3,4-dihydro-2-oxo-1H-[1,8]naphthyridinyl;
      • [0548] 2-oxo-3,3-bis(trifluoromethyl)-2,3-dihydro-1H-indol-6-yl;
      • [0549] 2-oxo-2,3-dihydro-1H-indol-6-yl;
      • [0550] 1′,2′-dihydro-spiro[cyclopropane-1,3′-[3H]indol]-6′-yl;
      • [0551] 3,3-dimethyl-2,3-dihydro-1H-indolyl optionally substituted with a substituent selected from pyrrolidin-1-yl-carbonyl, methylcarbonyl, and methylsulfonyl; and
      • [0552] 4,4-dimethyl-1,2,3,4-tetrahydro-1H-isoquinolinyl;
• [0553] 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 phenyloxy, optionally substituted 4-6 membered heterocyclyl-C₁-C₆-alkyl, optionally substituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionally substituted 4-6 membered heterocyclyl, 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, optionally substituted 4-6 membered heterocyclylcarbonyl-C_1-4-alkyl, optionally substituted 4-6 membered heterocyclyl-C_1-4-alkylcarbonylamino, optionally substituted 4-6 membered heterocyclyl-oxycarbonylamino, C_1-2-haloalkyl, C₁₄-aminoalkyl, nitro, amino, C_1-3-alkylsulfonylamino, hydroxy, cyano, aminosulfonyl, C_1-2-alkylsulfonyl, halosulfonyl, C_1-4-alkylcarbonyl, amino-C_1-4-alkylcarbonyl, C_1-3-alkylamino-C_1-4-alkylcarbonyl, C_1-3-alkylamino-C_1-4-alkylcarbonylamino, C_1-4-alkoxycarbonyl-C_1-4-alkyl, 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_1-3-alkylsulfonylamino-C_1-3-alkoxy, C_1-4-hydroxyalkyl,

[0554]

• • [0555] and C_1-4-alkoxy;
  • [0556] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, Boc-aminoethyl, hydroxy, oxo, fluorosulfonyl, methylsulfonyl, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, 4-pyridylmethyl, 4-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, 2-methyl-2-(4-pyrimidinyl)ethyl, 2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, 2-methyl-2-(pyrazol-5-yl)ethyl, 2-methyl-2-(1-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, 1-(4-morpholinyl)-2,2-dimethylethyl, 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, 1-(pyrrolidin-1-yl)-2-methylpropyl, 2-methyl-2-(pyrrolidin-1-yl)ethyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl, pyrrolidin-1-yl-carbonyl, pyrrolidin-1-yl-carbonyl, 4-pyridylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl, CH₃O—C (═O)—CH₂—, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, methylsulfonylamino, dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—, 4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—, cyclohexyl-N(CH₃)—, (4-pyrimidinyl)amino, (2-methylthio-4-pyrimidinyl)amino, 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-(pyrrolidin-2-ylmethoxy)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, 3-tetrahydrofuryloxy, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, 3-tetrahydrofurylmethoxy, pyrrolidin-2-ylmethoxy, 1-methylcarbonyl-pyrrolidin-2-ylmethoxy, 1-Boc-pyrrolidin-2-ylmethoxy, pyrrolidin-1-ylmethoxy, 1-methyl-pyrrolidin-2-ylmethoxy, 1-isopropyl-pyrrolidin-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy, (1-pyrrolidinyl)ethoxy, piperdin-4-ylmethoxy, piperdin-3-ylmethoxy, 1-methylpiperdin-4-yloxy, methylsulfonylaminoethoxy, isopropoxy, methoxy and ethoxy;
    • [0557] more preferably chloro, oxo, methylsulfonyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, 2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, methylcarbonyl, pyrrolidin-1-yl-carbonyl, 4-pyridylcarbonyl, methylsulfonylamino, dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—, 4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl, 4-pyridylmethyl, 2-pyrrolidinylmethyl, 3-tetrahydrofurylmethoxy, azetidin-3-ylmethoxy, 3-tetrahydrofuryloxy, piperdin-3-ylmethoxy, 1-methylcarbonyl-pyrrolidin-2-ylmethoxy, 1-methyl-pyrrolidin-2-ylmethoxy, 1-isopropyl-pyrrolidin-2-ylmethoxy and methylsulfonylaminoethoxy;
    • [0558] particularly 2-methyl-2-(1-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl, 2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, 1-(4-morpholinyl)-2,2-dimethylethyl, pyrrolidin-1-yl-carbonyl, CH₃O—C(═O)—CH₂—, methylsulfonylamino, dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—, 4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—, 1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl, 3-tetrahydrofuryloxy, 1-methylcarbonyl-pyrrolidin-2-ylmethoxy, and methylsulfonylaminoethoxy; and
• [0559] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl; preferably —CF₃; and
• [0560] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-3-alkyl, 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 pharmaceutically acceptable derivatives thereof.

[1138]

• [1139] wherein each of A¹ and A² is independently C, CH or N;
• [1140] wherein ring A is selected from
  • [1141] a) 5- or 6-membered partially saturated heterocyclyl,
  • [1142] b) 5- or 6-membered heteroaryl,
  • [1143] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl,
  • [1144] d) 9-, 10- or 11-membered fused heteroaryl;
  • [1145] e) naphthyl, and
  • [1146] f) 4-, 5- or 6-membered cycloalkenyl;
• [1147] wherein X is

[1148]

• [1149] wherein Z is oxygen or sulfur;
• [1150] wherein Y is selected from

[1151]

• [1152] wherein p is 0 to 2,
• [1153] 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;
• [1154] 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;
• [1155] wherein R^d is cycloalkyl;
• [1156] wherein R is selected from
  • [1157] a) substituted or unsubstituted 5-6 membered heterocyclyl, b) substituted aryl, and
  • [1158] c) substituted or unsubstituted fused 9-14-membered bicyclic or tricyclic heterocyclyl;
    • [1159] wherein substituted R is substituted with one or more substituents independently selected from halo, —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³, R³—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;
• [1160] wherein R¹ is selected from
  • [1161] a) substituted or unsubstituted 6-10 membered aryl,
  • [1162] b) substituted or unsubstituted 5-6 membered heterocyclyl,
  • [1163] c) substituted or unsubstituted 9-14 membered bicyclic or tricyclic heterocyclyl,
  • [1164] d) cycloalkyl, and
  • [1165] e) cycloalkenyl,
    • [1166] wherein substituted R¹ is substituted with one or more substituents independently selected from halo, —OR —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, halosulfonyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, lower alkyl substituted with R², lower alkenyl substituted with R², and lower alkynyl substituted with R²;
• [1167] 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;
• [1168] wherein R³ is selected from H, lower alkyl, phenyl, heterocyclyl, C₃-C₆-cycloalkyl, phenylalkyl, heterocyclylalkyl, C₃-C₆ cycloalkylalkyl, and lower haloalkyl;
• [1169] 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—,
• [1170] wherein R⁴ is optionally substituted with hydroxy;
• [1171] wherein R⁵ is selected from H, lower alkyl, phenyl and lower aralkyl;
• [1172] wherein R^5a is selected from H, lower alkyl, phenyl and lower aralkyl;
• [1173] wherein R⁶ is selected from H or C_1-6-alkyl; and
• [1174] 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

[1193]

[1195]

[1197]

[1199]

[1201]

[1206]

[1208]

[1210]

[1212]

[1214]

[1217]

[1219]

[1221]

[1223]

[1230]

[1232]

[1234]

[1236]

[1240]

[1243]

[1247]

[1250]

[1252]

[1254]

[1256]

[1258]

[1260]

[1262]

[1264]

[1266]

[1268]

[1270]

[1272]

[1274]

[1276]

[1278]

[1280]

[1282]

[1284]

[1286]

[1288]

[1290]

[1292]

[1294]

[1296]

[1298]

[1300]

[1303]

[1329]
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 XXXV—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-nitrobenzyl)-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 LXXXVIX N-Boc-(2-chloropyrimidin-4-yl)-methylamine

Preparation XC Methanesulfonic Acid 1-Boc-azetidin-3-ylmethyl Ester

Preparation XC—Methanesulfonic Acid 1-Boc-azetidin-3-ylmethyl Ester

Preparation XCI—N-(2-bromo-5-nitrophenyl)acetamide

Preparation XCII—N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

Preparation XCIII—1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone

Preparation XCIV—3,3-dimethyl-6-nitroindoline

Preparation XCV—1-Acetyl-6-amino-3,3-dimethylindoline

Preparation XCVI—4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenylamine

Preparation XCVII—2-bromo-1-tert-butyl-4-nitrobenzene

Preparation XCVIII—4-(2-tert-butyl-5-nitrophenyl)pyridine

Preparation XCIX—4-(2-tert-butyl-5-nitrophenyl)-1-methylpyridinium

Preparation C—4-tert-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

Preparation CI—[1-(4-amino-phenyl)-ethyl]carbamic Acid tert-butyl Ester

Preparation CII—1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine

Preparation CIII—4-(tert-butyl)-2-(4-methylpiperazinyl)phenylamine

Preparation CIV—{2-[4-(tert-butyl)-2-aminophenoxy]ethyl}dimethylamine

Preparation CV—2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline

Preparation CVI—tert-butyl 4-[(6-nitro-3,3-dimethylindolinyl)methyl]piperidinecarboxylate

Preparation CVII—3,3-dimethyl-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indol-6-ylamine

Preparation CVIII—(2-chloro-(3-pyridyl))-N-(4-phenoxyphenyl)carboxamide

Preparation CIX—1-(1-methyl(4-piperidyl))-6-nitroindoline

Preparation CX—1-(1-methyl-4-piperidyl)indoline-6-ylamine

Preparation CXI—N-(2-bromo-5-nitrophenyl)acetamide

Preparation CXII—N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

Preparation CXIII—1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone

Preparation CXIV—3,3-dimethyl-6-nitroindoline

Preparation CXV—3,3-dimethyl-1-(4-methyl-piperazin-1-yl)-6-nitro-2,3-dihydro-1H-indole

Preparation CXVI—3,3-dimethyl-1-(1-methyl(4-piperidyl))indoline-6-ylamine

Preparation CXVII—3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole

Preparation CXVIII—3-(1-methyl-4-piperidyl)indole-5-ylamine

Preparation CXIX—{3-[3-amino-5-(trifluoromethyl)phenyl]propynyl}dimethylamine

Preparation CXX—{3-[3-amino-5-(trifluoromethyl)phenyl]propyl}dimethylamine

Preparation CXXI—4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane

Preparation CXXII—5-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-3-(trifluoro-methyl)phenylamine

Preparation CXXIII—4-phenylpiperidine

Preparation CXXIV—1-methyl-4-phenylpiperidine

Preparation CXXV—4-(1-methyl-4-piperidyl)phenylamine

Preparation CXXVI—1-piperidylprop-2-en-1-one

Preparation CXXVII—1-(tert-butyl)-2-bromo-4-nitrobenzene

Preparation CXXVIII—(2E)-3-[2-(tert-butyl)-5-nitrophenyl]-1-piperidylprop-2-en-1-one

Preparation CXXIX—3-(5-amino-2-tert-butylphenyl)-1-piperidin-1-yl-propenone

Preparation CXXX—4-(tert-butyl)-3-(3-piperidylpropyl)phenylamine

Preparation CXXXI—3-(3-nitrophenyl)-1-(4-methylpiperazinyl)propan-1-one

Preparation CXXXII—3-(3-aminophenyl)-1-(4-methylpiperazinyl)propan-1-one

Preparation CXXXIII—1-(2-morpholin-4-ylethyl)indol-6-ylamine

Preparation CXXXIV—methyl 2-methyl-2-(4-nitrophenyl)propanoate

Preparation CXXXV—3-methyl-3-(4-nitrophenyl)butan-1-one

Preparation CXXXVI—4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenylamine

Preparation CXXXVII—4-{2,2,2-trifluoro-1-[2-(2-methoxy)ethoxy]-1-(trifluoromethyl)ethyl}phenylamine

Preparation CXXXVIII—2-fluoropyridine-3-carbonyl chloride

Preparation CXXXIX—N-(3-Amino-5-chloro-phenyl)-2-dimethylamino-acetamide

Preparation CXL—2-amino-4-nitro-benzamide

Preparation CXLI—6-nitro-3H-quinazolin-4-one

Preparation CXLII—6-amino-3H-quinazolin-4-one

Preparation CXLIII—(2,4-dinitro-phenyl)-acetic Acid Methyl Ester

Preparation CXLIV—6-amino-1,3-dihydro-indol-2-one

Preparation CXLV—3-Methyl-but-2-enoic Acid (6-bromo-pyridin-2-yl)-amide

Preparation CXLVI—3-Methyl-but-2-enoic Acid (6-amino-pyridin-2-yl)-amide

Preparation CXLVII—7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

Preparation CXLVIII—2-[1-(3-Amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic Acid tert-butyl Ester

Preparation CXLIX—Pyrimidine-4-carbaldehyde Oxime

Preparation CL—C-Pyrimidin-4-yl-methylamine Dihydrogen Chloride

Preparation CLI—2-(2,4-Dinitro-phenyl)-3,3,3-trifluoro-2-trifluoromethyl-propionic Acid Methyl Ester

Preparation CLII—6-Amino-1-hydroxy-3,3-bis-trifluoromethyl-1,3-dihydro-indol-2-one

Preparation CLIII—6-Amino-3,3-bis-trifluoromethyl-1,3-dihydro-indol-2-one

Preparation CLIV—N-[3-(2-Amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide

Preparation CLV —2-Chloro-N-[3-(2-methanesulfonylamino-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

Preparation CLVI—2-Methyl-2-(4-nitro-phenyl)-propionic Acid

Preparation CLVII—2-Methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole

Preparation CLVIII—2-Methyl-5-[1-methyl-1-(4-amino-phenyl)-ethyl]-[1,3,4]oxadiazole

Preparation CLIX—4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-pyrimidine

Preparation CLX—5-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-1H-pyrazole

Preparation CLXI—2-tert-Butyl-5-nitro-phenylamine

Preparation CLXII—2-Bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide

Preparation CLXXIII—N-(2-tert-Butyl-5-nitro-phenyl)-2-dimethylamino-acetamide

Preparation CLXIV—N-(5-Amino-2-tert-butyl-phenyl)-2-dimethylamino-acetamide

Preparation CLXV—5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide

Preparation CLXVI—1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole

Preparation CLXVII—6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole

Preparation CLXVIII—Ethyl 6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole-1-carbamate

Preparation CLXIX—Ethyl 6-amino-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole-1-carbamate

Preparation CLXX—4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-3,6-dihydro-2H-pyridine-1-carboxylic Acid Ethyl Ester

Preparation CLXXI—4-[1-Methyl-1-(4-amino-phenyl)-ethyl]-3,6-dihydro-2H-pyridine-1-carboxylic Acid Ethyl Ester

Preparation CLXXII: 3,3-dimethyl-6-nitroindoline 3-Methyl-but-2-enoic acid (3-acetylamino-phenyl)-amide

Preparation CLXXIII—N-(4,4-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-acetamide

Preparation CLXXIV: 7-Amino-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one

Preparation CLXXV—4,4-Dimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine

Preparation CLXXVI—N-(4,4-Dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoronicotinamide

Preparation CLXXVII—4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline

Preparation CLXXVIII—1-Ethyl-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline

Preparation CLXXIX: 1-Ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine

Preparation CLXXX—1-(4-Nitro-phenyl)-cyclopropanecarbonitrile

Preparation CLXXXI—C-[1-(4-Nitro-phenyl)-cyclopropyl]-methylamine

Preparation CLXXXII—2,2,2-Trifluoro-N-[1-(4-nitro-phenyl)-cyclopropylmethyl]-acetamide

Preparation CLXXXIII—1-(7-Nitro-4-spiro-1′-cyclopropane-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone

Preparation CLXXXIV—7-Nitro-4-spiro-1′-cyclopropane-1,2,3,4-tetrahydroisoquinoline

Preparation CLXXXV—tert-Butyl N-[7-nitro-4-spiro-1′-cyclopropane-3,4-dihydro-1H-isoquinoline-2-carbamate

Preparation CLXXXVI: tert-Butyl N-[7-amino-4-spiro-1′-cyclopropane-3,4-dihydro-1H-isoquinoline]carbamate

Preparation CLXXXVII—4-methyl-6-[2-(1-methyl-ppyrrolidin-2-yl)-ethyl]-pyrimidin-2-ylamine

Preparation CLXXXVIII—(6-bromo-pyridin-2-yl)3-Methyl-but-2-enoic-amide

Preparation CLXXXIX—(6-amino-pyridin-2-yl) 3-Methyl-but-2-enoic-amide

Preparation CXC—7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

Preparation CXCI—2-[1-(3-Amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic Acid tert-butyl Ester

Preparation CXCII—N-(3-Amino-5-chloro-phenyl)-2-dimethylamino-acetamide

General Procedure for the Preparation of 2,6-diamonipyridines

Preparation CXCIII—2-Methyl-2-(4-nitrophenyl)propionic Acid

Preparation CXCIV—2-Methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole

Preparation CXCV—2-Methyl-5-[1-methyl-1-(4-amino-phenyl)-ethyl]-[1,3,4]oxadiazole

Preparation CXCVI—4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-pyrimidine

Preparation CXCVII—5-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-1H-pyrazole

Preparation CXCVIII—2-Methyl-2-(4-nitro-phenyl)-1-pyrrolidin-yl-propan-1-one

Preparation CXCIX—4-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl-phenylamine

Preparation CC—1-methyl-1-(4-nitro-phenyl)-ethylamine

Preparation CCI—[1-(4-Amino-phenyl)-1-methyl-ethyl]-(2-methylsulfanyl-pyrimidin-4-yl)-amine

Preparation CCII—2-(2,2,2-Trifluoro-ethoxy)-isonicotinonitrile

Preparation CCIII—C-[2-(2,2,2-Trifluoro-ethoxy)-pyridin-4-yl]-methylamine Hydrogen Chloride

Preparation CCIV—2-Bromomethyl-3-nitro-benzoic Acid Methyl Ester

Preparation CCV4-Nitro-2,3-dihydro-isoindol-1-one

Preparation CCVI—4-Amino-2,3-dihydro-isoindol-1-one

Preparation CCVII—Pyridin-4-ylmethyl-carbamic Acid tert-butyl Ester

Preparation CCVIII—(1-Oxy-pyridin-4-ylmethyl)-carbamic Acid tert-butyl Ester

Preparation CCIX—C-(1-Oxy-pyridin-4-yl)-methylamine

Preparation CCX—2-(4-Methoxy-benzylamino)-isonicotinonitrile

Preparation CCXI—(4-Aminomethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine

Preparation CCXII—4-Aminomethyl-pyridin-2-ylamine

Preparation CCXIII—2-Methylamino-isonicotinonitrile

Preparation CCXIV—(4-Aminomethyl-pyridin-2-yl)-methyl-amine

Preparation CCXV—3-Fluoro-pyridine 1-oxide

Preparation CCXVI—3-Fluoro-pyridine-2-carbonitrile

Preparation CCXVII—C-(3-Fluoro-pyridin-2-yl)-methylamine

Preparation CCXVIII: 5-Bromo-pyridine-2-carbonitrile

Preparation CCXIX—5-Fluoro-pyridine-2-carbonitrile

Preparation CCXX—C-(5-Fluoro-pyridin-2-yl)-methylamine

Preparation CCXXI—1H-Pyrrolo[2,3-b]pyridine 7-oxide

Preparation CCXXII—4-chloro-1H-pyrrolo[2,3-b]pyridine

Preparation CCXXIII—1-(4-iodo-pyrrolo[2,3-b]pyridin-1-yl)-ethanone

Preparation CCXXIV—1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

Preparation CCXXV—1-(4-aminomethyl-pyrrolo[2,3-b]pyridin-1-yl)-ethanone

Preparation CCXXVI—N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide

Preparation CCXXVII—C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine Hydrogen Chloride Salt

General Procedure for the Preparation of 2-amino-4-methylaminopyridines

Preparation CCXXVIII—2-aminoisonicotinonitrile

Preparation CCXXIX—2-amino-4-methylaminopyridine

Preparation CCXXX—(2-Pyrrolidin-1-yl-pyridin-4-yl)-methylamine

Preparation CCXXXI—(2-Morpholin-4-yl-pyridin-4-yl)-methylamine

Preparation CCXXXII—3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-fluorene

Preparation CCXXXIII—3,9,9-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-ylamine(156)

Preparation CCXXXIV—2-Chloro-5-nitro-phenol

Preparation CCXXXV—3-(5-Amino-2-chloro-phenoxymethyl)-azetidine-1-carboxylic Acid tert-butyl Ester

Preparation CCXXXVI: 3-(Benzotriazol-1-yloxy)-6-chloro-pyridazine-4-carboxylic Acid (4-tert-butyl-phenyl)-amide

Preparation CCXXXVII—3-Hydroxymethyl-azetidine-1-carboxylic Acid Benzyl Ester

Preparation CCXXXVIII—3-Methanesulfonyloxymethyl-azetidine-1-carboxylic Acid Benzyl Ester

Preparation CCXXXIX—3-Nitro-5-trifluoromethyl-phenol

Preparation CCXL—3-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-azetidine-1-carboxylic Acid Benzyl Ester

Preparation CCXLI—3-(3-amino-5-trifluoromethyl-phenoxymethyl)-azetidine-1-carboxylic Acid Benzyl Ester

Preparation CCXLII—2-Methylamino-pyrimidine-4-carbonitrile

Preparation CCXLIII—(4-Aminomethyl-pyrimidin-2-yl) Methylamine

Preparation CCXLIV—6-Hydroxy-pyrimidine-4-carbaldehyde Oxime

Preparation CCXLV—6-Chloro-pyrimidine-4-carbonitrile

Preparation CCXLVI—6-Methylamino-pyrimidine-4-carbonitrile

Preparation CCXLVII—(6-Aminomethyl-pyrimidin-4-yl)-methyl-amine

Preparation CCXLVIII—6-aminomethyl Quinoline

Preparation CCXLIX—3-nitro-5-(trifluoromethyl)phenylamine

Preparation CCL—N-(3-nitro-5-(trifluoromethyl)phenyl)methanesulfonamide

Preparation CCLI—(3S)-tetrahydro-3-furanyl 3-nitro-5-(trifluoromethyl)phenylcarbamate

Preparation CCLII—N-(2-((3-nitro-5-(trifluoromethyl)phenyl)oxy)ethyl)-methanesulfonamide

Preparation CCLIII—N-(2-((3-amino-5-(trifluoromethyl)phenyl)oxy)ethyl)methanesulfonamide

Preparation CCLIV-(2R)-1-acetyl-2-(((3-nitro-5-(trifluoromethyl)phenyl)oxy)methyl)pyrrolidine

Preparation CCLV—3-(2-Chloro-5-nitro-phenoxymethyl)-azetidine-1-carboxylic Acid tert-butyl Ester

EXAMPLE 1

[1840]

N-(4-Chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide

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

Step B—Preparation of of {3-[(tert-butoxy)carbonylamino](2-thienyl)}-N-(4-chlorophenyl)carboxamide

Step C—Preparation of N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide

EXAMPLE 2

[1845]

N-Phenyl{3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide

EXAMPLE 3

[1847]

N-(4-Chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

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

Step B—Preparation of N-(4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 4

[1850]

N-(3,4-Dichlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide

EXAMPLE 5

[1852]

N-(3-Chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 6

[1854]

N-(4-Chlorophenyl){3-[(4-pyridylmethyl)amino](2-pyridyl)}carboxamide

EXAMPLE 7

[1856]

N-(4-Chlorophenyl){3-[(6-quinolylmethyl)amino](2-pyridyl)}carboxamide

EXAMPLE 8

[1858]

N-(3,4-Dichlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}-carboxamide

EXAMPLE 9

[1860]

N-(4-Chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

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

Step B—Preparation of N-(4-chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide

EXAMPLE 10

[1863]

N-(3,4-Dichlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 11

[1865]

N-(3-Fluoro-4-methylphenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 12

[1867]

{6-Chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(4-pyridylmethyl)carboxamide

EXAMPLE 13

[1869]

N-(3,4-Dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 14

[1871]

N-(4-Chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 15

[1873]

{6-Chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(3-fluorophenyl)carboxamide

EXAMPLE 16

[1875]

N-(3-Chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 17

[1877]

N-(4-Chlorophenyl){3-[(4-pyridylmethylene)amino](4-pyridinecarboxamide

EXAMPLE 18

[1879]

N-(4-Chlorophenyl){3-[(4-pyridylmethyl)amino](4-pyridyl)}carboxamide

EXAMPLE 19

[1881]

N-(3-Fluoro-4-methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 20

[1883]

N-(4-Chlorophenyl){2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 21

[1885]

N-(4-Chlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}carboxamide

EXAMPLE 22

[1887]

N-(4-Chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide

Step A—Preparation of 5-bromo-2-hydroxynicotinic Acid

Step B—Preparation of 5-bromo-2-chloronicotinic Acid

Step C—Preparation of 5-bromo-2-chloro-N-(4-chlorophenyl)nicotinamide

Step D—Preparation of 5-(3-thiophene)-2-chloro-N-(4-chlorophenyl)nicotinamide

Step E—Preparation of N-(4-chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide

EXAMPLE 23

[1893]

N-(4-Chlorophenyl){5-(4-methoxyphenyl)-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide

EXAMPLE 24

[1895]

N-(4-Chlorophenyl){5-bromo-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide

EXAMPLE 25

[1897]

N-(4-Isopropylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

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

Step B: Preparation of N-[4-(isopropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide Hydrochloride