Substituted amine derivatives and methods of use

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

DESCRIPTION OF THE INVENTION

[0015] A class of compounds useful in treating cancer and angiogenesis is defined by Formula I
wherein each of A¹ and A² is independently C, CH or N;

• [0016] wherein ring A is selected from
  • [0017] a) 5- or 6-membered partially saturated heterocyclyl,
    • [0018] preferably dihydropyran, dihydrothienyl, dihydrofuryl, oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl, dihydro-oxazolyl, dihydro-isothiazolyl, dihydro-isoxazolyl, imidazolinyl and pyrazolinyl,
  • [0019] b) 5- or 6-membered heteroaryl,
    • [0020] preferably
      • [0021] I) 5-membered heteroaryl selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl,
        • [0022] even more preferably 5-membered heteroaryl selected from
        • [0023] specifically
      • [0024] II) preferably 6-membered heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl,
        • [0025] even more preferably 6-membered heteroaryl selected from
        • [0026] more specifically
  • [0027] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl,
    • [0028] preferably tetrahydroquinolinyl,
  • [0029] d) 9- or 10-membered fused heteroaryl,
    • [0030] preferably
      • [0031] i) fused 9-membered fused heteroaryl selected from benzothienyl, benzothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuryl, indazolyl and isoindolyl, and
      • [0032] ii) fused 10-membered heteroaryl selected from quinolyl, isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl,
  • [0033] e) aryl, and
  • [0034] f) 4-, 5- or 6-membered cycloalkenyl,
    • [0035] preferably 5-membered cycloalkenyl,
      • [0036] more preferably cyclopentadienyl or cyclopentenyl;
• [0037] wherein X is
  • [0038] preferably X is selected from
    • [0039] more preferably X is
• [0040] wherein Z is oxygen or sulfur;
• [0041] wherein R is selected from
  • [0042] a) substituted or unsubstituted 4-6 membered heterocyclyl,
    • [0043] preferably substituted or unsubstituted 5-6 membered heteroaryl comprising one or more nitrogen atoms,
      • [0044] more preferably pyrazolyl, triazolyl, pyridyl, pyrimidinyl, and pyridazinyl,
        • [0045] even more preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, triazolyl, 4-pyrimidinyl and 4-pyridazinyl,
        • [0046] most preferably 4-pyridyl,
  • [0047] b) substituted aryl,
    • [0048] preferably substituted phenyl,
      • [0049] more preferably optionally substituted
        • [0050] (heterocyclyl-substituted phenyl), and
  • [0051] c) substituted or unsubstituted 9-14-membered bicyclic or tricyclic heterocyclyl,
    • [0052] preferably substituted or unsubstituted 9-10 membered bicyclic or 13-14 membered tricyclic heterocyclyl,
      • [0053] more preferably substituted or unsubstituted 9-10 membered fused heterocyclyl,
        • [0054] even more preferably indazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzotriazolyl, 2,3-dihydrobenzofuryl, 1,2-dihydroquinolyl, naphthyridinyl and quinazolinyl,
        • [0055] even more preferably 5-indazolyl, 6-indazolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, indolyl, isoindolyl, benzotriazolyl, 2,3-dihydrobenzofuryl, 1,2-dihydroquinolyl, quinozalinyl, 4-isoquinolyl, 5-isoquinolyl, naphthyridinyl and 6-isoquinolyl,
        • [0056] especially preferred is 6-indazolyl;
  • [0057] 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, —NR³C(O)NR³R³, cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, nitro, oxo, alkylaminoalkoxyalkoxy, cyano, alkylaminoalkoxy, lower alkyl substituted with R², lower alkenyl substituted with R², and lower alkynyl substituted with R²;
    • [0058] preferably halo, —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, C_3-6-cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, nitro, C_1-4-alkylamino-C_1-4-alkoxy-C_1-4-alkoxy, cyano, C_1-4-alkylamino-C_1-4-alkoxy, C_1-2-alkyl substituted with R², C_2-3-alkenyl substituted with R², and C_2-3-alkynyl substituted with R²,
      • [0059] more preferably halo, hydroxy, C_1-4-alkyl, C_1-2-alkoxy, optionally substituted 4-6 membered heterocyclyl-C_1-2-alkoxy, amino, C_1-2-alkylamino, aminosulfonyl, —NR³C(O)R³, —NR³C(O)R³, C_3-6-cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, nitro, C_1-2-alkylamino-C_1-2-alkoxy-C_1-2-alkoxy, cyano, C_1-2-alkylamino-C_1-2-alkoxy, C_1-2-alkylamino-C_1-2-alkyl, C_1-2-alkylamino-C_2-3-alkynyl, C_1-2-hydroxyalkyl, C_1-2-aminoalkyl, C_1-2-haloalkyl, optionally substituted 4-6 membered heterocyclyl-C_2-3-alkenyl, and optionally substituted 4-6 membered heterocyclyl-C_2-3-alkynyl,
        • [0060] even more preferably chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, 1-methylpiperidinylmethoxy, aminosulfonyl, cyclohexyl, dimethylaminopropynyl, dimethylaminoethoxy, 3-(4-morpholinyl)propyn-1-yl, dimethylaminoethoxyethoxy, optionally substituted piperidinyl, morpholinyl, optionally substituted piperazinyl, optionally substituted phenyl, methyl, ethyl, propyl, cyano, hydroxymethyl, aminomethyl, nitro and trifluoromethyl;
• [0061] wherein R¹ is selected from
  • [0062] a) substituted or unsubstituted 6-10 membered aryl,
    • [0063] preferably phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl,
      • [0064] more preferably phenyl, tetrahydronaphthyl, and naphthyl,
  • [0065] b) substituted or unsubstituted 4-6 membered heterocyclyl,
    • [0066] preferably 5-6 membered heteroaryl,
      • [0067] more preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, furyl and pyrrolyl,
  • [0068] c) substituted or unsubstituted 9-14 membered bicyclic or tricyclic heterocyclyl,
    • [0069] preferably 9-10 membered bicyclic or 13-14 membered tricyclic heterocyclyl,
      • [0070] more preferably indazolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, 2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, benzo[d]isothiazolyl, benzothienyl, tetrahydroquinolyl, benzofuryl, dihydrobenimidazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzodioxanyl and quinazolinyl,
  • [0071] d) cycloalkyl,
    • [0072] preferably C_3-6-cycloalkyl,
      • [0073] more preferably cyclohexyl, and
  • [0074] e) cycloalkenyl,
    • [0075] wherein substituted R¹ is substituted with one or more substituents independently selected from halo, oxo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, —NR³C(O)NR³R³, optionally substituted cycloalkyl, optionally substituted 4-6 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,
      • [0076] preferably halo, —OR³, oxo, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR³), —(C₁-C₄ alkylenyl)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, C_1-C₆-alkylamino-C_1-C₆-alkoxy, C_1-C₆-alkylamino-C_1-C₆-alkoxy-C_1-C₆-alkoxy, halosulfonyl, optionally substituted 4-6 membered heterocyclylcarbonylalkyl, C_1-4-alkoxycarbonylamino-C_1-6-alkyl,
      • [0077]  optionally substituted C_3-6-cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, optionally substituted phenyl-C_1-6-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C_1-C₆-alkylenyl, 4-6 membered heterocyclyl-C_2-C₆-alkenylenyl, C_1-4-alkyl, cyano, C_1-4-hydroxyalkyl, nitro and C_1-4-haloalkyl,
        • [0078] more preferably halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 4-6 membered heterocyclyl-C_1-4-alkylcarbonyl, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, 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,
      • [0079]  and C_1-4-alkoxy, and
        • [0080] even more 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;
• [0081] 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 phenylalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted heteroarylalkyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, C_1-4-alkoxy-C_1-4-alkoxy and C_1-4-alkoxy-C_1-4-alkoxy-C_1-4-alkoxy, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl,
• [0082] preferably H, halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, C_3-6-cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, C_1-6-alkyl, cyano, C_1-4-hydroxyalkyl, C_1-4-carboxyalkyl, nitro, C_1-3-alkoxy-C_1-2-alkoxy, C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkoxy, C_2-3-alkenyl, C_2-3-alkynyl and C_1-4-haloalkyl,
  • [0083] more preferably H, halo, hydroxy, C_1-2-alkoxy, C_1-2-haloalkoxy, amino, C_1-2-alkylamino, optionally substituted 4-6 membered heterocyclyl-C_1-2-alkylamino, aminosulfonyl, C_3-6-cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, C_1-4-alkyl, cyano, C_1-2-hydroxyalkyl, C_1-3-carboxyalkyl, nitro, C_2-3-alkenyl, C_2-3-alkynyl and C_1-2-haloalkyl, and
    • [0084] even more preferably H, chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, dimethylamino, aminosulfonyl, carboxymethyl, cyclopropyl, optionally substituted phenyl, methyl, ethyl, propyl, cyano, hydroxymethyl, nitro, propenyl, propynyl and trifluoromethyl and unsubstituted or substituted heteroaryl selected
      • [0085] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0086] wherein R³ is selected from H, lower alkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C₃-C₆-cycloalkyl, optionally substituted phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted C₃-C₆ cycloalkylalkyl, and lower haloalkyl,
  • [0087] preferably H, C_1-4-alkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-4-alkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C_1-4-alkyl, optionally substituted C₃-C₆ cycloalkyl and C_1-2-haloalkyl,
    • [0088] more preferably H, methyl, phenyl, cyclopropyl, cyclohexyl, benzyl, morpholinylmethyl, 4-methylpiperazinylmethyl, azetidinyl, azetidinylmethyl, 4-methylpiperdinylmethyl, 4-morpholinylmethyl, 4-morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, 1-piperdinylethyl, 1-piperdinylpropyl, 1-pyrrolidinylpropyl and trifluoromethyl;
• [0089] wherein R⁴ is independently 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 replaced with an oxygen atom or an —NH—, wherein R⁴ is optionally substituted with hydroxy,
  • [0090] preferably a direct bond or R^4a;
• [0091] wherein R^4a is selected from C_2-4-alkylenyl where one of the CH₂ groups may be replaced with an oxygen atom or an —NH—, wherein R^4a is optionally substituted with hydroxy;
  • [0092] preferably ethyl, butyl, and
• [0093] wherein R⁵ is selected from H, lower alkyl, optionally substituted phenyl and optionally substituted lower aralkyl,
  • [0094] preferably H, methyl or ethyl,
    • [0095] more preferably H;
• [0096] wherein R^5d is selected from H, lower alkyl, optionally substituted phenyl and lower aralkyl,
  • [0097] preferably H, methyl or ethyl,
    • [0098] more preferably H;
• [0099] wherein R⁷ is selected from H, C_1-6-alkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-6-alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-alkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C_1-C₆-alkyl, C_1-4-alkoxy-C_1-4-alkyl and C_1-4-alkoxy-C_1-4-alkoxy-C_1-4-alkyl,
  • [0100] preferably 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-C_1-C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl;
• [0101] wherein R^c is selected from H, methyl and optionally substituted phenyl; and
• [0102] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl, preferably —CF₃;
• [0103] wherein R¹⁴ is selected from H, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl and optionally substituted C₃-C₆ cycloalkyl;
• [0104] 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 R⁵ is methyl and when R is 4-methylpiperidyl;
• [0105] further provided A is not pyridyl when X is —C(O)NH—, when R⁵ is H, when R² is 6-methyl and when R is indazolyl;
• [0106] further provided A is not phenyl when X is —C(O)NH—, when R¹ is phenyl, 4-bromophenyl, 2-methylphenyl, 4-methoxyphenyl, when R⁵ is H and when R is 4-pyridyl;
• [0107] further provided A is not phenyl when X is —C(O)NH—, when R¹ is phenyl, when R⁵ is H and when R is 2-oxobenzopyan-4-yl;
• [0108] further provided A is not phenyl when X is —C(O)NH—, when R¹ is phenyl, 4-chlorophenyl, 3-nitrophenyl, 4-methoxyphenyl, when R⁵ is H and when R is 4-imidazolinyl;
• [0109] further provided A is not phenyl when X is —C(O)NH—, when R⁵ is H, when R⁵ is substituted benzyl and when R is substituted triazinyl;
• [0110] further provided A is not phenyl when X is —C(O)NH—, when R¹ is phenyl or 2-chlorophenyl, when R⁵ is H and when R is 4-quinazolinyl;
• [0111] further provided A is not phenyl when X is —C(O)NH—, when R¹ is phenyl, when R⁵ is H and when R is isoquinolin-1-yl;
• [0112] further provided A is not phenyl when X is —C(O)NH—, when R¹ is 2-chlorophenyl or 4-chlorophenyl, when R⁵ is H and when R is 3-chloroisoquinolin-1-yl;
• [0113] further provided A is not phenyl when X is —C(O)NH—, when R¹ is 1-ethylpiperid-3-yl or 1-ethylpiperid-4-yl, when R⁵ is H and when R is 8-trifluoromethylquinolin-4-yl;
• [0114] further provided A is not phenyl when X is —C(O)NH—, when R¹ is 1-ethylpiperid-3-yl, when R⁵ is H and when R is 8-chloroquinolin-4-yl;
• [0115] further provided A is not phenyl when X is —C(O)NH—, when R¹ is halo substituted phenyl, 1-butylpiperid-4-yl, 1-ethylpiperid-3-yl or 1-ethylpiperid-4-yl, when R⁵ is H and when R is 7-chloroquinolin-4-yl; and
• [0116] further provided R is not unsubstituted 2-thienyl, unsubstituted 2-pyridyl or unsubstituted 3-pyridyl.

[0117] The invention also relates to compounds of Formula II

• [0118] wherein R is selected from unsubstituted or substituted 9-or 10-membered fused nitrogen-containing heteroaryl,
  • [0119] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
  • [0120] more preferably 6-indazolyl,
  • [0121] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
    • [0122] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0123] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0124] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0125] cycloalkyl,
    • [0126] preferably cyclohexyl,
  • [0127] 4-6 membered heterocyclyl,
    • [0128] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0129] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
    • [0130] 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;
  • [0131] wherein substituted R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, 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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0132]  and C_1-4-alkoxy,
  • [0133] 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;
• [0134] wherein R² is one or more substituents independently selected from
  • [0135] H,
  • [0136] halo,
  • [0137] hydroxy,
  • [0138] amino,
  • [0139] C_1-6-alkyl,
  • [0140] C_1-6-haloalkyl,
  • [0141] C_1-6-alkoxy,
  • [0142] C_1-2-alkylamino,
  • [0143] aminosulfonyl,
  • [0144] C_3-6-cycloalkyl,
  • [0145] cyano,
  • [0146] C_1-2-hydroxyalkyl,
  • [0147] nitro,
  • [0148] C_2-3-alkenyl,
  • [0149] C_2-3-alkynyl,
  • [0150] C_1-6-haloalkoxy,
  • [0151] C_1-6-carboxyalkyl,
  • [0152] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0153] unsubstituted or substituted phenyl and
  • [0154] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0155] 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
    • [0156] thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0157] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0158]  preferably direct bond, ethyl, butyl, and
• [0159] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0160] preferably —CF₃; and
• [0161] 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-C_1-C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl.

[0162] The invention also relates to compounds of Formula III

[0208] The invention also relates to compounds of Formula IV

• [0209] wherein A³ is selected from CR² and N;
• [0210] wherein A⁴ is selected from CR² and N; provided one of A³ and A⁴ is not CR²;
• [0211] wherein R is selected from
  • [0212] unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0213] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
    • [0214] more preferably 5-indazolyl and 6-indazolyl,
      • [0215] even more preferably 6-indazolyl,
    • [0216] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
      • [0217] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0218] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0219] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0220] cycloalkyl,
  • [0221] preferably cyclohexyl,
  • [0222] 4-6 membered heterocyclyl,
  • [0223] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0224] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0225] preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, 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, benzo[d]isothiazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
  • [0226] wherein R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, 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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0227]  and C_1-4-alkoxy,
  • [0228] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl, methylpiperidyl, 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, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0229] wherein R² is one or more substituents independently selected from
  • [0230] H,
  • [0231] halo,
  • [0232] hydroxy,
  • [0233] amino,
  • [0234] C_1-6-alkyl,
  • [0235] C_1-6-haloalkyl,
  • [0236] C_1-6-alkoxy,
  • [0237] C_1-2-alkylamino,
  • [0238] aminosulfonyl,
  • [0239] C_3-6-cycloalkyl,
  • [0240] cyano,
  • [0241] C_1-2-hydroxyalkyl,
  • [0242] nitro,
  • [0243] C_2-3-alkenyl,
  • [0244] C_2-3-alkynyl,
  • [0245] C_1-6-haloalkoxy,
  • [0246] C_1-6-carboxyalkyl,
  • [0247] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0248] unsubstituted or substituted phenyl and
  • [0249] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0250] 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
    • [0251] thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0252] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0253]  preferably direct bond, ethyl, butyl, and
• [0254] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0255] preferably —CF₃; and
• [0256] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl-C_1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C_1-C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl.

[0257] The invention also relates to compounds of Formula V

• [0258] wherein A⁵ is selected from S, O and NR⁶;
• [0259] wherein R is selected from
  • [0260] unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0261] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
    • [0262] more preferably 5-indazolyl and 6-indazolyl, even more preferably 6-indazolyl,
  • [0263] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
    • [0264] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0265] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0266] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0267] cycloalkyl,
  • [0268] preferably cyclohexyl,
  • [0269] 4-6 membered heterocyclyl,
  • [0270] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0271] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0272] preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, benzo[d]isothiazolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
  • [0273] wherein R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, 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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0274]  and C_1-4-alkoxy,
  • [0275] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl, methylpiperidyl, 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, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0276] wherein R² is one or more substituents independently selected from
  • [0277] H,
  • [0278] halo,
  • [0279] hydroxy,
  • [0280] amino,
  • [0281] C_1-6-alkyl,
  • [0282] C_1-6-haloalkyl,
  • [0283] C_1-6-alkoxy,
  • [0284] C_1-2-alkylamino,
  • [0285] aminosulfonyl,
  • [0286] C_3-6-cycloalkyl,
  • [0287] cyano,
  • [0288] C_1-2-hydroxyalkyl,
  • [0289] nitro,
  • [0290] C_2-3-alkenyl,
  • [0291] C_2-3-alkynyl,
  • [0292] C_1-6-haloalkoxy,
  • [0293] C_1-6-carboxyalkyl,
  • [0294] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0295] unsubstituted or substituted phenyl and
  • [0296] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0297] 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
    • [0298] thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0299] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0300]  preferably direct bond, ethyl, butyl, and
• [0301] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0302] preferably —CF₃;
• [0303] wherein R⁶ is H or C_1-2-alkyl, preferably H or methyl; and
• [0304] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl-C_1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C_1-C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl.

[0305] The invention also relates to compounds of Formula VI

• [0306] wherein A⁵ is selected from S, O and NR⁶;
• [0307] wherein R is selected from
  • [0308] unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0309] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
    • [0310] more preferably 5-indazolyl and 6-indazolyl,
      • [0311] even more preferably 6-indazolyl,
    • [0312] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
      • [0313] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0314] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0315] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0316] cycloalkyl,
  • [0317] preferably cyclohexyl,
  • [0318] 4-6 membered heterocyclyl,
  • [0319] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0320] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0321] preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, benzo[d]isothiazolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
  • [0322] wherein R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, 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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0323]  and C_1-4-alkoxy,
  • [0324] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl, methylpiperidyl, 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, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0325] wherein R² is one or more substituents independently selected from
  • [0326] H,
  • [0327] halo,
  • [0328] hydroxy,
  • [0329] amino,
  • [0330] C_1-6-alkyl,
  • [0331] C_1-6-haloalkyl,
  • [0332] C_1-6-alkoxy,
  • [0333] C_1-2-alkylamino,
  • [0334] aminosulfonyl,
  • [0335] C_3-6-cycloalkyl,
  • [0336] cyano,
  • [0337] C_1-2-hydroxyalkyl,
  • [0338] nitro,
  • [0339] C_2-3-alkenyl,
  • [0340] C_2-3-alkynyl,
  • [0341] C_1-6-haloalkoxy,
  • [0342] C_1-6-carboxyalkyl,
  • [0343] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0344] unsubstituted or substituted phenyl and
  • [0345] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0346] 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
    • [0347] thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0348] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0349]  preferably direct bond, ethyl, butyl, and
• [0350] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0351] preferably —CF₃;
• [0352] wherein R⁶ is H or C_1-2-alkyl, preferably H or methyl; and
• [0353] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl-C_1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-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.

[0354] The invention also relates to compounds of Formulas VIIa and VIIb

• [0355] wherein A⁵ is selected from S, O and NR⁶;
• [0356] wherein R is selected from
  • [0357] unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0358] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
    • [0359] more preferably 5-indazolyl and 6-indazolyl,
      • [0360] even more preferably 6-indazolyl,
  • [0361] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
    • [0362] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0363] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0364] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0365] cycloalkyl,
  • [0366] preferably cyclohexyl,
  • [0367] 4-6 membered heterocyclyl,
  • [0368] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0369] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0370] preferably 1,2-dihydroquinolyl, -1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, 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, benzo[d]isothiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
  • [0371] wherein R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkyl, optionally substituted 4-6 membered heterocyclyl-C_2-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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0372]  and C_1-4-alkoxy,
  • [0373] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl, methylpiperidyl, 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, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0374] wherein R² is one or more substituents independently selected from
  • [0375] H,
  • [0376] halo,
  • [0377] hydroxy,
  • [0378] amino,
  • [0379] C_1-6-alkyl,
  • [0380] C_1-6-haloalkyl,
  • [0381] C_1-6-alkoxy,
  • [0382] C_1-2-alkylamino,
  • [0383] aminosulfonyl,
  • [0384] C_3-6-cycloalkyl,
  • [0385] cyano,
  • [0386] C_1-2-hydroxyalkyl,
  • [0387] nitro,
  • [0388] C_2-3-alkenyl,
  • [0389] C_2-3-alkynyl,
  • [0390] C_1-6-haloalkoxy,
  • [0391] C_1-6-carboxyalkyl,
  • [0392] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0393] unsubstituted or substituted phenyl and
  • [0394] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0395] 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
    • [0396] thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0397] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0398]  preferably direct bond, ethyl, butyl, and
• [0399] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0400] preferably —CF₃;
• [0401] wherein R⁶ is H or C_1-2-alkyl, preferably H or methyl; and
• [0402] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl-C_1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-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.

[0403] The invention also relates to compounds of Formulas VIIIa and VIIIb

• [0404] wherein A⁵ is selected from S, O and NR⁶;
• [0405] wherein R is selected from
  • [0406] unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0407] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
    • [0408] more preferably 5-indazolyl and 6-indazolyl, even more preferably 6-indazolyl,
  • [0409] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
    • [0410] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0411] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0412] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0413] cycloalkyl,
  • [0414] preferably cyclohexyl,
  • [0415] 4-6 membered heterocyclyl,
  • [0416] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0417] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0418] preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, 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, benzo[d]isothiazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
  • [0419] wherein R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, 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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0420]  and C_1-4-alkoxy,
  • [0421] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl, methylpiperidyl, 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, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0422] wherein R² is one or more substituents independently selected from
  • [0423] H,
  • [0424] halo,
  • [0425] hydroxy,
  • [0426] amino,
  • [0427] C_1-6-alkyl,
  • [0428] C_1-6-haloalkyl,
  • [0429] C_1-6-alkoxy,
  • [0430] C_1-2-alkylamino,
  • [0431] aminosulfonyl,
  • [0432] C_3-6-cycloalkyl,
  • [0433] cyano,
  • [0434] C_1-2-hydroxyalkyl,
  • [0435] nitro,
  • [0436] C_2-3-alkenyl,
  • [0437] C_2-3-alkynyl,
  • [0438] C_1-6-haloalkoxy,
  • [0439] C_1-6-carboxyalkyl,
  • [0440] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0441] unsubstituted or substituted phenyl and
  • [0442] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0443] 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
    • [0444] thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0445] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0446]  preferably direct bond, ethyl, butyl, and
• [0447] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0448] preferably —CF₃;
• [0449] wherein R⁶ is H or C_1-2-alkyl, preferably H or methyl; and
• [0450] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl-C_1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C_1-C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl.

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

• [0452] wherein A⁵ is selected from S, O and NR⁶;
• [0453] wherein R is selected from
  • [0454] unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0455] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
    • [0456] more preferably 5-indazolyl and 6-indazolyl, even more preferably 6-indazolyl,
  • [0457] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
    • [0458] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0459] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0460] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0461] cycloalkyl,
  • [0462] preferably cyclohexyl,
  • [0463] 4-6 membered heterocyclyl,
  • [0464] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0465] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0466] preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, 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, benzo[d]isothiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
  • [0467] wherein R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, 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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0468]  and C_1-4-alkoxy,
  • [0469] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl, methylpiperidyl, 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, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0470] wherein R² is one or more substituents independently selected from
  • [0471] H,
  • [0472] halo,
  • [0473] hydroxy,
  • [0474] amino,
  • [0475] C_1-6-alkyl,
  • [0476] C_1-6-haloalkyl,
  • [0477] C_1-6-alkoxy,
  • [0478] C_1-2-alkylamino,
  • [0479] aminosulfonyl,
  • [0480] C_3-6-cycloalkyl,
  • [0481] cyano,
  • [0482] C_1-2-hydroxyalkyl,
  • [0483] nitro,
  • [0484] C_2-3-alkenyl,
  • [0485] C_2-3-alkynyl,
  • [0486] C_1-6-haloalkoxy,
  • [0487] C_1-6-carboxyalkyl,
  • [0488] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0489] unsubstituted or substituted phenyl and
  • [0490] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0491] 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
    • [0492] thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0493] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0494]  preferably direct bond, ethyl, butyl, and
• [0495] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0496] preferably —CF₃;
• [0497] wherein R⁶ is H or C_1-2-alkyl, preferably H or methyl; and
• [0498] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl-C_1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C_1-C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl.

[0499] The invention also relates to compounds of Formula X

• [0500] wherein A⁵ is selected from S, O and NR⁶;
• [0501] wherein A 6is selected from N and CR²;
• [0502] wherein R is selected from
  • [0503] unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
    • [0504] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl,
    • [0505] more preferably 5-indazolyl and 6-indazolyl, even more preferably 6-indazolyl,
  • [0506] where 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, 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, optionally substituted heterocyclyl-C_2-4-alkynyl, and optionally substituted heterocyclylalkoxy,
    • [0507] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy;
• [0508] wherein R¹ is selected from unsubstituted or substituted aryl,
  • [0509] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl and naphthyl,
  • [0510] cycloalkyl,
  • [0511] preferably cyclohexyl,
  • [0512] 4-6 membered heterocyclyl,
  • [0513] preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl and pyridazinyl, and
  • [0514] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
  • [0515] preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl, 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, benzo[d]isothiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;
  • [0516] wherein R¹ is substituted with one or more substituents selected from halo, C_1-4-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₄-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C_2-C₄-alkenylenyl, 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, C_1-2-haloalkyl, C_1-4-aminoalkyl, nitro, amino, hydroxy, 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,
  • [0517]  and C_1-4-alkoxy,
  • [0518] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, pyrrolidinylpropyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, methylpiperazinyl, methylpiperidyl, 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, 1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;
• [0519] wherein R² is one or more substituents independently selected from
  • [0520] H,
  • [0521] halo,
  • [0522] hydroxy,
  • [0523] amino,
  • [0524] C_1-6-alkyl,
  • [0525] C_1-6-haloalkyl,
  • [0526] C_1-6-alkoxy,
  • [0527] C_1-2-alkylamino,
  • [0528] aminosulfonyl,
  • [0529] C_3-6-cycloalkyl,
  • [0530] cyano,
  • [0531] C_1-2-hydroxyalkyl,
  • [0532] nitro,
  • [0533] C_2-3-alkenyl,
  • [0534] C_2-3-alkynyl,
  • [0535] C_1-6-haloalkoxy,
  • [0536] C_1-6-carboxyalkyl,
  • [0537] 5-6-membered heterocyclyl-C_1-6-alkylamino,
  • [0538] unsubstituted or substituted phenyl and
  • [0539] unsubstituted or substituted 4-6 membered heterocyclyl;
  • [0540] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;
• [0541] wherein R⁴ is selected from a direct bond, C_1-4-alkyl, and
• [0542]  preferably direct bond, ethyl, butyl, and
• [0543] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl,
  • [0544] preferably —CF₃;
• [0545] wherein R⁶ is H or C_1-2-alkyl, preferably H or methyl;
• [0546] wherein R⁷ is selected from H, C_1-3-alkyl, optionally substituted phenyl-C_1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C_1-C₃-alkyl, C_1-3-alkoxy-C_1-2-alkyl and C_1-3-alkoxy-C_1-3-alkoxy-C_1-3-alkyl; and
• [0547] wherein
  • [0548] a) R¹⁰ is
  • [0549]  R¹¹ is —NHR, R¹² is H, and R¹³ is H; or
  • [0550] b) R¹⁰ is —NHR, R¹¹ is
  • [0551]  R¹² is H, and R¹³ is H; or
  • [0552] c) R¹⁰ is H, R¹¹ is —NHR, R¹² is
  • [0553]  and R¹³ is H; or
  • [0554] d) R¹⁰ is H, R¹¹ is
  • [0555]  R¹² is —NHR, and R¹³ is H; or
  • [0556] e) R¹⁰ is H, R¹¹ is H, R¹² is
  • [0557]  and R¹³ is —NHR; or
  • [0558] f) R¹⁰ is H, R¹¹ is H, R¹² is —NHR, and R¹³ is

[0559] The invention also relates to compounds of Formula XI

• [0560] wherein R is selected from unsubstituted or substituted 9-or 10-membered fused nitrogen-containing heteroaryl selected from 6-indazolyl, 1-oxo-2,3-dihydro-1H-isoindol-4-yl, 2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl, and 4-oxo-3,4-dihydro-quinazolin-6-yl;
• [0561] wherein R¹ is selected from unsubstituted or substituted
  • [0562] aryl,
  • [0563] cycloalkyl,
  • [0564] 5-6 membered heteroaryl and
  • [0565] 9-10 membered bicyclic and 11-14 membered tricyclic heterocyclyl,
  • [0566] 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,
  • [0567] 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,
    • [0568] even more preferably
      • [0569] phenyl substituted with one or more substituents selected from chloro, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, methylsulfonylamino, dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—, 4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—, 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, and methylsulfonylaminoethoxy;
      • [0570] 4,4-dimethyl-3,4-dihydro-2-oxo-1H-quinolinyl;
      • [0571] 4,4-dimethyl-1,2,3,4-tetrahydro-1H-quinolinyl;
      • [0572] 4,4-dimethyl-3,4-dihydro-2-oxo-1H-[1,8]naphthyridinyl
      • [0573] 3,3-dimethyl-2,3-dihydro-1H-indolyl optionally substituted with a substituent selected from pyrrolidin-1-yl-carbonyl, methylcarbonyl, and methylsulfonyl; and
      • [0574] 4,4-dimethyl-1,2,3,4-tetrahydro-1H-isoquinolinyl;
• [0575] 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-C_1-C₄-alkylenyl, C_1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C_1-C₆-alkyl, optionally substituted 4-6 membered heterocyclyl-C_2-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, C_1-4-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,
• [0576]  and C_1-4-alkoxy;
• [0577] 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, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl, 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;
  • [0578] even more preferably chloro, oxo, methylsulfonyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, pyrrolidin-1-yl-carbonyl, methylsulfonylamino, dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH₂—C(═O)—NH—, 4-morpholinyl-CH₂—C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—, methyl, 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-pyrrolidin-2-ylmethoxy, and methylsulfonylaminoethoxy;
    • [0579] particularly 2-methyl-2-(1-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-4-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;
• [0580] wherein R^e and R^f are independently selected from H and C_1-2-haloalkyl; preferably —CF₃; and
• [0581] 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-C_1-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.

[0785] The present invention also comprises a method of treating angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically-effective amount of a compound of Formula I

• [0786] wherein each of A¹ and A² is independently C, CH or N;
• [0787] wherein ring A is selected from
  • [0788] a) 5- or 6-membered partially saturated heterocyclyl,
  • [0789] b) 5- or 6-membered heteroaryl,
  • [0790] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl,
  • [0791] d) 9- or 10-membered fused heteroaryl,
  • [0792] e) aryl, and
  • [0793] f) 4-, 5- or 6-membered cycloalkenyl;
• [0794] wherein X is
• [0795] wherein Z is oxygen or sulfur;
• [0796] wherein R is selected from
  • [0797] a) substituted or unsubstituted 4-6 membered heterocyclyl,
  • [0798] b) substituted aryl, and
  • [0799] c) substituted or unsubstituted fused 9-14-membered bicyclic or tricyclic heterocyclyl;
    • [0800] 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 4-6 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;
• [0801] wherein R¹ is selected from
  • [0802] a) substituted or unsubstituted 6-10 membered aryl,
  • [0803] b) substituted or unsubstituted 4-6 membered heterocyclyl,
  • [0804] c) substituted or unsubstituted 9-14 membered bicyclic or tricyclic heterocyclyl,
  • [0805] d) cycloalkyl, and
  • [0806] e) cycloalkenyl,
    • [0807] 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 4-6 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;
• [0808] 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 4-6 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;
• [0809] wherein R³ is selected from H, lower alkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C₃-C₆-cycloalkyl, optionally substituted phenylalkyl, optionally substituted 4-6 membered heterocyclylalkyl, optionally substituted C₃-C₆ cycloalkylalkyl, and lower haloalkyl;
• [0810] wherein R⁴ is selected from a direct bond, C_2-4-alkylenyl, C_2-4-alkenylenyl and C_2-4-alkynylenyl, where one of the CH₂ groups may be substituted with an oxygen atom or an —NH—, wherein R⁴ is optionally substituted with hydroxy;
• [0811] wherein R⁵ is selected from H, lower alkyl, optionally substituted phenyl and lower aralkyl;
• [0812] wherein R¹⁴ is selected from H, phenyl, 4-6 membered heterocyclyl and C₃-C₆ cycloalkyl;
• [0813] and pharmaceutically acceptable derivatives thereof;
• [0814] provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl.
  Combinations

General Synthetic Procedures

[0832] The compounds of the invention can be synthesized according to the following procedures of Schemes 1-31, wherein the substituents are as defined for Formulas I-XI, above, except where further noted.
Substituted carboxamides 3 can be prepared from the corresponding halo analogs 1 by the process outlined in Scheme 1. Substituted amino acids 2 are prepared from the corresponding chloro compounds 1 such as by reacting with an amine at a suitable temperature, such as about 80° C. The acid 2 is coupled with an amine, preferably in the presence of a coupling agent such as EDC, to form the corresponding amide 3.

[0836] The amination is preferably carried out in an inert, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, for example DMF or dimethylacetamide, a cyclic ether, for example THF or dioxane, or a nitrile, for example CH₃CN, or in a mixture thereof, at an appropriate temperature, for example in a temperature range of from about 40° C. to about 180° C., and if necessary under an inert gas atmosphere, for example a nitrogen or argon atmosphere.

[0839] Additionally, where A is a pi-electron rich heterocycle, the addition of KF, such as 40% KF on alumina in IpOH, at a temperature over about 100° C., preferably about 160° C., can be used in the formation of 3 from 1B.

[0840] Substituted carboxamides 3 can be prepared from the corresponding bromo/chioro analogs 5 by the process outlined in Scheme 3. The bromo/chloro acid 5 is coupled with an amine, preferably in the presence of a coupling agent such as EDC, to form the corresponding bromo substituted amide 6. Suzuki coupling with the bromo amide 6 and suitable boronic acids provides the substituted amide 4. Substituted amino-amides 3 are prepared from the corresponding chloro compounds 4 as described in Scheme 2.

[0841] Substituted pyridines can be prepared by the process outlined in Scheme 4. A solution of sodium hypobromite is freshly prepared and added to a 2-hydroxynicotinic acid 7 and heated, preferably at a temperature at about 50° C. Additional sodium hypobromide may be needed to form the bromo compound 8. The 5-bromo-2-hydroxynicotinic acid 8 is reacted with thionyl chloride, preferably at a temperature >RT, more preferably at about 80° C. to form the 2-chloronicotinic acid analog 9. The acid is coupled with an amine, preferably in the presence of EDC, HOBT, and DIEA to form the corresponding substituted amide 10. Suzuki coupling with the bromo amide and suitable boronic acids, provides the substituted nicotinamide 11. 2-Amino-nicotinamides 12 are prepared from the corresponding chloro compounds 11 such as by reacting with substituted amines at a suitable temperature, such as about 80° C.

[0842] Alkylated indazoles can be prepared by the process outlined in Scheme 5. To a solution of 6-nitroindazole 13 in a solvent such as THF is added strong base, such as NaH at a temperature below RT, preferably at about 0° C. Alkylhalides, such as where R″ is methyl, are added and reacted at a temperature about RT to give 1-alkyl-6-nitro-1H-indazole 14. The nitro indazole 14 is hydrogenated, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C to give the 1-substituted-6-amino-1H-indazole 15.

[0843] Brominated indazoles can be prepared by the process outlined in Scheme 6. NBS is slowly added to an acidic solution, such as a mixture of TFA:H₂SO₄ (5:1) and tert-butyl-4-nitrobenzene 16 at a temperature of about RT to yield the brominated compound 17.

[0844] Substituted anilines can be prepared by the process outlined in Scheme 7. A mixture of 1-(substituted)-2-bromo-4-nitrobenzene 18 (where R^x is a substituent selected from those available for substituted R²) and N-methylpiperazine is heated, such as with or without solvent, preferably without solvent, at a temperature above RT, preferably at a temperature above about 100° C., and more preferably at a temperature at about 130° C. to give the 1-[5-(substituted)-2-nitrophenyl]-4-methylpiperazine 19. The nitro compound 19 is hydrogenated, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C to furnish 4-(substituted)-2-(4-methylpiperazinyl)phenylamine 20.

[0845] Tricyclic heterocycles can be prepared by the process outlined in Scheme 8. 7-Nitro-2,3,4-trihydroisoquinolin-1-one 21 is heated in POCl₃ at a temperature above RT, preferably at a temperature sufficient for reflux, to form the 1-chloro-7-nitro-3,4-dihydroisoquinoline 22. The 1-chloro-7-nitro-3,4-dihydroisoquinoline 22 is dissolved in a solvent, such as THF, and H₂NNH₂ is added. The reaction is heated with HC(OEt)₃ at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 115° C. to give the nitro-substituted tricyclic. Hydrogenation, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, gives 2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline 23.

[0846] Indazolyl ethers can be prepared by the process outlined in Scheme 9. 6-Nitro-1H-2-hydroindazol-3-one 24 is protected such as with Boc₂O and DMAP in CH₂Cl₂ at a temperature of about RT, to give the protected 6-nitro-2-hydroindazol-3-one. The protected 6-nitro-2-hydroindazol-3-one is reacted with an alcohol (where R^x is an appropriate substituent selected from the possible substituents on R¹) and Ph₃P in a solvent, such as THF, and DEAD, at a temperature of about RT, to give the protected 6-nitro(indazol-3-yl) ether. The nitro intermediate is hydrogenated, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, to give the protected 6-amino(indazol-3-yl) ether 25. The amine 25 is coupled with 2-chloronicotinic acid in a solvent, such as an alcohol, preferably pentanol, at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 130° C. to give the coupled and deprotected compound 26.

[0847] Indolinyl substituted carboxamides can be prepared from the corresponding nitro indoline 27 by the process outlined in Scheme 10. For example, 3,3-dimethyl-6-nitroindoline 27 is alkylated, such as with N-protected-4-formylpiperidine in the presence of NaHB(OAc)₃ and acid, such as glacial AcOH, and solvent, such as dichloromethane, at a temperature of about RT, to afford the alkylated indane 28. Hydrogenation of the alkylated indane 28, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, in the presence of a solvent, such as an alcohol, preferably MeOH, to give the amino intermediate 29. Alternatively, other hydrogenation methods can be used, such as Fe powder with NH₄Cl. Coupling of the amine 29, such as with 2-chloronicotinic acid and DIEA, HOBt and EDC, in a solvent such as CH₂Cl₂ at a temperature of about RT provides the protected carboxamide 30, which upon deprotection and alkylation yields other compounds of the invention, 31 and 32, respectively. Alternatively, amine 29 is reacted with 2-fluoronicotinoyl chloride to form a 2-fluoronicotinamide, which can be alkylated, such as in Scheme 10.

[0848] Substituted anilines can be prepared by the process outlined in Scheme 11 (where R^x is a substituent selected those available for substituted R¹, preferably haloalkyl and alkyl). 1-Methyl-4-piperidinone is added to a solution of strong base such as LiHMDS, in a solvent such as THF, at a temperature below RT, preferably lower than about −50° C., more preferably at about −78° C. Tf₂NPh is reacted with the enolate at a temperature of about RT, to give 1-methyl-4-(1,2,5,6-tetrahydro)pyridyl-(trifluoromethyl)sulfonate. A mixture of the triflate intermediate, bis(pinacolato)diboron, potassium acetate, PdCl₂(dppf), and dppf in a solvent such as dioxane and heated at a temperature above RT, preferably at a temperature above about 50° C., and more preferably at a temperature at about 80° C. to give 4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane 34. The substituted aniline 35 is formed from the 1,3,2-dioxaborolane 34 such as with treatment with an amine in the presence of PdCl₂(dppf) and base, such as K₂CO₃, in a solvent such as DMF at a temperature above RT, preferably at a temperature above about 50° C., and more preferably at a temperature at about 80° C.

[0849] Substituted anilines can be prepared by the process outlined in Scheme 12. 4-Cyano-4-phenylpiperidine hydrochloride 36 is treated with base, such as KOH, at a temperature above RT, preferably at a temperature above about 100° C., and more preferably at a temperature at about 160° C., to provide the phenyl piperidine 37. Alkylation of the phenyl piperidine 37, such as with formaldehyde and NaCNBH₃ in a solvent such as CH₃CN, with sufficient acid to maintain the reaction pH near 7, to provide the alkylated piperidine 38. Nitration of the phenylpiperidine 38, such as with H₂SO₄ and fuming HNO₃ at a temperature below RT, and preferably at about 0° C., gives the nitro intermediate 39. Hydrogenation of the nitro intermediate 39, such as with an H₂ atmosphere in the presence of a catalyst, such as Pd/C, in the presence of a solvent, such as an alcohol, preferably MeOH, to give the amino intermediate 40.

[0850] Substituted amides can be prepared by the process outlined in Scheme 13. 3-Nitrocinnamic acid 41 is coupled with 1-methylpiperazine in the presence of EDC and a solvent such as CH₂Cl₂, at a temperature of about RT gives the carboxamide 42.

[0851] 1,2,3,6-Tetrahydro-pyridyl substituted anilines are prepared such as by the procedure described in Scheme 14. Nitrobenzenes 43 are brominated, such as with bromine in the presence of acid, H₂SO₄ for example, or with NBS to yield the 3-bromo derivative 44. Suzuki coupling of the bromo-derivative 44 and a substituted pyridylboronic acid, such as at a temperature above RT, preferably above about 50° C., and more preferably at about 80° C., yields the pyridyl derivative 45. Alkylation of the nitrophenyl-pyridine 45, such as by treatment with iodomethane, preferably above about 50° C., and more preferably at about 80° C., yields the pyridinium compound 46, which upon reduction, such as by NaBH₄, yields the tetrahydyropyridine 47.

[0854] Sulfonamide substituted anilines can be prepared from nitrobezenesulfonyl chlorides 52. Coupling of nitrobezenesulfonyl chlorides 52 with reactive heterocyclic compounds, such as substituted piperazines, piperidines, and the like, in a protic solvent such as EtOH, such as at a temperature about RT, yields the nitrobezenesulfonamides 52. Reduction of the nitro benzenesulfonamide, such as with iron powder, preferably above about 50° C., and more preferably at about 80° C., yields the aniline 53.

[0856] Reduction of the nitrobenzenes 55, such as with iron powder, at a temperature above about 50° C., and preferably at about 80° C., yields the aniline 56. Hydrogenation, such as with H₂ atmosphere in the presence of a catalyst, such as 10% Pd/C, is also possible.

[0859] Alternatively, piperazinyl substituted anilines 65 can be prepared by the treatment of a fluoro-nitro-substituted aryl compounds 63. The fluoro-nitro-substituted aryl compounds 63 and 1-substituted piperazines are heated, preferably neat, at a temperature above about 50° C., and preferably at about 90° C., to yield the piperazinyl-nitroaryl compounds 64. Hydrogenation, such as with H₂ atmosphere in the presence of a catalyst, such as 10% Pd/C, gives the substituted aniline 65.

[0861] Alternatively, substituted amino-indolines 71 are prepared from the nitroindoline 66. Nitroindoline 66, is reacted with an acid chloride to form an amide. Further treatment with a primary or secondary amine, preferably a secondary amine, such as in the presence of NaI, at a temperature above about 50° C., and preferably at about 70° C. yields the nitroindoline 69. The nitro compound 69 is hydrogenated, such as with H₂ in the presence of a catalyst, such as Pd/C, to yield the amino-indoline) 70. The carbonyl is reduced, such as with BH₃-THF yields 1-aminoalkyl-indolines 71.

[0862] Substituted indolines are prepared such as by the procedures described in Scheme 19. Substituted acetamides 73 are prepared from the coupling of halo-5-nitroanilines 72 (where LG is bromo or chloro, preferably chloro) and an acylating agent, such as acetyl chloride or acetic anhydride, under standard coupling chemistry, such as with DIEA, and DMAP, at a temperature of about RT, in a suitable solvent, such as CH₂Cl₂, DMF and/or DMAC. The N-(2-methylprop-2-enyl)acetamide 74 is prepared from the acetamide 73, such as by the treatment of base, such as NaH in a suitable solvent such as NMP or anhydrous DMF and a 3-halo-2-methylpropene such as 3-bromo-2-methylpropene or 3-chloro-2-methylpropene, at a temperature between about 0° C. and RT, and preferably at about RT; or with CSCO₃ at a temperature above RT, preferably above about 50° C. and more preferably above about 60° C. Cyclization of the N-(2-methylprop-2-enyl)acetamide 74, such as by the Heck-type reaction (treatment with Pd(OAc)₂ in the presence of base, for example tetraethyl-ammonium chloride, sodium formate, and NaOAc) at a temperature above about 50° C., and preferably at about 80° C., yields the protected (3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone 75. Deprotection, such as with strong acid such as HCl or AcOH at a temperature above about 50° C., and preferably at about 70-80° C., yields the 3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl 76. Alternatively, the protected dihydro-6-nitro indoline 75 can be reduced, such as with Fe, or with 10% Pd/C in the presence of an excess of NH₄CO₂H, or with H₂ in the presence of a catalyst to form the protected dihydro-6-amino indoline 75a.

[0863] Substituted anilines are prepared such as by the procedures described in Scheme 20. Nitrophenyl esters 78 are formed from the acid 77, such as by treatment with MeOH and acid. Alkylation of the ester 78, such as by treatment with base, followed by alkyl halide, yields the branched alklyl compounds 79. Reduction of the ester 79, such as with BH₃, yields the alcohol 80. The aldehyde 81 is prepared from the alcohol 80, such as by treatment with TPAP in the presence of N-methylmorpholine-N-oxide. Subsequent treatment with methoxymethyltriphenylphosphonium chloride and KHMDS yields 81. Coupling of the aldehyde 81 and morpholine, such as with NaBH(OAc)₃ yields the tertiary amine 82. Reduction of the nitro compound, such as with acid, for example AcOH, and zinc yields the aniline 83.

[0864] Substituted aniline compounds are prepared such as by the procedure described in Scheme 21 (where R^x is a substituent selected those available for substituted R¹, preferably haloalkyl and alkyl). Alkynyl-aniline 90, prepared similar to that described in Scheme 22, is hydrogenated such as with H₂ in the presence of a catalyst, such as Pd(OH)₂, to yield the substituted alkyl 91.

[0865] Substituted bromophenyl compounds are prepared such as by the procedure described in Scheme 22. Bromine is added to a optionally substituted nitrobenzene 92, silver(II)sulfate and acid, such as H₂SO₄, to provide the bromo derivative 93.

[0866] Substituted anilines are prepared such as by the procedure described in Scheme 23 (where R^t and R^v are alkyl, or together with the nitrogen atom form a 4-6 membered heterocyclic ring). Acryloyl chloride 94 is reacted with an amine, preferably a secondary amine, such as at a temperature between about 0° C. and about RT, to form the amide 95. A bromo-nitrobenzene 93 is reacted with the amide 95, such as in the presence of base, for example TEA, together with Pd(OAc)₂ and Pd(PPh₃)₄, at a temperature above about 50° C., and preferably at about 120° C., such as in a sealed container, to form the substituted alkene 96. Hydrogenation of the alkene 96, such as with H₂-in the presence of a catalyst, for example Pd/C catalyst yields the substituted aniline 97. Reduction of the amide 97, such as with LiALH₄, at a temperature above about 50° C., and preferably at about 80° C. yields the aniline 98.

[0867] Substituted indoles are prepared such as by the procedure described in Scheme 24. A nitroindole 99 is coupled with a halo compound, in the presence of base, for example K₂CO₃. Heating at a temperature above about 50° C., and preferably at about reflux yields the substituted-nitro-1H-indole 100. Hydrogenation similar to conditions described above yield the amino derivative 101.

[0868] Substituted aminomethyl compounds are prepared such as by the procedure described in Scheme 25. NaH is added to an alcohol and heated at a temperature above about RT, and preferably at about 50° C., to form the sodium alkoxide, which is added to a halo compound 102, such as a 2-chloro-4-cyanopyridine and heated at a temperature above about 50° C., and preferably at about 70° C. to form the ether 103. Hydrogenation yields the aminomethyl derivative 104.

[0869] Substituted anilines are prepared such as by the procedure described in Scheme 26. Treatment with the haloalkyl alcohol 105 with an alcohol, such as in the presence of DEAD and PPh₃ yields the ether 107 or 106.

[0870] Functionalized pyridines are prepared such as by the procedure described in Scheme 27. 2-Fluoropyridine 108 is treated with base, such as LDA, at a temperature below about 0° C., and preferably at about −78° C., and quenched with a stream of dry CO₂ to form the nicotinic acid 109. Alternatively, solid CO₂ (dry ice) can be used, preferably dried with N₂ prior to use. The acid 109 is converted to the acid halide 110, such as by treatment with thionyl chloride and heating at a temperature above about 50° C., and preferably at about reflux.

[0871] Chloro-substituted pyridines 113 are prepared such as by the procedure described in Scheme 28. 2-Chloronicotinic acid 112 is activated with ethyl chloroformate, in the presence of base, such as TEA, at a temperature of about RT. Reaction with an amine produces amide 113. Alternatively, the amine can be coupled with the acid chloride 111, such as with polymer-supported DIEA. Excess acid chloride is removed by treating the reaction mixture with polymer-supported trisamine resin, to form amide 113.

[0872] Amino-substituted indoles 116 are prepared such as by the procedure described in Scheme 291. Nitroindoline 114 is reacted with N-methyl-4-piperidone in the presence of NaOMe at a temperature above about 50° C., and preferably at about reflux, to form the 3-substituted indole 115. Hydrogenation as previously discussed yields the amino indole 116.

[0873] Substituted carboxamides 118 can be prepared from the corresponding phenols 117 of the invention, by the process outlined in Scheme 30. A carboxamide 117 is coupled with an alcohol, such as 4-hydroxy-N-methylpiperidine, in the presence of DEAD and triphenylphosphine, in a solvent such as THF, at a temperature of about RT, provides the ether 118.

[0898] The compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below:
The invention expressly includes all tautomeric forms of the compounds described herein.

EXAMPLE 1

[1390]

N-(4-Chlorophenyl)[2-(6-quinolylamino)(3-pyridyl)]carboxamide

EXAMPLE 2

[1393]

N-(4-Chlorophenyl)[2-(5-isoquinolylamino)(3-pyridyl)]carboxamide

EXAMPLE 3

[1395]

N-(4-Chlorophenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 4

[1398]

N-(4-Chlorophenyl)[2-(1H-indazol-5-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 5

[1400]

2-(1H-Indazol-6-ylamino)-N-(4-isopropyl-phenyl)nicotinamide

EXAMPLE 6

[1403]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[3-(methylethyl)phenyl]carboxamide

EXAMPLE 7

[1405]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[4-(methylpropyl)phenyl]carboxamide

EXAMPLE 8

[1407]

N-[4-(tert-Butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 9

[1409]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[3-(trifluoromethyl)phenyl]carboxamide

EXAMPLE 10

[1411]

N-[3-(tert-Butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 11

[1413]

[2-(Benzotriazol-6-ylamino)(3-pyridyl)]-N-[4-(tert-butyl)phenyl]carboxamide

EXAMPLE 12

[1415]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-(3-phenylpyrazol-5-yl)carboxamide

EXAMPLE 13

[1417]

N-3-aminosulfonyl(4-chloro-phenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 14

[1419]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-(4-methyl-2-oxo-1,2-dihydroquinol-7-yl)carboxamide

EXAMPLE 15

[1421]

N-[4-(Methylethyl)phenyl]{2-[(4-methyl-2-oxo(7-hydroquinolyl))amino](3-pyridyl)}carboxamide

EXAMPLE 16

[1423]

N-[5-(tert-Butyl)isoxazol-3-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 17

[1425]

N-[5-(tert-Butyl)-1-methylpyrazol-3-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 18

[1427]

N-[4-(tert-Butyl)(1,3-thiazol-2-yl)][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 19

[1429]

N-[5-(tert-Butyl)(1,3,4-thiadiazol-2-yl)][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 20

[1431]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenyl]carboxamide

EXAMPLE 21

[1433]

{2-[(1-Methyl(1H-indazol-6-yl))amino](3-pyridyl)}-N-[4-(methylethyl)phenyl]carboxamide

EXAMPLE 22

[1436]

N-[4-(tert-Butyl)phenyl]{2-[(7-bromo(1H-indazol-6-yl))amino](3-pyridyl)}carboxamide

EXAMPLE 23

[1438]

2-(1H-Indazol-6-ylamino)-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]nicotinamide

EXAMPLE 24

[1440]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-({4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}carboxamide

EXAMPLE 25

[1443]

N-[5-(tert-Butyl)-2-methoxyphenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 26

[1445]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-{6-[4-(trifluoromethyl)piperidyl](3-pyridyl)}carboxamide

EXAMPLE 27

[1447]

2-(1H-Indazol-6-ylamino)-N-(1-oxo-1,2,3,4-tetrahydro-isoguinolin-7-yl)-nicotinamide

EXAMPLE 28

[1449]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[4-(methylethoxy)phenyl]carboxamide

EXAMPLE 29

[1451]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}carboxamide

EXAMPLE 30

[1453]

N-(4-{(1S)-1-[(Methylethyl)amino]ethyl}phenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 31

[1455]

N-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 32

[1457]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[3-(4-methylpiperazinyl)phenyl]carboxamide

EXAMPLE 33

[1459]

N-[4-(tert-Butyl)-2-(4-methylpiperazinyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 34

[1461]

N-{2-[2-(Dimethylamino)ethoxy]-5-(tert-butyl)phenyl}[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 35

[1463]

N-{3-[2-(Dimethylamino)ethoxy]phenyl}[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 36

[1465]

N-(3-Hydroxy-4-methoxyphenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 37

[1467]

N-{3-[2-(Dimethylamino)ethoxy]-4-methoxyphenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 38

[1469]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[4-methoxy-3-(1-methyl(4-piperidyl)oxy)phenyl]carboxamide

EXAMPLE 39

[1471]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-(5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolin-2-yl)carboxamide

EXAMPLE 40

[1473]

[2-({3-[2-(Dimethylamino)ethoxy](1H-indazol-6-yl)}amino)(3-pyridyl)]-N-[4-(tert-butyl)phenyl]carboxamide

EXAMPLE 41

[1476]

N-[3,3-Dimethyl-1-(4-piperidylmethyl)indolin-6-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 42

[1478]

N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 43

[1480]

2-(1H-Indazol-6-ylamino)-N-(4-phenoxy-phenyl)-nicotinamide

EXAMPLE 44

[1483]

[2-(1H-Indazol-5-ylamino)(3-pyridyl)]-N-(4-phenoxyphenyl)carboxamide

EXAMPLE 45

[1485]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-(4-phenylphenyl)carboxamide

EXAMPLE 46

[1487]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[4-(methylsulfonyl)phenyl]carboxamide

EXAMPLE 47

[1489]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[1-(1-methyl(4-piperidyl))indolin-6-yl]carboxamide

EXAMPLE 48

[1491]

N-[3,3-Dimethyl-1-(1-methyl(4-piperidyl))indolin-6-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 49

[1493]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[3-(1-methyl(4-piperidyl))indol-5-yl]carboxamide

EXAMPLE 50

[1495]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[4-(trifluoromethyl)phenyl]carboxamide

EXAMPLE 51

[1497]

N-{3-[3-(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}[2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 52

[1499]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[5-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-3-(trifluoromethyl)phenyl]carboxamide

EXAMPLE 53

[1501]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[4-(1-methyl(4-piperidyl))phenyl]carboxamide

EXAMPLE 54

[1503]

N-[4-(tert-Butyl)-3-(3-piperidylpropyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 55

[1505]

N-[3-((1E)-4-Pyrrolidinylbut-1-enyl)-4-(tert-butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 56

[1507]

N-[4-(tert-Butyl)-3-(3-pyrrolidinylpropyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 57

[1509]

N-[4-(tert-Butyl)-3-(3-morpholin-4-ylpropyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 58

[1511]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-{3-[3-(4-methylpiperazinyl)-3-oxopropyl]phenyl}carboxamide

EXAMPLE 59

[1513]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-{4-[3-(4-methylpiperazinyl)-3-oxopropyl]phenyl}carboxamide

EXAMPLE 60

[1515]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-{3-[3-(4-methylpiperazinyl)propyl]phenyl}carboxamide

EXAMPLE 61

[1517]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-{4-[3-(4-methylpiperazinyl)propyl]phenyl}carboxamide

EXAMPLE 62

[1519]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-[1-(2-morpholin-4-ylethyl)indol-6-yl]carboxamide

EXAMPLE 63

[1521]

N-[4-(1,1-Dimethyl-3-morpholin-4-ylpropyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 64

[1523]

2-(1H-indazol-6-ylamino)-N-(4-{2,2,2-trifluoro-1-[2-(2-methoxy-ethoxy)-ethoxy]-1-trifluoromethyl-ethyl)}-phenyl)-nicotinamide

EXAMPLE 65

[1525]

[2-(1H-Indazol-6-ylamino)(3-pyridyl)]-N-{4-[2,2,2-trifluoro-1-(2-piperidylethoxy)-1-(trifluoromethyl)ethyl]phenyl}carboxamide

EXAMPLE 66

[1527]

N-[4-(tert-Butyl)phenyl][6-fluoro-2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide

EXAMPLE 67

[1530]

[6-Fluoro-2-(1H-indazol-6-ylamino)(3-pyridyl)]-N-[4-(methylethyl)phenyl]carboxamide

EXAMPLE 68

[1532]

[6-Fluoro-2-(1H-indazol-6-ylamino)(3-pyridyl)]-N-[3-(trifluoromethyl)phenyl]carboxamide

EXAMPLE 69

[1534]

{2-[(1-(2-Pyridyl)pyrrolidin-3-yl)amino](3-pyridyl)}-N-[3-(trifluoromethyl )phenyl]carboxamide

EXAMPLE 70

[1537]

2-(1H-Indazol-6-ylamino)-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 71

[1540]

2-(1H-Indazol-6-ylamino)-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 72

[1542]

2-(1H-Indazol-6-ylamino)-N-[3-(1-methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 73

[1544]

2-(1H-Indazol-6-ylamino)-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 74

[1545]

2-(1H-Indazol-6-ylamino)-N-[3-(piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 75

[1547]

2-(1H-Indazol-6-ylamino)-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 76

[1549]

N-(3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-116-benzo[d]isothiazol-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 77

[1551]

2-(1H-Indazol-6-ylamino)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-nicotinamide

EXAMPLE 78

[1553]

2-(1H-Indazol-6-ylamino)-N-[3-(1-methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

EXAMPLE 79

[1555]

2-(1H-Indazol-6-ylamino)-N-[3-(1-isopropyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

EXAMPLE 80

[1557]

N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 81

[1559]

2-(1H-Indazol-6-ylamino)-N-[4-pentafluoroethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-nicotinamide

EXAMPLE 82

[1561]

N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 83

[1563]

2-(1H-Indazol-6-ylamino)-N-[4-pentafluoroethyl-3-(2S-pyrrolidin-2-ylmethoxy)-phenyl]-nicotinamide

EXAMPLE 84

[1565]

2-(1H-Indazol-6-ylamino)-N-[4-pentafluoroethyl-3-(2R-pyrrolidin-2-ylmethoxy)-phenyl]-nicotinamide

EXAMPLE 85

[1567]

2-(1H-Indazol-6-ylamino)-N-[3-(pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 86

[1569]

2-(1H-Indazol-6-ylamino)-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 87

[1571]

N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 88

[1573]

2-(1H-Indazol-6-ylamino)-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide

EXAMPLE 89

[1575]

N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 90

[1577]

2-(1H-Indazol-6-ylamino)-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide

EXAMPLE 91

[1579]

N-(3-Bromo-5-trifluoromethyl-phenyl)-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 92

[1581]

2-(1H-Indazol-6-ylamino)-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide

EXAMPLE 93

[1583]

N-[4-tert-Butyl-3-(piperidin-4-ylmethoxy)-phenyl]-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 94

[1585]

N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 95

[1587]

1-Boc-2-(2-tert-Butyl-5-{[2-(1H-indazol-6-ylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-pyrrolidine

EXAMPLE 96

[1589]

N-[4-tert-Butyl-3-(pyrrolidin-2-ylmethoxy)-phenyl]-2-(1H-indazol-6-ylamino)-nicotinamide

EXAMPLE 97

[1591]

2-(1H-Indazol-6-ylamino)-N-[3-(2S-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide