Substituted 2,3-dihydro-1H-isoindol-1-one derivatives and methods of use

专利摘要:

公开号:AU2004269000A1
申请号:U2004269000
申请日:2004-08-25
公开日:2005-03-10
发明作者:Jeffrey A. Adams；Benny C. Askew Jr.；Michael Croghan；Daniel Elbaum；Julie Germain；Gregory J. Habgood；Scott Harried；Aiwen Li；Nobuko Nishimura；Rana Nomak；Andrew Tasker；Christopher Tegley；Kevin Yang
申请人:Amgen Inc；
IPC主号:C07D401-12

专利说明:
WO 2005/021532 PCTIUS2004/027595 SUBSTITUTED 2,3-DIHYDRO-1H-ISOINDOL-1-ONE DERIVATIVES AND METHODS OF USE 5 FIELD OF THE INVENTION This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cancer and angiogenesis 10 related disorders. BACKGROUND OF THE INVENTION Protein kinases represent a large family of proteins 15 which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes abl, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, c-fms', CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, 20 CDK9, CDK1O, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt 1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p 3 8 , PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become an 25 important therapeutic target. Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularisation, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, 30 psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post 35 transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias).
WO 2005/021532 PCTIUS2004/027595 -2 At the center of the network regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth, and in a wide number of pathological anomalies and diseases, lies 5 the angiogenic factor known as Vascular Endothelial Growth Factor"(VEGF; originally termed 'Vascular Permeability Factor", VPF), along with its cellular receptors (see G. Breier et al., Trends in Cell Biology, 6:454-456 (1996)). VEGF is a dimeric, disulfide-linked 46-kDa 10 glycoprotein related to "Platelet-Derived Growth Factor" (PDGF); it is produced by normal cell lines and tumor cell lines; is an endothelial cell-specific mitogen; shows angiogenic activity in in vivo test systems (e.g. rabbit cornea); is chemotactic for endothelial cells and monocytes; 15 and induces plasminogen activators in endothelial cells, which are involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of isoforms of VEGF are known, which show comparable biological activity, but differ in the type of cells that 20 secrete them and in their heparin-binding capacity. Tn addition, there are other members of the VEGF family, such as "Placenta Growth Factor"(PlGF) and VEGF-C. VEGF receptors (VEGFR) are transmembranous receptor tyrosine kinases. They are characterized by an 25 extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-1 (also known as flt 1), VEGFR-2 (also known as KDR), and VEGFR-3. A large number of human tumors, especially gliomas and 30 carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF released by tumor cells stimulates the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner and through the improved blood supply, accelerate tumor WO 2005/021532 PCT/US2004/027595 -3 growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo is shown in studies in which VEGF expression or VEGF 5 activity was inhibited. This was achieved with anti-VEGF antibodies, with dominant-negative VEGFR-2 mutants which inhibited signal transduction, and with antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumor cell lines in vivo as a 10 result of inhibited tumor angiogenesis. Angiogenesis is regarded as an absolute prerequisite for tumors which grow beyond a diameter of about 1-2 mm; up to this limit, oxygen and nutrients may be supplied to the tumor cells by diffusion. Every tumor, regardless of its 15 origin and its cause, is thus dependent on angiogenesis for its growth after it has reached a certain size. Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: 1) Inhibition of the growth of vessels, especially 20 capillaries, into avascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between cell death and proliferation; 2) Prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and 3) Inhibition 25 of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11:77-114 (2001). 30 VEGF's are unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and the formation of edema. Indeed, vascular hyperpermeability and edema that is associated with WO 2005/021532 PCT/US2004/027595 -4 the expression or administration of many other growth factors appears to be mediated via VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous 5 tissues, hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke VEGF/VPF-mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange and macromolecular extravasation, which is often accompanied by 10 diapedesis, can result in excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Hence, VEGF mediated hyperpermeability can significantly contribute' to disorders with these etiologic features. As such, regulators of angiogenesis have become an important 15 therapeutic target. WO 9854170 describes substituted 2-(2,6 dioxopiperidin-3-yl)phthalimides and 1-oxoisolindones. WO 98/25899 describes N- (imidobenzoyl)phenylalanials. WO 90/05722 describes the preparation of N-phenylphthalimides. 20 Compounds of the current invention have not been described as inhibitors of angiogenesis such as for the treatment of cancer. DESCRIPTION OF THE INVENTION 25 A class of compounds useful in treating cancer and angiogenesis is defined by Formula I Ri Z-N 0 x Y R6 WO 2005/021532 PCT/US2004/027595 -5 wherein X is CH or N; wherein Y is selected from C 1
-
3 -alkyl, C 2
-
3 -alkenyl, 0, S(0), and NR 4 ; wherein Z is C=O or CHR 5 ; 5 wherein R is selected from a) substituted or unsubstituted 6-10 membered aryl, b) substituted or unsubstituted 4-6 membered heterocyclyl, c) substituted or unsubstituted 9-14 membered fused 10 heterocyclyl, d) substituted or unsubstituted aryl-C- 2 -alkyl, e) substituted or unsubstituted heterocyclyl-C 1 2 -alkyl, and f) lower alkyl; 15 where substituted R is substituted with one or more substituents selected from halo, -OR 3 , -SR 3 , -S0 2
R
3
,
C0 2
R
3 , -C(0)NR 3
R
3 , -C(O)R', -NR 3
R
3 , -SO 2 NR R 3 , -NR 3 C (0) OR',
-NR
3
C(O)R
3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, 20 alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R 2 ; wherein R' is selected from unsubstituted or substituted a) 6-10 membered aryl, b) 5-6 membered heterocyclyl, 25 c) 9-14 membered fused heterocyclyl, d) cycloalkyl, e) cycloalkenyl, f) lower alkyl, and g) lower alkenyl, 30 wherein substituted R 1 is substituted with one or more substituents independently selected from halo, -OR, SR 3 , -CO 2
R
3 , -C(O)NR 3 R', -C(O)R, -NR 3
R
3 , oxo, -OC(0)R 3 , -pS 2
R
3 , -SO 2
NR
3
R
3 , -NR 3 C (0) OR 3 , -NR 3 C (0) R 3 , -NR 3 C (0) NR 3
R
3 , optionally substituted cycloalkyl, optionally WO 2005/021532 PCTIUS2004/027595 -6 substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, aminoalkylcarbonylamino, alkylaminoalkylcarbonylamino, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower alkyl 5 substituted with one or more R; wherein R 2 is selected from H, halo, -OR 3 , amino, C 1
-
3 alkylamino, C 1
-
3 -dialkylamino, C 1
-
3 -alkyl, optionally substituted phenyl, optionally substituted phenyl-C 1
-
3 alkyl, 4-6 membered heterocyclyl, and optionally 10 substituted 4-6 membered heterocyclyl-Ci-C 3 -alkyl; wherein R 3 is independently selected from H, lower alkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 3
-C
6 cycloalkyl, optionally substituted phenylalkyl, 15 optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted C 3
-C
6 cycloalkylalkyl and lower haloalkyl; wherein R 4 is independently selected from H, and lower alkyl; 20 wherein R 5 is independently selected from H, -OR 3 , and lower alkyl; and wherein R 6 is selected from H, halo, -OR 3 , -SR3, -C0 2
R
3 , SOR 3 , -C(O)NR 3
R
3 , -C(O)R 3 , -NR 3
R
3 , -S0 2
R
3 , -SO 2
NR
3
R
3 , NR 3 C (O) OR 3 , -NR 3 C (O) R 3 , -NR 3 C (O)NR 3
R
3 , optionally 25 substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, nitro, lower alkyl substituted with one or more 2 2 R , lower alkenyl substituted with one or more R and lower alkynyl substituted with one or more R; 30 and pharmaceutically acceptable derivatives thereof. The invention also relates to compounds of Formula I wherein Y is NH; wherein X is CH; wherein Z is CHR 5 ; and wherein R 5 is independently selected from H, -OH, and WO 2005/021532 PCTIUS2004/027595 -7 methyl; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I wherein R is unsubstituted or substituted 9-10 membered 5 fused nitrogen-containing heteroaryl and optionally further substituted 9-10 membered fused N-containing oxo-substituted heterocycyl; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I 10 wherein R is selected from quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, isoquinolin-5-yl, 2-oxo-1,2-dihydroquinol-7 yl, 1-oxo-2,3-dihydro-1H-isoindol-4-yl, quinazolin-6-yl, 4 oxo-3,4-dihydro-quinazolin-6-yl, indazol-5-yl, indazol-6-yl, indol-5-yl, isoindol-4-yl, benzimidazol-5-yl, 2-oxo-2,3 15 dihydro-lH-benzimidazol-5-yl and benzotriazol-6-yl; wherein R is optionally substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, 1-methylpiperidinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy; and 20 pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I wherein R is substituted or unsubstituted 6-membered nitrogen containing heteroaryl-C 1 2 -alkyl or 9-10 membered 25 nitrogen containing fused heteroaryl-C 2 2 -alkyl; wherein substituted R is substituted with one or more substituents independently selected from halo, amino, C 1 3 -alkoxy, hydroxyl, C 3 -alkyl and C 2 -haloalkyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of 30 the above or below embodiments. The invention also relates to compounds of Formula I wherein R is substituted or unsubstituted selected from (3 pyridyl)- (CH 2
)
2 -, (4-pyridyl) -CH 2 -, (4-pyrimidinyl)-CH 2 -, (5 pyrimidinyl)-CH 2 -, (6-pyrimidinyl)-CH 2 -, (4-pyridazinyl)-CH 2
-
WO 2005/021532 PCTIUS2004/027595 -8 (6-pyridazinyl) -CH 2 -, 5-indazolyl-CH 2 -, 4-quinolinyl-CH 2 -, 6-quinolinyl-CH 2 -, pyrrolo [2, 3-b] pyridin-4-y-CH 2 -, pyrrolo[2,3-blpyridin-5-yl-CH-, 5-isoquinolinyl-CH 2 - and 4 quinazolinyl-CH 2 -; wherein R is unsubstituted or substituted 5 with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 10 The invention also relates to compounds of Formula I wherein R is selected from indazol-6-yl, (3-pyridyl)-(CH 2
)
2 , (4-pyridyl)-CH 2 -, pyrrolo[2,3-blpyridin-4-yl-CH 2 -, pyrrolo[2,3-b]pyridin-5-yl-CH 2 -, 6-quinolinyl-CH 2 - and 4 quinolinyl-CH 2 -; and pharmaceutically acceptable derivatives 15 thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I wherein R 6 is one or more substituents independently selected from H, halo, hydroxy, C 1 2 -alkoxy, C 1 2 -haloalkoxy, 20 amino, C 1 2 -alkylamino, optionally substituted 5-6 membered heterocyclyl-C 1 2 -alkylamino, aminosulfonyl, C 3
-
6 -cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, C 1 4 -alkyl, cyano, C 1 2 -hydroxyalkyl, C 1 a carboxyalkyl, nitro, C 2
-
3 -alkenyl, C 2
-
3 -alkynyl and C 1 2 25 haloalkyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I wherein R 6 is one or more substituents independently 30 selected from H, chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, dimethylamino, aminosulfonyl, carboxymethyl, cyclopropyl, optionally substituted phenyl, methyl, ethyl, propyl, cyano, hydroxymethyl, nitro, propenyl, propynyl, trifluoromethyl 35 and unsubstituted or substituted heteroaryl selected from WO 2005/021532 PCTIUS2004/027595 -9 thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I 5 wherein R 6 is H; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I wherein R 1 is selected from unsubstituted or substituted 9 10 11 and 14 membered bicyclic saturated or partially saturated heterocyclyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I 15 wherein R' is selected from 1,2-dihydroquinolyl, 1,2,3,4 tetrahydroquinolinyl, 1,4-benzodioxanyl, 2-oxo-1,2 dihydroquinol-7-yl, 1-oxo-1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1,1-dioxo-benzo[d]isothiazolyl, 2,3-dihydro-lH indolyl, 2,3-dihydro-benzofuryl, 1,2,3,4-tetrahydro 20 isoquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, and 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl; where R is unsubstituted or substituted with one or more substituents selected from bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, 25 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 30 (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, WO 2005/021532 PCTIUS2004/027595 - 10 pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl, pyrrolidin-l-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, 5 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 10 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 15 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 20 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-isopropy-pyrrol 2-ylmethoxy, 1-Boc-piperidin-4-ylmethoxy, piperidin-4 25 ylmethoxy, 1-methylpiperidin-4-yloxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I 30 wherein R 1 is selected from unsubstituted or substituted 5-6 and 9-10 membered bicyclic heteroaryl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments, optionally substituted with one or more substituents selected from halo, C 1 6 -alkyl, WO 2005/021532 PCTIUS2004/027595 - 11 optionally substituted C 3 -6cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-Cl.C 4 alkylenyl, C 2 -haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-CC 4 -alkyl, 5 optionally substituted 4-6 membered heterocyclyl-C 2
-C
4 alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C 4 -alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, 10 optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 4-6 membered heterocyclyl-C 4 alkylcarbonyl, C 1 2 -haloalkyl, C 1 4 -aminoalkyl, nitro, amino, hydroxy, cyano, aminosulfonyl, C 2 -alkylsulfonyl, C- 4 15 alkylcarbonyl, Ca 3 -alkylamino-C 3 -alkylcarbonylamino, C 3 alkylamino-C 3 -alkyl, C 3 -alkylamino-Cl 3 -alkoxy, C1 3 alkylamino-C 3 - alkoxy-Cl 3 - alkoxy, CI-alkoxycarbonyl, CI4 Rb Ra hydroxyalkyl, 0 and C 1 4 -alkoxy; wherein R4 is selected from H, methyl, H, piperidinylethyl and 20 methoxyethoxyethyl; and wherein Ra and Rb are independently selected from H and trifluoromethyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I 25 wherein R' is selected from thienyl, indolyl, pyridyl, 2,1,3-benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, quinazolinyl, furyl and pyrrolyl; optionally substituted with one or more substituents 30 selected from morpholinylmethyl, 1-methylpiperazin-4 ylmethyl, 1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2 methyl-2-(l-methylpiperidin-4-yl)ethyl, morpholinylethyl, 1- WO 2005/021532 PCTIUS2004/027595 - 12 (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 5 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, 3-ethoxycarbonyl-2-methyl-fur-5-yl, 4 10 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, azetidin-3-ylmethoxy, 1-Boc azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2 15 ylmethoxy, pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperidin-4-ylmethoxy, piperidin-4-ylmethoxy, 1-methylpiperidin-4-yloxy, 1,1 di(trifluoromethyl)-1-( piperidinylethoxy)methyl, 4 methylpiperazinylsulfonyl, Boc-piperidin-1-ylmethylcarbonyl, 20 4-methylpiperazin-1-ylcarbonylethyl, dimethylaminomethyl carbonylamino, bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl, cyclohexyl, phenyl, phenylmethyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, 25 methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1,1-di(trifluoromethyl)-1 30 hydroxymethyl, 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, isopropoxy, WO 2005/021532 PCTIUS2004/027595 - 13 methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I 5 wherein R' is selected from phenyl optionally substituted with one or more substituents selected from halo, C 1 --alkyl, optionally substituted C 3 6 -cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-ClC 4 alkylenyl, C 1 2 -haloalkoxy, optionally substituted phenyloxy, 10 optionally substituted 4-6 membered heterocyclyl-CC 4 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 2
.C
4 alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C 4 -alkoxy, 15 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, Cl 2 -haloalkyl, C 1 4 -aminoalkyl, nitro, amino, 20 hydroxy, cyano, aminosulfonyl, C 1 2 -alkylsulfonyl, C- 4 alkylcarbonyl, C 1 3 -alkylamino-Cl- 3 -alkylcarbonylamino, C- 3 alkylamino-C 1 3 -alkyl, C 1 3 -alkylamino-C- 3 -alkoxy, C- 3 alkyl amino- C- 3 -alkoxy-C 1 3 -alkoxy, C 1 4 -alkoxycarbonyl, C 1 4 hydroxyalkyl, 0 and C 1 4 -alkoxy; wherein R' is 25 selected from H, methyl, H, piperidinylethyl and methoxyethoxyethyl; and wherein Ra and Rb are independently selected from H and trifluoromethyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 30 The invention also relates to compounds of Formula I wherein R 1 is selected from phenyl optionally substituted with one or more substituents selected from morpholinylmethyl, 1-methylpiperazin-4-ylmethyl, 1- WO 2005/021532 PCTIUS2004/027595 - 14 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 5 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, 10 pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, 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), 15 imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, 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-piperidin-4-ylmethoxy, piperidin-4-ylmethoxy, 1 20 methylpiperidin-4-yloxy, 1,1-di(trifluoromethyl)-1 (piperidinylethoxy)methyl, 4-methylpiperazinylsulfonyl, Boc piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1 ylcarbonylethyl, dimethylaminomethyl-carbonylamino, bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc 25 aminoethyl, hydroxy, oxo, aminosulfonyl, cyclohexyl, phenyl, phenylmethyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, 30 trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1,1-di(trifluoromethyl)-1 hydroxymethyl, 1,1-di(trifluoromethyl)-1 (methoxyethoxyethoxy) methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1-(N- WO 2005/021532 PCTIUS2004/027595 - 15 isopropylamino)ethyl, 2-(N-isopropylamino)ethyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or 5 below embodiments. The invention also relates to compounds of Formula I wherein R' is Rx 1-~ RY wherein each of Rx and RY is independently selected 10 from H, bromo, chloro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, 1, 1-di (trifluoromethyl) -1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy, ethoxy, 4-methylpiperazinylsulfonyl, morpholinylmethyl, 4 15 methylpiperazinylmethyl, 4-methylpiperazinylpropyl, 4 isopropylpiperazinylmethyl, 4-methylpiperidinylmethyl, 4 aminopiperidinylmethyl, 4-methylamino-piperidinylmethyl, 4 dimethylamino-piperidinylmethyl, 3-dimethylaminopyrrolidin 1-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, 20 dimethylaminoethyl, dimethylaminoethoxy, piperidinylethoxy, morpholinylethyloxy, 4-methylpiperazinylethoxy, 4 isopropylpiperazinylmethoxy, piperidin-4-methoxy, 4 methylpiperidin-1-ylmethoxy, 1-methylpyrrolidin-2-ylmethoxy, 1-methylpyrrolidin-3-ylmethoxy, 1-isopropylpyrrolidin-2 25 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 3 (dimethylamino)pyrrolidin-1-ylethoxy, 2-(N,N dimethylamino)acetylamino and 2-(N,N dimethylamino)ethylamino; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or 30 below embodiments. The invention also relates to compounds of Formula I wherein R' is selected from chloro, tert-butyl, WO 2005/021532 PCTIUS2004/027595 - 16 trifluoromethyl, pentafluoroethyl, 1,1-di(trifluoromethyl) 1-hydroxymethyl, and trifluoromethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 5 The invention also relates to compounds of Formula I wherein each of Ry is selected from H, bromo, chloro, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 1,1 di (trifluoromethyl) -1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy, ethoxy, 4 10 methylpiperazinylsulfonyl, morpholinylmethyl, 4 methylpiperazinylmethyl, 4-methylpiperazinylpropyl, 4 isopropylpiperazinylmethyl, 4-methylpiperidinylmethyl, 4 aminopiperidinylmethyl, 4-methylamino-piperidinylmethyl, 4 dimethylamino-piperidinylmethyl, 3-dimethylaminopyrrolidin 15 1-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, dimethylaminoethyl, dimethylaminoethoxy, piperidinylethoxy, morpholinylethyloxy, 4-methylpiperazinylethoxy, 4 isopropylpiperazinylmethoxy, piperidin-4-methoxy, 4 methylpiperidin-1-ylmethoxy, 1-methylpyrrolidin-2-ylmethoxy, 20 1-methylpyrrolidin-3-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 3 (dimethylamino)pyrrolidin-1-ylethoxy, 2-(N,N dimethylamino)acetylamino and 2-(N,N dimethylamino)ethylamino; and pharmaceutically acceptable 25 derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I wherein R' is selected from substituted or unsubstituted phenyl-C 1 2 -alkyl; and pharmaceutically acceptable 30 derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I wherein R' is selected from 3-trifluoromethylphenylmethyl, 3-trifluoromethylphenylethyl, 3-methoxyphenylmethyl, WO 2005/021532 PCTIUS2004/027595 - 17 phenylethyl, 4-methoxyphenylethyl, 3, 4-dimethoxyphenylethyl, 4-methylphenylethyl, 2-fluorophenylethyl, 3 fluorophenylethyl, 2-chlorophenylethyl, 4-chlorophenylethyl, 3,4-dichlorophenylethyl, and 3,5-dichlorophenylethyl; and 5 pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula II Ro N R5 .- NH 7 'k,
IR
7 10 wherein R' is selected from unsubstituted or substituted a) 6-10 membered aryl, b) 5-6 membered heterocyclyl, c) 9-14 membered fused heterocyclyl, and d) phenyl-Ci- 3 -alkyl, 15 wherein substituted R 1 is substituted with one or more substituents independently selected from halo, -OR', SR 3 , -CO 2
R
3 , -C(O)NR 3
R
3 , -C(O)R 3 , -NR 3
R
3 , oxo, -OC(O)R 3 , -S0 2
R
3 , -SO 2
NR
3
R
3 , -NR 3 C (0) OR 3 , -NR 3 C (O) R', -NRC (0 )NR 3
R
3 , optionally substituted cycloalkyl, optionally 20 substituted 4-9 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower alkyl substituted with one or more R2 wherein R2 is selected from H, halo, hydroxy, alkoxy, 25 optionally substituted phenyl, optionally substituted phenyl-Ci..
3 -alkyl, 4-6 membered heterocyclyl, and optionally substituted 4-6 membered heterocyclyl-Ci-C 3 alkyl; wherein R 3 is independently selected from H, lower alkyl, 30 optionally substituted phenyl, optionally substituted 3-6 WO 2005/021532 PCTIUS2004/027595 - 18 membered heterocyclyl, optionally substituted C 3 -C6 cycloalkyl, optionally substituted phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted C 3
-C
6 cycloalkylalkyl and lower 5 haloalkyl; wherein R 5 is H, methyl or hydroxy; and wherein R 7 is selected from substituted or unsubstituted 6 membered and 9-10 membered heteroaryl; where substituted
R
7 is substituted with one or more substituents selected 10 from halo, -OR 3 , -SR 3 , ~SO 2
R',-CO
2 R, -C(O)NR 3
R
3 , -C(O)R 3
NR
3
R
3 , -SO 2
NR
3 R', -NR 3 C(0)OR 3 , -NR 3 C(0)R 3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R 2 ; 15 and pharmaceutically acceptable derivatives thereof. The invention also relates to compounds of Formula II wherein R 1 is selected from phenyl substituted with one or more substituents independently selected from halo, -OR, SR, -C0 2
R
3 , -C(O)NR 3
R
3 , -C(O)R 3 , -NR 3
R
3 , oxo, -OC(O)R 3 , -S0 2
R
3 , 20 -SO 2
NR
3
R
3 , -NR 3 C (O)OR 3 , -NR 3 C (O)R 3 , -NR 3 C (O) NR 3
R
3 , optionally substituted C 3
-
6 -cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, Ca- 3 alkylamino-C1- 3 alkoxy, C- 3 -alkylamino-C 1 3 -alkoxy-C 1 3 alkoxy, nitro, and lower alkyl substituted with one or more 25 R 2 ; wherein R 2 is selected from H, fluoro, hydroxy, amino,
C
1 3 -alkylamino, C- 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, 30 piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R 3 is independently selected from H, C 1 4 alkyl, C 1 2 -fluoroalkyl, optionally substituted phenyl, WO 2005/021532 PCTIUS2004/027595 - 19 optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-Ci- 2 -alkyl wherein the heterocyclyl 5 ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 10 The invention also relates to compounds of Formula II wherein R 1 is selected from phenyl substituted with 1-3 substituents independently selected from bromo, chloro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec butyl, trifluoromethyl, pentafluoroethyl, 1,1 15 di(trifluoromethyl)-1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula II 20 wherein R' is selected from substituted or unsubstituted 5-6 membered or 9-10 membered fused partially unsaturated heterocyclyl and heteroaryl; wherein substituted R' is substituted with one or more substituents independently selected from halo, -OR 3 , -SR 3 , -C0 2
R
3 , -C(O)NR 3 R', -C(O)R, 25 NR 3
R
3 , oxo, -OC(O)R 3 , -S0 2
R
3 , -SO 2
NR
3
R
3 , -NR 3 C (O) OR 3 , NR 3 C (0) R', -NR 3 C (0) NR 3
R
3 , optionally substituted C 3 -6 cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower 30 alkyl substituted with one or more R2 wherein R2 is selected from H, fluoro, hydroxy, amino,
C
1
-
3 -alkylainino, Ci- 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, WO 2005/021532 PCTIUS2004/027595 - 20 piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R 3 is independently selected from H, Csa 5 alkyl, C 1 2 -fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C 1 2 -alkyl wherein the heterocyclyl 10 ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula II 15 wherein R' is a substituted or unsubstituted ring selected from pyrazol-5-yl, 2-oxo-1,2-dihydroquinol-7-yl, 1-oxo 1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1,1-dioxo benzo[d]isothiazolyl, benzothiazolyl, 2,3-dihydro-1H indolyl, 2,3-dihydro-benzofuryl, 1,2,3,4-tetrahydro 20 isoquinolyl, quinolyl, isoquinolyl, 1,2,3,4 tetrahydroquinolyl and 5,6,7-trihydro-1,2,4-triazolo[3,4 ajisoquinolyl; wherein substituted R 1 is substituted with 1 3 substituents independently selected from bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, hydroxy, 25 aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, isopropyl-piperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4 30 morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, 1 methylpyrrolidinylmethyl, pyrrolidinylpropyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, methyl, WO 2005/021532 PCTIUS2004/027595 - 21 ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, 1,1 di (trifluoromethyl) -1-hydroxymethyl, 1,1 di (trifluoromethyl) -1- (piperidinylethoxy)methyl, 1,1 5 di (trifluoromethyl) -1- (methoxyethoxyethoxy) methyl, 1 hydroxyethyl, 2-hydroxyethyl, hydroxybutyl, di fluoromethoxy, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1- (N isopropylamino) ethyl, 2- (N-isopropylamino) ethyl, dimethylaminopropyl, dimethylami!noethoxy, 4-chlorophenoxy, 10 phenyloxy, 1-methylpiperidin-4-yloxy, piperidin-4-yloxy, piperidinylethoxy, morpholinylethyloxy, 4 methylpiperazinylethoxy, 4-isopropylpiperazinylethoxy, piperidin-4-methoxy, 4-methylpiperidin-1-ylmethoxy, 1 methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2 15 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1 methylpyrrolidin-3-ylmethoxy, 3- (dimethylamino) pyrrolidin-1 ylethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 20 The invention also relates to compounds of Formula II wherein R' is substituted with 1-3 substituents independently selected from chloro, fluoro, amino, aminoethyl, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, 25 pentafluoroethyl, nonafluorobutyl, 1, 1-di (trifluoromethyl) 1-hydroxymethyl, methylcarbonyl, trifluoromethoxy, 1 methylpiperidin-4-yloxy, piperidin-4-yloxy, piperidinylethoxy, morpholinylethyloxy, 4 methylpiperazinylethoxy, 4-isopropylpiperazinylethoxy, 30 piperidin-4-methoxy, 4-methylpiperidin-1-ylmethoxy, 1 methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1 methylpyrrolidin-3-ylmethoxy, 3- (dimethylamino) pyrrolidin-l ylethoxy, isopropoxy, methoxy and ethoxy; and WO 2005/021532 PCTIUS2004/027595 - 22 pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula II wherein R1 is selected from 3 -trifluoromethylphenylmethyl, 5 3-trifluoromethylphenylethyl, 3-methoxyphenylmethyl, phenylethyl, 4-methoxyphenylethyl, 3,4-dimethoxyphenylethyl, 4-methylphenylethyl, 2-fluorophenylethyl, 3 fluorophenylethyl, 2-chlorophenylethyl, 4 -chlorophenylethyl, 3,4-dichlorophenylethyl, and 3,5-dichlorophenylethyl; and 10 pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula II wherein R' is selected from substituted or unsubstituted 6 membered nitrogen containing heteroaryl, where substituted 15 R 7 is substituted with one or more substituents selected from halo, -OR 3 , -SR 3 , -SO 2
R
3
,-CO
2
R
3 , -C(O)NR 3
R
3 , -C(0)R 3 , NR 3
R
3 , -SO 2
NR
3
R
3 , -NR 3 C(O) OR', -NR 3 C (0) R 3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, 20 oxo, lower alkyl substituted with one or more R 2 ; wherein R 2 is selected from H, fluoro, hydroxy, amino,
C
1 3 -alkylamino, C 1 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, 25 piperidin-1-yl, 1-methylpiperidin-4-yl, l-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R 3 is independently selected from H, C 4 alkyl, C- 2 -fluoroalkyl, optionally substituted phenyl, 30 optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C.
2 -alkyl wherein the heterocyclyl WO 2005/021532 PCTIUS2004/027595 - 23 ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 5 The invention also relates to compounds of Formula II wherein -R 7 is selected from 4 -pyridyl, 4 -pyrimidinyl, 5 pyrimidinyl, 6-pyrimidinyl, 4-pyridazinyl and 6-pyridazinyl; -- -and-pha-rmaeeu-tical-ly-accepta-bie-deri-vatives ~thereof; in -eonj-unc tion- w-h-ny-of-tUbo or helow-emibodiments. 10 The invention also relates to compounds of Formula II wherein R is selected from substituted or unsubstituted 9 10 membered nitrogen containing heteroaryl, where substituted
R
7 is substituted with one or more substituents selected from halo, -OR 3 , -SR 3 , -S0 2
R
3 , -C0 2 R, -C(O)NR 3
R
3 , 15 C (0) R 3 , -NR 3
R
3 , -SO 2
NRR
3 , -NR 3 C (O) OR 3 , -NR 3 C (O)R 3 , Boc, optionally substituted 3-9 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R ; wherein R 2 is selected from H, fluoro, hydroxy, amino, 20 C 1 3 -alkylamino, Cs 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 25 2-yl; and wherein R3 is independently selected from H, C 1 4 alkyl, C 1 2 -fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, 30 optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C 1 2 -alkyl wherein the heterocylyl ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; WO 2005/021532 PCTIUS2004/027595 - 24 and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula II wherein R 7 is selected from 5-indazolyl, 4-quinolinyl, 6 5 -f-inolinyl,~ pyrrolo[2,3-b]pyridin-4-yl, pyrrolo [2,3 -b-lpyridin-3-yl7 5~-isoquinolinyl and 4-quinazolinyl; and pharmaceutically acceptable derivatives thereof; in -een-j-u-nction-with-any-of -the-above-or below--flodiment s. The-inverrti--on~also-relat-e-s to -cbrtipounds of Formula II 10 wherein R 1 is selected from 4-tertbutylphenyl, 3,3-dimethyl 2, 3-dihydroindolyl, 1-acetyl-3, 3-dimethyl-2, 3 dihydroindolyl, 3-tert-butylpyrazol-5-yl, 4,4-dimethyl 1,2,3, 4-tetrahydroisoquinolin-7-yl, 4, 4-dimethyl-2- (3 pyrrolo [2, 3-b]pyridinyl) -1,2,3, 4 -tetrahydroisoquinolin-7-yl, 15 and 4,4-dimethyl-2-(Boc)-1,2,3,4-tetrahydroisoquinolin-7-yl; wherein R" is H; and wherein R 7 is selected from 6 quinolinyl, pyrrolo[2, 3-b]pyridin-3-yl, 4-pyridyl and .3 aminopyrid-4-yl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below 20 embodiments. The invention also relates to compounds of Formula III R1 N 0
R
5 NH / -RY N III wherein Ra is selected from unsubstituted or substituted 25 a) 6-10 membered aryl, b) 5-6 membered heterocyclyl, c) 9-14 membered fused heterocyclyl, and d) phenyl-C 1
-
3 -alkyl, wherein substituted R 1 is substituted with one or more 30 substituents independently selected from halo, -OR 3 , - WO 2005/021532 PCTIUS2004/027595 - 25 SR 3 , -C0 2
R
3 , -C(O)NR 3
R
3 , -C (0) R 3 , -NR 3
R
3 , oxo, -OC (O) R 3 , -S0 2
R
3 , -SO 2
NR
3
R
3 , -NR 3 C (0) OR 3 , -NR 3 C (0) R 3 , -NR 3 C (0) NR 3
R
3 , optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, optionally 5 ~-substi tUted phenyl, cyano, alkylaminoalkoxy, al-kylaminratkoxyalkoxy, nitro; and lower alkyl substituted with one or more R2 -- wherein=R2-i-s-select-ed-f-rom-H--ha-o-hydroxy-- alkoxy, -- p--pt-i-nail-y-substituted--_phenyl, pt-ionalry -substituted 10 phenyl-Ci_ 3 -alkyl, 4-6 membered heterocyclyl, and optionally substituted 4-6 membered heterocyclyl-C.
1
C
3 ~alkyl; wherein R3 is independently selected from H, lower alkyl, optionally substituted phenyl, optionally substituted 3-6 15 membered heterocyclyl, optionally substituted
C
3
-C
5 cycloalkyl, optionally substituted phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted
C
3 -CG cycloalkylalkyl and lower haloalkyl; 20 wherein R 5 is H, methyl or hydroxy; and wherein R 7 is selected from substituted or unsubstituted 6 membered and 9-10 membered heteroaryl; where substituted
R
7 is substituted with one or more substituents selected from halo, -OR 3 , -SR 3 , -S0 2 R3,_C0 2
R
3 , -C(0)NR 3
R
3 , -C(O)R 3 _ 25 NR 3
R
3 , -SO 2
NR
3
R
3 , -NR 3 C (0) OR 3 , -NR 3 C (0) R 3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R2 and pharmaceutically acceptable derivatives thereof. 30 The invention also relates to compounds of Formula III wherein R' is selected from phenyl substituted with one or more substituents independently selected from halo, -OR, SR', -C0 2 R, -C(O)NR 3
R
3 , -C (0) R 3 , -NR 3
R
3 , oxo, -OC(O)R 3 , -S0 2
R
3 ,
-SO
2
NR
3
R
3 , -NR 3 C (O) OR 3 , -NR 3 C (0) R 3 , -NR 3 C (0) NR 3
R
3 , optionally WO 2005/021532 PCTIUS2004/027595 - 26 substituted C3-6-cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, Ci-3-alkylamino-C- 3 -alkoxy, C1-alkyl-amino-C3-alkoxy-C 1 3 alkoxy, nitro, and lower alkyl substituted with one or more -- 5--R ; wherein~R2 .s--salected from H, fluoro, hydroxy, amino, - C--Gr-3--akylamino, Cf--jdialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from n--orphol-in-yl,-p-iper-a-i-n-4--y1-r--1--methy-lpiperaz in=-4 -yl, p ip er-i-d-in -1- y1-r7--me thyjp ipe(r idi-q=4-=y-,-_l-B oc --p iperi din-4 10 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R3 is independently selected from H, C 1 4 --alkyl; .Ci 2 -fluoroalkyl,- optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, 15 optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C 1 2 -alkyl wherein the heterocyclyl ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives 20 thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III wherein R' is selected from phenyl substituted with 1-3 substituents independently selected from bromo, chloro, 25 methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec butyl, trifluoromethyl, pentafluoroethyl, 1,1 di (trifluoromethyl) -1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in 30 conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III wherein R' is selected from substituted or unsubstituted 5-6 membered or 9-10 membered fused partially unsaturated heterocyclyl and heteroaryl; wherein substituted R 1 is WO 2005/021532 PCTIUS2004/027595 - 27 substituted with one or more substituents independently selected from halo, -OR, -SR 3
-CO
2
R
3 , -C (0) NR 3
R
3 , -C (O)R, NR 3
R
3 , oxo, - -OC (0) R 3 , -S0 2
R
3 , _SO 2
NR
3 R, -NR 3 C (0) OR, NR 3 C (0) R , -NR 3 C (O) NR 3
R
3 , optionally substituted
C
3
.
6 5 cyel--krl, ostThriTly substituted 4-6 membered -heteroc &Iyc-,~~~gt-iaa1ly substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower -- a-Lk-y-1-subs-t-i-t--tedhw-i t-h-ne-or-more--R-wherein-R 2 is se -x n ,_-C -3alkylamino, C 1 10 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin 4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1 methylpiperidin-4-yl, 1-Boc-piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin-2-yl; and wherein R 3 15 is independently selected from H, C 1
_
4 - alkyl, C1- 2 fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 20 membered heterocyclyl-Ci- 2 -alkyl wherein the heterocyclyl ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 25 The invention also relates to compounds of Formula III wherein R' is a substituted or unsubstituted ring selected from pyrazol-5-yl, 2-oxo-1,2-dihydroquinol-7-yl, 1-oxo 1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1, 1-dioxo benzo[d]isothiazolyl, benzothiazolyl, 2,3-dihydro-1H 30 indolyl, 2, 3-dihydro-benzofuryl, 1,2,3, 4-tetrahydro isoquinolyl, quinolyl, isoquinolyl, 1,2,3,4 tetrahydroquinolyl and 5,6, 7-trihydro-1,2,4-triazolo[3,4 a]isoquinolyl; wherein substituted R 1 is substituted with 1 3 substituents independently selected from bromo, chloro, WO 2005/021532 PCTIUS2004/027595 - 28 fluoro, iodo, nitro, amino, cyano, aminoethyl, hydroxy, aminosulfonyl, 4 -methylpiperazinylsulfbnyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, isopropyl-piperazinylmethyl, 5 -- mt-hYIPi:yerazl5j2iYyI pyl, morpholinylpropyl, methyTiperidiny1-ethyl-,-indipholinylethyl, 1- (4 morpholinyl) -2, 2 -dimethylpropyl, piperidinylethyl, -p-ipe-r-i-di-nylmethyl=-p-i-peri -iny-l-propyl-,- -1 - -- me-thy-pyrrolidinyirethy_, -p-yrrolidinylpro;yl, 10 methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, methyl, ethyl; -propyl; is~p t ropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, 1,1 di (trifluoromethyl) -1-hydroxymethyl, 1, 1 15 di (trifluoromethyl) -1- (piperidinylethoxy)methyl, 1,1 di (trifluoromethyl) -1- (methoxyethoxyethoxy) methyl, 1 hydroxyethyl, 2-hydroxyethyl, hydroxybutyl, difluoromethoxy, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1-(N isopropylamino) ethyl, 2- (N-isopropylamino) ethyl, 20 dimethylaminopropyl, dimethylaminoethoxy, 4 -chlorophenoxy, phenyloxy, 1-methylpiperidin-4-yloxy, piperidin-4-yloxy, piperidinylethoxy, morpholinylethyloxy, 4 methylpiperazinylethoxy, 4 -isopropylpiperazinylethoxy, piperidin-4-methoxy, 4 -methylpiperidin-1-ylmethoxy, 1 25 methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1 methylpyrrolidin-3-ylmethoxy, 3- (dimethylamino) pyrrolidin-1 ylethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in 30 conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III wherein R1 is substituted with 1-3 substituents independently selected from chloro, fluoro, amino, aminoethyl, hydroxy, methyl, ethyl, propyl, isopropyl, WO 2005/021532 PCTIUS2004/027595 - 29 butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl--nonafluorobutyl, 1,1-di(trifluoromethyl) 1-hydroxymethyl, methylcarbonyl, trifluoromethoxy, 1 methylpiperidin-4-yloxy, piperidin-4-yloxy, -5 pigerifdihigldthoky, morpholinylethyloxy, 4 methy-lpp-azinYlsthoxy, 4-isopropylpiperazinylethoxy, piperidin-4-methoxy, 4-methylpiperidin-1-ylmethoxy, 1 =methy-lpyr-re--i-di-n -2-ytmet-hoxy-,---i-sopropylpyrrol idin-2 -ylmethoxyyrl-'4sprppylpyrrolidin-3-ylmethoxy, 1 10 methylpyrrolidin-3-ylmethoxy, 3- (dimethylamino) pyrrolidin-l ylethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III 15 wherein R' is selected from 3-trifluoromethylphenylmethyl, 3 -trifluoromethylphenylethyl, 3 -methoxyphenylmethyl, phenylethyl, 4-methoxyphenylethyl, 3, 4-dimethoxyphenylethyl, 4-methylphenylethyl, 2-fluorophenylethyl, 3 fluorophenylethyl, 2-chlorophenylethyl, 4-chlorophenylethyl, 20 3, 4-dichlorophenylethyl, and 3, 5-dichlorophenylethyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III wherein R 7 is selected from substituted or unsubstituted 6 25 membered nitrogen containing heteroaryl, where substituted
R
7 is substituted with one or more substituents selected from halo, -OR 3 , -SR 3 , -SO 2
R
3
,-CO
2
R
3 , -C(0)NR 3
R
3 , -C(0)R 3 _
NR
3
R
3 , -SO 2
NR
3
R
3 , -NR 3 C (0) OR 3 , -NR 3 C (O) R 3 , optionally substituted 3-6 membered heterocyclyl, optionally 30 substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R2 wherein R 2 is selected from H, fluoro, hydroxy, amino,
C
1 3 -alkylamino, C 1 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from WO 2005/021532 PCTIUS2004/027595 - 30 morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R 3 is independently selected from H, C 1 4 5 alkyl, C 1 2 -fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C 1 2 -alkyl wherein the heterocyclyl 10 ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III 15 wherein R 7 is selected from 4-pyridyl, 4-pyrimidinyl, 5 pyrimidinyl, 6-pyrimidinyl, 4-pyridazinyl and 6-pyridazinyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III 20 wherein R 7 is selected from substituted or unsubstituted 9 10 membered nitrogen containing heteroaryl, where substituted R 7 is substituted with one or more substituents selected from halo, -OR 3 , -SR, -SO 2
R
3 ,-C0 2 R, -C(O)NR 3 R _
C(O)R
3 , -NR 3
R
3 , -SO 2
NR
3
R
3 , -NR 3 C(O)OR, -NR 3 C (O)R 3 , Boc, 25 optionally substituted 3-9 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R2 wherein R 2 is selected from H, fluoro, hydroxy, amino,
C
1 3 -alkylamino, C 1 3 -dialkylamino, optionally substituted 30 phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R 3 is independently selected from H, CI 4
-
WO 2005/021532 PCTIUS2004/027595 - 31 alkyl, C 1
-
2 -fluoroalkyl, optionally substituted phenyl, optionally substituted-3-6- membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted -5--3=6--membered~ heterdcyclyl-C 1
.
2 -alkyl wherein the heterocyclyl -ring ts-select-ed-from sele-cted from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and -pharmaceut- ical-ly--a-eeeptabl-e - der-i-va-t-ives-thereof; in -eondu-ncti on wi-t-h-n127of-the--above or :below embodiments. 10 The invention also relates to compounds of Formula III wherein R 7 is selected from 5-indazolyl, 4-quinolinyl, 6 -- uinolinyl, pyrrolo[2,3-blpyridin-4-yl, pyrrolo[2,3 b]pyridin-3-yl, 5-isoquinolinyl and 4 -quinazolinyl; and pharmaceutically acceptable derivatives thereof; in 15 conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula III wherein R 1 is selected from 4-tertbutylphenyl, 3,3-dimethyl 2,3-dihydroindolyl, 1-acetyl-3,3-dimethyl-2,3 dihydroindolyl, 3-tert-butylpyrazol-5-yl, 4,4-dimethyl 20 1, 2 ,3,4-tetrahydroisoquinolin-7-yl, 4,4-dimethyl-2-(3 pyrrolo[2,3-b]pyridinyl)-1, 2
,
3
,
4 -tetrahydroisoquinolin-7-yl, and 4,4-dimethyl-2-(Boc)-1,2,3, 4 -tetrahydroisoquinolin-7-yl; wherein R 5 is H; and and wherein R 7 is selected from 6 quinolinyl, pyrrolo[2,3-b]pyridin-3-yl, 4-pyridyl and 3 25 aminopyrid-4-yl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. A family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically 30 acceptable derivatives thereof as follows: 2-(4-(1,1-dimethylethyl)phenyl)-7-((4-pyridinylmethyl) amino)-2,3-dihydro-1H-isoindol-l-one; WO 2005/021532 PCTIUS2004/027595 - 32 7- [ (quinolin-6-ylmethyl) -amino] -2- [3- (tetrahydro-furan-3 yloxy) -5-trifluoromethyl-phenyl] -2, 3-dihydro-isoindol-1 one; 4, 4-dimethyl-7- {l-oxo-7- [ (quinolin-6-ylmethyl) -amino ]-1,3 -5 --- dihydro-isoindol-2-yl}-3,4-dihydro-1H-isoquinoline-2 - carboxri- ad~id tert-:butyl~ es ter; 2- (4-tert-butyl-phenyl) -7- [ (2-methoxy-pyridin-4-ylmethyl) -=am-i-no-2--3--i-hydro-iso-i-ndo-1-1=one-;-- -2 -- C4--s-ec-buty---phenyl) -7- [ (pyridin=43ylme thyl) -amino] -2, 3 10 dihydro-isoindol-1-one; 2- (4-sec-butyl-phenyl) -7- (4-fluoro-benzylamino) -2, 3-dihydro - isoindol-1-one; 2- (4-sec-butyl-phenyl) -7- [ (quinolin-6-ylmethyl) -amino] -2,3 dihydro-isoindol-1-one; 15 2- (4-sec-butyl-phenyl) -7-[ (2-methoxy-pyridin-4-ylmethyl) amino]-2,3-dihydro-isoindol-1-one; 2-[4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-7-[(quinolin-6 ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; 2- [4- (2-methoxy-1,1-dimethyl-ethyl) -phenyl]-7- [ (pyridin-4 20 ylmethyl) -amino] -2,3-dihydro-isoindol-1-one; 2- (4-phenoxy-phenyl) -7- [ (quinolin-6-ylmethyl) -amino] -2,3 dihydro-isoindol-1-one; 2- (4-phenoxy-phenyl) -7- [ (pyridin-4-ylmethyl) -amino] -2,3 dihydro-isoindol-1-one; 25 7- [(2 -methoxy-pyridin-4-ylmethyl) -amino] -2- (4-phenoxy phenyl) -2, 3-dihydro-isoindol-1-one; 2- (4-tert-butyl-phenyl) -7-[ (quinolin-6-ylmethyl) -amino] -2,3 dihydro-isoindol-1-one; 2- [4,4-dimethyl-2- (1H-pyrrolo[2,3-b]pyridin-3-ylmethyl) 30 1,2,3, 4 -tetrahydro-isoquinolin-7-yl]-7-(1H-pyrrolo[2,3 b]pyridin-3-ylamino) -2, 3-dihydro-isoindol-1-one; 2- (1-acetyl-3, 3-dimethyl-2, 3-dihydro-1H-indol-6-yl) -7 [ (pyridin-4-ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; WO 2005/021532 PCTIUS2004/027595 - 33 2- ( 3 ,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-7- [ (pyridin-4 -ylmethyl) -amino] -2;3-dihydro i soindol -1-one; 7- [ (pyridin-4-ylmethy-l) -amino) -2- ( 4 -trifluoromethyl-phenyl) 2, 3 -dihydro-isoindol-1-one; --- 5-- -2=T3~te-tyr71p-Enyl) -7-~ (pyrfdin-4-ylmethyl) -amino] -2,3 -di-hydroi-soTi-d-oT~~12ae; 2- (4., 4-dimethyl-1, 2,3, 4-tetrahydro-isoquinolin-7-yl) -7 - [-(-pyr-idin--4y-1methyl )--anino-] 2 ihyro inl1oe; ---- dhdr s no-1-one; -2--phenet-hyl-7--[-(pyridin=4-=ylm-e-thyl~).-amino] -2_,-3=dihydro 10 isoindol-l-one; 2- [2- (4-methoxy-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) - -- artin-o] - 2 ,3 -dihydro-isoindol-1-one; 2- [2- (3, 4-dimethoxy-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 15 7- [ (pyridin-4-ylmethyl) -amino] -2- (2-p-tolyl-ethyl)-2,3 dihydro-isoindol-l-one; 2- [2- (2-fluoro-phenyl) -ethyl] -7-[ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-l-one; 2- [2- (4-chloro-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) 20 amino]-2,3-dihydro-isoindol-l-one; 2- [2- (2-chloro-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) amino]-2,3-dihydro-isoindol-l-one; 2- [2- (3, 4-dichloro-phenyl) -ethyl) -7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-l-one; 25 2- [2- (3-fluoro-phenyl)-ethyl]-7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-l-one; 7- [ (pyridin-4-ylmethyl) -amino] -2- [2- (3-trifluoromethyl phenyl) -ethyl] -2, 3-dihydro-isoindol-l-one; 2- [2- (2, 4-dichloro-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) 30 amino]-2,3-dihydro-isoindol-1-one; 2- (4-tert-butyl-phenyl) -7- [ (lH-pyrrolo [2, 3-b]pyridin-3 ylmethyl) -amino] -2, 3 -dihydro-isoindol-1-one; 2- (4-tert-butyl-phenyl) -7-ethylamino-2 , 3-dihydro-isoindol-1 one; WO 2005/021532 PCTIUS2004/027595 - 34 4, 4-dimethyl-7- {1-oxo-7- [ (lH-pyrrolo [2, 3 -b] pyridin-3 ylmethyl) -amino ] -1, 3 -dihydro-i soindol-2-yl} -3, 4-dihydro 1H-isoquinoline-2-carboxylic acid tert-butyl ester; 2- (4, 4-dimethyl-1,2,3, 4-tetrahydro-isoquinolin-7-yl) -7- [1H 5 -pyrro [2;3 blpyridin-3-ylmethyl) -amino] -2, 3-dihydro --soindol-1-one6 2- (3-methoxy-benzyl) -7- [ (quinolin-6-ylmethyl) -amino] -2,3 -d-i-hydr-e-i-s e-i-nd-1-1--ene-; -- 2--(-3--me-thoxy-benzyl --7 z[(.prdin=4 -ylnthy1) --amino] -2, 3 10 dihydro-isoindol-1-one; 2- [3- (tetrahydro-furan-2ylmethoxy) -5-trifluoromethyl phenyl] -7- (te trahydro-pyran-4-ylamino) -2, 3-dihydro isoindol-1-one; 7- (4-f luoro-benzylamino) -2- [3- (tetrahydro-furan-3-yloxy) -5 15 trifluoromethyl-phenyl] -2, 3-dihydro-isoindol-1-one; 7- [ (pyridin-4-ylmethyl) -amino ]-2- [3-(tetrahydro-furan-3 yloxy) -5-trifluromethyl-phenyl] -2, 3-dihydro-isoindol-1 one; 7- [(2, 3-dihydro-benzofuran-5ylmethyl) -amino] -2- [3 20 (tetrahydro-furan-2-ylmethoxy)-5-trifluromethyl-phenyl] 2, 3-dihydro-isoindol-1-one; 7- (4-f luoro-benzylamino) -2- [3- (tetrahydro-furan-2-ylmethoxy) -5-trifluromethyl-phenyl]-2,3-dihydro-isoindol-1-one; 7- [ (pyridin-4-ylmethyl) -amino] -2- [3- (tetrahydro-furan-2 25 ylmethoxy) -5-trifluoromethyl-phenyl] -2, 3-dihydro isoindol-1-one; 7- [ (2-methoxy-pyridin-4-ylmethyl) -amino] -2- (4 trifluoromethoxy-phenyl) -2, 3-dihydro-isoindol-1-one; 7-[(pyridin-4-ylmethyl)-amino]-2-(4-trifluoromethoxy 30 phenyl)-2, 3-dihydro-isoindol-1-one; 2- (5-tert-butyl-2H-pyrazol-3-yl) -7- [ (pyridin-4-ylmethyl) amino] -2,3-dihydro-isoindol-1-one; 2- (5-tert-butyl-2H-pyrazol-3-yl) -7- [ (2-methoxy-pyridin-4 ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; WO 2005/021532 PCTIUS2004/027595 - 35 7-[(quinolin-6-ylmethyl)-amino]-2-(4 -trifluoromethoxy phenyl) -2, 3 -dihydro-isoindol-1-one; 7-[ (pyridin-4-ylmethyl) -amino] -2- ( 3 -trifluoromethoxy phenyl) -2, 3 -dihydro-isoindol-1-one; 5 - 7 --- H-quinolin-4=ylmethyl) -amino] -2- ( 4 -trifluromethoxy --- pheny-1) - 2 7 3 -dihydro-isoindol-1-one; 2-(4-phenyl-thiazol-2-yl)-7-[(pyridin-4-ylmethyl)-amino] -2, 3dihydro-i-s-e i-ndol_---ene.; N-(.2=ter t -butyl -5-----xo -- (-pyridin=4 _methyl)=amino] -1, 3 10 dihydro-isoindol-2-yl}-phenyl)
-
2 -piperidin-1-yl acetamide; N- (-2-tert-butyl-5-{1-oxo-7 [(quinolin-6-ylmethyl) -amino] 1, 3 -dihydro-isoindol-2-yl}-phenyl)
-
2 -piperidin-1-yl acetamide; 15 N- (2-tert-butyl-5-(1-oxo-7- [ (pyridin-4-ylmethyl) -amino] -1,3 dihydro-iscindol-2-yl}-phenyl)-2-morpholin-4-yl acetamide; N-(2-tert-butyl-5-{1-oxo-7-[(quinolin-6-ylmethyl)-amino] 1, 3-dihydro-isoindol-2-yl}-phenyl) -2-morpholin-yl 20 acetamide; 7- [ (pyridin-4-ylmethyl) -amino) -2-m-tolyl-2, 3-dihydro isoindol-1-one; 2- (3-chloro-phenyl)-7- [ (pyridin-4-ylmethyl) -amino -2,3 dihydro-isoindol-1-one; 25 7-[(pyridin-4-ylmethyl)-amino]- 2 -p-tolyl-2,3-dihydro isoindol-1-one; 7- [ (pyridin-4-ylmethyl) -amino] -2- (3-trifluoromethyl-benzyl) 2, 3-dihydro-isoindol-1-one; 2- ( 4 -pentafluoroethyl-phenyl) -7- [ (pyridin-4-ylmethyl) 30 amino]-2,3-dihydro-isoindol-l-one; N- (2-tert-butyl-5-{1-oxo-7- [ (pyridin-4-ylmethyl) -amino] -1,3 dihydro-isoindol-2-yl} -phenyl) - 2 -dimethylamino-acetamide; WO 2005/021532 PCTIUS2004/027595 - 36 4, 4-dimethyl-7-{7- [([1, 8 ]naphthryridin-4-ylmethylene) -amino] -1-oxo-1, 3 -dihydro-isoindol-2-yl} -3, 4 -dihydro-1H isoquinoline-2-carboxylic acid tert-butyl ester; 2- (4-tert-butyl-phenyl) -7- [ ( 2 -chloro-pyridin-4-ylmethyl) 5 mino]~-2~ 3-d-ihydro-isboindol-1-one; 2=-t44=dimethyl-1, 2 , 3, 4-tetrahydro-isoquinolin-7-yl) -7 [(quinolin-6-ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; 2 -(4-=t-bu-t-y-pheny-1)--7--(2-pyr idin-4-yl-vinyl) -2,3 -dihydro -i-se-indo-1--1- one-; _ __ ____ 10 2- (4-tert-butyl-phenyl) -7- (2-pyridin-2-yl-vinyl) -2,3 dihydro-isoindol-1-one; 2= (~4--t-bttyl-phenyl) -7- (2-pyridin-4 -yl-ethyl) -2, 3-dihydro isoindol-1-one; 2-(4-t-butyl-phenyl)-7-(pyridin-4-ylmethoxy)-2,3-dihydro 15 isoindol-1-one; (S) -2- (4- t-butyl-phenyl) -7- (1-pyridin-4-yl-ethoxy) -2,3 dihydro-isoindol-1-one; (R) -2- (4- t-butyl-phenyl) -7- (1-pyridin-4-yl-ethoxy) -2,3 dihydro-isoindol-1-one; 20 2- (4-t-butyl-phenyl) -7- [(2-methylamino-pyrimidin-4 ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; 2- (4-t-butyl-phenyl) -7- (pyridin-3-ylamino) -2, 3-dihydro isoindol-1-one; 2- (4-t-butyl-phenyl) -7- (pyridin-4-ylamino) -2, 3-dihydro 25 isoindol-1-one; 2- (4-t-butyl-phenyl) -7- (quinolin-5-ylamino) -2, 3-dihydro isoindol-1-one; 2- (4- t-btyl-phenyl) -7- (quinolin-6-ylamino) -2, 3-dihydro isoindol-1-one; 30 2- (4-t-butyl-phenyl) -7- (2-pyridin-3-yl-ethylamino) -2,3 dihydro-i soindol-1-one; (S) - 2-(4-t-butyl-phenyl) -7- (1-pyridin-4-yl-ethylamino)-2,3 dihydro-isoindol-1-one; WO 2005/021532 PCTIUS2004/027595 - 37 (R) -2- (4-t-butyl-phenyl) -7- (1-pyridin-4-yl-ethylamino) -2,3 -dihydro-isoindol-1--one; 2- (4-ter t-butyl-phenyl) -1-hydroxy-4- [ (pyridin-4-ylmethyl) amino] -1, 2 -dihydro-pyrrolo[3,4-cpyridin-3-one; 5 2(-4=rteitht1h-ih7e-n1) 24-[ (pyriai-4-ylmethyl) -amino]-1,2 --di-hydro=pyrrole[3-, 4-~c]pyridin-3-one; 2- (4-tert-Butyl-phenyl) -4- [ ( 2 -methylamino-pyrimidin-4 --yl-me-thyl-)-am--nei---12--dihydro-pyrrol o [ 3,4 - c ] pyridin- 3 - one;
--
2 -- (- 4 -tert-butyl-,pheny-)-=4=[-T2methoxy-p-2'Tdin-4-y1methyl) 10 amino]-1,2-dihydro-pyrrolo[3, 4 -clpyridin-3-one; 4-[(2-amino-pyridin-4-ylmethyl)-amino]-2-(4-tert-butyl phenyl) -1, 2-dihydro-pyrrolo [3 , 4 -c]pyridin-3-one; 2- (4-tert-butyl-phenyl) -4- (4-fluoro-benzylamino) -1,2 dihydro-pyrrolo[3,4-c]pyridin-3-one; 15 2- (4-tert-butyl-phenyl) -4- (1H-indazol-6-ylamino) -1,2 dihydro-pyrrolo [3, 4-c]pyridin-3-one; 2- (4-tert-butyl-phenyl) -3-methyl-7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 2- (4-tert-butyl-phenyl)-3-hydroxy-3-methyl-7-[(pyridin-4 20 ylmethyl) -amino] -2,3-dihydro-isoindol-l-one; 7- (pyridin-4-ylamino) -2- [3- (tetrahydro-furan-3-yloxy) -5 trifluoromethyl-phenyl] -2, 3-dihydro-isoindol-1-one; 2-biphenyl-4-yl-4- [ (pyridin-4-ylmethyl) -amino ]-1, 2-dihydro pyrrolo[3,4-c]pyridin-3-one; 25 2
-(
4 ,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4 [(pyridin-4-ylmethyl) -amino] -1, 2-dihydro-pyrrolo [3,4 c] pyridin-3-one; 2-4-tert-butyl-phenyl) -4- [ (pyridin-4-ylmethyl) -amino] -1,2 dihydro-indazol-3-one; and 30 2- (4-tert-butyl-phenyl) -4- [(pyridin-4-ylmethyl) -amino] isoindole-1,3-dione. Indications Compounds of the present invention would be useful 35 for, but not limited to, the prevention or treatment of WO 2005/021532 PCTIUS2004/027595 - 38 angiogenesis related diseases. The compounds of the invention have kinase--inhibitory activity, such as VEGFR/KDR inhibitory activity. The compounds of the invention are useful in therapy as antineoplasia agents or to minimize 5 de--eterious -effects of VEGF. --- Gempounds of the -invention would be useful for the treatment of neoplasia-including cancer and metastasis, including-blmt-no-t-limi-ted-t-.care-i-noma-such-as -cancer of the-bladder, breast, colon, kidney, liver, lung (including 10 small cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,
T
15 cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin 20 (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, 25 osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma). Preferably, the compounds are useful for the treatment of neoplasia selected from lung cancer, colon cancer and breast cancer. 30 The compounds also would be useful for treatment of ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and WO 2005/021532 PCT/US2004/027595 - 39 neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases sudh as gastric ulcer; pathological, but non-malignant, conditions such as hemangibfnas, including infantile hemaginomas, angiofibroma of the nasopharynx and 5 vascular necrosis of bone; and disorders of the female Tdj5fductiv esys-en such as endometriosis. The compounds --- are-al-sc useful-for the-treatiment of ed-enrrf6,~d conditions of--vui arhyr-enbi-t7- ~ ~Th6 6unds~-~f-the7inventaon a-e. -useful-in -therapy 10 of proliferative diseases. These compounds can be used for the treatment of an inflammatory rheumatoid or rheumatic disease, especially of manifestations at the locomotor apparatus, such as various inflammatory rheumatoid diseases, especially chronic polyarthritis including rheumatoid 15 arthritis, juvenile arthritis or psoriasis arthropathy; paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, such as systemic Lupus erythematosus, poly-myositis, dermato-myositis, systemic sclerodermia or mixed collagenosis; postinfectious 20 arthritis (where no living pathogenic organism can be found at or in the affected part of the body), seronegative spondylarthritis, such as spondylitis ankylosans; vasculitis, sarcoidosis, or arthrosis; or further any combinations thereof. An example of an inflammation related 25 disorder is (a) synovial inflammation, for example, synovitis, including any of the particular forms of synovitis, in particular bursal synovitis and purulent synovitis, as far as it is not crystal-induced. Such synovial inflammation may for example, be consequential to 30 or associated with disease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis deformans. The present invention is further applicable to the systemic treatment of inflammation, e.g. inflammatory diseases or conditions, of the joints or locomotor apparatus in the WO 2005/021532 PCTIUS2004/027595 - 40 region of the tendon insertions and tendon sheaths. Such inf-lammation may be, for example, be consequential to or associated with disease or further (in a broader sense of the invention) with surgical intervention, including, in 5- ~prt~i-ular ~biationi such as insertion endopathy, myo f ascralfifad2aiif~eiid-tendomyos is . The present invention .-is--fHurther- espeei-a-ll-y applicable-to the treatment of inflammat ion--eg-. -i-n-f-1-amma- orydisna-s-e--or-c-ondi-t i air-o f -connective- ti-ssues- including- dermatonfiyd6itil -and -myositis. 10 These compounds can be used as active agents against such disease states as arthritis, atherosclerosis, psoriasi-s~,~~hendniomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, 15 fractures, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy or macular degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and 20 hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein- Leventhal syndrome)) since such diseases require a proliferation of blood vessel 25 cells for growth and/or metastasis. Further, some of these compounds can be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, brain tumor-associated cerebral 30 edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, and other diseases where vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease. The compounds will also be useful in WO 2005/021532 PCTIUS2004/027595 - 41 treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g. fibrosis, cirrhosis and carpal tunnel syndrome). 5 The compounds of the present invention are also useful -in-the treatment of ulcers including bacterial, fungal, Mooren ulcers and -ulcerative-coliti-s-. The c.ompoumds-of-the-present invention are also useful in -the-treatment of- -conditions wherein undesired 10 angiogenesis, edema, or stromal deposition occurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis, following trauma, radiation, stroke, endometriosis, ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis, 15 synovitis, Crohn's disease, sickle cell anemia, Lyme disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic inflammation, chronic occlusive pulmonary disease, asthma, and inflammatory rheumatoid or rheumatic disease. The compounds 20 are also useful in the reduction of subcutaneous fat and for the treatment of obesity. The compounds of the present invention are also useful in the treatment of ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial 25 keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, glaucoma, conjunctivitis, Stargardt's disease and Eales disease in addition to retinopathy and macular degeneration. The compounds of the present invention are also useful 30 in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, arteriosclerosis, vascular occlusion and carotid obstructive disease. The compounds of the present invention are also useful in the treatment of cancer related indications such as solid WO 2005/021532 PCTIUS2004/027595 - 42 tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor- induced pleural or pericardial 5 effurizns, afrinalignant ascites. The-comrourda--~-f the-esent -invention are also useful in the treatment -of d-i-abetic conditions-such--as diabetic -et-i-nepa-thy- and--m-i-e-roa-ng-i-opa-hy---- The-compounds--of-th-i-is-en aa.o-act-as 10 inhibitors of other protein kinases, e.g. tie-2, lck, src, fgf, cmet, ron, ckit and ret, and thus be effective in the treatment of diseases associated with other-protein kinases. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of 15 companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. As used herein, the compounds of the present invention include the pharmaceutically acceptable derivatives 20 thereof. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a sindle compound, salt and the like. 25 Definitions The term "treatment" includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a pre clinically evident stage of disorders in individuals). 30 A "pharmaceutically-acceptable derivative " denotes any salt, ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly) a compound of WO 2005/021532 PCTIUS2004/027595 - 43 this invention, or a metabolite or residue thereof, characterized-by the ability to inhibit-angiodenesis. The phrase "therapeuticallyeffective" is intended to qualify the amount of each agent, which will achieve the 5 goal atf-improvement i d disore'severity and the frequency niagent by itself, while avoiding adverse--s-ide-effects -typically associated with alternative tzheapi-es-.Fa r--eZap-I-, ffeFctive radplas tic -therapeutic-agen-ts-prol-ong 'the~ffuyv-i il7ty of the patient, 10 inhibit the rapidly-proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm. The teri 'H" -denotes a single -hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical. 15 Where the term "alkyl" is used, either alone or'within other terms such as "haloalkyl" and "alkylamino", it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. 20 Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term "alkylenyl" embraces bridging divalent alkyl radicals such 25 as methylenyl and ethylenyl. The term "lower alkyl substituted with R 2 " does not include an acetal moiety. The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. More preferred alkenyl 30 radicals are "lower alkenyl" radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower WO 2005/021532 PCTIUS2004/027595 - 44 alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "a-lkynyl" denotes linear or branched radicals having at least one carbon-carbon triple bond and having two - 5 --- to-abt twelve carbon atoms. More preferred alkynyl r 1 -n radils having two to about six.carbon atoms.- Mos-t-preferred-are--lower alkynyl radicals .having t-wo--e-bout-=four c-a-rbon atoms. Examples of such rad-iea-l-s -include-propar.gyr,--bumynyl , and the like. 10 The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms. ~ r - -The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, 15 dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different 20 halo radicals. "Lower haloalkyl" embraces radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, 25 trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include 30 trifluoromethyl and pentafluoroethyl. The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower WO 2005/021532 PCTIUS2004/027595 - 45 hydroxyalkyl" radicals having one to six carbon atoms and -one or more hydroxyl ra-dicals. Examples of such radicals include hydroxymethyl, -hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are 5-ower hycdroxfalky)lYradicals having one to three carbon - -The -term al-koxy"-embrace -linear--or-branched oxy -- c-n-t-a-i-n-i-ng-radi-ca--s-eaahhaving-a--kyl-portions---of one to --- about-ten c-ar);m--a-t-qms- - eflired ~alkoxy-radicals -are 10 "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxf~ and tert-butexy. Even -more -preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo 15 atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, 20 fluoroethoxy and fluoropropoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner. The term "aryl" embraces aromatic radicals such as 25 phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl. Said "aryl" group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino. Phenyl substituted with -O-CH 2 -0- forms the aryl 30 benzodioxolyl substituent. The term " heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings WO 2005/021532 PCTIUS2004/027595 - 46 containing -o-0-,-o-S- or -S-S- portions. Said "heterocyclyl" group- may have 1-to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano,- lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino. -5- Examplesmbf saturated heterocyclic radicals include - --- se-t-ur-ated--3-to-6-=membe-d-Tatetanto6ocyclic groups containing . to-4. nitrogen atoms- -e .g-.--py-rrolidiny-l--imidazolidinyl -piper-i-n-yl;=p y-r-ro-iny----p-i-per-a-z-iny-l--;-s-aturated 3 to 6 membe-redhe-t-er-emenoyc-lic--g up-containing_1 .to .2 oxygen 10 atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2- sulfur atoms and 1 to 3 nitrogen atoms- [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, 15 dihydropyranyl, dihydrofuryl and dihydrothiazolyl. Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2 20 pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3 triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 25 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4 30 oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5 thiadiazolyl].
WO 2005/021532 PCTIUS2004/027595 - 47 The term also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, 5 -i-nde-1-i-z-inyl, benzimidazolyl, quinolyl, isoquinolyl, -indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1, 5-blpyridazinyl] ;- unsa-tura-t-ed-condensed heterocycli c_group-conta-i-ning-1---2-oxygen--atoms and 1 to 3 riitrogen-atoms-[-e-g-.-benz-oxazo-l-yl-,-ben-zoxadiazolyl] 10 unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl];-and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, 15 benzothienyl, 2
,
3 -dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, 20 oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, 25 isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl. Particular examples of non-nitrogen containing heteroaryl include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3 thienyl, benzofuryl, benzothienyl, and the like. 30 Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, WO 2005/021532 PCTIUS2004/027595 - 48 isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4 tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro 5 1, 2
-
4 -tei-azol-of3-;--4.a-i-soquinolyl, 3, 4-dihydro-2H ben-zo-44Exaz-i-ny~lbenzo[-1-~4]dioxanyl, 2,3-dihydro-lH-1i' benzo[d]isothiazol-6-yl, dihydropyranyl-, di-hydrofuryl and dihydrothiazo -Ly-,and-the-1-i-ke-.--- The-term-"su-14enyl--rwhether-usPd alone -or -linked to 10 other terms such as alkylsulfonyl, denotes respectively divalent. radicals
-SO
2 -. The terms "sulfamyl," "aminosulfonyl" and "sulfonamidyl", denotes a sulfonyl radical substituted with' an amine radical, forming a sulfonamide
(-SO
2
NH
2 ) 15 The term "alkylaminosulfonyl" includes "N alkylaminosulfonyl" where sulfamyl radicals are independently substituted with one or two alkyl radical(s). More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having one to six carbon atoms. 20 Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl. The terms "carboxy" or "carboxyl", whether used alone 25 or with other terms, such as "carboxyalkyl", denotes -C0 2 H. The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -(C=O)-. The term "aminocarbonyl" denotes an aide group of the formula
-C(=O)NH
2 30 The terms "N-alkylaminocarbonyl" and "N,N dialkylaminocarbonyl" denote aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are "lower alkylaminocarbonyl" WO 2005/021532 PCTIUS2004/027595 - 49 having lower alkyl radicals as described above attached to an aminocarbonyl radical.
The terms "N-arylaminocarbonyl" and "N-alkyl-N arylaminocarbonyl" denote aminocarbonyl radicals 5 - --substituted,-respect-iT-y, with one aryl radical, or one -alky-1-and one- ary-1-radica------ The terms. "hat-erocyclylalkylenyl "-,and .etaro~cycly.alky-" !ombra e-heteree-yc-l-c-substituted alkyl radicals. -More- preferr-edhet-erocyc-lyal-kyl radicals are "5 10 or 6-membered heteroarylalkyl" radicals having alkyl portions of one to six carbon atoms and a 5- or 6-membered heteroaryl radical-. :Even more preferred--are lower heteroarylalkylenyl radicals having alkyl portions of one to - three carbon atoms. Examples include such radicals as 15 pyridylmethyl and thienylmethyl. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having- one to six carbon atoms. Even more preferred are 20 "phenylalkylenyl" attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. 25 The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of "alkylthio" is methylthio, 30
(CH
3 S-) The term "haloalkylthio" embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower WO 2005/021532 PCTIUS2004/027595 - 50 haloalkylthio radicals having one to three carbon atoms. An example- of "haloalkylthio" is trifluoromethylthio. The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino" where amino groups are independently 5 -subs-tt-u-ted w-it-h--one--a--kyl- radical- afnd with two alkyl . madicaIs-respeet-vely. Morpre-f-erred' alkylamino radicals --are _"lower alkylamino" .radicals -having- one or two alkyl radi-calsof one__ta-srix carbon- atoms, attached to a nitrogen atom...-Evenmore -pre-f-er-r-ed-a-r-e--lower-a-lkylamino radi-cals 10 having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, -N,-N-dimethylamino, N, N-diethylamino and the like. The term "arylamino" denotes amino groups which have 15 been substituted with one or two aryl radicals, such as N phenylamino. The arylamino radicals may be further substituted on the aryl ring portion of the radical. The term "heteroarylamino" denotes amino groups which have been substituted with one or two heteroaryl radicals, 20 such as N-thienylamino. The ".heteroarylamino" radicals may be further substituted on the heteroaryl ring portion of the radical. The term "aralkylamino" denotes amino groups which have been substituted with one or two aralkyl radicals. 25 More preferred are phenyl -Cr-C 3 -alkylamino radicals, such as N-benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion. The terms "N-alkyl-N-arylamino" and "N-aralkyl-N alkylamino" denote amino groups which have been 30 independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group. The term "aminoalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one WO 2005/021532 PCTIUS2004/027595 - 51 of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include -5 -ami-nomethyl ,-aminoethyl; aminiffopropyl, aminobutyl and aminohexyl.--- Even-more -preferred are lower aminoalkyl radicals having-one-to.. three- carbon-atoms. The-termt"alkylamin-oalkyl="-embraees-a-l-ky - dicals .sUsti-tuted-wi-th-ag-1--amine-r-ad-ilca- Moretpref erred 10 -alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl 15 substituted, such as N-methylaminomethyl, N,N-dimethyl aminoethyl, N,N-diethylaminomethyl and the like. The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with alkylamino radicals. More preferred -lkylaminoalkoxy radicals are "lower alkylaminoalkoxy" 20 radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxy,
N,N
25 dimethylaminoethoxy, N,N-diethylaminoethoxy and the like. The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of 30 one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N, N- WO 2005/021532 PCTIUS2004/027595 - 52 dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy and the like. The term "carboxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one 5 --- o-fhi-ch-may-be-subst-i-tU-ted -with one or more carboxy -ad-i-ea-1-s--- More-preferred-czrb-nyaIkyl radicals are "lower _- carboxyalky-1"..-radicals -having -one-to--six- carbon atoms and one--carboxy-madi-ca-l-Examp--es-e-f s-ueh-radi-cals--inc-1ude carboxynme-thy--r-earboxypropy-l-and-the:-l1-ke-:--- Even- more. 10 pr-ef-erred are lower carboxyalkyl radicals having one to three CH 2 groups. The term "halosulfonyl" embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and 15 fluorosulfonyl. The term "arylthio" embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of "arylthio" is phenylthio. The term "aralkylthio" embraces aralkyl radicals as 20 described above, attached to a divalent sulfur atom. More preferred are phenyl-Ca-C 3 -alkylthio radicals. An example of "aralkylthio" is benzylthio. . The term "aryloxy" embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. 25 Examples of such radicals include phenoxy. The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having optionally substituted phenyl radicals 30 attached to lower alkoxy radical as described above. The term "heteroaryloxy" embraces optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom.
WO 2005/021532 PCTIUS2004/027595 - 53 The term "heteroarylalkoxy" embraces oxy-containing heteroarylalkyl radicals-attached through an oxygen atom to other radicals. - More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy" radicals having optionally -5-ted-t -r-Hals attached to lower alkoxy r-dcaT as de-scrtbedT-abuve . -_ ~--~-The-term-"-ylealkyl"- includes saturated carbocyclic groups-.- -Rrefrre-y-=ak- rnjicue-iC-Tng -M-r-e-pre-f-err-ed-compouns--~i-n-ds--- cycr-o];styl, 1c-yclopropyl, 10 Ehd&ayclohexyl. The term "cycloalkenyl" includes carbocyclic groups -having one or more-carbon-carbon double bonds including "cycloalkyldienyl" compounds. Preferred cycloalkenyl groups include C 3
-C
6 rings. More preferred compounds include, for 15 example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl. The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements. 20 The term "Formulas I-III" includes any sub formulas. The compounds of the invention are endowed with kinase inhibitory activity, such as KDR inhibitory activity. The present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable 25 salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of an angiogenesis mediated disease state, including those described previously. The compounds of the present invention are useful in the manufacture of an anti-cancer medicament. The 30 compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of KDR. The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of WO 2005/021532 PCTIUS2004/027595 - 54 a compound of Formulas I-III in association with a least one pharmaceutically-acceptable carrier, adjuvant or diluent. The.-present- invention also comprises a method of treating angiogenesis related disorders in a subject having 5 rstsibleto sucraisorder, the method comprising -t-reatn-th asilbjec tht aherapeuftically-effective amount df~&-ch6inpound of Formula--I-III. -COMNA-T-iONS 10 While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a 15 combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. The phrase "co-therapy" (or "combination-therapy"), in 20 defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co 25 administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. Specifically, the administration of compounds of the 30 present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents. If formulated as a fixed dose, such combination 35 products employ the compounds of this invention within the WO 2005/021532 PCTIUS2004/027595 - 55 accepted dosage ranges. Compounds of Formula I may also be administered sequentially- with- known- anticancer or cytotoxic agents when a combination formulation is--inappropriate. The invention is not limited in the sequence of administration; -5- c-empou-nds-o-f-t-he-i-nvention may be administered either prior to=,-simultaneus--with--or after administration of the known anticancer or cytotoxic -agent. -Currently-,=standa-rd-t-reat-ment-of-primary-tumors .- consists-of-.surg-ia-1-e-x-eis-ien-followed-by-eithexr-adiation 10 or IV administered chemotherapy. The typical chemotherapy regime consists of either DNA alkylating agents, DNA - - --- nt-erca-lating-agent-s-- CDK inhibitors, or -mi-crotubule poisons. The chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting 15 toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like. There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for 20 treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category 25 of miscellaneous agents. A first family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents. Suitable antimetabolite 30 antineoplastic agents may be selected from but not limited to the group consisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow WO 2005/021532 PCTIUS2004/027595 - 56 DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, _-Yoshitomi DMDC,--dox-if-luridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, -floxuridine, fludarabine phosphate, 5 fluorouracil, N- (2 '-furanidyl) -5-fluorouracil, Daiichi -5- -Seiyaku-FO-~1-52 isopropyprrol-izine, Lilly LY-188011, -= ie-ito1-y-2646-8-Wthoben-i---tlotrexate, Wellcome MZPES.~ norspermidine.,.-NCI--NSC-127716, NCI NSC-264880, NCI NSC=3-9-6-61,--NCI-NS 6-1-2-5-6-7-r -Warner.=Lambert-PALA~-pentos tatin, -pi-r-i-t-r-exi-m-,-p--i amyc i-n---A-sahi -Chemnt~PJAC7.Tak§eda-TAC 10 -788 ''thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin. -A-second-fanily of~ &ntineoplastic agents which may be used in combination with compounds of the present invention -consists of alkylating-type antineoplastic agents. Suitable 15 alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakndfaga CA-102, carboplatin, carmustine, Chinoin-139, 20 Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspircmustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont 25 FCE-24517, estramustine phosphate sodium, fotemustine, United G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, 30 semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol. A third family of antineoplastic agents which may be used in combination with compounds of the present invention WO 2005/021532 PCTIUS2004/027595 - 57 consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, 5 aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN 3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol Mye-r-s-BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, 10 bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, 15 esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE 21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, 20 Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, 25 porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM 5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 30 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin. A fourth family of antineoplastic agents which may be used in combination with compounds of the present invention WO 2005/021532 PCTIUS2004/027595 - 58 consists of a miscellaneous family of antineoplastic agents, including tubulin-interact-ing agents, topoisomerase II inhibitors, topoisomerase I- inhibitors and hormonal agents, selected from but not limited to the group consisting of c 5" carotene~, a-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin~iC-52, alstonine, amonafide, amphethinile, amsac-rine, ~Angio stat~,~ arikiYiomiydin~ ahi-n'oplas ton A10 , anti-neoplaston-A27 antineoplas~Eon A3, antineoplaston A5, antinp-aston A~iHenkel APD ,-aphidicol-in- g-lycinate, 10 asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes 15 CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert
CI
958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, 20 DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine, etoposide, 25 etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF 5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, 30 Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives, methylanilinoacridine, Molecular Genetics MGI- WO 2005/021532 PCTIUS2004/027595 - 59 136, minactivin, mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16; N- (reti-noy1) amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, ---- Ner-mes-a-ng--N-I-NSC-145-8T3~-NCI~NSC-361456, NCI NSC-604782, -2-NC--I=NSC-95=57 ocreoti-de-;--Ono--ONO-r127 cquizanocine, Akzo Or g-101.72_ paclitaxel,pancrat-istati-n, -pa-z-elliptine 7 Warner mLabert=-D=1117-O7,=Warner-=T-amber-t-PD--l-1-59-34-7-Warner- Laimbert EPD-1.311-41-,-P-i-erre-Fa-bre--PE-1-0)17-ICRT--ept-d- D,. 10 piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron -proteas-e-nexin-T---Tobishi -RKA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline 15 SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm
SP
10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, 20 taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin TT 82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, 25 vinzolidine, withanolides and Yamanouchi YM-534. Alternatively, the present compounds may also be used in co-therapies with other anti-neoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, 30 amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, WO 2005/021532 PCTIUS2004/027595 - 60 denileukin diftitox, deslorelin, dexrazoxane, dilazep, docet-axel, docosanfdl,~doxercalcifeol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, 5 daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin -beta,-etopos-ide--;htsphte, exemestane, exisulind, f-drz-oT--filgrart!im, finasteride, fludarabine phosphate, ~lformeanfe,.--fotsmusti-ne-,--gall-ium nitrate, -gemcitabine, 10 gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon 15 alfa-2a, interferon alfa-2b, interferon alfa-NI, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural interferon gamma-la, interferon gamma-lb, interleukin-1 beta, 'iobenguane, irinotecan, 20 irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, 25 mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, 30 paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase, rhenium Re WO 2005/021532 PCTIUS2004/027595 - 61 186 etidronate, RII retinamide, rituximab, romurtide, -samarium (153 Sm) -lexidronam, sargramostim- sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, -5 eniposi- thalifdomide, thymalfasin, tositumomab- iodine 131, -trtastuzumab,- treos-ul-fan-,--- t-re-tine i-n,-- -tril-ostane ; t-rimetrexate-,--ript-or-e-l-i-n-=-t-umer -nec-ros-i-s-fa-ct-or-al-h-; -natur-a-l-,-uben-i-mex,-b--adder-cancer-va-cri aruyama 10 va-ccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer, or -- zo-i-edroni-c -a-c-idT--at-arei;~-AE~941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, 15 diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SDO1 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab 20 tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1 25 iodine 131 MAb (Techniclone), polymorphic epithelial mucin yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), 30 rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York WO 2005/021532 PCTIUS2004/027595 - 62 University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or valspodar. 5 Alternatively, the present compounds may also be used Jn co-therapies-with other anti-neoplastic agents, such as other kinase inhibit t-ors-incl.uding p38 inhibitors and CDK inhibitors, TNF inhibLtorsmeta-l-1-oma-trix-proteases inhibitors (MMP), -COX-2 inhibitors including cele-coxib, 10 rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's, SOD mimics or 0 3 inhibitors. The present invention comprises -processes for the preparation of a compound of Formula I-Ill. Also included in the family of compounds of Formula I-III 15 are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. 20 Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I-III may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic 25 acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, 30 ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4 -hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2 -hydroxyethanesulfonic, toluenesulfonic, WO 2005/021532 PCTIUS2004/027595 - 63 sulfanilic, cyclohexylaminosulfonic, camphoric, .camphorsulfonic,- digluconic-, cyclop-ent-anepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2 -hydroxy-ethanesulfonic, nicotinic, 2 ~5--naphtha-l-enesu--f-iic, oxalic, palrhic,'~pectinic, persulfuric, -n- pr~pinic, succinic, tar-tari_c,. .thiocyanic,--mesy-lic, -undecanoic-, st-earic, algenic, hydroy-yu-t-yri -al1-ic,~~gal ac t-ari c and~ galadtUronic -aci-d- Sui-ta-b-le-phErinaceuticaiJLy- acceptablebase--addition 10 salts of compounds of Formula I-III include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassin, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as 15 caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine,
N
ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the 20 invention by reacting, for example, the appropriate acid or base with the compound of Formula I-III. GENERAL SYNTHETIC PROCEDURES 25 The compounds of the invention can be synthesized according to the following procedures of Schemes 1-7, wherein the substituents are as defined for Formulas I-III, above, except where further noted.
WO 2005/021532 PCTIUS2004/027595 - 64 Scheme 1 Br
CO
2 H K CO 2 Me CO 2 Me K2CO3, Me1 NBS, AIBN, -- - - -------------------- - I L RT L reflux L L "N0 2 0H, ~- -- 3 or I.---- IPEA, ref-tix RI-NH 2 RR N H 2 /Pd/C o N R=CHO _____ Q NaBH(OAc) 3 ' if R L O NH RT
NH
2 ifL=N0 2 4 6 5
R
7 5 Compounds of Formula I can be prepared by the following procedure wherein a 2 -methyl-6-nitro-benzoic acid 1, for example, is esterified followed by benzylic bromination. This general procedure can be used for L = 10 NO 2 , OH or a halogen (e.g. Br, Cl, or I). If L = NO 2 , reaction of the benzylbromide 3 with an amine in the presence of base, such as IPEA, followed by cyclization affords the 7 -nitro-oxindole 4. The 7 -nitro-oxindole 4 can be reduced under standard hydrogenation conditions and 15 alkylated under standard reductive amination conditions such as with an aldehyde, to afford compounds 6 of Formula I.
WO 2005/021532 PCTIUS2004/027595 - 65 Scheme 2 Ri I R if L = OH N O if L = OH I 0 _ __ N 0
-H
N ROH, PPh 3 , 2. RNH 2 , Pd(OAc) 2 , 7I 8 __dppf, Cs203- 4 R ifL=Br_ 7 Pd(OAc) 2 , P(O-tol) 3
R
1 INN O H2, Pd/C 9 R 10 R 5 If L is OH, then the 7 -hydroxy-oxindole can be reacted with an alcohol under standard Mitsunobu conditions to afford the corresponding alkoxy compound 7. Also, if L = OH, then the 7-hydroxy-oxindole can be converted to the triflate and reacted with an amine using standard Buchwald 10 coupling conditions to provide amines 8. Further, if L = halogen (Br, Cl, or I), then the 7 -bromo-oxindole, for example, can be reacted with an olefin under standard Heck conditions to afford the corresponding vinyl compound 9 which can be reduced under standard hydrogenation conditions 15 to provide the substituted alkyl compounds 10.
WO 2005/021532 PCTIUS2004/027595 - 66 Scheme 3 O-7 N -- 78c HO N l- ciR1 Li N C RNH2 H N F-- NaHCO 11 ii1 H 3 0+ N 1112 N F 1 12 13 -EE35iH7K~ reflux RNH2 IPEA microwave Ri /_RI HO R1 N N O RNH2 O IPEA 16 N microwave N F N NH R 15 R 14 5 Compounds of Formula I where X = N, can be prepared by reaction of a 2-fluoro-nicotinic acid chloride 11, for example, with an amine to afford the amide 12 which can then be lithiated, quenched (such as with DMF), and cyclized under acidic conditions to give the 6-aza-7-fluoro-3 10 hydroxy-oxindole 13. The 6-aza-7-fluoro-3-hydroxy-oxindole 13 can be reacted with an amine to give the 7-amino-6-aza-3 hydroxy-oxindole 14 or the 6-aza-7-fluoro-3-hydroxy-oxindole can be reacted with triethylsilane then reacted with an amine to afford the 7-amino-6-aza-oxindole 16. 15 WO 2005/021532 PCTIUS2004/027595 - 67 Scheme 4 01 OHO Clio O HN N(OPr) 2 N i N N(-- PrPr)) F 1. LDA, -78 0 C -N( N F 1. R:-NH 2 .7- 2 - -:- - 2. NaHB(OAc) 3 N -F 19 R 7DIEA N H' EtOH:HC1 R o O reflux N(IsoPr) 2 R N 16 20 R 5 The 7 -amino-6-aza-oxindole 16 can also be prepared by lithiation of 2 -fluoro-N,N-diisopropylnicotinamide 17 followed by quenching, such as with DMF, to give the 4 formyl- 2 -fluoro-N,N-diisopropylnicotinamide 18. The 4formyl- 2 -fluoro-N,N-diisopropylnicotinamide can be reacted 10 with an amine to give the 4 -aminomethyl-2-fluoro-N,N diisopropylnicotinamide 19 which can be reacted with another amine then cyclized under acidic conditions to afford the 7 amino-6-aza-oxindole 16. 15 WO 2005/021532 PCTIUS2004/027595 - 68 Scheme 5 O O (Xrb ref lux OH (COC24 2 2 O rDfF(catalytic) O
N
2 ONO2
NO
2 0 23 21 -- 22 MengBr - 80C Br O CuCN 78o Br O Br NH Et 3 SiH, TFA, Br' 0 NO O ap N 2 6rfu reflux 010260
ONO
2 N0 2 0 25 24 reflux
R-NH
2 HO R3 R 14 H2, Pd/C o RT 27 NO 2 2 30 NaBH 4 R 7 CHO NiCl-6H 2 0 R7CHO N~aBH (OAc ) 3. ClCH 2
CH
2 Cl HO R1 HO ,R 1 HO RI R 7 CHO N ,RR NaBH (OAc) 3 NR7 ClCH2CH2Cl NH2 N"R7 29 28 H 31 5 3-Substituted oxindoles can be prepared from 7 nitrophthalic anhydride 21, for example, which can be reacted with MeOH to give the 3 -nitro-phthalic acid-2-methyl ester 22 by known procedures. The 3 -nitro-phthalic acid-2 methyl ester 22 is converted to the corresponding acid 10 chloride 23 then reacted with a methyl Grignard reagent to afford the methyl-ketone 24. The methyl-ketone 24 can be converted to the bromo-ketone 25 and cyclized to the 3 bromomethyl-7-nitro-3H-isobenzofuran-l-one 26 which can be reacted with an amine to afford the 3 -hydroxy-3-methyl-7 15 nitro-oxindole 27. The 3 -hydroxy-3-methyl-7-nitro-oxindole WO 2005/021532 PCT/US2004/027595 - 69 27 can be reduced to the corresponding 7-amino-3-hydroxy-3 methyl-oxindole 28 which can then be alkylated by reductive amination to give compound 29. Alternatively, the 3 hydroxy-3-methyl-7-nitro-oxindole 27 can be reduced to the 5 - 7 -amino-3-methyl-oxindole 30 undei- standard hydrogenation conditions and alkylated by reductive aniinition to give compound 31. Scheme 6 10 RR
CO
2 H O N N
SCO
2 H R'-NH 2
H
2 /Pd/C 150 OC NO2 RT NH2 2 1,2-di-cl-ph 33 32 21
R
7 -CHO NaBH(OAc) 3 , RT O R 1 N 0 NH 34 R7 Substituted isoindole-1,3-diones 34 (e.g. 7-amino isoindole-1,3-diones) can be prepared by reaction of 3 15 nitro-phthalic acid 32 with an amine at high temperature to give the 7-nitro-isoindole-1,3-diones 21 which can be reduced to the 7 -amino-isoindole-1,3-diones 33 under standard hydrogenation conditions and alkylated under standard reductive amination conditions such as with an 20 aldehyde to give isoindole-1,3-diones 34.
WO 2005/021532 PCTIUS2004/027595 - 70 Scheme 7
R
1 N I N if L = SCH3 NN [01 0 -~ - 1. NaS-t-Bu,-DMF 2. NaH, R 2 Br S_ S(0)1_2 R 41 42 5 Compounds of Formula I can be prepared by the procedure described in Scheme 8 wherein Y is S, SO or S02, and L is SMe, similar to that described by A. Pinchart, et al., Tetrahedron Letters, 40:5479-5482 (1999). The thio derivatives 16 (L = SMe) are reacted, after deprotection, 10 with a suitable bromide and standard alkylation conditions, such as with base and substituted halides to form the oxindole 41. The thiol can be oxidized to the sulfone or sulfoxide 42. 15 The starting compounds defined in Schemes 1-7 may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt forming group is present and the reaction in salt form is possible. If so desired, one compound of Formula I can be 20 converted into another compound of Formula I or a N-oxide thereof; a compound of Formula I can be converted into a salt; a salt of a compound of Formula I can be converted into the free compound or another salt; and/or a mixture of isomeric compounds of Formula I can be separated into the 25 individual isomers. N-Oxides can be obtained in a known matter by reacting a compound of Formula I with hydrogen peroxide, oxone, or a peracid, e.g. 3 -chloroperoxy-benzoic acid, in an inert solvent, e.g. dichloromethane, or a mixture of water and an WO 2005/021532 PCTIUS2004/027595 - 71 alcohol such as MeOH or EtOH, at a temperature between about -10 to 35 'C, such as about 0 C to RT. If one or more other functional groups, for example carboxy, hydroxy, amino, or mercapto, are or need to be 5--protected--in a compounrT Formula I or in the preparation - cO od orlI~ use they should not take part in-the reaction, these are such groups as are usually used in the synthesis of peptide compounds, and also of cephalosporins and penicil-1-ins; as well as nucleic acid 10 derivatives and sugars. The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, 15 solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to 20 physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and hereinafter. The protection of such functional groups by such 25 protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference works, such as J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in T.W. Greene, Protective Groups in Organic 30 Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, eds. E. Gross and J. Meienhofer, Academic Press, London and New York (1981), in Methoden der organischen Chemie (Methods of Organic Chemistry), Houben Weyl, 4 th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart (1974), in H-D.
WO 2005/021532 PCTIUS2004/027595 - 72 Jakubke and H. Jescheit, Aminosauren, Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide und Derivate 5 (Chemistry 6f~Car5hydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart (1974). In the additional process steps, carried out as desired, functional groups of the starting compounds which shoul-d-not--ta-ke- parti-ir-the r-c-t-daffifbEe present in 10 unp"atected form or may be protected, for example, by one or more of the protecting groups mentioned above under _"protW-tinggroupEi"~. The protecting groups are then wholly or partly removed according to one of the methods described there. 15 Salts of a compound of Formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of Formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. A salt with two acid molecules (for 20 example a dihalogenide of a compound of Formula I) may also be converted into a salt with one acid molecule per compound (for example, a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from 130 to 170 25 *C, one molecule of the acid being expelled per molecule of a compound of Formula I. Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, 30 or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide. All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the WO 2005/021532 PCTIUS2004/027595 - 73 presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically 5 -cation-exchangers, for example in the H* form, depending on -the-t-ype---o-f-reaction -and/or reactants at reduced, normal, or el-eyated -temperature-,- for-examp-l-e-in- -the- range from about -1-=C-9-0-C1 C--preferably-from-about --80 0 C to about -50-C--~f-o^ e5 eat -aoe-8 -QC- to-about-60-C, -at RT, at 10 about -20 "C to about 40 *C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen. Salts may be present in all starting compounds and 15 transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed. In certain cases, typically in hydrogenation processes, it is possible to achieve stereoselective 20 reactions, allowing, for example, recovery of individual isomers. The solvents from which those can be selected which are suitable for the reaction in question include, for example, water, esters, typically lower alkyl-lower 25 alkanoates, e.g., EtOAc, ethers, typically aliphatic ethers, e.g., Et 2 0, or cyclic ethers, e.g., THF, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically MeOH, EtOH or 1-propanol, IPOH, nitriles, typically
CH
3 CN, halogenated hydrocarbons, typically
CH
2 Cl 2 , 30 acid amides, typically DMF, bases, typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g., AcOH, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g., acetic anhydride, cyclic, linear, or branched hydrocarbons, WO 2005/021532 PCTIUS2004/027595 - 74 typically cyclohexane, hexane, 'or isopentane, or mixtures of these solvents, e.g., aqueous solutions, unless otherwise stated in the description of the process. Such solvent mixtures may also be used in processing, for example in 5-chromatigraphy. The-invent-i-or-rejates also to those forms of the process -in -whi-ch -one-star-ts- -f-rom-a-compound- obtainable at -any-stage- as -a--tr-ans-ien-t-and-c-a-rri-es-out-the--mi-ss ing steps, -e-r-breaks- o-f-f-the-processatany--s-t-age.,_or-forms.- a starting 10 material under the reaction conditions, or uses said starting material in the form of a reactive derivative or - salt-or produces a compound obtainable by means of the process according to the invention and processes the said compound in situ. In the preferred embodiment, one starts 15 from those starting materials which lead to the compounds described above as preferred. The compounds of Formula I, including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization 20 (present as solvates). New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In the preferred embodiment, such starting materials are used and reaction conditions so 25 selected as to enable the preferred compounds to be obtained. Starting materials of the invention, are known, are commercially available, or can be synthesized in analogy to or according to methods that are known in the art. 30 In the preparation of starting materials, existing functional groups which do not participate in the reaction should, if necessary, be protected. Preferred protecting groups, their introduction and their removal are described above or in the examples.
WO 2005/021532 PCTIUS2004/027595 - 75 All remaining starting materials are known, capable of being prepared- according to know~ pifodesses, or commercially obtainable; in particular, they can be prepared using processes as described in the examples. 5- Compounds of he present invention can possess, in genera, one or more asymmetric carbon atoms and are thus -capabe- of-- ex-isting in--the- form -of optical isomers as well -a-as--irnthe-formt-of racemic-a mixtures~ thereof. -The-opti-cal--gomers can-be-.obtained-by resolution of the 10 racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then 15 separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the 20 separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.- The synthesized diastereoisomers can be 25 separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using optically active starting 30 materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.. The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, scalemic mixtures, single enantiomers, WO 2005/021532 PCTIUS2004/027595 - 76 individual diastereomers and diastereomeric mixtures. All such isomeric forms- of -these -compounds are expressly included in the present invention. The compounds of this invention may also be -5-----epresented in multiple tautomeric forms, for example, as 10 The invention expressly includes all tautomeric forms of the compounds described herein. The compounds may also occur in cis- or trans- or E or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present 15 invention. All crystal forms of the compounds described herein are expressly included in the present invention. Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn 20 unattached to a specific atom, whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen). The compounds of this invention may contain heterocyclic ring systems attached to another ring system. 25 Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system. Alternatively, a compound of any of the formulas delineated herein may be synthesized according to any of the processes delineated herein. In the processes delineated 30 herein, the steps may be performed in an alternate order and may be preceded, or followed, by additional protection/ WO 2005/021532 PCTIUS2004/027595 - 77 deprotection steps as necessary. The processes may further comprise use of appropriate reaction conditions, including inert solvents, additional-reagents, such as bases (e.g., LDA, DIEA, pyridine, K 2 C0 3 , and the like), catalysts, and 5 sal-ttformdof the above. The intermediates may be isolated r or without- purification. Purification-methods-are- known in the -art-and include, for -examp-1-e crys-ta-lliz-ati-on, chromatography (liquid and gas -phase-and--the-1-i-ke)--Xtrla-tiof,~~-disti.lation,-.tr-ituration, 10 reverse phase HPLC and the like. Reaction conditions such as temperature, duration, pressure, and atmosphere (inert gas7 Inbi-ent)~ aie-knowni in the art and may be adjusted as appropriate for the reaction. As can be appreciated by the skilled artisan, the 15 above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various 20 synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the inhibitor compounds described herein are 25 known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); L. Fieser and M. 30 Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2 nd edition. (2001); M. Bodanszky, A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne: WO 2005/021532 PCTIUS2004/027595 - 78 Reductions by the Alumino- and Borohydrides in Organic -Synthesis, 2 "d edition, -Wiley=VCH-1997); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). 5(The---ompounds-offhlisiinvention may be modified by - wp--ei-ng-- appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase- bi-ological penetration into a- given biological compartment (e.g., blood, lymphatic 10 system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. The following examples contain detailed descriptions of the methods of preparation of compounds of Formula I. 15 These detailed descriptions fall within the scope, and serve to exemplify, the above-described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the 20 invention. Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents such as DMF, THF, CH 2 Cl 2 and toluene were obtained from the Aldrich Chemical Company. All reactions 25 involving air- or moisture-sensitive compounds were performed under a nitrogen atmosphere. Flash chromatography was performed using Aldrich Chemical Company silica gel (200-400 mesh, 60A) or Biotage pre-packed column. Thin layer chromatography (TLC) was performed with Analtech gel 30 TLC plates (250 i). Preparative TLC was performed with Analtech silica gel plates (1000-2000 i). Preparative HPLC was conducted on a Beckman or Waters HPLC system with 0.1%
TFA/H
2 0 and 0.1% TFA/CH 3 CN as mobile phase. The flow rate was at 20 mL/min. and gradient method was used. All WO 2005/021532 PCTIUS2004/027595 - 79 examples were purified to > 90% purity as determined by -high-performance liquid chromatography. All compounds showed NMR spectra consistent with their assigned structures. Unless otherwise indicated all 1 H NMR spectra 5-wre run-an-rhker 400 MHz instrument. Mass spectral data -was-detaiTicTby eJ.Erosprayionization technique. Mass -spectra- (MS)- were determined on a Perkin Elmer -~ SCIEX API - -16-5=eleet-re-spr-ay-mass--spectrome-ter(po-s-i-tive~-aid/or -negativet--or--anHP-IOL1]SD~TCI-MSIWi~th-ei lectrospray 10 ionization and quadrupole detection. Microwave synthesis was performed in a Personal Chemistry7 Smith Synthesizer.. ~r - ar-tTre by weight, reactions were run at RT and temperatures are in Degrees centigrade unless otherwise indicated. 15 The following abbreviations are used: AcOH, HOAc- acetic acid AIBN - 2 ,2-azobisisobutyronitrile atm- atmosphere 20 CH 3 CN - acetonitrile ATP - adenosine triphosphate
NH
4 Cl - ammonium chloride
NH
4 0H - ammonium hydroxide BINAP - 2,2'-bis (diphenylphosphino) -1,1 'binaphthyl 25 BH 3 - borane BSA - bovine serum albumin n-BuLi - N-butyllithium
CC
4 - carbon tetrachloride CeCO 3 - cesium carbonate 30 TMSCl - 4 -chlorotrimethylsilane DDQ - 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone
CH
2 C1 2 - dichloromethane WO 2005/021532 PCTIUS2004/027595 - 80 DEA diethylamine DIEA - - di-isopropylethylamine DIAD diisopropyl azodicarboxylate EDC - 1- ( 3 -dimethylaminopropyl) -3
--
~~ thglcarbodiimide hydrochloride DEF ~ imethylformamide IDMSO =-------dimethy--su1-f oxide --- 1DPPA-- diphenl-phspry--azide -- d-pp- -1jeyl- -op-exph-no~-flexro-cene 10 DMAP dimethylaminopyridine DEAD diethylazidocarboxylate - DTT----- - dithiothreitol EtOH ethanol EtOAc ethyl acetate 15 Et 2 O ethyl ether eq equivalent FeSO 4
-
ferric sulfate g - gram h - hour 20 HBr hydrobromic acid HCl hydrochloric acid
H
2
-
hydrogen HOBt hydroxybenzotriazole iPrOH isopropanol 25 LAH lithium aluminum hydride LDA lithium diisopropylamide LiOH lithium hydroxide m-CPBA m-chloroperbenzoic acid MgSO 4 - magnesium sulfate 30 MnCl 2
-
manganese chloride MeOH methanol Ph 3
P*CH
2 OMeCl - (methoxymethyl) -triphenylphosphonium chloride Mel methyl iodide WO 2005/021532 PCTIUS2004/027595 - 81 NMO - 4-methylmorpholine N-oxide
CH
3
NH
2 - methylamine
HNO
3 - nitric acid mg - milligram 5 mL - milliliter min - minutes NBS - N-bromosuccinimide NiCl 2 - nickel chloride
N
2 - nitrogen 10 Pd/C- palladium on carbon Pd(OAc) 2 - palladium acetate Pd(PPh 3
)
4 - palladium tetrakis triphenylphosphine Pd 2 (dba)3 - tris(dibenzylideneacetone)di-palladium POCl 3 - phosphoryl chloride 15 PCl 5 - phosphorous pentachloride
P
2 0 5 - phosphorous pentoxide PBr 3 - phosphorous tribromide Pt/C - platinum on carbon
K
2 C0 3 - potassium carbonate 20 KNO 3 - potassium nitrate t-BuOK - potassium t-butoxide psi - pounds per square inch RT - room temperature NaOAc - sodium acetate 25 NaN 3 - sodium azide NaHCO 3 - sodium bicarbonate NaBH 4 - sodium borohydride Na 2
CO
3 - sodium carbonate NaCl - sodium chloride 30 NaCN - sodium cyanide NaCNBH 3 - sodium cyanoborohydride Na 2 Cr 2
O
2 - sodium dichromate NaH - sodium hydride NaOH - sodium hydroxide WO 2005/021532 PCTIUS2004/027595 - 82 NaI - sodium iodide NaNO 3 - sodium nitrate Na 2
SO
4 - sodium sulfate NaOt-Bu - sodium t-butoxide 5 NaHB(OAc) 3 - Vdoi~5zETicetoxyborohydride -HSOc - - -- sdlfuric ~adid Bu 4 NBr te-trabutyl anmoni-um bromide Bu 4 NI - - - tet-r-abutyl-ammon-ium-iodide -t-BuOH- -t-_euyllxglio-l__ 10 t-BuOMe, MTBE - tert-butylmethylether Boc - tert-butyloxycarbonyl THF - ~ ~ tetrahydrofuran TPAP - tetrapropylammonium perruthenate SOCl 2 - thionyl chloride 15 TEA, Et 3 N - triethylamine TFA - trifluoroacetic acid PPh 3 - triphenylphosphine
H
2 0 - water PS-TsNHNH 2 - polystyrene tosyl hydrazine 20 Zn - zinc Preparation 1. methyl 2-methyl-6-nitro-benzoate To a solution of 2-methyl-6-nitro-benzoic acid (5.6 g, 30.9 mmol, 1.0 eq, Aldrich) and acetone (100 mL) was added 25 crushed K 2 C0 3 (21.4 g, 154.6 mmol, 5 eq) and Mel (9.6 mL, 154.6 mmol, 5.0 eq). The reaction was heated to reflux for 15 h then cooled to RT, filtered and concentrated in vacuo. The filtrate was dissolved in EtOAc, washed with H 2 0 and brine, dried (MgSO 4 ) and concentrated in vacuo to give the 30 desired compound as a reddish-brown oil which upon standing at RT crystallized to tan needles.
WO 2005/021532 PCTIUS2004/027595 - 83 Preparation 2. methyl 2 -bromomethyl-6-nitro-benzoate To a solution of methyl 2 -methyl-6-nitro-benzoate (21 g, 108 mmol) and CCl 4 (200 mL) was added NBS (3 g, 17 mmol) and AIBN (1 g, 6 mmol).- The reaction was heated to reflux. 5 Each h afterward, 3 g of NBS and 1 g of AIBN was added until a total of 22.2 g of NBS and 6.3 g of AIBN had been added. The reaction was stirred for a total of 18 h. The mixture was cooled and filtered to remove white precipitate. The filtrate was concentrated in vacuo and extracted with EtOAc. 10 The organic layer was washed with H 2 0 and brine (3x each), dried (MgSO 4 ) and concentrated in vacuo to give the crude material as an orange oil. After 2 days at 20 *C the crude compound crystallized. The crystals were washed with Et 2 0 and filtered to give the desired bromide. The filtrate was 15 concentrated in vacuo without heat to half-volume whereupon a yellow precipitate formed which was filtered to afford additional bromide. Preparation 3. 2-( 4 -tert-butyl-phenyl)
-
7 -nitro-2, 3-dihydro 20 isoindol-1-one. To a solution of methyl 2-bromomethyl-6-nitro-benzoate (0.73 mmol, 1 eq.) and t-BuOH (3 mL) in a sealed reaction vial was added 4 -t-butylaniline (0.73 mmol, 1 eq) and DIEA (0.38 mL, 3 eg). The reaction was stirred at RT for 30 min 25 then heated at 170 *C for 10 min in a microwave. A yellow solid was filtered and washed with t-BuOH and H 2 0 then dried under high-vacuum to afford 2-( 4 -tert-butyl-phenyl)-7-nitro 2 ,3-dihydro-isoindol-1-one. MS m/e 311 (M+H)*. 30 Preparation 4. quinolin-6-yl-methanol Following the procedure described by C. Kaslow and W. Clark, JOC 18:55 (1953), to a stirred solution of quinoline 6-carboxylic acid methyl ester (10 g, 53 mmol) in THF (200 mL) at 0 *C was added LiAlH 4 (1.3 g, 14.9 mmol) by small WO 2005/021532 PCTIUS2004/027595 - 84 portion. The resulting mixture was stirred at 0 *C for 2 h and at RT for 3 h. Acetone (10 mL) was added followed by MgSO 4 x 10H 2 0. The resulting mixture was stirred for 1.5 h at RT and filtered over a silica pad. Solvents were removed 5 to give quinolin-6-yl-methanol. Preparation 5. quinoline-6-carbaldehyde To a stirred solution of quinolin-6-yl-methanol '(1.14 g, 7.16 mmol) in CH 2 C1 2 (100 mL) at 0 *C were added N 10 methylmorpholine N-oxide (1.25 g, 10.7 mmol), 4 A molecular sieves (500 mg) and TPAP (60 mg). The mixture was stirred at RT until the starting material was consumed, then filtered through a Celite" pad. Solvent was evaporated to give the aldehyde. 15 Preparation 6. 1-(2-methoxy-1,1-dimethyl-ethyl)-4-nitro benzene To a stirred solution of 2 -methyl-2-(4-nitro-phenyl) propan-1-ol (prepared by the method described in W002/66470) 20 (200 mg, 1 nmol) in THF (15 mL) was added NaH (43 mg, 60% in oil) at 0 C. The mixture was stirred at 0 *C for 20 min, MeI (0.22 mL, 1.5 mmol) was added and the mixture was stirred for 2 h at 0 *C then overnight at RT. H 2 0 was added and the mixture was extracted with EtOAc. The organic phase 25 was dried, filtered and evaporated to give 1-(2-methoxy-1,1 dimethyl-ethyl)- 4 -nitro-benzene. Preparation 7. 4- (2-methoxy-,1-dimethyl-ethyl) -phenylamine 1-(2-Methoxy-1,1-dimethyl-ethyl)-4 -nitro-benzene (1 30 eq) was dissolved in THF (40 mL/mmol) at 0 'C and HOAc (20 eq) was added, followed by Zn dust (30 eq). The mixture was stirred at RT until the starting material was consumed and was filtered on silica pad. Solvent was evaporated, the WO 2005/021532 PCTIUS2004/027595 - 85 residue was dissolved in CH 2 Cl 2 and washed with NaOH 1M. The organic phase was dried, filtered and evaporated to give the amine. 5- -Parati 5n-8 .~2-bom--6y-me tyl~-benzoic acid methyl ester ~~ Taid (495 g) and K 2 C0 3 (16.26 -g) -were-suspended- in- acetone -(150 mL) . MeI (7.5 mLY as -added--and-the- -tfixture-wag -heated-a flu-ci-3 5 h. The --sol-dwa-s-renroved-by-f-itrati-n d-the ilt-ra twas 10 concentrated. The residue was taken into EtOAc and washed with saturated NH 4 Cl, H 2 0 and saturated NaCl. The organic hnsewas dried over MgSO 4 , filtered, and concentrated to yield 2-bromo-6-methyl-benzoic acid methyl ester as an orange oil. 15 Preparation 9. 2-bromo-6-bromomethyl-benzoic acid methyl ester 2-Bromo-6-methyl-benzoic acid methyl ester (2.18 g), NBS (4.89 g), and AIBN (0.486 g) were taken into CCl 4 (15 20 mL) and heated at reflux for 8 h. After cooling to RT, the solid was removed by filtration, and the filtrate was concentrated to give an orange oil as crude material. Purification by chromatography (silica gel, 100 g, 5-15% EtOAc/hexanes) afforded 2-bromo-6-bromomethyl-benzoic acid 25 methyl ester as colorless oil. Preparation 10. 7-bromo-2- (4-t-butyl-phenyl) -2, 3-dihydro isoindol-1-one 2-Bromo-6-bromomethyl-benzoic acid methyl ester (214 30 mg) and 4-t-butylaniline (93 mg) were put into a microwave reaction vial along with 2 mL of iPrOH. The reaction was subjected to 170 *C, 5 min of microwave. The solvent was evaporated and the residue was purified by silica gel chromatography (25 g, 10 - 20% EtOAc/hexanes) to afford 7- WO 2005/021532 PCTIUS2004/027595 - 86 bromo-2-(4-t-butyl-phenyl)-2,3-dihydro-isoindol-1-one as a white powder. Preparation 11. 2-bromomethyl-6-hydroxy-benzoic acid ethyl 57 seter 2-Hydroxy-6-methyl-benzoic acid ethyl ester (4.046 g), ------ N-BS--(-4--786 g)--and-AIBN-(I--3-4-g-)-were weighed into a round bottom-f-l-as-k-equ±pped--with--a--reflux condenser. CCl 4 (40 mL) -was-added and-the-mixture was heated-at-reflux-for 2 h. 10 After cooling to RT, solid was removed by filtration and the filtrate was concentrated to give a yellow oil as crude, which solidified upon standing. The crude was purified by silica gel chromatography (300 g, 0-5% EtOAc/hexanes) to afford 2-bromomethyl-6-hydroxy-benzoic acid ethyl ester as a 15 white solid. Preparation 12. 2-(4-t-butyl-phenyl)-7-hydroxy-2,3-dihydro isoindol-l-one 2-Bromomethyl-6-hydroxy-benzoic acid ethyl ester 20 (2.005 g), and 4-t-butylaniline (1.616 g) were put into 4 microwave reaction tubes along with 4.2 mL of iPrOH in each tube. The tubes were subjected to 170 *C, 10 min of microwave. The resulting precipitate was collected via filtration and washed with iPrOH to obtain 2-(4-t-butyl 25 phenyl)-7-hydroxy-2,3-dihydro-isoindol-1-one as a white solid. Preparation 13. (S)-4-(1-azido-ethyl)-pyridine (R)-l-Pyridin-4-yl-ethanol (0.160 g) was dissolved in 30 THF (10 mL) and cooled to 0 'C. nBuLi (2.5 M in hexanes, 0.52 mL) was added slowly and the reaction was stirred at 0 'C for 5 min. Toluenesulfonyl chloride (0.250 g) was added and the stirring was continued for 30 min. NaN 3 (0.30 g) was added, the reaction was warmed to RT and stirred WO 2005/021532 PCTIUS2004/027595 - 87 overnight. The mixture was added to H 2 0 and the layers were separated. The aqueous layer was extracted with Et 2 0 and the combined organic phases were dried over Na 2
SO
4 , filtered and evaporated in vacuo to yield a yellow oil. This crude materials was~puri ied by silica gel chromatography (30 g, 33 to-75% Et2OT/hfes wT 1% Et 3 N) to afford (S) -4- (1-azido ethy-1--pyrid-ine -as- a--clear-oil-; -Prpa ak L i--4---S--pr -- 4yT-thyl anfine . 10 (S)-4- (1-Azido-ethyl)-pyridine (0.170 g) and 10% Pd/C (0.052 g) were mixed in EtOAc (10 mL) and stirred at RT inder balloon pressure of H 2 for 3 h. Catalyst was removed by filtration through a pad of Celite. The filtrate was concentrated to give a pale yellow oil. The crude was 15 purified by silica gel chromatography (30 g, 1-10% MeOH/
CH
2 Cl 2 ) to afford (S)-pyridin-4-yl-ethylamine as a pale yellow oil. Preparation 15. 5-nitro-2-tert-butylaniline 20 Concentrated H 2
SO
4 (1 L) was cooled to -10 'C with a dry ice-iPrOH bath in a 2L 3-neck round bottom flask fitted with a mechanical stirrer and temperature probe. 2-t Butylaniline (109 g, 730 mmol) was added, giving a clumpy solid. Once the temperature of the mixture was stabilized 25 at -10 'C, KNO 3 (101 g, 1001 mmol) was added portion wise, as the solid, over 4 h, maintaining the temperature between -20 and -5 *C. Once all of the KNO 3 was added, the reaction was stirred overnight with gradual warming to RT. The reaction was quenched by diluting with water then extracted 30 with EtOAc (3x). The EtOAc extracts were washed multiple times with saturated NaHCO 3 (aq), until gas evolution ceased, then with brine. The EtOAc extracts were combined, dried over anhydrous Na 2
SO
4 , filtered and concentrated under reduced pressure giving a black oil. The oil was eluted WO 2005/021532 PCTIUS2004/027595 - 88 through a 36 x 7 cm column of silica gel with a 5%; 10%; 15%; 25%; and 50% EtOAc:Hexanes step gradient (2 L each step) giving a red solid. 5 Preparation 16. 2-bromo-N- (2-tert-butyl-5-nitro-phenyl) ac~tafi~de~~ ----- 5--N-i tro-2 --te-rt--buty-l-ani-line- t7-0,---359-mrio r) aud-a -- -ea-t-a--yt-i-c-amount-of--DMP-were-d-ssnl-ve-d-in' THF~(I 5 L)~~under -- Na._Et N (109g1dand he solution was 10 cooled to 0 *C. Bromoacetyl bromide (207 g, 1023 mmol) was added and the reaction was gradually warmed to RT with stirring overnight. The reaction was partially concentrated under reduced pressure, then treated with H 2 0 and extracted with EtOAc (3x). The EtOAc extracts were washed with brine, 15 combined, dried over anhydrous Na 2
SO
4 , filtered and concentrated under reduced pressure giving a black oil. This oil was eluted through a 38 x 7 cm column of silica gel with 95:5:0.5 CH 2 Cl 2 :MeOH:NH 4 0Haq) eluant giving a brown solid. 20 Preparation 17. N, (5-nitro-2-tert-butylpheny) -2-piperidin-1 yl-acetamide: 2-Bromo-N- (2-tert-butyl-5-nitro-phenyl) -acetainide (2.58 g, 8.2 mmol) and K 2
CO
3 (2.27 g, 16.4 mmol) were 25 combined in a round bottom flask under N 2 . THF (100 mL) was added and the mixture cooled to 0 *C under N 2 . Piperidine (1.05 g, 12.3 mmol) was added to the mixture and the mixture was gradually warmed to RT with stirring overnight. The reaction was quenched by filtering it under vacuum and 30 concentrating the filtrate under reduced pressure. The recovered material was eluted through a column of silica gel with a 5 to 50% EtOAc:Hexanes linear gradient giving a brown solid. 35 WO 2005/021532 PCTIUS2004/027595 - 89 Preparation 18. N- (5-nitro-2-tert-butylphenyl) -2-morpholin 4 -yl-acetamide N- (5-Nitro-2- tert-butylphenyl) -2-morpholin-4-yl acetamide was prepared similar to that described in 5~~--~Pfejt5ration 1~7,substituting morpholine for piperidine, -- tvtili a tan soridr Preparation 19. N- (5-amino--2- tert-butylphenyl) -2-piperidin -- =laetamide: : __ 10 N- (5-Nitro-2-tert-butylpheny) -2-piperidin-1-yl acetamide (1.77 g, 5.5 mmol) was dissolved in EtOH (100 mL) -and~4 -dioxane~ (10 mL). The solution was degassed under vacuum with stirring. A catalytic amount of 5% Pd/C was added (as a slurry in EtOH). The mixture was degassed 15 again, then the reaction vessel was charged with H 2 gas (balloon) and stirred overnight at RT. The reaction was filtered through Celite* with MeOH and the filtrate was concentrated under reduced pressure. The recovered material was eluted through a column-of silica gel with a 5 to 40% 20 (90:10:1 CH2Cl 2 :MeOH:NH 4 0Haq)) to CH 2 C1 2 linear gradient giving a brown foamy solid. MS: 290 (M+I). Calc'd. for
C
17
H
2 7
N
3 0 - 289.42. Preparation 20. N- (5-amino-2-ter t-butylphenyl) -2-morpholin 25 4-yl-acetamide N-(5-Amino-2-tert-butylphenyl)-2-morpholin-4-yl acetamide was prepared similarly to that described in Preparation 19, substituting N-(5-nitro-2-tert-butylphenyl) 2 -morpholin-4-yl-acetamide for N- (5-nitro-2-tert 30 butylpheny)-2-piperidin-1-yl-acetamide, giving a brown solid. MS: 292 (M+1) . Calc'd. for C 16
H
25
N
3 0 2 - 291.39.
WO 2005/021532 PCT/US2004/027595 - 90 EXAMPLE I N N 5 2-(4-(1,1-Dimethylethyl)phenyl)-7-((4 pyridinylmethyl) amino) -2, 3-dihydro-1H-isoindol-1-one Step A: Preparation of 7-amino-2-(4-tert-butyl-phenyl)-2,3 dihydro-isoindol-1-one 10 A solution of 2- (4-tert-butyl-phenyl) -7-nitro-2,3 dihydro-isoindol-1-one (110 mg, 0.35 mmol) and EtOAc (50 mL) was hydrogenated over 10% Pd/C (80 mg) at 1 atm and RT. After 2.5 h, the mixture was filtered through Celite* and concentrated in vacuo to afford the desired amine as a 15 yellow solid. Step B: Preparation of 2- (4- (1,1-dimethylethyl)phenyl)-7 ((4-pyridinylmethyl) amino) -2, 3-dihydro-1H-isoindol-l-one To a solution of 7-amino-2-(4-tert-butyl-phenyl)-2,3 20 dihydro-isoindol-1-one (Step A, 99 mg, 0.35 mmol) and CH 2 Cl 2 (10 mL) was added 4-pyridylcarboxaldehyde (94 mg, 0.88 mmol) and NaBH(OAc) 3 . The reaction was stirred at RT. After 3 h, the reaction was quenched with H 2 0 and extracted with EtOAc. The organic layer was washed with H 2 0 and brine, dried 25 (MgSO 4 ) and concentrated in vacuo to give a yellow oil. Purification by silica gel flash chromatography (10-50% EtOAc:Hexanes) afforded the desired product as a light yellow oil which crystallized on standing at RT to give a WO 2005/021532 PCTIUS2004/027595 - 91 white solid. MS (ES+) : 372 (M+H)*. Calc'd for C 24
H
25
N
3 0 371.47. The following compounds (2-63) were prepared similar to the 5 method described in Example 1: Table 1 Ex. Structure Mol Mol MS Formula Weight (MH+) 2 F F FC OC 29
H
24
F
3
N
3 0 3 519.53 520.2 7 0 NN 7- [ (quinolin-6-ylmethyl) amino] -2- [3- (tetrahydro furan-3-yloxy) -5 trifluoromethyl-phenyl ]-2,3 dihydro-isoindol-1-one 3 NO 0
C
34
H
36
N
4 0 3 548.69 549.0 60 NH 4, 4-dimethyl-7-{1-oxo-7 [(quinolin-6-ylmethyl) amino] -1, 3-dihydro-isoindol 2-yl} -3, 4-dihydro-1H isoquinoline-2-carboxylic acid tert-butyl ester WO 2005/021532 PCTIUS2004/027595 - 92 4
C
2 sH 27
N
3 0 2 401.50 402.0 N O NH OMe- Nr 2- (4-tert-butyl-phenyl) -7 -- [ (2-methoxy-pyridin-4 ylmethyl) -amino -2, 3-dihydro isoindol-1-one 5
C
24
H
25
N
3 0 371.49 372.2 N NH K-N 2- (4-sec-butyl-phenyl) -7 [(pyridin-4-ylmethyl) -amino] 2, 3-dihydro-isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 93 6
C
25
H
2 5
FN
2 0 388.49 389.1 N K0 NH F 2- (4-sec-butyl-phenyl) -7- (4 fluoro-benzylamino) -2, 3 dihydro-isoindol-1-one 7 / C 28
H
27
N
3 0 421.55 422.2 N NH 'CN 2- (4-sec-butyl-phenyl) -7 [(quinolin-6-ylmethyl) amino] -2, 3-dihydro-isoindol 1-one WO 2005/021532 PCTIUS2004/027595 - 94 8
C
25
H
27
N
3 0 2 401.51 402.2 N NH N 2- (4-sec-butyl-phenyl) -7- [(2 methoxy-pyridin-4-ylmethyl) - -- ami-no]-2-3-d-ihydro-isoindol 1-one 9 OMe
C
29
H
29
N
3 0 2 451.57 452.1 N O NH 2- [4- (2-methoxy-1, 1-dimethyl ethyl) -phenyl] -7- [ (quinolin 6-ylmethyl) -amino] -2,3 dihydro-isoindol-1-one 10 OMe
C
25
H
27
N
3 0 2 401.51 402.1 N NN NH, 2- [4- (2-methoxy-1, 1-dimethyl ethyl) -phenyl] -7- [ (pyridin-4 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 95 11
C
3 oH 23
N
3 0 2 457.54 458.2 N N0 NH ' -- -N 2- (4-phenoxy'phenyl) -7 [ (quinolin-6-ylmethyl) amino]-2,3-dihydro-isoindol 1-one 12 /
C
26
H
21
N
3 0 2 407.48 408.2 N 0 NH N 2- (4-phenoxy-phenyl) -7 [(pyridin-4-ylmethyl) -amino] 2, 3-dihydro-isoindol-1-one 13
C
30
H
23
N
3 0 2 437.50 438.3 N O NH N 7- [ (2-methoxy-pyridin-4 ylmethyl) -amino] -2- (4 phenoxy-phenyl) -2,3 -dihydro isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 96 14 / C 28
H
27
N
3 0 421.5 422.0 N 0 N CO N N 2- (4-tert-butyl-phenyl) -7 [(quinolin-6-ylmethyl) amino] -2, 3-dihydro-isoindol 1-one 15 N c
C
35
H
33
N
7 0 567.7 567.2 NH H N jN N H 2-[4,4-dimethyl-2-(1H pyrrolo[2,3-b]pyridin-3 ylmethyl) -1,2,3, 4-tetrahydro isoquinolin-7-yl]-7-(1H pyrrolo[2,3-b]pyridin-3 ylamino) -2, 3-dihydro isoindol-1-one 16 N C 2 6
H
26
N
4 0 2 426.52 427.0 .. Ac N 'N 0 N H KN 2- (1-acetyl-3 , 3-dimethyl-2, 3 dihydro-1H-indol-6-yl) -7 [(pyridin-4-ylmethyl) -amino] 2, 3-dihydro-isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 97 17 TNH C 2 4
H
24
N
4 0 384.48 385.0 N N H KN 2- (3, 3-dimethy1-2, 3-dihydro 1H-indol-6-yl) -7- [ (pyridin-4 -y--methyl) -amino] -2 , 3-dihydro isoindol-1-one 18 CF 3 OY2i 3N30 383.37 384.0 N N N; N 7- [ (pyridin-4-ylmethyl) amino]-2-(4-trifluoromethyl phenyl) -2, 3-dihydro-isoindol 1-one 19 N9 P * - C 24
H
2 sN 3 0 371.48 372.0 N 0 N H KN 2- (3-tert-butyl-phenyl) -7 [(pyridin-4-ylmethyl) -amino] 2 ,3-dihydro-isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 98 20 / NH
C
25
H
26
N
4 0 398.51 399.0 - N O N N H 2-(4,4-dimethyl-1,2,3,4 tetrahydro-isoquinolin-7-yl) 7- [ (pyridin-4ylmethyl) amino] -2, 3-dihydro-isoindol 1-one 21
C
22
H
21
N
3 0 343.42 344.0 N r 0 N H KN 2-phenethyl-7- [ (pyridin-4 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one 22 OMe
C
23
H
23
N
3 0 2 373.45 374.0 N N H I 2- [2- (4-methoxy-phenyl) ethyl]-7-[(pyridin-4 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 99 23 Me /OMe
C
2 4
H
2 5
N
3 0 3 403.47 404.0
N
O N H - -- - N- 2- [2- (3, 4-dimethoxy-phenyl) - --- ethyl-] -7---[ (Pyridin--4 ylmethyl) -amino ]-2, 3-dihydro isoindol-l-one 24 Me
C
23
H
23
N
3 0 357.45 358.0 N N N H N 7- [ (pyridin-4-ylmethyl) amino] -2- (2-p-tolyl-ethyl) 25 2, 3-dihydro-isoindol-1-one 25 F C 22
H
20
FN
3 0 361.41 362.0 NI 0 N ,-N 2- [2- (2-fluoro-phenyl) ethyl] -7- [(pyridin-4 ylmethyl) -amino J-2, 3-dihydro isoindol-l-one WO 2005/021532 PCTIUS2004/027595 - 100 26 CI
C
2 2
H
2 0 ClN 3 0 377.87 378.0 N 0 N H 2- [2- (4-chloro-phenyl) -ethyl] -7- -E (pyridin-4 ylmethyl) -amino] -2, 3-dihydro isoindol -1-one 27 CI C 22
H
20 ClN 3 0 377.87 378.0 N 0~ H KI 2- [2- (2-chloro-phenyl) -thyl ] -7-j[ (pyr idi-n-4 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one 28 CI / Ci
C
22 HisC1 2
N
3 0 412.31 413.0 N N H KN 2-[2-(3,4-dichloro-phenyl) ethyl ]-7- [ (pyridin-4 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 101 29 /F
C
2 2
H
2 0
FN
3 0 361.41 362.0 N 0 J. -. N 2-[2-(3-fluQro-.1henyl) ethyl] -7- [ (pyridin-4 ylmethyl) -anini5-]23dihydro isoindol-1-one 30 N CF 3
C
22
H
20
FN
3 0 411.42 412.0 N N H KI 7- [ (pyridin-4-ylmethyl) amino]-2-[2-(3 tri fluoromethyl-phenyl) ethyl]-2,3-dihydro-isoindol 1-one 31 CI / C 2 2 Hi 9 C1 2
N
3 0 412 .31 413 .0 Cl N HN 2- [2- (2 , 4-dichloro-phenyl) ethyl]-7-[(pyridin-4 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 102 32 / C 26
H
2 6
N
4 0 410.51 411.0 N O NH NH 2-(ktertybrtyl_-rhenyl) -7 [(1H-pyrrolo[2,3-blpyridin-3 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one 33 C 20
H
24
N
2 0 308.42 309.0 N NH 2--(4-tert-butyl-phenyl) -7 ethylamino-2, 3-dihydro isoindol-1-one 34 a l -oC 3 2
H
3 5
N
5 0 3 537.65 538.0 N NH NH 4,4-dimethyl-7-{1-oxo-7-[ (13 pyrrolo [2, 3-b]pyridin-3 ylmethyl) -amino] -1, 3-dihydro isoindo1-2-yl}-3,4-dihydro 1H-isoquinoline-2 -carboxylic acid tert-butyl ester WO 2005/021532 PCTIUS2004/027595 - 103 35 w ~ NH C 2 7
H
2 7 NsO 437.54 438.0 N NH NH 2- (4,4-dimethyl-1,2,3,4 tetrahydro-isoquinolin-7-yl) 7- [lH-pyrrol [2,3-b]pyridin-3 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one 36 N
C
26
H
23
N
3 0 2 409.49 410.0 0 O NH N 2- (3-methoxy-benzyl) -7 [(quinolin-6-ylmethyl) amino] -2, 3-dihydro-isoindol 1-one 37 N C 22
H
21
N
3 0 2 359.43 360.0 NH N 2- (3-methoxy-benzyl) -7 [(pyridin-4-ylmethyl) -amino] 2, 3-dihydro-isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 104 38 F 3 C O C 25
H
27
F
3
N
2 0 4 476.50 477.0 N O NH 2- [3- (tetrahydro-furan-2 ylmethoxy) -5-trifluoromethyl phenyl] -7- (tetrahydro-pyran 4-ylamino) -2, 3-dihydro isoindol-1-one 39
F
3 C
C
26
H
22
F
4
N
2 0 3 486.47 487.0 N O NH F 7-(4-fluoro-benzylamino)-2 [3-(tetrahydro-furan-3 yloxy) -5-trifluoromethyl phenyl] -2, 3-dihydro-isoindol 1-one WO 2005/021532 PCTIUS2004/027595 - 105 40
F
3 C
C
25
H
22
F
3
N
3 0 3 469.47 470.0 N O 0 NH
N
7- [ (pyridin-4-ylmethyl) -amino ] -2- [ 3 - ( tetraiyT dlro furan-3-yloxy) -5 trifluromethyl-phenyl]-2,3 dihydro-isoindol-1-one 41
F
3 C
C
29
H
27
F
3
N
2
O
4 524.54 547.0 0 M+Na N 0 NH
K
0 7- [(2, 3-dihydro-benzofuran-5 ylmethyl) -amino] -2- [3 (tetrahydro-furan-2 ylmethoxy) -5-trifluromethyl phenyl] -2 , 3-dihydro-isoindol 1-one 42
C
27
H
24
F
4
N
2 0 3 500.50 523.0 M+Na WO 2005/021532 PCTIUS2004/027595 - 106 F 3 C / N O 0 NH F 7- (4-f luoro-benzylamino) -2 [3-(tetrahydro-furan-2 yliethoxy)~-5-tzifluromethyl phenyl] -2, 3-dihydro-isoindol 1-one 43
F
3 C
C
26
H
24
F
3
N
3 0 3 483.49 484.0 N NH N 7- [ (pyridin-4-ylmethyl) amino]-2-[3-(tetrahydro furan-2 -ylmethoxy) -5 trifluoromethyl-phenyl]-2,3 dihydro-isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 107 44 FF /s _ , F
C
2 2 Hj 8
F
3
N
3 0 3 429.40 430.0 N 0 N H N OsCH 3 7- [(2-methoxy-pyridin-4 ylmethyl) -amino] -2- (4 trifluoromethoxy-phenyl)-2,3 dihydro-isoindol-1-one 45 FF
OC
2 lH 6
F
3
N
3 0 2 399.38 400.0 N 0 NH 7- [ (pyridin-4-ylmethyl) amino ]-2- (4-trifluoromethoxy phenyl) -2, 3-dihydro-isoindol 1-one 46 N
C
21
H
23 Ns0 361.45 362.0 N N H 0 N N 'N 2-(5-tert-butyl-2H-pyrazol-3 yl) -7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol 1-one WO 2005/021532 PCT/US2004/027595 - 108 47 N
C
2 2
H
25
N
5 0 2 391.48 392.0 N H ' 0
CH
3 2- (5-tert-butyl 2H--pyrazol-3 yl) -7- [ (2-methoxy-pyridin-4 ylmethyl) -amino] -2, 3-dihydro isoindol-1-one F O<F C 25 HisF 3
N
3 0 2 449.42 450.0 F N N' H 7- [(quinolin-6-ylmethyl) amino]-2-(4-trifluoromethoxy phenyl) -2, 3-dihydro-isoindol 1-one 49 F F F C 2 lH 16
F
3
N
3 0 2 399.38 400.0 N 0 NH 7- [ (pyridin-4-ylmethyl) amino ]-2- (3-trifluoromethoxy phenyl) -2, 3-dihydro-isoindol 1-one WO 2005/021532 PCTIUS2004/027595 - 109 50 F O*F F
C
2 5 HiF 3
N
3 0 2 449.44 450.0 N 7- [ (quinolin-4-ylmethyl) amino] -2- (4-trifluromethoxy phenyl) -2, 3-dihydro-isoindol ~ 1-ori 51
C
2 3 HisN 4 0S 398.49 399.0 N N N 0 N H N 2- (4-phenyl-thiazol-2-yl) -7 [(pyridin-4-ylmethyl)-amino] 2, 3-dihydro-isoindol-1-one 52 NH C 31
H
37
N
5 0 2 511.67 512.0 N 0 N OG NH N N- (2-tert-butyl-5-{1-oxo-7 [(pyridin-4ylmethyl) -amino] 1, 3-dihydro-isoindol-2-yl) phenyl) -2 -piperdin-1-yl acetamide WO 2005/021532 PCTIUS2004/027595 -110 53 / NH C 35
H
3 9 N.90 2 561.73 562.0 N N 0 0 NH N- (2-tert-butyl-5-{l-xo7 [(quinolin-6-ylmethyl) amino] -1, 3-dihydro-isoindol. 2 -yl }-phenyl) -2 -piperdin-1 yl-acetarnide 54H N IH C 30
H
35
N
5 0 3 513.65 514.0 N 0 N NH0 N N- (2-tert-butyl-5-{1-oxo-7 [C(pyridin-4-ylmethyl) -amino] 1, 3-dihydro-isoindol-2-yl) phenyl) -2 -morpholin-4-yl acetamide WO 2005/021532 PCTIUS2004/027595 - 111 55 H
C
34
H
37
N
5 0 3 563.71 564.0 N 0 N 0- O N'H N-(2-tert-butyl-5-{1-oxo-7 [(quinolin-6--Ylmethyl) amino] -1, 3-dihydro-isoindol 2-yl} -phenyl) -2-morpholin-yl acetamide 56 N
C
21
H
19
N
3 0 329.40 330.2 N NH 'N 7- [ (pyridin-4-ylmethyl) amino] -2- (3-methylphenyl) 2, 3-dihydro-isoindol-1-one 57 a -CI N X/C 20 Hl 6 ClN 3 0 349.10' 350.2 N NH N 2- (3-chloro-phenyl) -7 [(pyridin-4-ylmethyl) -amino] 2, 3-dihydro-isoindol-1-one WO 2005/021532 PCT/US2004/027595 - 112 58 Ij
C
21 .Hl 9
N
3 0 329.15 330.2 N O NH -C, N 7- [ (pyridin-4-ylmethyl) amino] -2- (4-methylphenyl ) 2, 3-dihydro-isoindol-1-one 59 N F C22HisF3N30 39.4 381 F F NH NH , N 7- [ (pyridin-4-ylmethyl) amino] -2- (3-trifluoromethyl benzyl) -2, 3-dihydro-isoindol 1-one 60 F F F F C 22 Hi 6
F
5
N
3 0 433.12 434.1 F N 0 NH 2- (4-pentafluoroethyl phenyl) -7- [ (pyridin-4 ylmethyl)-amino]-2,3-dihydro isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 113 61 NH N-
C
28
H
33
N
5 0 2 471.26 472.2 N O NH N_ N-(2-tert-butyl-5-{1-oxo-7 [(pyridin-4-ylmethyl) -amino] 1, 3-dihydro-isoindol-2-yl} phenyl) -2 -dimethyl amino acetamide 62
C
33
H
33 NsO 3 547.65 548.0 N NI N 4, 4-dimethyl-7-{7 [([1,8]naphthryridin-4 ylmethylene) -amino] -1-oxo 1, 3-dihydro-isoindol-2-yl} 3, 4-dihydro-1H-isoquinoline 2-carboxylic acid tert-butyl ester WO 2005/021532 PCTIUS2004/027595 - 114 63 / C 2 4
H
24 ClN 3 0 405.92 406.0 N O NH tCI 1N 2- (4-tert-butyl-phenyl) -7 [(2-chloro-pyridin-4 ylmethyl) -amino -2, 3-dihydro isoindol-1-one EXAMPLE 64 NH N 0 NH 5 N 2-(4,4-Dimethyl-1,2,3,4-tetrahydro-isouinolin-7-y)-7 [(quinolin-6-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one 10 The title compound was prepared by treatment of 4,4 dimethyl-7- {1-oxo-7- [ (quinolin-6-ylmethyl) -amino] -1,3 dihydro-isoindol-2-yl) -3, 4-dihydro-1H-isoquinoline-2 carboxylic acid tert-butyl ester (Example 3) with TFA in
CH
2 C1 2 . MS (m/z) = 449.0 (M+H)* Calc'd for C 2 9H 2 8 N40: 448.5. 15 WO 2005/021532 PCT/US2004/027595 - 115 EXAMPLE 65 N 0 N 5 2- (4-t-Butylphenyl) -7- (2-pyridin-4-yl-vinyl) -2, 3-dihydro isoindol-1-one 7-Bromo-2- (4-t-butyl-phenyl) -2, 3-dihydro-isoindol-1 one (0.14 g), 4-vinylpyridine (0.55 mL), Pd(OAc) 2 (1.2 mg), 10 tri-o-tolylphosphine (27.3 mg), and 2 mL of Et 3 N were added into a microwave reaction tube and subjected to 120 *C, 10 min of microwave (2X) . H20 and CHCl were added and the layers were separated. The aqueous phase was extracted with CHCl 3 (3X) . The combined organic phases were washed with 15 H 2 0, dried over Na 2
SO
4 , filtered, then evaporated in vacuo to yield a light brown residue as crude product. The crude was purified by silica gel chromatography (25 g, 10-50% EtOAc/hexanes) to afford 2-(4-t-butylphenyl)-7-(2-pyridin-4 yl-vinyl)-2,3-dihydro-isoindol-1-one as an off-white solid: 20 MS: (ES+) 369(M+H). Calc'd. for C 25
H
24
N
2 0 - 368.47. Example 66 was prepared according to procedure set out in Example 65. 25 WO 2005/021532 PCT/US2004/027595 - 116 EXAMPLE 66 N 5 2- (4-tert-Butyl-phenyl) -7- (2-pyridin-2-yl-vinyl) -2,3 dihydro-isoindol-1-one MS: 369N[M~+HI]Calc'd for C 25
H
24
N
2 0 - 368.47. 10 EXAMPLE 67 N N 2-(4-t-Butyl-phenyl) -7- (2-pyridin-4-yl-ethyl)-2,3-dihydro 15 isoindol-1-one 2- (4-t-Butylphenyl) -7- (2-pyridin-4-yl-vinyl) -2,3 dihydro-isoindol-l-one (92 mg, Example 67) and 10% Pd/C (22 mg) were weighed into a flask. EtOH (7 mL) was added and 20 the mixture was stirred under balloon pressure of Hz at RT for 8.5 h. Catalyst was removed by filtration and the filtrate was concentrated to give a white solid as crude WO 2005/021532 PCT/US2004/027595 - 117 product. The crude was purified by silica gel chromatography (25 g, 10-50% EtOAc/hexanes) to afford 2-(4 t-butyl-phenyl) -7- (2-pyridin-4-yl-ethyl) -2, 3-dihydro isoindol-l-one as a white solid. NS: (ES+) 371(M+H). Calc'd. 5 for C 25
H
26
N
2 0 - 370.49. EXAMPLE 68 N O 0 N 10 2- (4- t-Butyl-phenyl) -7- (pyridin-4-ylmethoxy) -2, 3-dihydro isoindol-1-one 2- (4-t-Butyl-phenyl) -7-hydroxy-2, 3-dihydro-isoindol-1 15 one (0.201 g), 4-hydroxymethylpyridine (96 mg) and PPh 3 (0.212 g) were dissolved in THF (20 mL). DIAD (0.16 mL) was added and the mixture was stirred at RT for 2 h. Solvent was evaporated and the residue was purified by silica gel chromatography (70 g, 100% EtOAc) to afford 2-(4-t-butyl 20 phenyl) -7- (pyridin-4-ylmethoxy) -2, 3-dihydro-isoindol-1-one as a white solid. MS: (ES+) 373(M+H). Calc'd. for C 24
H
24
N
2 0 2 - 372.46. Examples 69-70 were synthesized in a manner as described in 25 Example 68: WO 2005/021532 PCT/US2004/027595 - 118 EXAMPLE 69 N 0 N 5 (S) -2- (4 -t-Buty1-phenyl ) -7 - (1-pyridin-4 -yl-ethoxy) -2, 3 dihydro-isoindol-1-one MS: (ES+) 387(M+H). Calc'd. for C 25
H
26
N
2 0 2 - 386.49. 10 EXAMPLE 70 N N N 15 (R) - 2- (4 - t -Bu tyl- phe nyl) - 7- (1 -pyr id in- 4 -yl - ethoxy) - 2, 3 dihydro-isoindol-1-one MS: (ES+) 387(M+H). Calc'd. for C 25
H
26
N
2 0 2 - 386.49.
WO 2005/021532 PCT/US2004/027595 - 119 EXAMPLE 71 N NH N 5 2- (4-t-Butyl-phenyl) -7- [ ( 2 -methylamino-pyrimidin-4 ylmethyl) -aminoJ -2, 3-dihydro-isoindol-1-one Step A: Preparation of trifluoromethanesulfonic acid 2-(4-t 10 butyl-phenyl) -3-oxo-2 , 3-dihydro-1H-isoindol-4-yl ester 2- ( 4 -t-Butyl-phenyl) -7-hydroxy-2, 3-dihydro-isoindol-l one (0.217 g) was dissolved into 10 mL of CH2C1 2 . Et 3 N (1.0 mL) and N-phenyltrifluoromethanesulfonimide (0.334 g) were added and the solution was stirred at RT for overnight. The 15 solvent was removed and the residue was taken into CH 2 Cl 2 and washed with saturated NaHCO 3 , dried over Na 2
SO
4 , filtered and evaporated to yield an off-white solid as crude material. The crude was purified by silica gel chromatography (70 g, 10-30% EtOAc/hexanes) to afford 20 trifluoromethanesulfonic acid 2-(4-t-butyl-phenyl)-3-oxo 2,3-dihydro-lH-isoindol-4-yl ester as a white solid. Step B: Preparation of 2- ( 4 -t-butyl-phenyl) -7-[ (2 methylamino-pyrimidin-4-ylmethyl) -amino] -2, 3-dihydro 25 isoindol-1-one Trifluoromethanesulfonic acid 2-(4-t-butyl-phenyl)-3 oxo- 2
,
3 -dihydro-lH-isoindol-4-yl ester- (42 mg, Step A), (4- WO 2005/021532 PCT/US2004/027595 - 120 aminomethyl-pyr imidin-2-yl) -methyl-amine (19 .2 mg), Pd (OAc) 2 (3.4 mg) , dppf (9.5 mg) , CeCO 3 (70 mg) and toluene (1 mL) were put into a microwave reaction tube and subjected to 120 *C, for a total of 55 min of microwave. The solid was 5 removed by filtration and solvent was evaporated. The resulting residue was purified by Gilson HPLC purification system to obtain 2- (4- t-butyl--phenyl) -7- [ (2-methylamino pyrimidin-4-ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one. MS: (ES+) 402(M+H). Calc'd. for C 24
H
27
N
5 0 - 401.50. 10 The following Examples (72-76) were synthesized in the same manner as in Example 71: Table 2 15 Ex. Structure Mol Mol MS Formula Weight (MH+) 72
C
23
H
23
N
3 0 357.45 358.0 N NH NH 2- (4-t-butyl-phenyl) -7 (pyridin-3-ylamino) -2,3 dihydro-isoindol-1-one I WO 2005/021532 PCTIUS2004/027595 - 121 73
C
23
H
23
N
3 0 357.45 358.0 N O NH 2- (4-t-butyl-phenyl) -7 (pyridin-4-ylamino) -2,3 dihydro-isoindol-1-one 74
C
27
H
25
N
3 0 407.51 408.0 N NH N 2- (4-t-butyl-phenyl) -7 (quinolin-5-ylamino) -2,3 dihydro-isoindol-1-one WO 2005/021532 PCTIUS2004/027595 - 122 75
C
27
H
25
N
3 0 407.51 408.0 N 0 NH 2- (4-t-butyl-phenyl) -7 (quinolin-6-ylamino) -2,3 dihydro-isoindol-1-one 76
C
25
H
27
N
3 0 385.50 386.0 N NH N 2- (4-t-butyl-phenyl) -7- (2 pyridin-3-yl-ethylamino) 2, 3-dihydro-isoindol-1-one WO 2005/021532 PCT/US2004/027595 - 123 EXAMPLE 77 N 0 NH N 5 (S)- 2
-(
4 -t-Butyl-phenyl)-7-(1-pyridin-4 -yl-ethylamino)-2, 3 dihydro-isoindol-1-one Trifluoromethaiesulfonic acid 2- (4- t-butyl-phenyl) -3 oxo-2,3-dihydro-1H-isoindol-4-yl ester (Example 71, Step A, 10 0.299 g) and (S)-pyridin-4-yl-ethylamine (0.080 g), Pd(OAc) 2 (0.0097 g), dppf (0.0261 g), CeCO 3 (0.469 g) and toluene (2 mL) were added to a microwave reaction tube and subjected to 150 *C, 20 min, and 170 *C, 20 min of microwave. The solid was removed by filtration and the filtrate was concentrated 15 and -purified by silica gel chromatography (30 g, 10-50% EtOAc/hexanes) to afford (S) -2- (4-t-butyl-phenyl)-7- (1 pyridin-4-yl-ethylamino) -2, 3 -dihydro-isoindol-1-one as yellow solid. MS: (ES+) 386 (M+H) . Calc'd. for C 2 5
H
2 7
N
3 0 385.50. 20 Example 78 was synthesized in the same manner as that described in Example 77.
WO 20105/021532 PCT/uS2004Io27595 - 124 EXAMPLE 78 N 0. NH N 5 (R) -2- C4-t-BUtyl-phenyl) -7- (31-pyridin-4-yl ethylaiino) -2, 3-dihydro-isoindol-l1-one MS: (ES+) 386 (M+H). Calcld. for C 25
H
27
N
3 0 -385.50. 10 EXAMPLE 79 HO N 0 N NH 2- (4-tertz-Butyl-pheny1) -l-hydroxy-4- [(pyridin-4-ylmethyl) 15 amino] -1, 2-di hydro-pyrrolo [ 3
,
4 -cjpyridin-3-one WO 2005/021532 PCTIUS2004/027595 - 125 Step A - Preparation of N-(4-tert-butyl-phenyl) -2-fluoro nicotinamide A mixture of 2-fluoro-nicotinoyl chloride (5.10 g, 32.0 mmol), 4-tert-butylaniline (5.20 mL, 32.0 mmol), and 5 NaHCO 3 (5.40 g, 64.0 mmol) in 50 mL of CH 2 C1 2 was stirred at RT for 2 h and filtered through Celitea. The solvents were removed and the titled"compound was obtained as a white solid after flash column chromatography. MS (ES*): 273.4 (M+H)*. Calc'd for C 16
H
17
FN
2 0 - 272.32 10 Step B - Preparation of 2 -(4-tert-butyl-phenyl)-4-fluoro-l hydroxy-1,2-dihydro-pyrrolo[3, 4-clpyridin-3-one To the solution of 2 ,2, 6 ,6-tetramethylpiperidine (5.0 ml, 30.0 nmol) in 60 mL of anhydrous THF at -78 *C was added 15 n-BuLi (2.5 M solution in hexanes, 16 mL, 40.0 mmol) under N2. The resulting mixture .was stirred at -78 0 C for 30 min, and a solution of N-(4-terL-butyl-phenyl)-2-fluoro nicotinamide_(2..72 g,-10..-O-mmol,- Step A) in 20 mL of THF was added dropwise. The mixture was stirred at -78 *C for 2 h, 20 DMF (4.6 mL, 60.0 mmol) was added dropwise. The mixture was stirred at -78 *C for 30 min, then gradually warmed to RT. 1N HCl was added to bring pH to 2, then Na 2
CO
3 was added to bring pH to 10. The mixture was extracted with EtOAc, the combined organic portions were dried with MgSO 4 , filtered, 25 and condensed. The titled compound was obtained as a light yellowish solid after column chromatography. MS (ES+): 301.2 (M+H)*. Calc'd for C 1 7
HI
7
FN
2 0 2 - 300.33. Step C - Preparation of 2
-(
4 -tert-butyl-phenyl)-1-hydroxy-4 30 [(pyridin-4-ylmethyl) -amino] -1, 2-dihydro-pyrrolo [3,4 c ]pyridin-3-one A mixture of 2- (4- tert-butyl-phenyl) -4-fluoro-1 hydroxy-1,2-dihydro-pyrrolo[3,4-cIpyridin-3 -one (0.11 g, 0.38 mmol, Step B) and 4 -(aminomethyl)pyridine (0.070 mL, WO 2005/021532 PCTIUS2004/027595 - 126 0.68 mmol) in 0.70 mL of DIEA and 1.0 ml of BuOH was subjected to microwave heating at 170 "C for 17 min. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (0 to 5% 5 of MeOH in CH 2 C1 2 ) to provide the titled compound as an off white solid. MS (ES*) : 389.1 (M+H)*. Calc'd for C 23
H
2 4
N
4 0 2 388.46. Step D - Preparation of 2-(4-tert-butyl-phenyl)-4-fluoro 10 1, 2-dihydro-pyrrolo[3, 4-c]pyridin-3-one To a mixture of 2-(4-tert-butyl-phenyl)-4-fluoro-1 hydroxy-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one (0.085 g, 0.28 mmol, Step C) and triethylsilane (0.029 mL, 1.80 mmol) in 6 mL of CH 2 Cl 2 was added TFA (0.62 mL, 7.80 mmol)at RT. 15 The mixture was heated at reflux for 2 h, and the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography (5 to 10% of.EtOAc in CH 2 C1 2 ), to yield the titled compound as a white solid. MS (ES*): 285.1 (M+H)*. Calc'd for C 17
H
17
FN
2 0- 284.33. 20 The following were synthesized in the same manner as that described in Example 77 and 79. Table 3 Ex. Structure Mol Mol MS Formula Weight (MH+) 80 N N C 23
H
24
N
4 0 372.46 373.4 2- (4-tert-butyl-phenyl) -4 [(pyridin-4-ylmethyl) amino]-1,2-dihydro pyrrolo[3,4-c]pyridin-3-one WO 2005/021532 PCT/US20041027595 - 127 81 Na C 23
H
2 6
N
6 0 402.49 403.4 - O 2- (4-tert-Butyl-phenyl) -4 ~---E2,methylamino-pyrimidin ___ 4-ylmeth-yl)_-amino) -1,2 dicido-pyrro lo [3,4 ---- clpyridin-3-one 82
/C
24
H
26
N
4 0 2 402.49 403..3 N N NH KNr 2- (4-tert-butyl-phenyl) -4 i(2-methoxy-pyriif7-4 ylmethyl) -amino) -1,2 dihydro-pyrrolo [3,4 a) pyridin-3-one____ 83
/C
23
H
25
N
5 0 387.48 388.4 N 0. N NH '1:: N NH 2 4-[(2-axnino-pyridin-4 ylmethyl) -amino] -2- (4-ter butyl-phenyl) -1, 2-dihydro ___pyrrolo[3 ,4-c) pyridin-3-one _____ ___ ___ WO 2005/021532 PCTIUS2004/027595 - 128 84
C
24
H
24
FN
3 0 389.47 390.2 N N NH F 2-(4-tert-butyl-phenyl)-4 (4-fluoro-benzyl-ami-no)-1, 2 dihydro-pyrrolo[3,4 c]pyridin-3-one 85
C
24
H
23
N
5 0 397.47 398.3 N O N NH NH N 2- (4-tert-butyl-phenyl) -4 (1H-indazol-6-ylamino)-1,2 dihydro-pyrrolo [3,4 c]pyridin-3-one EXAMPLE 86 N NH
-A
WO 2005/021532 PCTIUS2004/027595 - 129 2- (4-tert-Butyl-pheny1l) -3-methyl-7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one Step A - Preparation of 3-nitro-phthalic acid 2-methyl ester 5 4-Nitro-isobenzofuran-1,3-dione (10.0 g, 51.8 mmol) in 50 mL of anhydrous MeOH was heated to reflux under N 2 overnight-.- The mixture was cooled to RT, poured into ice cold-water, and the precipitates were collected by filtrat-ion,_ then~~dri-e- to-give -the titled compound as a 10 white solid. Step B - Preparation of 2 -chlorocarbonyl-6-nitro-benzoic acid methyl ester Oxalyl chloride (5.4 mL, 62.4 mmol) was added to a 15 suspension of 3-nitro-phthalic acid 2-methyl ester (11.7 g, 52.0 mmol, Step A) in 150 mL of anhydrous CH 2 Cl 2 at RT. A few drops of DMF were added, then the mixture was heated to reflux for 2 h, and cooled to RT. The mixture was washed with NaHC0 3 (aq) , brine, dried over MgSO 4 , filtered, and 20 condensed to give the titled compound as a white solid. Step C - Preparation of 2 -acetyl-6-nitro-benzoic acid methyl ester To a suspension of copper(I)cyanide (5.70 g, 63.6 25 mmol) in 200 mL of anhydrous THF at -78 *C was added methyl magnesium bromide (1.4 M in toluene and THF, 43 mL, 59.3 mmol) . The mixture was stirred at -20 *C for 20 min, then cooled to -78 *C. A solution of 2-chlorocarbonyl-6-nitro benzoic acid methyl ester (11.6 g, 47.8 mmol, Step B) in 30 30 mL of THF was added. The mixture was cooled at -10 *C, and slowly warmed to RT, quenched with NH 4 Cl (aq) , and extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO 4 , filtered, condensed, and purified WO 2005/021532 PCTIUS2004/027595 - 130 by flash column chromatography, to provide the titled compound as a white solid. Step D - Preparation of 2
-(
2 -bromoacetyl)-6-nitro-benzoic 5 acid methyl ester. The mixture of 2 -acetyl-6-nitro-benzoic acid methyl ester (8.20 g, 36.7 mmol, Step C) and 5,5-dibromobarbituric acid (7.35 g, 25.7 mmol) in 200 mL of THF was heated to reflux under N 2 for 64-h. The solvents were removed, and 10 the residue was partitioned between EtOAc and Na 2
CO
3 (aq). The organic portion was dried over MgSO 4 , filtered, condensedjand the titled compound was obtained as a white solid after flash column chromatography (5 to 20% of EtOAc in hexanes). 15 Step E - Preparation of 3-bromomethyl-7-nitro-3H isobenzofuran-l-one TFA (50 mL) was added to a mixture of 2-(2-bromo acetyl)-6-nitro-benzoic acid methyl ester (3.47 g, 11.5 20 mmol, Step D) and 20 mL of triethylsilane in 70 mL of anhydrous CH 2 Cl 2 . The mixture was stirred at 70 *C for 48 h, the volatiles were removed under reduced pressure, and hexanes were added to the residue. The titled compound was collected by filtration as an off-white solid. 25 Step F - Preparation of 2-(4-tert-butyl-phenyl)-3-hydroxy-3 methyl-7-nitro-2, 3-dihydro-isoindol-1-one The mixture of 3-bromomethyl-7-nitro-3H-isobenzofuran 1-one (0.50 g, 1.84 mmol, Step E) and 4 -tert-butylaniline 30 (1.20 mL, 7.36 mmol) in 20 mL of THF was slowly warmed to RT from 0 *C, then heated to reflux for 24 h. After cooling to RT, the mixture was diluted with H 2 0, and extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO 4 , filtered, condensed, and the titled WO 2005/021532 PCTIUS2004/027595 - 131 compound was obtained as a light yellowish solid after column chromatography (10 to 35 % of EtOAc in hexanes). Step G - Preparation of 7 -amino-2-(4-tert-butyl-phenyl)-3 5 metHyil-2,~3-dihydro-isoindol-l-one - Tnhe mixtureb-f-2- (4-tert-butyl-phenyl) -3-hydroxy-3 methyl-7-nitr-273-di-hydro-i-so-indol--one (170 mg, Step F) -*-,and-PdC-(-1-0-wt% --3-5 my)-i-1-0--mTr--of--MeOH-was placed under Hrand-st-irre-dat-RT-f'or-19~h~.~~~The mixture was filtered 10 through Celite*, condensed, and the titled compound was obtained as a colorless oil after flash column chromatography (5 to 35%- of EtOAc in hexanes). MS (ES*): 295.1 (M+H)*. Calc'd for C 1 9
H
2 2
N
2 0 - 294.39. 15 Step H - Preparation of 2
-(
4 -tert-butyl-phenyl)-3-methyl-7 (pyridin-4-ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one The mixture of 7-amino-2- (4- tert-butyl-phenyl) -3 methyl-2,3-dihydro-isoindol-1-one (0.11 g, 0.37 mmol, Step G), 4-pyridinecarboxaldehyde (.0.14 mL, 0.93 mmol), and 20 NaBH(OAc) 3 (0.41 g, 1.85 mmol) in 5 mL of 1, 2 -dichloroethane was stirred at RT for 48 h, and diluted with 20 mL of EtOAc. 1.0 N HCl (aq) was added to bring pH to 1 - 2. After stirring for 30 min, NaHCO 3 (aq) was added to bring pH to 10. The organic portion was washed with brine, condensed, 25 and the titled compound was obtained as a white solid after flash column chromatography (0 to 35 % of EtOAc in CH 2 C1 2 ). MS (ES+): 386.3 (M+H)*. Calc'd for C 25
H
2 7
N
3 0 - 385.50 Step I - Preparation of 7 -aamino-2-(4-tert-butyl-phenyl) - 3 30 hydroxy-3-methyl-2, 3-dihydro-isoindol-1-one NaBH 4 (0.091 g, 2.36 mmol) was added in small portions to the mixture of 2-( 4 -tert-butyl-phenyl)-3-hydroxy-3 methyl-7-nitro-2,3-dihydro-isoindol-1-one (0.20 g, 0.59 mmol, Step H) and NiC12-6H 2 0 (0.28 g, 1.18 mmol) in 10 mL of WO 2005/021532 PCTIUS2004/027595 - 132 MeOH at 0 *C over 30 min. The mixture was stirred at RT for 30 min, filtered through Celite*, and condensed. The titled compound was obtained as a white solid after flash column chromatography (0 to 25% of EtOAc in CH 2 C1 2 )- MS (ES*): 5-_ 311.1 (M+H)*. Calc'd for C 1 9
H
2 2
N
2 0 2 - 310.39. Example 87 was synthesized in the same manner as that d~scribe ~ii~Example 86. 10 EXAMPLE 87 OH N O /NH NH 2- (4-tert-Butyl-phenyl) -3-hydroxy-3-methyl-7- [(pyridin-4 ylmethyl) -amino]-2, 3-dihydro-isoindol-1-one 15 White solid. MS (ES*): 402.6 (M+H)*. Calc'd for C 25
H
27
N
3 0 2 401.50 EXAMPLE 88 20 F N F N O OF WO 2005/021532 PCTIUS2004/027595 - 133 7 - (Pyridin-4 -ylamino) -2- [ 3- (tetrahydro- furan-3 -yloxy) -5 trifluoromethyl-pheny1] -2, 3-dihydro-isoindol-1-one Step A: Preparation of 3-hydroxy-5-nitrobenzotrifluoride 5 3 Methoxy-5-nitrobenzotrifluoride (40 g, 181 mmol, 1 eq)-anT-|iyisi-diniuihydirochloride (167 g, 1448 mmol, 8 eq) were heated together to 210 *C in an djben vessel for 2.5 h. The-darkniture was coo-ed -a iartition&edbetween~EtOAc adr2H T. The Et5Oc -fayer was -washed -(6x) with 2 N HCl, 10 and once with brine. After drying over Na 2
SO
4 the solution was filtered and stripped. The crude material was placed under vacuum for 7 days to provide a brownish solid which was used without further purification. 15 Step B: Preparation of 3 -(3-nitro-5-trifluoromethyl-phenoxy) -tetrahydro-furan 3-Hydroxy-5-nitrobenzotrifluoride (5 g, 24.1 mmol, 1 eq), (S)-3-hydroxytetrahydrofuran (1.9 mL, 24.1 mmol, 1 eq), PPh 3 (6.3 g, 24.1 mmol, 1 eg) were dissolved in 43 mL of 20 THF. The solution was cooled to -20 *C. DIAD (4.8 mL, 24.6 mmol, 1.02 eq) was added in 22 mL of THF over the course of 2 h while the temperature was maintained between -10 and -20 *C. After the addition was complete the reaction was stirred for 3 days at RT. The solvent was removed in vacuo. 25 The residue was stirred with ~ 250 mL of hexane for 45 min during which time triphenylphosphine oxide precipitated as a white solid. The solid was removed by filtration and the filtrate was washed twice with 2 N NaOH and once with brine. After drying over Na 2
SO
4 the solution was filtered and the 30 solvent removed under reduced pressure. The crude material was purified by chromatography on a Biotage system eluting with a gradient of 5 to 15% EtOAc:hexane to yield the desired compound.
WO 2005/021532 PCTIUS2004/027595 - 134 Step C: Preparation of 3-(tetrahydro-furan-3-yloxy)-5 trifluoromethyl-phenylamine The nitrobenzotrifluoride (Step B, 6.026 g, 21.7 mmol, 1 eq) was dissolved in MeOH (210 mL). 10% Pd/C (600 mg (10 wt%)) was 5 carefully added to the reaction. The suspension was sparged with H2 and~ stirred undeF a H~ a~tm for 4 h. The mixture was filtered through a Celite* pad and the solvent removed in vacuo to yield the desired amine which was used without further purification. 10 Step D: Preparation of 7-amino-2-[3-(tetrahydro-furan-3 yloxy) -5-trifluoromethyl-phenyl -2, 3-dihydro-isoindol-l-one The indolone was prepared similar to that described in Preparation 3 and Example 1. 15 Step E: Preparation of 7-(pyridin-4-ylamino)-2-[3 (tetrahydro-furan-3-yloxy) -5-trifluoromethyl-phenyl J-2,3 dihydro-isoindol-1-one 4-Chloropyridine-HCl salt (39 mg, 0.26 mmol, 1 eq) was combined with 7-amino-2- (3- ( (3R) -tetrahydro-3-furanyloxy) -5 20 (trifluoromethyl)phenyl) -2,3-dihydro-1H-isoindol-1-one (Step A, 100 mg, 0.26 mmol, 1 eq) . K 2
CO
3 (36 mg, 0.26 mmol, 1 eq) was added followed by 1 mL of N-methylpyrrolidine. The resulting mixture was heated to 140 *C for 2 h. The reaction was cooled to RT. 25 In a separate vessel 4-chloropyridine-HCl salt (22.7 mg, 0.2 mmol, 1 eq) was partitioned between Et 2 0 and saturated NaHCO 3 . The ether layer was washed once with saturated NaHCO 3 , once with 1 N NaOH, and once with brine. After drying over Na 2
SO
4 , the organic solution was filtered 30 and the solvent removed in vacuo. To this yellow oil was added 7-amino-2- (3- ( (3R) -tetrahydro-3-furanyloxy) -5 (trifluoromethyl)phenyl)-2,3-dihydro-1H-isoindol-1-one (Step A, 75 mg,_0.2 mmol, 1 eq). The mixture was heated to 140 *C in an open flask for 30 min. 4 M HCl 200 pL in dioxane was WO 2005/021532 PCTIUS2004/027595 - 135 added and the mixture was heated for an additional 30 min. After- cooling-to RT the two lots were combined and the crude material was purified by reverse phase HPLC. The desired fractions were stripped of organics. Saturated NaHCO 3 was 5 added to the remaining suspension. The aqueous was extracted Vith~ CH 2 Cl 2 . The CH 2 C1 2 was dried over Na 2
SO
4 , filtered and the solvent -removed -in vacuo to provide an of f - wh-i-t-e-sel-id.MS-mfz-=-4-567--M+H-]+, Calc'd for C 2 4
H
20
F
3
N
3 0 3 = -455 .- 4-4. 10 EXAMPLE 89 N N NH - N 2-Biphenyl-4-yl-4- [(pyridin-4-ylmethyl) -amino] -1, 2-dihydro pyrrolo[3,4-cJpyridin-3-one 15 Step A - Preparation of 2-fluoro-4-formyl-N,N-diisopropyl nicotinamide To a solution of diisopropylamine (1.7 mL, 12.2 nmol) in THF (50 mL) at -78 *C was added n-BuLi (6.1 mL, 2.0 M 20 hexanes) dropwise under N 2 . The reaction was stirred for 30 min and 2-fluoro-N,N-diisopropyl-nicotinamide (2.75 g, 12.2 mmol) was added dropwise in a solution of THF (15 mL). The reaction was stir for 1 h, then DMF (3 mL, 36 mmol, 3 eq) was added in one portion. The reaction was stirred at -78 25 *C for 5 min then warmed to RT over 1 h. The reaction was quenched with NH 4 Cl (saturated, 100 mL), and extracted with WO 2005/021532 PCTIUS2004/027595 - 136 EtOAc (2 x 100 mL). The combined organics were washed with brine (saturated, 200 mL) , dried with Na 2
SO
4 , and purified by passing through a plug of SiO 2 to give pure title compound as a white solid. MS (ES+): 253.1 (M+H)*. 5 Step~B -- o ylaminomethyl) fluoro-N,N-diisopropyl-nicotinamide To a soluti~6n of~2-fluboro-4-formyl-N,N-diisopropyl nicotinamide (580.mg, 2.3 mmol, Step A) in 1,2 10 dichloroethane (20 mL) was added p-biphenylamine (380 mg, 2.3 mmol). The reaction was stirred for 5 min and NaBH(OAc) 3 (1.4 g, 6.9 mmol, 3 eg) was added in one portion. The reaction was stirred at RT overnight then quenched by the addition of aqueous NaHCO 3 (30 mL). The quenched 15 reaction was stirred for 1 h and extracted with EtOAc (3 x 75 mL). The combined organics were washed with brine, dried with Na 2
SO
4 , filtered and concentrated to provide crude material. The crude material was purified by SiO 2 column chromatography to give pure title compound as a white foamy 20 solid. MS (ES*): 406.2 (M+H)*. Step C - Preparation of 4-(biphenyl-4-ylaminomethyl)-N,N diisopropyl-2-[ (pyridin-4-ylmethyl) -amino]-nicotinamide To a microwave tube was added 4-(biphenyl-4 25 ylaminomethyl) -2-fluoro-N,N-diisopropyl-nicotinamide (240 mg, 0.59 mmol, Step B), t-BuOH (3 mL), DIEA (1 mL, and aminomethyl pyridine (0.2 mL). The contents of the microwave tube were stirred for 5 min and subjected to microwave heating at 200 *C for 1 h. The volatiles were 30 removed under reduced pressure, and the residue was purified by flash column chromatography (15% MeOH in EtOAc). MS (ES*): 494.2 (M+H)*.
WO 2005/021532 PCT/US2004/027595 - 137 Step D - Preparation of 2-biphenyl- 4 -yl-4- [ (pyridin-4 ylmethyl) -amino] -l, 2 -dihydro-pyrrolo[3, 4 -c]pyridin-3-one A solution of 4 -(biphenyl-4-ylaminomethyl)-N,N diisopropyl-2- [ (pyridin-4-ylmethyl) -amino] -nicotinamide (13 5 mg, -0.026 mmol, Step C) in absolute EtOH (3 mL) and HCl (12 NT~~~1E)-~-s-he-at-d t6-3fefldx for 2 days, then concentrated ---- in vacuo----The-- crude material was dissolved in 1:1 DMSO to - MeOH-(-2--mIr)--and-puri-fi-ed-by-reverse-h-ase-HPLC ~(10-'~95% CHjCN in H 2 0). MS (ES*): 393.2 (M+H)*. 10 EXAMPLE 90 / NH N N NH -N 15 2- (4, 4-Dimnethyl-1, 2, 3,4-tetrahydro-isoquinolin-7-yl) -4 [(pyridin-4-ylmethyl) -amino] -1, 2-dihydro-pyrrolo [3,4 c]pyridin-3-one The compound was prepared according to method 20 described in Example 89. MS (ES*): 400.2 (M+H)*.
WO 2005/021532 PCT/US2004/027595 - 138 EXAMPLE 91 N 0 NH 5 2- (4-tert-Butyl-phenyl) -4- [(pyridin-4-ylmethyl) -amino] isoindole-1,3-dione Step A - Preparation of 2-(4-tert-butyl-phenyl)-4-nitro isoindole-1,3-dione 10 In a 25 mL round bottomed flask, 3-nitrophthalic acid (1 g, 4.7 mmol) was suspended in 1,2-dichlorobenzene (3 mL). To this was added 4-tert-butylaniline (3 mL, 18.8 mmol). The reaction was heated to 150 *C, resulting in a blood red solution. The reaction was held at 150 0 C for 2.5 h, then 15 poured into a 125 mL Erlenmeyer flask. Precipitation began to occur and 50 mL of Et 2 0 was added to the flask. The suspension was stirred for 15 h and filtered. The filtered cake was washed copiously with Et 2 0 and dried in vacuo at 30 *C for 4 h to afford a white brittle powder. No further 20 purification was performed on this compound. MS (ES+): 325.1(M+H)*. Calc'd for C 18
H
16
N
2 0 4 - 324.33. Step B - Preparation of 4-amino-2-(4-tert-butyl-phenyl) isoindole-1,3-dione 25 In a 100 mL round bottomed flask, 2-(4-tert-butyl phenyl)-4-nitro-isoindole-1,3-dione (980 mg, 3.02 mmol) was WO 2005/021532 PCT/US2004/027595 - 139 dissolved in MeOH (30 mL). To this was added 10% Pd/C (100 mg) under a stream of N 2 . The flask was purged of oxygen and subjected to a balloon of H2 for 2 h. The reaction was filtered through a bed of Celite*, and the resulting filter 5 cake was washed with EtOH. The filtrate was concentrated to a yellowish residue which was subjected to flash chromatography over silica gel eluting with 20% EtOAc in hexanes to give a yellow foam. MS (ES+): 295.2 (M+H)*. Calc'd for C 1 8 HiBN 2 0 2 - 294.35. 10 Step C - Preparation of 2
-(
4 -tert-butyl-phenyl)-4-[(pyridin 4-ylmethyl)-amino]-isoindole-1,3-dione In a 25 mL round bottomed flask, 4 -a-mino-2-(4-tert butyl-phenyl)-isoindole-1,3-dione (30 mg, 0.101 mmol, Step 15 B) was dissolved in 1,2-dichloroethane (10 m). To this was added 4-pyridinecarboxaldehyde (0.05 mL, 0.524 mmol). The reaction was stirred for 1 h under N 2 . NaBH(OAc) 3 (40 mg, 0.188 mmol) was added and the suspension was stirred for 6 h. The reaction was quenched with saturated NaHCO 3 solution 20 (50 mL). The reaction was rotary evaporated to remove the 1,2-dichloroethane. The product was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over Na 2
SO
4 , filtered and concentrated to afford an oil. The oil was purified by flash chromatography on 25 silica gel eluting with 30% EtOAc in hexanes. MS (ES+): 386.1 (M+H)*. Calc'd for C 2 4
H
2 3
N
3 0 2 - 385.46. Other compounds included in this invention are set forth in Tables 4-5 below.
WO 2005/021532 PCT/US2004/027595 - 140 Table 4 R 5 # z # R* R x z 92. 4-chlorophenyl - -4-pyridyl-CH 2 - N NH CH 93. 5-benzimidazolyl 3-pyridyl-(CH 2
)
2 - N - CH 94. 2-chlorophenyl 4-pyridyl-CH 2 - N NMe CH 95i 2-quinolinyl 4-pyridyl-CH 2 - N NMe CH 10 96. 2-benzthiazolyl 4-pyridyl N (CH 2
)
2 CH CI N 4 zNH 2 N Me 97. N CH NH CH H3 I N 98. H CH CH=CH- CH WO 2005/021532 PCT/US2004/027595 - 141 Table 5
N-R
1 NH 0 -9 9-.. _2 - chlorophenyl 4-pyridy 100. 5-benzimidazolyl 4-pyridyl 101. 4-chlorophenyl 4-pyridyl 102. 2-quinolinyl 4-pyridyl 10 103. 2-benzthiazolyl 4-pyridyl 104. 6-benzimidazolyl 3-CH 3 NH(C=O) -4-pyridyl 105. 4-chlorophenyl 3-CH 3 NH(C=O)-4-pyridyl 106. 3,4-dichlorophenyl 3-CH 3 NH (C=O) -4-pyridy. 107. 4-fluorophenyl 4-quinolyl 15 108. 3-chlorophenyl 4-quinolyl IR 109. 3 -CH- 3 (C=0) NH-phenyl 110. 3-f luorophenyl 4-quinolyl 111. 3-fluoro-4-iuethoxyphenyl 4-quinolyl 20 112. 3-fluoro-4-methylphenyl 4-quinolyl 113. 4-bromophenyl 6 ,7-diiethoxy-4-quinolyl 114. 4-broio-3-CF 3 phenyl 3-methyl-4-pyridyl 115. 4-bromophenyl 3-CH 3 CC=O)II-4-pyridy 116. 4-phenoxyphenyl 3 -CH 3 NH (C=0) -phenyl 25 117. 3-phenoxyphenyl 3-CH 3 NH (C=O) -phenyl 118. 4-biphenyl 2-MeNH-4-pyrimidinyl 119. 4-cyclohexyphenyl 2-MeNH-4-pyrimidinyl WO 2005/021532 PCT/US2004/027595 - 142 Table 5 (cont.) N-RI NH 0 R7 5 # ___ __I
R
7 120. 5-isoindolyl 2 -MeNH-4-pyrimidinyl fO 121. 4-pyridyl
CH
3 O N N 10 122. CH 3 0 N q a NQ N 123'. 3-CH 3 NH (C=O) -4-pyridyl N 124. 3-CH 3 NH (C=O) -4-pyridy1 15 1 NN 125 .
H
WO 2005/021532 PCTIUS2004/027595 - 143 Table 5 (cont.) ON-R' NH 7 # Me N Me R __ T 126. N ~NcA 127. H C N 128. 2 -MeNH-4-pyrimidinyl 10 129. ON 130. H 1 N 131.
H
WO 2005/021532 PCTIUS2004/027595 - 144 Table 5 (cont.) N-R' NH O
R
7 5 1O--N H3C 132.- H CN 133. H 134. 3,4-dichlorophenyl 4-pyridyl 10 135. 3-chloro-4-methylphenyl 4-pyridyl _Me f__Me 136. N N 0 137. H 138. H 15 WO 2005/021532 PCTIUS2004/027595 - 145 Although the pharmacological properties of the compounds of Formulas I-III vary with structural change, in general, activity possessed by compounds of Formula I-III may be demonstrated in vivo. The pharmacological properties 5 of the compounds of this invention may be confirmed by a number of pharmacological in vitro assays. The exemplified pharmacological assays which follow have been carried out with the compounds according to the invention and their salts. -CUp-urids of-the present invention showed inhibition 10 of KDR kinase at doses less than 50 pM. -BIOLOGICAL EVALUATION HUVEC Proliferation Assay 15 Human Umbilical Vein Endothelial cells are purchased from Clonetics, Inc., as cryopreserved cells harvested from a pool of donors. These cells, at passage 1, are thawed and expanded in EBM-2 complete medium, until passage 2 or 3. The cells are trypsinized, washed in DMEM + 10% FBS + 20 antibiotics, and spun at 1000 rpm for 10 min. Prior to centrifugation of the cells, a small amount is collected for a cell count. After centrifugation, the medium is discarded, and the cells are resuspended in the appropriate volume of DMEM + 10% FBS + antibiotics to achieve a 25 concentration of 3x10 5 cells/mL. Another cell count is performed to confirm the cell concentration. The cells are diluted to 3x10 4 cells/mL in DMEM + 10% FBS + antibiotics, and 100 pL of cells are added to a 96-well plate. The cells are incubated at 37 *C for 22 h. 30 Prior to the completion of the incubation period, compound dilutions are prepared. Five-point, five-fold serial dilutions are prepared in DMSO, at concentrations 400-fold greater than the final concentrations desired. 2.5 pL of each compound dilution are diluted further- in a total 35 of 1 mL DMEM + 10% FBS + antibiotics (400x dilution).
WO 2005/021532 PCTIUS2004/027595 - 146 Medium containing 0.25% DMSO is also prepared for the 0 pM compound sample. At the 22 h timepoint, the medium is removed from the cells, and 100 pjL of each compound dilution is added. The cells are incubated at 37 *C for 2-3 h. 5 During the compound pre-incubation- period, the growth factors are diluted to the appropriate concentrations. Solutions of DMEM + 10% FBS + antibiotics, containing either VEGF or bFGF at the following concentrations: 50, 10, 2, 0.4,. 0.08, and 0 ng/mL are prepared. For the compound 10 treated cells, solutions of VEGF at 550'ng/mL or bFGF at 220 ng/mL for 50 ng/mL or 20 ng/mL final concentrations, respectively, are prepared since 10 yL of each will be added to the cells (110 pL final volume). At the appropriate time after adding the compounds, the growth factors are added. 15 VEGF is added to one set of plates, while bFGF is added to another set of plates. For the growth factor control curves, the media on wells B4-G6 of plates 1 and 2 are replaced with media containing VEGF or bFGF at the varying concentrations (50 - 0 ng/mL). The cells are incubated at 20 37 *C for an additional 72 h. At the completion of the 72 h incubation period, the medium is removed, and the cells are washed twice with PBS. After the second wash with PBS, the plates are tapped gently to remove excess PBS, and the cells are placed at -70 *C for 25 at least 30 min. The cells are thawed and analyzed using the CyQuant fluorescent dye (Molecular Probes C-7026), following the manufacturer's recommendations. The plates are read on a Victor/Wallac 1420 workstation at 485 nm/530 nm (excitation/emission). Raw data are collected and 30 analyzed using a 4-parameter fit equation in XLFit. ICso values are then determined. Examples 1, 15-17, 20, 32, 35, 46, 64, 80 and 83 inhibited VEGF-stimulated HUVEC proliferation at a level below 500 nm.
WO 2005/021532 PCTIUS2004/027595 - 147 Angiogenesis Model To determine the effects of the present compounds on 5 angiogenesis in vivo, selective compounds are tested in the rat corneal neovascularization micropocket model or the angiogenesis assay of-Passaniti, Lab. Invest., 67:519-528 (1992)-.
10 Rat Corneal Neovascularization Micropocket Model In Life Aspects: Female Sprague Dawley rats weighing approximately 250 g were randomized into one of five treatment groups. Pretreatment with the vehicle or compound 15 was administered orally, 24 h prior to surgery and continued once a day for seven additional days. On the day of surgery, the rats were temporarily anesthetized in an Isofluorane gas chamber (delivering 2.5 liters/min oxygen + 5% Isofluorane). An othoscope was then placed inside the 20 mouth of the animal to visualize the vocal cords. A tip blunted wire was advanced in between the vocal cords and used as a guide for the placement of an endotracheal Teflon tube (Small Parts Inc. TFE-standard Wall R-SWTT-18).. A volume-controlled ventilator (Harvard Apparatus, Inc. Model 25 683) was connected to the endotracheal tube to deliver a mixture of oxygen and 3% Isofluorane. Upon achieving deep anesthesia, the whiskers were cut short and the eye areas and eyes gently washed with Betadine soap and rinsed with sterile saline. The corneas were irrigated with one to two 30 drops of Proparacaine HCl ophthalmic topical anesthetic solution (0.5%) (Bausch and Lomb Pharmaceuticals, Tampa FL). The rat was then positioned under the dissecting microscope and the corneal surface brought into focus. A vertical incision was made on the midline of the cornea using a 35 diamond blade knife. A pocket was created by using fine WO 2005/021532 PCTIUS2004/027595 - 148 scissors to separate the connective tissue layers of the stroma, tunneling towards the limbus of the eye. The distance between the apex of the pocket and the limbus was approximately 1.5 mm. After the pocket had been made, the 5 soaked nitrocellulose disk filter (Gelman Sciences, Ann Arbor MI.) was inserted under the lip of the pocket. This surgical procedure was performed on both eyes. rHu-bFGF soaked disks were placed into the right eye, and the rHu VEGF soaked disks were placed into the left eye. Vehicle 10 soaked disks were placed in both eyes. The disk was pushed into position at the desired distance from thelimbal vessels. Ophthalmic antibiotic ointment was applied to the eye to prevent drying and infection. After seven days, the rats were euthanized by CO 2 asphyxiation, and the eyes 15 enucleated. The retinal hemisphere of the eye was windowed to facilitate fixation, and the eye placed into formalin overnight. Post Mortem Aspects: After 24 h in fixative, the corneal region of interest was dissected out from the eye, 20 using fine forceps and a razorblade. The retinal hemisphere was trimmed off and the lens extracted and discarded. The corneal dome was bisected and the superfluous cornea trimmed off. The iris, conjunctiva and associated limbal glands were then carefully teased away. Final cuts were made to 25 generate a square 3x3 mm containing the disk, the limbus, and the entire zone of neovascularization. Gross Image Recording: The corneal specimens were digitally photographed using a Sony CatsEye DKC5000 camera (A.G. Heinz, Irvine CA) mounted on a Nikon SMZ-U stereo 30 microscope (A.G. Heinz). The corneas were submerged in distilled water and photographed via trans-illumination at approximately 5.0 diameters magnification. Image analysis: Numerical endpoints were generated using digital micrographs collected from the whole mount WO 2005/021532 PCTIUS2004/027595 - 149 corneas after trimming and were used for image analysis on the Metamorph image analysis system (Universal Imaging Corporation, West Chester PA). Three measurements were taken: Disk placement distance from the limbus, number of 5 vessels intersecting a 2.0 mm perpendicular line at the midpoint of the disk placement distance, and percent blood vessel area of the diffusion determined by thresholding. General Formulations: 10 0.1% BSA in PBS Vehicle: 0.025 g of BSA was added to 25.0 mL of sterile 1 X phosphate buffered saline, gently shaken until fully dissolved, and filtered at 0.2 pm. Individual 1.0 mL samples were aliquoted into 25 single use 15 vials, and stored at -20 *C until use. For -the rHiu-bFGF disks, a vial of this 0.1% BSA solution was allowed to thaw at room temperature. Once thawed, 10 p.L of a 100 mM stock solution of DTT was added to the 1 mL BSA vial to yield a final concentration of 1 mM DTT in 0.1% BSA. 20 rHu-VEGF Dilutions: Prior to 'the disk implant surgery, 23.8 pl -of the 0.1% BSA vehicle above was added to a 10 ig rHu-VEGF lyophilized vial yielding a final concentration of 10 iM. rHu-bFGF; Stock concentration of 180 ng/pil: 25 R&D rHu- bFGF: Added 139 iL of the appropriate vehicle above to the 25 ig vial lyophilized vial. 13.3 IiL of the [180 ng/pL] stock vial and added 26.6 pL of vehicle to yield a final concentration of 3.75 pM concentration. Nitro-cellulose disk preparation: The tip of a 20 30 gauge needle was cut off square and beveled with emery paper to create a punch. This tip was then used to cut out =0.5 mm diameter disks from a nitrocellulose filter paper sheet (Gelman Sciences). Prepared disks were then placed into Eppendorf microfuge tubes containing solutions of either WO 2005/021532 PCTIUS2004/027595 - 150 0.1% BSA in PBS vehicle, 10 pM rHu-VEGF (R&D Systems, Minneapolis, M1T), or 3.75 PM rHu-bFGF (R&D Systems, Minneapolis, MR) and allowed to soak for 45-60 min before use. Each nitrocellulose filter disk absorbs approximately 5~~ 1~jir~f soluiioln7 ~I tie r icropocket assay, compounds of the present invention will inhibit angiogenesis at a dose of less than -50 mgkgday~ ---- --- - -Tum~-~or~ideri -- 10 A431 cells (ATCC) are expanded in culture, harvested id injected subcutaneously into 5-8 week old female nude mice (CD1 nu/nu, Charles River Labs) (n=5-15). Subsequent administration of compound by oral gavage (10 - 200 15 mpk/dose) begins anywhere from day 0 to day 29 post tumor cell challenge and generally continues either once or twice a day for the duration of the experiment. Progression of tumor growth is followed by three dimensional caliper measurements and recorded as a function of time. Initial 20 statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe post hoc testing for multiple comparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control. Compounds of the present invention are active at doses less than 150 mpk. 25 Rat Adjuvant Arthritis Model: The rat adjuvant arthritis model (Pearson, Proc. Soc. Exp. Biol. 91, 95-101 (19.56)) is used to test the anti 30 arthritic activity of compounds of the formula I, or salts thereof. Adjuvant Arthritis can be treated using two different dosing schedules: either (i) starting time of immunization with adjuvant (prophylactic dosing); or from day 15 when the arthritic response is already established WO 2005/021532 PCTIUS2004/027595 - 151 (therapeutic dosing). Preferably a therapeutic dosing schedule is used. Rat Carrageenan-induced Analgesia Test 5 The rat carrageenan analgesia test was performed with materials, reagents and procedures essentially as described by Hargreaves, et al., Pain, 32:77 (1988). Male Sprague - -B-Daw-l-ey-rats-were-t-r-eated-as previously described for the 10 Carrageenan Foot Pad Edema test. 3 h after the injection of the carrageenan, the rats were placed in a special plexiglass container with a transparent floor having a high intensity lamp as a radiant- heat source, positionable under the floor. After an initial 20 min period, thermal 15 stimulation was begun on either the injected foot or on the contralateral uninjected foot. A photoelectric cell turned off the lamp and timer when light was interrupted by paw withdrawal. The time until the rat withdraws its foot was then measured. The withdrawal latency in seconds was 20 determined for the control and drug-treated groups, and percent inhibition of the hyperalgesic foot withdrawal determined. Formulations 25 Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula I in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" 30 materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such.a route, and in a dose effective for the treatment intended. The WO 2005/021532 PCTIUS2004/027595 - 152 compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, 5 intraperitoneally, subcutaneously, intramuscularly intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The pharmaceutica-l-l-y-act-ive- compounds of this 10 invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. For oral administration, the pharmaceutical 15 composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. For 20 example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg or 5 to 1000 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be 25 determined using routine methods. The amount of compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and 30 medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose WO 2005/021532 PCTIUS2004/027595 - 153 of about 0.01 to 500 mg/kg, preferably between about 0.1 and about 50 mg/kg, and more preferably about 0.1 and about 20 mg/kg body weight may be appropriate. The daily dose can be administered in one to four doses per day. 5 For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of --- admin-istration. If administered -per-os-,- the compounds may be admixed with_lactose,.sucrose,_starch-powder ,-cellulose 10 esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated 15 for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of psoriasis and other skin conditions, it 20 may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for 25 penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, 30 preferably one or two times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, WO 2005/021532 PCTIUS2004/027595 - 154 but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible 5 ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for-example at -least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,-mannitol, - sorbitol, 10 glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound-which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and 15 related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably transdermal administration will be accomplished using a patch either of the reservoir and porous membrane type or of 20 a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the 25 skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The oily phase of the emulsions of this invention may 30 be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a WO 2005/021532 PCTIUS2004/027595 - 155 lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s)- with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the o.il and fat m&ke up the so-called emulsifying ointment base - - whcho-ra-thi oily -dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers -- s-u-i-t-ab-le-for-use-in the-fo-rmui-ati-on--o-f-thle praisent --- inven t±on -inn-lude-Tumoff 6-0 rf. nve Lirinc-udeTren~ .0Spac .0~~_-,catostearyl-alcohol, 10 myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other ~ -t-finoe1 known in-the art; The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic 15 properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other 20 containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexy1 palmitate or a blend of branched 25 chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. 30 Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such WO 2005/021532 PCTIUS2004/027595 - 156 formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile 5 injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending 10 agents. The compounds may be dissolved in H 2 0, polyethylene glycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, NaCl, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the 15 pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or H 2 0, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80). 20 The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are H 2 0, Ringer's 25 solution, and isotonic NaCl solution. In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the 30 preparation of injectables. For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol.
WO 2005/021532 PCTIUS2004/027595 - 157 Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid - 5 tathe-rectal-temperature and will therefore melt in the - -- rectum-and-re-lease- the- -drug. The. pharmaceutical compositions may be subjected to - -- conventional-pharmaceutica-l-operations-such- as *s-ter-i-]-i-aat-i-en-and/-or--may- contain-_conventional-adjuvants., 10 such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents. 15 The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended 20 claims. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the 25 invention to adapt it to various usages and conditions. No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention. All mentioned references, patents, applications and 30 publications, are hereby incorporated by reference in their entirety, as if here written.

权利要求:
Claims (34)
[1] 1. A compound of Formula I R1 Z-N 5 R I wherein X is CH or N; wherein Y is selected from C 1 _ 3 -alkyl, C 2 . 3 -alkenyl, 0, S(O),, and NR 4 ; 10 wherein Z is C=0 or CHR 5 ; wherein R is selected from a) substituted or unsubstituted
[2] 6-10 membered aryl, b) substituted or unsubstituted 4-6 membered heterocyclyl, 15 c) substituted or unsubstituted
[3] 9-14 membered fused heterocyclyl, d) substituted or unsubstituted aryl-C 1 . 2 -alkyl, e) substituted or unsubstituted heterocyclyl-C 1 . 2 -alkyl, and 20 f) lower alkyl; where substituted R is substituted with one or more substituents selected from halo, -OR, -SR -S0 2 R 3 _ C0 2 R 3 , -C (0) NRR 3 , -C (0) R 3 , -NR 3 R 3 , -SO 2 NR 3 R 3 , -NR 3 C(O)OR 3 , -NR 3 C(0)R 3 , optionally substituted 3-6 membered 25 heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R 2 , wherein R 1 is selected from unsubstituted or substituted a) 6-10 membered aryl, WO 2005/021532 PCT/US2004/027595 - 159 b) 5-6 membered heterocyclyl, c) 9-14 membered fused heterocyclyl, d) cycloalkyl, e) cycloalkenyl, 5 f~rJw-ral717Eid )dliwe-al-keny17-~ -wherein--subst-it-uted R' is substituted with one-or more -subs-t-i--uent-s-i-ndependent--s-se-lect-ed from halo, -OR 3 R- -) C-0)-,--T3R3,-oo OC (0) R 3 , 10 -SO 2 R 3 , -SO 2 NR 3 R 3 , -NR 3 C (0) OR 3 , -NR 3 C (0) R 3 , -NR 3 C (O) NR 3 R 3 , optionally. substituted cycloalkyl, optionally subfftittd-4-6 membered heterocyclyl, optionally substituted phenyl, cyano, aminoalkylcarbonylamino, alkylaminoalkylcarbonylamino, alkylaminoalkoxy, 15 alkylaminoalkoxyalkoxy, nitro, and lower alkyl substituted with one or more R2 wherein R2 is selected from H, halo, -OR 3 , amino, C 1 3 alkylamino, Cs3-dialkylamino, C 1 3 -alkyl, optionally substituted phenyl, optionally substituted phenyl-Cl- 3 20 alkyl, 4-6 membered heterocyclyl, and optionally substituted 4-6 membered heterocyclyl-ClC 3 -alkyl; wherein R3 is independently selected from H, lower alkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 3 -C6 25 cycloalkyl, optionally substituted phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted C 3 -C 6 cycloalkylalkyl and lower haloalkyl; wherein R4 is independently selected from H, and lower 30 alkyl; wherein R5 is independently selected from H, -OR 3 , and lower alkyl; and wherein R 6 is selected from H, halo, -OR, -SR 3 , -C0 2 R 3 , SOR 3 , -C(O)NRR 3 , -C(O)R, -NR 3 R 3 , -SO 2 R 3 , -SO 2 NR 3 R 3 , - WO 2005/021532 PCTIUS2004/027595 - 160 NR 3 C (O) OR 3 , -NR 3 C (0) R 3 , -NR 3 C(O)NR 3 R3, optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, nitro, lower alkyl substituted with one or more 5 R 2 , lower alkenyl substituted with one or more R 2 and lower alkynyl substituted with one or more R Wa and pharmaceutically acceptable-derivatives thereof. 2. Compound of Claim-1 wherein Y is NH; wherein X is 10 CH; wherein Z is CHR 5 ; and wherein R 5 is independently selected from H, -OH, and methyl; and pharmaceutically acceptable derivatives thereof.. 3. Compound of Claim 1 wherein R is unsubstituted or 15 substituted 9-10 membered fused nitrogen-containing heteroaryl and optionally further substituted 9-10 membered fused N-containing oxo-substituted heterocycyl; and pharmaceutically acceptable derivatives thereof. 20 4..Compound of Claim 3 wherein R is selected from quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, isoquinolin-5 yl, 2-oxo-1,2-dihydroquinol-7-yl, 1-oxo-2,3-dihydro-1H isoindol-4-yl, quinazolin-6-yl, 4-oxo-3,4-dihydro quinazolin-6-yl, indazol-5-yl, indazol-6-yl, indol-5-yl, 25 isoindol-4-yl, benzimidazol-5-yl, 2 -oxo-2,3-dihydro1H benzimidazol-5-yl and benzotriazol-6-yl; wherein R is optionally substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, 1-methylpiperidinylmethoxy, 30 dimethylaminoethoxyethoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof. 5. Compound of Claim 1 wherein R is substituted or unsubstituted 6-membered nitrogen containing heteroaryl-C 1 . 2 - WO 2005/021532 PCTIUS2004/027595 - 161 alkyl or 9-10 membered nitrogen containing fused heteroaryl CI- 2 -alkyl; wherein substituted R is substituted with one or more substituents independently selected from halo, amino, Ci- 3 -alkoxy, hydroxyl, C 1 - 3 -alkyl and CI-2-haloalkyl; and 5 pharinaceutically acceptable derivatives thereof. - -6. Compound of Claim 5 -whereirr R- is substituted or -uns-u-bst-i-tut-ed-sel-e cted-from-(-3-=pyri-dy-) (CH) 2 -, (4 pyridy-]) -C-Hy- (4=pyriiddinyl) CH2~~~, -(5tp-yrimi'dinyl) -CH2 10 (6-pyrimidinyl) -CH 2 -, (4-pyridazinyl) -CH 2 -, (6-pyridazinyl) CH 2 -, 5-indazolyl-CH 2 -, 4-quinolinyl-CH2-, 6-quinolinyl-CH 2 -, pyrrolo [2, 3-b]pyridin-4-yl-CH 2 -, pyrrolo [2, 3-b]pyridin-5-yl CH 2 -, 5-isoquinolinyl-CH2- and 4 -quinazolinyl-CH 2 -; wherein R is unsubstituted or substituted with one or more 15 substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof. 7. Compound of Claim 1 wherein R is selected from 20 indazol-6-yl, (3-pyridyl)-(CH 2 ) 2 -, (4-pyridyl)-CH 2 -, pyrrolo [2 ,3-bjpyridin-4-yl-CH 2 -, pyrrolo [2, 3-b]pyridin-5-yl CH 2 -, 6-quinolinyl-CH 2 - and, 4-quinolinyl-CH 2 -; and pharmaceutically acceptable derivatives thereof. 25 8. Compound of Claim 1 wherein R6 is one or more substituents independently selected from H, halo, hydroxy, CI- 2 -alkoxy, CI- 2 -haloalkoxy, amino, CI-2-alkylamino, optionally substituted 5-6 membered heterocyclyl-C- 2 alkylamino, aminosulfonyl, C3- 6 -cycloalkyl, optionally 30 substituted 5-6 membered heterocyclyl, optionally substituted phenyl, C 1 . 4 -alkyl, cyano, Cl- 2 -hydroxyalkyl, C 1 . 3 carboxyalkyl, nitro, C 2 - 3 -alkenyl, C 2 - 3 -alkynyl and C 1 - 2 haloalkyl; and pharmaceutically acceptable derivatives thereof. WO 2005/021532 PCTIUS2004/027595 - 162 9. Compound of Claim 7 wherein R 6 is one or more substituents independently selected from H, chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, 5 dimeth rlami-noaminosulfonyl, carboxymethyl, cyclopropyl, opt i~6h5allynbstituted phenyl, methyl, ethyl, propyl, cyano, hydroxymethyl, nitro, propenyl, propynyl:-,-~trifluoromethyl and unsubstituted or substituted heteroaryl selected from thienyl,-fur-anyl~, ~5-tidyrl, ~imidiz'ol-yI, ana[lpyrazolyl; and 10 pharmaceutically acceptable derivatives thereof.
[4] 10. Compound of Claim 8 wherein R6 is H; and pharmaceutically acceptable derivatives thereof. 15 11. Compound of Claim 1 wherein R 1 is selected from unsubstituted or substituted 9-11 and 14 membered bicyclic saturated or partially saturated heterocyclyl; and pharmaceutically acceptable derivatives thereof. 20 12. Compound of Claim 11 wherein R' is selected from 1, 2-dihydroquinolyl, 1,2,3, 4 -tetrahydroquinolinyl, 1,4 benzodioxanyl, 2 -oxo-1,2-dihydroquinol-7-yl, 1-oxo-1,2,3,4 tetrahydro-isoquinolyl, 2,3-dihydro-1,1-dioxo benzo [dl isothiazolyl, 2, 3-dihydro-1H-indolyl, 2, 3-dihydro 25 benzofuryl, 1,2, 3 , 4 -tetrahydro-isoquinolyl, 2 , 3 ,4,4a,9,9a hexahydro-1H-3-aza-fluorenyl, and 5,6, 7-trihydro-1, 2,4 triazolo[3,4-alisoquinolyl;- where R' is unsubstituted or substituted with one or more substituents selected from bromo, chloro, fluoro, iodo, nitro, amino, cyano, 30 aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl, 4 methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, 1-methylpiperazin-4-ylmethyl, 1 methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1 y1methyl, 1-methylpiperidin-4-ylmethyl, 2-methyl-2- (1- WO 2005/021532 PCTIUS2004/027595 - 163 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, yL-eri-din=4-=ylp-rpyr, -1-Boc-piperidin-4-ylpropyl, piperidin 1-ylpropyl, pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl, 1 Boc-pyrrolidin-2-ylpropy- -pyrrolidin-1-ylmethyl, pyrroli-din-2-y-lmethyl-,--l-Boc-pyrrol-±diir-2-ylmethyl, -py-rre-fidi-nylpropen -yrrolidinylbuti-yl, fluorosulfonyl, 10 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 15 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, 20 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 25 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 30 piperidin-4-ylmethoxy, piperidin-4-ylmethoxy, 1 methylpiperidin-4-yloxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof. WO 2005/021532 PCTIUS2004/027595 - 164 13. Compounds of Claim 1 wherein R' is selected from unsubstituted or substituted 5-6 and 9-10 membered bicyclic heteroaryl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below 5 --- embodiments.optionally substituted with one or more substituents selected from halo, C 1 . 6 -alkyl, optionally substituted C3-6-cycloalkyl, -copt-i-onally substituted phenyl, optionally-subst-i-tuted-pheny-1--C -alkylenyl, C 1 -2 -haloalkoxy:,-optionally substituted phenyloxy,, optionally. 10 substituted 4-6 membered heterocyclyl-C 1 ..C 4 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 2 -C 4 -alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-Ca4-alkoxy, optionally 15 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, Ci- 4 -aminoalkyl, nitro, amino, hydroxy, cyano, 20 aminosulfonyl, C12-alkylsulfonyl, C1.4-alkylcarbonyl, C 1 . 3 alkylamino-CI-3-alkylcarbonylamino, Ci-3-alkylamino-C 13 -alkyl, C 1 -3 -alkylamino-C 1 .3-alkoxy, C 1 .. 3 -alkylamino-C 1 -3-alkoxy-C 1 .. 3 Rb Ra alkoxy, C1.4-alkoxycarbonyl, C1.4-hydroxyalkyl, 0 and CI. 4 -alkoxy; wherein Rc is selected from H, methyl, H, 25 piperidinylethyl and methoxyethoxyethyl; and wherein Ra and R are independently selected from H and trifluoromethyl; and pharmaceutically acceptable derivatives thereof; in conjunction with any of the above or below embodiments. 30
[5] 14. Compounds of Claim 13 wherein R is selected from thienyl, indolyl, pyridyl, 2 ,1, 3 -benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, WO 2005/021532 PCT/US2004/027595 - 165 quinazolinyl, furyl and pyrrolyl; oPtionally substituted with one or more substituents selected from morpholinylmethyl, 1-methylpiperazin-4-ylmethyl, 1 methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1 - 5-ymethylT 1-ethylpiperidin-4-ylmethyl, 2-methyl-2- (1 - -methylpiperidii 4-yl)-ethyl,~ morpholinylethyl, 1-(4 .. morpholinyl) -2, 2 -dimethylpropyl, piperidin-4-ylethyl, 1-Boc piperidin-4-y-ethy--,- pi-per-i-di-n-1-y-1-ethyl-; -- Boc-piperidin-4 -ylethyl-, -p-i-per-i-d-i-n-4-y-methyli--go!piper.idin-4-ylmethy1, 10 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, 3-ethoxycarbonyl 15 2-methyl-fur-5-yl, 4 -methylpiperazin-I-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, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, pyrrol-2 20 ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy. 1 methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperidin-4-ylmethoxy, piperidin-4-ylmethoxy, 1 methylpiperidin-4-yloxy, 1, 1-di (trifluoromethyl) -l (piperidinylethoxy)methyl, 4 -methylpiperazinylsulfonyl, Boc 25 piperidin-1-ylmethylcarbonyl, 4 -methylpiperazin-1 ylcarbonylethyl, dimethylaminomethyl-carbonylamino, bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc aminoethyl, hydroxy, oxo, aminosulfonyl, cyclohexyl, phenyl, phenylmethyl, fluorosulfonyl, methylsulfonyl, 30 methylcarbonyl, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1, 1-di (trifluoromethyl) -1- WO 2005/021532 PCTIUS2004/027595 - 166 hydroxymethyl, 1,1-di (trifluoromethyl) -i (methoxyethoxyethoxy) methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, -1-aminoethyl, 2 -aminoethyl, 1- (N isopropylamino) ethyl, 2- (N-isopropylamino) ethyl, -5 d-i-m-etKTh1minoeth5j5J; 4-chlorophenoxy, phenyloxy, isopropoxy, nethoxyand~ ethoxy; an7 pharmaceutically acceptable -- derivatives thereof;--in--conjunction -with any-oif the above or -be-1ow-embod-iments- 10
[6] 15. Compound of Claim 1 wherein R 1 is selected from phenyl optionally substituted with one or more substituents - optionally substituted C 3 - 6 cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C 1 -C 4 -alkylenyl, C1-2-haloalkoxy, 15 optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-Ci..C 4 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 2 -C 4 -alkenyl,' optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 20 membered heterocyclyl-Ci-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-Cl- 4 alkylcarbonyl, C1.. 2 -haloalkyl, C 1 . 4 25 aminoalkyl, nitro, amino, hydroxy, cyano, aminosulfonyl, C 1 2-alkylsulfonyl, C14-alkylcarbonyl, C13-alkylamino-C 1 - 3 alkylcarbonylamino, C13-alkylamino-C- 3 .- alkyl, C 1 3 alkylamino-C 1 3 -alkoxy, Cl -alkylamino-C3-alkoxy-Ca-alkoxy, R Ra C14-alkoxycarbonyl, C 1 4 -hydroxyalkyl, 0 and C 1 4 30 alkoxy; wherein Rc is selected from H, methyl, H, piperidinylethyl and methoxyethoxyethyl; and wherein Ra and R are independently selected from H and trifluoromethyl; and pharmaceutically acceptable derivatives thereof. WO 2005/021532 PCTIUS2004/027595 - 167 16. Compound of Claim 13 wherein R 1 is selected from phenyl optionally substituted with -one or more substituents selected from morpholinylmethyl, 1-methylpiperazin-4 5---y-lmethyl-r1aI--thlfVibeazin-4-ylpropyl, morpholinylpropyl, -TPiridir=n1ylmethyl~I-methfIiperidin-4 -ylmethyl, 2 methyl-2- (-1-methy-lpipe-ridin-4-yl) ethyl- morpholinylethyl, 1 -(4=morpholiny--)--2-,2-&di-methylpropyl-,-iperiLdi--=4-ylethyl, 1 Beec-p-per-i--in-4-yltethyl-7-piper-idif=17--e-th,1-JBoc - 10 piperidin-4-ylethyl, piperidin-4-ylmethyl, 1-Boc-piperidin 4-ylmethyl, piperidin-4-ylpropyl, 1-Boc-piperidin-4 -ylpropyr,-piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2 ylpropyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc 15 pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, 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 20 trifluoromethyl-1-piperidinyl, 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-piperidin-4-ylmethoxy, piperidin-4-ylmethoxy, 1-methylpiperidin-4-yloxy, 1,1 25 di (trifluoromethyl) -1- (piperidinylethoxy) methyl, 4 methylpiperazinylsulfonyl, Boc-piperidin-1-ylmethylcarbonyl, 4 -methylpiperazin-1-ylcarbonylethyl, dimethylaminomethyl carbonylamino, bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, 30 aminosulfonyl, cyclohexyl, phenyl, phenylmethyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, metihoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, WO 2005/021532 PCTIUS2004/027595 - 168 trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1,1-di(trifluoromethyl)-1 hydroxymethyl, 1,1-di(trifluoromethyl)-1 (methoxyethoxyethoxy) methyl, 1-hydroxyethyl, 2-hydroxyethyl, 5 --- trifluoromethoxy, 1-aminoethyl, 2 -aminoethyl, 1- (N - -sopropylamino) ethyl 2- (N-isopropylamino) ethyl, dimethylaminoethoxy, 4 --chlorophenoxy, phenyloxy,- isopropoxy, ethoxy-and-et-hoxy; and pharmaceutically acceptable derivatives thereof. 10
[7] 17. Compound of Claim 1 wherein R 1 is Rx RY wherein each of Rx and RY is independently selected from H, 15 bromo, chloro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, 1, 1-di (trifluoromethyl) -1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy, ethoxy, 4 methylpiperazinylsulfonyl, morpholinylmethyl, 4 20 methylpiperazinylmethyl, 4 -methylpiperazinylpropyl, 4 isopropylpiperazinylmethyl, 4 -methylpiperidinylmethyl, 4 aminopiperidinylmethyl, 4 -methylamino-piperidinylmethyl, 4 dimethylamino-piperidinylmethyl, 3 -dimethylaminopyrrolidin 1-ylmethyl, 1-methylpyrrolidin:-2-ylmethyl, 25 dimethylaminoethyl, dimethylaminoethoxy, piperidinylethoxy, morpholinylethyloxy, 4 -methylpiperazinylethoxy, 4 isopropylpiperazinylmethoxy, piperidin-4-methoxy, 4 methylpiperidin-1-ylmethoxy, 1-methylpyrrolidin-2-ylmethoxy, 1-methylpyrrolidin-3-ylmethoxy, 1-isopropylpyrrolidin-2 30 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 3 (dimethylamino)pyrrolidin-1-ylethoxy, 2-(N,N dimethylamino)acetylamino and 2-(N,N- WO 2005/021532 PCTIUS2004/027595 - 169 dimethylamino) ethylamino; and pharmaceutically acceptable derivatives thereof.
[8] 18. Compound of Claim 17 wherein R7 is selected from 5 chTao; te-Yt~ntyl, trifluoromethyl, pentafluoroethyl, 1,1 di(trif1Iuor-o-eth-I) -l-hydrboxyinethyl, and trifluoromethoxy; and-pharmaceutically -acceptable derivatives thereof. - 19- Compound-of-Claim--17 wherein-each of R is selected 10 from H, bromo, chloro, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 1., 1-di (trifluoromethyl) -1-hydroxymethyl, tfruoromethoxy, difluoromethoxy, isopropoxy, methoxy, ethoxy, 4 -methylpiperazinylsulfonyl, morpholinylmethyl, 4 metbylpiperazinylmethyl, 4 -methylpiperazinylpropyl, 4 15 isopropylpiperazinylmethyl, 4 -methylpiperidinylmethyl, 4 aminopiperidinylmethyl, 4 -methylamino-piperidinylmethyl, 4 dimethylamino-piperidinylmethyl, 3-dimethylaminopyrrolidin 1-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, dimethylaminoethyl, dimethylaminoethoxy, piperidinylethoxy, 20 morpholinylethyloxy, 4 -methylpiperazinylethoxy, 4 isopropylpiperazinylmethoxy, piperidin-4-methoxy, 4 methylpiperidin-1-ylmethoxy, 1-methylpyrrolidin-2-ylmethoxy, 1-methylpyrrolidin-3-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 3 25 (dimethylamino)pyrrolidin-1-ylethoxy, 2-(N,N dimethylamino) acetylamino and 2- (N,N dimethylamino) ethylamino; and pharmaceutically acceptable derivatives thereof. 30 20. Compound of Claim 1 wherein R1 is selected from substituted or unsubstituted phenyl-C.. 2 -alkyl; and pharmaceutically acceptable derivatives thereof. WO 2005/021532 PCTIUS2004/027595 - 170 21. Compound of Claim 20 wherein R 1 is selected from 3-trifluoromethylphenylmethyl, 3-trifluoromethylphenylethyl, 3-methoxyphenylmethyl, phenylethyl, 4-methoxyphenylethyl, 3, 4-dimethoxyphenylethyl, 4-methylphenylethyl, 2 5 -fluorophenylethyl ,3-fluorophenylethyl, 2-chlorophenylethyl, -hlorojienylethyl, 3, 4dichlorophenylethyl, and 3,5 -- d-ichlorophenylethyl; and -pharmaceutically acceptable - derivatives -thereof E. -__ 10 22. Compound of Claim 1 of Formula I R 5 R KNH KR7 wherein R 1 is selected from unsubstituted or substituted. 15 a) 6-10 membered aryl, b) 5-6 membered heterocyclyl, c) 9-14 membered fused heterocyclyl, and d) phenyl-C- 3 -alkyl, wherein substituted R 1 is substituted with one or more 20 substituents independently selected from halo, -OR 3 , SR 3 , -CO 2 R 3 , -C(O)NR 3 R, -C(O),R 3 , -NR 3 R 3 , oxo,. -OC (0) R 3 , -SO 2 R 3 , -SO 2 NR 3 R 3 , -NR 3 C(O)OR 3 , -NR 3 C(O)R, -NR 3 C(O)NRR 3 , optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, optionally 25 substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower alkyl substituted with one or more R 2 ; wherein R 2 is selected from H, halo, hydroxy, alkoxy, optionally substituted phenyl, optionally substituted WO 2005/021532 PCTIUS2004/027595 - 171 phenyl-C 1 - 3 -alkyl, 4-6 membered heterocyclyl, and optionally substituted 4-6 membered heterocyclyl-C.-C3 alkyl; wherein R3 is independently selected from H, lower alkyl, 5~ ptiIly substituted phenyl, optionally substituted 3-6 - memberedterd-yclyl~,~ optionally substituted C 3 -C 6 cycloalkyl,- eptiona-l-ly- substituted -phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optional-y--substtte-d:.C 3 -yC-ycloalkylalky -and -lower 10 haloalkyl; wherein R 5 is H, methyl or hydroxy; and -whieri R is selected from substituted or unsubstituted 6 membered and 9-10 membered heteroaryl; where substituted R7 is substituted with one or more substituents selected 15 from halo, -OR 3 , -SR3, -SO 2 R 3 ,-C0 2 R 3 , -C(O)NR 3 R 3 , -C(0)R 3 , NR 3 R 3 , -SO 2 NR 3 R 3 , -NR 3 C (O) OR, -NR 3 C (0) R 3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R 2 ; 20 and pharmaceutically acceptable derivatives thereof.
[9] 23. Compound of Claim 22 wherein R1 is selected from phenyl substituted with -one or more substituents independently selected from halo, -OR 3 , -SR 3 , -C0 2 R 3 , 25 C(O)NRR 3 , -C(O)R 3 , -NR 3 R 3 , oxo, -OC(O)R 3 , -S0 2 R 3 , -SO 2 NR 3 R 3 , NR 3 C (0) OR 3 , -NR 3 C (0) R 3 , -NR 3 C (O) NR 3 R 3 , optionally substituted C 3 - 6 -cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, C 1 - 3 alkylamino-Ci-3 -alkoxy, CI-3-alkylamin-C 1 . -3 -alkoxy-C.. 3 -alkoxy, 30 nitro, and lower alkyl substituted with one or more R2 wherein R 2 is selected from H, fluoro, hydroxy, amino, Ci-3-alkylamino, C1.3-dialkylamino, optionally- substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, WO 2005/021532 PCTIUS2004/027595 - 172 piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R3 is independently selected from H, C 1 . 4 5 - ~[Ikyl, ~CI 2 -fluoroalkyl, optionally substituted phenyl, -- optionally substituted 3-6 membered heterocyclyl selected -- from morpho-linyl-,-pi-peraz-i-n--4-yl-- -and pi-peridin-4-yl, ---- opt-i-onal-ly substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C 1 2 -alkyl wherein the heterocylyl 10 ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof. 15 24. Compound of Claim 23 wherein R1 is selected from phenyl substituted with 1-3 substituents independently selected from bromo, chloro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 20 trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof.
[10] 25. Compound of Claim 22 wherein R 1 is selected from substituted or unsubstituted 5-6 membered or 9-10 membered 25 fused patially unsaturated heterocyclyl and heteroaryl; wherein substituted R 1 is substituted with one or more substituents independently selected from halo, -OR , -SR , C0 2 R 3 , -C(0)NR 3 R 3 , -C(0)R 3 , -NR 3 R 3 , oxo, -OC(0)R 3 , -S0 2 R 3 , SO 2 NR 3 R 3 , -NR 3 C (0) OR 3 , -NR 3 C (0) R', -NR 3 C (0) NR 3 R 3 , optionally 30 substituted C 3 . 6 -cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower alkyl substituted with one or more R2 WO 2005/021532 PCTIUS2004/027595 - 173 wherein R 2 is selected from H, fluoro, hydroxy, amino, C 1 - 3 -alkylamino, C1. 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, 5 p-rfiidh-in-yl~~-methylpiperidin-4-y, 1-Boc-piperidin-4 -yl, pyrraTid- 1 ,~: >9rrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl-;-and -- wherein- R'isr-indep-endent-y 1-tdfrom H, alkyl-Cc-2~f&lu-o-alkyl,-optiodnallyisubstituted -phenyl-,- 10 optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-CI- 2 -alkyl wherein the heterocylyl ring is selected from selected from azetidin-3-yl, pyrrol-2 15 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof.
[11] 26. Compound of Claim 25 wherein R 1 is a substituted or .unsubstituted ring selected from pyrazol-5-yl, 2-oxo-1,2 20 dihydroquinol-7-yl, 1-oxo-., 2,3 ,4-tetrahydro-isoquinolyl, 2, 3-dihydro-1, 1-dioxo-benzo[d] isothiazolyl, benzothiazolyl, 2, 3-dihydro-1H-indolyl, 2,3-dihydro-benzofuryl, 1,2,3,4 tetrahydro-isoquinolyl, quinolyl, isoquinolyl, 1,2,3,4 tetrahydroquinolyl and 5, 6,7-trihydro-1,2,4-triazolo[3,4 25 a]isoquinolyl; wherein substituted R' is substituted with 1 3 substituents independently selected from bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, 30 methylpiperazinylmethyl, isopropyl-piperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1- (4 morpholinyl) -2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, 1- WO 2005/021532 PCTIUS2004/027595 - 174 methylpyrrolidinylmethyl, pyrrolidinylpropyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, 5 trifluoromethyl, pentafluoroethyl, nonafluorobutyl, 1,1 d-triflfuoromethrl) -I-hydroxymethyl, 1,1 di (t-r-i fluoromethyl-)- l-tpi-peridinylethoxy)-mathyl, 1, 1 d-i-(-t-rif-l-uoromehthyl-) (e-th-oxyeth-oxythtoxy)methyl, 1 hydroxyethyl,r2=hydzoxyethyl, hydroxybu-tyl,_ di-fluoromethoxy, 10 trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1- (N isopropylamino) ethyl, 2- (N-isopropylamino) ethyl., dimethylaminopropyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, 1-methylpiperidin-4-yloxy, piperidin-4-yloxy, piperidinylethoxy, morpholinylethyloxy, 4 15 methylpiperazinylethoxy, 4-isopropylpiperazinylethoxy, piperidin-4-methoxy, 4 -methylpiperidin-1-ylmethoxy, 1 methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1 methylpyrrolidin-3-ylmethoxy, 3- (dimethylamino) pyrrolidin-l 20 ylethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof.
[12] 27. Compound of Claim 26 wherein R 1 is substituted with 1-3 substituents independently selected from chloro, fluoro, 25 amino, aminoethyl, hydroxy, methyl,. ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, 1, 1-di (trifluoromethyl) 1-hydroxymethyl, methylcarbonyl, trifluoromethoxy, 1 methylpiperidin-4-yloxy, piperidin-4-yloxy, 30 piperidinylethoxy, morpholinylethyloxy, 4 methylpiperazinylethoxy, 4 -isopropylpiperazinylethoxy, piperidin-4-methoxy, 4-methylpiperidin-1-ylmethoxy, 1 methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1- WO 2005/021532 PCTIUS2004/027595 - 175 methylpyrrolidin-3-ylmethoxy, 3- (dimethylamino) pyrrolidin-1 ylethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof. 3 _28~. Compound of Claim 22 wherein R' is selected from -3zrifliffoinmethylihe-nylmethyl, 3 -tri fluoromethylphenylethyl, - 3-methoxyphenylmethyl, phenylethyl, 4-methoxyphenylethyl, 3, 4--Tdiiethoxypheny-ethyl---4=Methylph-enyl ethyl, 2 -flurophenylethyr,_~-3 -ffibfopheny~Lethyl., 2-chlorophenyl ethyl, 10 4-chlorophenylethyl, 3,4-dichlorophenylethyl, and 3,5 dichlorophenylethyl; and pharmaceutically acceptable derivatives thereof.
[13] 29. Compound of Claim 22 wherein R 7 is selected from 15 substituted or unsubstituted 6 membered nitrogen containing heteroaryl, where substituted R 7 is substituted with one or more substituents selected from halo, -OR , -SR 3 , _S0 2 R 3 , C0 2 R 3 , -C(O)NR 3 R 3 , -C(O)R', -NR 3 R 3 , -SO 2 NR 3 R 3 , -NR 3 C (O) OR, NR 3 C(O)R 3 , optionally substituted 3-6 membered heterocyclyl, 20 optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R 2 ; wherein R2 is selected from H, fluoro, hydroxy, amino, Ci- 3 -alkylamino, C 1 .- 3 -dialkylamino, optionally substituted 25 phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and 30 wherein R 3 is independently selected from H, C 1 . 4 alkyl, CI- 2 -fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted WO 2005/021532 PCTIUS2004/027595 - 176 3-6 membered heterocyclyl-Ci- 2 -alkyl wherein the heterocylyl ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-l-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof. 5 ------ 30. Compound of Claim 29 wherein R 7 is selected from 4 pyridyl, 4-pyrimid-i-nyl-,-5-pyrimidinyl, 6-pyrimidinyl, 4 -- p yridaz-iny-ny-and--pharmaceutically aceept-ab-le derivatives- thereof. 10
[14] 31. Compound of Claim 22 wherein R 7 is selected from substituted or unsubstituted-9-10 membered nitrogen containing heteroaryl, where substituted R 7 is substituted with one or more substituents selected from halo, -OR, 15 SR, -S0 2 R 3 ,-CO 2 R 3 , -C(O)NRR 3 , -C(O)R, -NR 3 R', -SO 2 NR 3 R, NR 3 C (0) OR 3 , -NR 3 C(O)RR, Boc, optionally substituted 3-9 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R 2 ; 20 wherein R2 is selected from H, fluoro, hydroxy, amino, C 1 - 3 -alkylamino, Ci-3-dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 25 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R3 is independently selected from H, CI 4 alkyl, C 1 - 2 -fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected 30 from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C 1 -2-alkyl wherein the heterocylyl ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; WO 2005/021532 PCTIUS2004/027595 - 177 and pharmaceutically acceptable derivatives thereof.
[15] 32. Compound of Claim 31 wherein R 7 is selected from 5 indazolyl, 4-quinolinyl, 6-quinolinyl, pyrrolo[2,3 5 b]pyridin-4-yl, pyrrolo [2, 3-b]pyridin-3-yl, 5-isoquinolinyl -id4-iia61yl; and pharmaceutically acceptable derivatives--thereof -33. Compoundof-Clim-22 herein R1 is selected from 10 4-tertbutylphenyl, 3, 3-dimethyl-2 , 3-dihydroindolyl, 1 acetyl-3,3-dimethyl-2,3-dihydroindolyl, 3-tert-butylpyrazol 5-yl, 4 , 4 -dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 4,4 dimethyl-2- (3-pyrrolo[2,3-b]pyridinyl) -1,2,3,4 tetrahydroisoquinolin-7-yl, and 4,4-dimethyl-2- (Boc) 15 1,2,3,4-tetrahydroisoquinolin-7-yl; wherein R 5 is H; and wherein R 7 is selected from 6-quinolinyl, pyrrolo[2,3 b]pyridin-3-yl, 4-pyridyl and 3-aminopyrid-4-yl; and pharmaceutically acceptable derivatives thereof. 20 34. Compound of Claim 22 and pharmaceutically acceptable salts thereof selected from 2-(4-(1,1-dimethylethyl)phenyl)-7-((4 pyridinylmethyl) amino) -2, 3 -dihydro-lH-isoindol-l-one; 25 2- (1-acetyl-3,3-dimethyl-2,3-dihdyro-H-indol-6-yl) -7 [(pyridin-4-ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; 2- (3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -7- [ (pyridin-4 ylmethyl) -amino ]-2, 3-dihydro-isoindol-l-one; 2- (4, 4-dimethyl-1,2,3, 4-tetrahydro-isoquinolin-7-yl) -7 30 [(pyridin-4ylmethyl) -amino ]-2, 3-dihydro-isoindol-l-one; 2- (4-tert-butyl-phenyl) -7- [ (1H-pyrrolo [2,3-b]pyridin-3 ylmethyl) -amino] - 2 ,3-dihydro-isoindol-l-one ; 2- (5-tert-butyl-2H-pyrazol-3-yl) -7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-l-one; WO 2005/021532 PCTIUS2004/027595 - 178 2- ( 4 , 4 -dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl) -7 [(quinolin-6-ylmethyl) -amino] -2, 3 -dihydro-isoindol-1-one; 4, 4-dimethyl-7-{1-oxo-7- [ (1H-pyrrolo [2, 3-b]pyridin-3 ylmethyl) -amino] -1,3-dihydro-isoindol-2-yl} -3, 4-dihydro 5 1H-isoquinoline-2-carboxylic acid tert-butyl ester; 2- (47T 4 tdimethr-l~,~ 3~,74 tetrahydro-isoquinolin-7-yl) -7- [1H pyrrol [2, 3 -b] py-r-idin-3-ylmethyl) -aminoj2-; 3=dihydro i-soindol-1-one=,--arId- - --2--f 4 --4diamethyl--2=-(ltiHpyrrolo [2, 3-b] pyridin-3 -ylmethyl) 10 1,2,3, 4 -tetrahydro-isoquinolin-7-yl-7-(1H-pyrrolo[2,3 b]pyridin-3-ylamino) -2, 3-dihydro-isoindol-1-one.
[16] 35. Compound of Claim 1 of Formula III R 5 R 1 N iO N NH 15 R 7 wherein R1 is selected from unsubstituted or substituted a) 6-10 membered aryl, b) 5-6 membered heterocyclyl, 20 c) 9-14 membered fused heterocyclyl, and d) phenyl-C 1 3 -alkyl, wherein substituted R 1 is substituted with one or more substituents independently selected from halo, -OR 3 , _ SR 3 , -C0 2 R 3 , -C(O)NRR 3 , -C(O)R 3 , -NR 3 R 3 , oxo, -OC(O)R 3 , 25 -SO 2 R 3 , -SO 2 NR 3 R 3 , -NR 3 C(O)OR 3 , -NR 3 C(O)R 3 , -NR 3 C (O) NR 3 R, optionally substituted cycloalkyl, optionally substituted 4-9 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, WO 2005/021532 PCTIUS2004/027595 - 179 alkylaminoalkoxyalkoxy, nitro, and lower alkyl substituted with one or more R2 . wherein R 2 is selected from H, -halo, hydroxy, alkoxy, optionally substituted phenyl, optionally substituted 5 phenyl-C 1 - 3 -alkyl, 4-6 membered heterocyclyl, and op-t-i-ohnlTysuibititnted 4-6 membered heterocyclyl-C 1 .C 3 -al-kyl; wherein R 3 is independently selected from H, lower alkyl, opt-ionall1,sutistitutled phe--yl,-optionally substituted 3-6 10 membered heterocyclyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted phenylalkyl, Thj5tiofially substituted 3-6 membered heterocyclylalkyl, optionally substituted C 3 -C 6 cycloalkylalkyl and lower haloalkyl; 15 wherein R 5 is H, methyl or hydroxy; and wherein R is selected from substituted or unsubstituted 6 membered and 9-10 membered heteroaryl; where substituted R 7 is substituted with one or more substituents selected from halo, -OR 3 , -SR 3 , -S0 2 R 3 ,-C0 2 R 3 , -C(O)NRR 3 , -C(O)R, 20 NR 3 R 3 , -SO 2 NR 3 R 3 , -NR 3 C (0) OR', -NR 3 C (0) R 3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R 2 and pharmaceutically acceptable derivatives thereof. 25
[17] 36. Compound of Claim 35 wherein R 1 is selected from phenyl substituted with one or more substituents independently selected from halo, -OR 3 , -SR 3 , -C0 2 R 3 , C (0) NRR 3 , -C (O) R 3 , -NR 3 R 3 , oxo, -OC(O)R 3 , -S0 2 R 3 , -SO 2 NR 3 R 3 , 30 NR 3 C(0)OR 3 , -NR 3 C(0)R 3 , -NR 3 C(O)NR 3 R 3 , optionally substituted C 3 _ 6 -cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, C 1 - 3 alkylamino-C 1 .- 3 -alkoxy, C 1 - 3 -alkylamino-Cl-3-alkoxy-C 1 . 3 -alkoxy, nitro, and lower alkyl substituted with one or more R2 WO 2005/021532 PCTIUS2004/027595 - 180 wherein R 2 is selected from H, fluoro, hydroxy, amino, Ci-3-alkylamino, C-3-dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, 5 piVeridin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 ylT--pyrroli-dir-1-y tyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl.; and where-in--Ri---s-i-ndependently--s-l-e-cted- from H, C 1 4 al-kyl-f-uf-flu-orgaky ,~~pItionally- substituted- phenyl,. 10 optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-Ci-2-alkyl wherein the heterocylyl ring is selected from selected from azetidin-3-yl, pyrrol-2 15 yl, pyrrol-1-yl, piperidin-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof.
[18] 37. Compound of Claim 36 wherein R 1 is selected from 20 phenyl substituted with 1-3 substituents independently selected from bromo, chloro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, 1, 1-di (trifluoromethyl) -1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy and 25 ethoxy; and pharmaceutically acceptable derivatives thereof.
[19] 38. Compound of Claim 35 wherein R' is selected from substituted or unsubstituted 5-6 membered or 9-10 membered fused patially unsaturated heterocyclyl and heteroaryl; 30 wherein substituted R1 is substituted with one or more substituents independently selected from halo, -OR 3 , -SR 3 _ C0 2 R 3 , -C(O)NR 3 R 3 , -C(0)R 3 , -NR 3 R 3 , oxo, -OC(O)R 3 , -S0 2 R 3 , _ SO 2 NR 3 R 3 , -NR 3 C (0) OR 3 , -NR 3 C (0) R 3 , -NR 3 C (0) NR 3 R 3 , optionally substituted C 3 6 -cycloalkyl, optionally substituted 4-6 WO 2005/021532 PCTIUS2004/027595 - 181 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower alkyl substituted with one or more R2; wherein R 2 is selected from H, fluoro, hydroxy, amino, 5 C 1 . 3 -alkylamino, C 1 . 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered-heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 10 2-yl; and wherein R 3 is independently selected from H, C 14 alkyl, C 1 2 -fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, 15 optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C 1 2 -alkyl wherein the heterocylyl ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof. 20
[20] 39. Compound of Claim 38 wherein R1 is a substituted or unsubstituted ring selected from pyrazol-5-yl, 2-oxo-1,2 dihydroquinol-7-yl, 1-oxo-1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1.,l-dioxo-benzo[dlisothiazolyl, benzothiazolyl, 25 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzofuryl, 1,2,3,4 tetrahydro-isoquinolyl, quinolyl, isoquinolyl, 1,2,3,4 tetrahydroquinolyl and 5,6,7-trihydro-1,2,4-triazolo[3,4 a]isoquinolyl; wherein substituted R' is substituted with 1-3 substituents independently selected from bromo, chloro, 30 fluoro, iodo, nitro, amino, cyano, aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, isopropyl-piperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, WO 2005/021532 PCTIUS2004/027595 - 182 methylpiperidinylmethyl, morpholinylethyl, 1- (4 morpholinyl) -2,2-dimethylpropyl, Piperidinylethyl, piperidinylmethyl, piperidinylpropyl, 1 methylpyrrolidinylmethyl, pyrrolidinylpropyl, 5 -- methylszulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, -methyl-piperzazinylcarborlylethyl, methoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, tri f-l-uer-ome-t-hy-l-,-pen-ta-f-l-uoroethyl-, onafluorobutyl;- 1, 1 d-i (-tri fluoromethy:j - hydroxymethyl;1.,1- . 10 di (trifluoromethyl) -1- (piperidinylethoxy)methyl, 1,1 di (trifluoromethyl) -1- (methoxyethoxyethoxy) methyl, 1 --hydrcxyethyl, 2-hydroxyethyl, hydroxybutyl, difluoromethoxy, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1- (N isopropylamino) ethyl, 2- (N-isopropylamino) ethyl, 15 dimethylaminopropyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, 1-methylpiperidin-4-yloxy, piperidin-4-yloxy, piperidinylethoxy, morpholinylethyloxy, 4 methylpiperazinylethoxy, 4 -isopropylpiperazinylethoxy, piperidin-4-methoxy, 4 -methylpiperidin-1-ylmethoxy, 1 20 methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1 methylpyrrolidin-3-ylmethoxy, 3- (dimethylamino) pyrrolidin-1 ylethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable derivatives thereof. 25
[21] 40. Compound of Claim 39 wherein R 1 is substituted with 1-3 substituents independently selected from chloro,- fluoro, amino, aminoethyl, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, 30 pentafluoroethyl, nonafluorobutyl, 1, 1-di (trifluoromethyl) 1-hydroxymethyl, methylcarbonyl, trifluoromethoxy, 1 methylpiperidin-4-yloxy, piperidin-4-yloxy, piperidinylethoxy, morpholinylethyloxy, 4 methylpiperazinylethoxy, 4 -isopropylpiperazinylethoxy, WO 2005/021532 PCTIUS2004/027595 - 183 piperidin-4-methoxy, 4 -methylpiperidin-1-ylmethoxy, 1 methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2 ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1 methylpyrrolidin-3-ylmethoxy, 3-(dimethylamino)pyrrolidin-1 5 -ylethoxy, isopropoxy, methoxy and ethoxy; and --- pharmaceutically acceptable derivatives thereof. _41_. Compou-nd-of1-a-i-m--3-wherein--R i selected from 3 -- tr-i-f--ur-methylpheny-Jmethyll, 3-trifluoromethylpheny-lethyl, 10 3 -methoxyphenylmethyl, phenylethyl, 4 -methoxyphenylethyl, 3, 4 -dimethoxyphenylethyl., 4 -methylphenylethyl, 2 fluorophenylethyl, 3 -fluorophenylethyl, 2-chlorophenylethyl, 4 -chlorophenylethyl, 3, 4 -dichlorophenylethyl, and 3,5 dichlorophenylethyl; and pharmaceutically acceptable. 15 derivatives thereof.
[22] 42. Compound of Claim 35 wherein R 7 is selected from substituted or unsubstituted 6 membered nitrogen containing heteroaryl, where substituted R 7 is substituted with one or 20 more substituents selected from halo, -OR 3 , -SR 3 , -SO 2 R,_ C0 2 R 3 , -C (O) NR 3 R 3 , -C (O) R 3 , -NR 3 R 3 , -SO 2 NR 3 R 3 , -NR 3 C (0) OR, NR3C (0) R 3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more 25 R 2 ; wherein R2 is selected from H, fluoro, hydroxy, amino, Ci- 3 -alkylamino, Ci_ 3 -dialkylamino, optionally substituted phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, 30 piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and wherein R 3 is independently selected from H, CI 4 alkyl, C-2-fluoroalkyl, optionally substituted phenyl, WO 2005/021532 PCTIUS2004/027595 - 184 optionally substituted 3-6 membered heterocyclyl selected from morpholinyl - piperazin-4-yl, and Piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted 3-6 membered heterocyclyl-C1--2-alkyl wherein the heterocylyl ---- 5---r4ng- is -selected-froi~~selected from azetidin-3-yl, pyrrol-2 y-PYir--Y1-lpilerdi=4-.yl ad piperazin-4-yl; andpharmace utically acceptable- derivatives thereof. -- C-empeu-nd -of-C--a im-4-2-wherein R 7 is selected from 4 10 pyridyl,. 4 -pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 4 pyridazinyl and 6-pyridazinyl; and pharmaceutically - -acceptable-derivatives thereof.
[23] 44. Compound of Claim 35 wherein R 7 is selected from 15 substituted or unsubstituted 9-10 membered nitrogen containing heteroaryl, where substituted R 7 is substituted with one or more substituents selected from halo, -OR, SR 3 , -SO 2 R3,-CO 2 R3, -C(0)NR 3 R 3 , -C(O)R 3 , -NR 3 R 3 , -SO 2 NR 3 R 3 _ NR 3 C(O)OR3, -NR 3 C(O)R 3 , Boc, optionally substituted 3-9 20 membered heterocyclyl, optionally substituted phenyl, alkylaminoalkoxyalkoxy, nitro, cyano, oxo, lower alkyl substituted with one or more R2 wherein R2 is selected from H, fluoro, hydroxy, amino, Ci-3-alkylamino, CI-3-dialkylamino, optionally substituted 25 phenyl, and 4-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, 1-methylpiperazin-4-yl, piperidin-1-yl, 1-methylpiperidin-4-yl, 1-Boc-piperidin-4 yl, pyrrolidin-1-yl, pyrrolidin-2-yl, and 1-Boc-pyrrolidin 2-yl; and 30 wherein R 3 is independently selected from H, CI- 4 alkyl, C1.2-fluoroalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl selected from morpholinyl, piperazin-4-yl, and piperidin-4-yl, optionally substituted phenylmethyl, optionally substituted WO 2005/021532 PCTIUS2004/027595 - 185 3-6 membered heterocyclyl-C 1 2 -alkyl wherein the heterocylyl ring is selected from selected from azetidin-3-yl, pyrrol-2 yl, pyrrol-1-yl, piperidin-4-yl and piperazin-4-yl; and pharmaceutically acceptable derivatives thereof. 4 .'Compoundof Claim 4 eren R 7 is selected from 5 indazolyl, 4-quinolinyl, 6-quinolinyl, pyrrolo[2,3 b] pyr-idin- 4-yl -pyr6I-&[-2-,3 bpyridin3~y15-isoquifidlinyl -and 4-qxina'zerliny1; and-~pharmaceuTiaeIy Nept-able 10 derivatives thereof. 6. Compouin of Claim 35 wherein R- is selected from 4-tertbutylphenyl, 3, 3-dimethyl-2, 3-dihydroindolyl, 1 acetyl-3,3-dimethyl-2,3-dihydroindolyl, 3-tert-butylpyrazol 15 5-yl, 4 , 4 -dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 4,4 dimethyl-2-(3-pyrrolo[2,3-b]pyridinyl)-1,2,3,4 tetrahydroisoquinolin-7-yl, and 4, 4-dimethyl-2- (Boc) 1, 2 ,3,4-tetrahydroisoquinolin-7-yl; wherein R 5 is H; and and wherein R 7 is selected from 6-quinolinyl, pyrrolo[2,3 20 b]pyridin-3-yl, 4-pyridyl and 3-aminopyrid-4-yl; and pharmaceutically acceptable derivatives thereof.
[24] 47. Compound of Claim 35 and pharmaceutically acceptable salts thereof selected from 25 2- (4-tert-Butyl-phenyl) -4- [ (pyridin-4-ylmethyl) -amino] -1,2 dihydro-pyrrolo [3, 4-c]pyridin-3-one; 2- (4- tert-Butyl-phenyl) -4- [ ( 2 -methylamino-pyrimidin-4 ylmethyl)-amino]-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one; 30 2- (4- tert-butyl-phenyl) -4- [ ( 2 -methoxy-pyridin-4-ylmethyl) amino]-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one; 4-[ (2-amino-pyridin-4-ylmethyl) -amino] -2- (4-tert-butyl phenyl)-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one; and WO 2005/021532 PCTIUS2004/027595 - 186 2- (4- tert-Butyl-phenyl) -l-hydroxy-4- [ (pyridin-4-ylmethyl) amino] -1, 2 -dihydro--pyrrolo [3, 4 -c]pyridin-3-one.
[25] 48. Compound of Claim 1 and pharmaceutically 5 acceptable-- a-1t-a--the-t-e-f~ -selected from 2- (4- (1, 1-dimethylethyl) phenyl-)-7-( ( 4 -pyridinylmethyl) amino) -2, 3 -dihydro-lH-isoindol-1-one; 7- [ (qu-i-nol-i-n--methyi-)---ami-no ]-=2-=-[ 3- (tetrahydto=furan-3- - 10 yloxy)-5-trifluoromethyl-phenyl]-2,3-dihydro-isoindo1-1 one; 4-4=dime-thyl=-71 co-7- [ (quinolin-6-ylmethyl) -amino] -1, 3 dihydro-isoindol-2-yl-3 , 4 -dihydro-1H-isoquinoline-2 carboxylic acid tert-butyl ester; 15 2- ( 4 -tert-butyl-phenyl) -7- [ ( 2 -methoxy-pyridin-4-ylmethyl) amino] -2, 3 -dihydro-isoindol-1-one; 2 -(4-sec-butyl-phenyl) -7- [ (pyridin-4-ylmethyl) -amino] -2,3 dihydro-isoindol-l-one; 2- (4-sec-butyl-phenyl) -7- ( 4 -fluoro-benzylamino) -2, 3-dihydro 20 isoindol-l-one; 2 -(4-sec-butyl-phenyl)-7-[(quinolin-6-ylmethyl)-amino]-2,3 dihydro-isoindol-l-one; 2- ( 4 -sec-butyl-phenyl) -7- [ ( 2 -methoxy-pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 25 2-1[4- ( 2 -methoxy-1,1-dimethyl-ethyl) -phenyl]-7- [ (quinolin-6 ylmethyl) -amino] -2, 3 -dihydro-isoindol-1-one; 2-[4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-7-[(pyridin-4 ylmethyl) -amino] -2, 3 -dihydro-isoindol-1-one; 2- ( 4 -phenoxy-phenyl) -7- [(quinolin-6-ylmethyl) -amino] -2,3 30 dihydro-isoindol-l-one; 2- ( 4 -phenoxy-phenyl) -7- [(pyridin-4-ylmethyl) -amino] -2,3 dihydro-isoindol-l-one; 7- [ ( 2 -methoxy-pyridin-4-ylmethyl) -amino] -2- (4-phenoxy phenyl) -2, 3-dihydro-isoindol-1-one; WO 2005/021532 PCTIUS2004/027595 - 187 2- ( 4 -tert-butyl-phenyl) -7- [ (quinolin-6-ylmethyl) -amino] -2,3 - dihydro-isoindol-1-one; 2- [4, 4-dimethyl-2 - (1H-pyrrolo [2, 3 -b] pyridin-3 -ylmethyl) 1, 2, 3, 4 -tetrahydro-isoquinolin-7-yl ] -7- (1H-pyrrolo [2, 3 5 blpyridin-3-ylamino) -2, 3-dihydro-isoindol-1-one; 2- (-I=acetyl-3, 3-diftthI:2, 3-dihydro-1H-indol-6-yl) -7 S[(-pyridin-4-y-1-met-hyl-)-amino-]--273-dihydro-isoindol-1-one; - --2 --(-33--d-imethyl- -3--di-hydro--H-i-ndo1-6 yl)7 -7= [~(pyridin-4 - - y-lmethy1-amin o 3=hydroisoindol-1- one;' 10 7-.[ (pyridin-4-ylmethyl) -amino] -2- ( 4 -trifluoromethyl-phenyl) 2, 3-dihydro-isoindol-1-one; 2- (3-tert-butyl-phenyl) -7- [(pyridin-4-ylmethyl) -amino] -2,3 dihydro-isoindol-1-one; 2- (4, 4-dimethyl-1,2,3, 4-tetrahydro-isoquinolin-7-yl) -7 15 [(pyridin-4ylmethyl) -amino] -2, 3 -dihydro-isoindol-1-one; 2-phenethyl-7- [ (pyridin-4-ylmethyl) -amino] -2, 3-dihydro isoindol-1-one; 2- [2- (4-methoxy-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 20 2- [2- (3, 4-dimethoxy-phenyl) -ethyl] -7- [(pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 7-[ (pyridin-4-ylmethyl)-amino] -2- (2-p-tolyl-ethyl) -2,3 dihydro-isoindol-1-one; 2- [2- (2-fluoro-phenyl) -ethyl] -7-[ (pyridin-4-ylmethyl) 25 amino] -2, 3-dihydro-isoindol-1-one; 2- [2- (4-chloro-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 2- [2- (2-chloro-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 30 2- [2- (3,4-dichloro-phenyl)-ethyl]-7- [(pyridin-4-ylmethyl) amino] -2, 3-dihydro-isoindol-1-one; 2- [2- (3-f luoro-phenyl) -ethyl] -7- [ (pyridin-4-ylmethyl) amino] -2, 3 -dihydro-isoindol-1-one; WO 2005/021532 PCTIUS2004/027595 - 188 7- [ (pyridin-4-ylmethyl) -amino] -2- [2- ( 3 -trifluoromethyl phenyl)-ethyl]-2,3-dihydro-isoindol-1-one; 2- [2- (2,4-dichloro-phenyl)-ethyl]-7- [ (pyridin-4-ylmethyl) amino] -2 , 3-dihydro-isoindol-1-one; -5 2- (4-tert- hbutylenyl) -7- [ (1H-pyrrolo [2, 3-b]pyridin-3 ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; 2- (4-ter t-butyl-phenyl) -7=ethylamino-2, 3-dihydio-isoindol-1 4-4- dii thyl--7 - 1~-5-0 7~-[-- prI273:bpyridin-3 10 ylmethyl) -amino] -1, 3-dihydro-isoindol-2-yl}-3, 4-dihydro 1H-isoquinoline-2-carboxylic acid tert-butyl ester; 9-~( 4-~aiinethyl-1,2i,3 , 4-tetrahydro-isoquinolin-7-yl) -7- [1H pyrrol[2,3-b]pyridin-3-ylmethyl)-amino]-2,3-dihydro isoindol-1-one; 15 2- (3-methoxy-benzyl) -7- [ (quinolin-6-ylmethyl) -amino] -2,3 dihydro-isoindol-1-one; 2-(3-methoxy-benzyl)-7-[(pyridin-4-ylmethyl)-amino]-2,3 dihydro-isoindol-1-one; 2- [3- (tetrahydro-furan-2ylmethoxy) -5-trifluoromethyl 20 phenyl] -7- (tetrahydro-pyran-4-ylamino) -2, 3-dihydro isoindol-1-one; 7- (4-fluoro-benzylamino) -2- [3- (tetrahydro-furan-3-yloxy) -5 trifluoromethyl-phenyl] -2, 3-dihydro-isoindol-1-one; 7- [ (pyridin-4-ylmethyl) -amino] -2- [3- (tetrahydro-furan-3 25 yloxy) -5-trifluromethyl-phenyl ] -2, 3 -dihydro-isoindol-1 one; 7- [(2, 3-dihydro-benzofuran-5ylmethyl) -amino] -2- [3 (tetrahydro-furan-2-ylmethoxy) -5-trifluromethyl-phenyl] 2, 3-dihydro-isoindol-1-one; 30 7- (4-fluoro-benzylamino) -2- [3- (tetrahydro-furan-2 ylmethoxy) -5-trifluromethyl-phenyl] -2, 3-dihydro-isoindol 1-one; WO 2005/021532 PCTIUS2004/027595 - 189 7-f (P~ridin-4-ylmethyl) -amino] -2- [3- (tetrahydro-furan-2 yimethoxy) -5--trifluoromethyl-pheny1] -2, 3-dihydro isoindol-1-one, 7- [( 2 -Iethoxy-pyridin-4-ylmethyl) -amino] -2- (4 5 - tiiluorom-etH-o i-pheiyl) -2, 3-dihydro-isoindol-l one; ~~ amno]-2- ( 4 -trifluoromethoxy phenyl) -- 2 ;-3-dihydro~i-oindo-- onre-; ---- ---- -(5-tr -u y- 2Hp r------y --- [ (PIDYr-adinf-4 -- yihethyl) 10 2- (5-tert-butyl-2H-pyrazol-3.yl) -7-f (2-Iethoxy-py'ridin-4 ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; 7-[F(quinolin-6-ylnethyi) -amino] -2- (4-trifluoromethoxy phenyl) -2 ,3-dihyclro-isoindol-1-one; 7- [(pyridin-4-ylmethyl) -amino] -2- (3-tri fluoromethoxy 15 phenyl) -2, 3-dihydro-isoindol-1-one; 7- Ii(quinolin-4-ylmethyl) -amino] -2- (4-trifluroinethoxy phenyl) -2, 3-dihydro-isoindol-1-one; 2- (4-phenyl-thiazol-2-yl) -7-[F(pyridin-4-ylmethyl) -amino] 2, 3-dihydro-isoindol-1-one; 20 N- C2-tert-butyl-5-(1-oxo-7-[F(pyridin-4ylmethy)-amino]1,3 dihydro-isoindo.-2-yll -phenyl) - 2 -piperidin-1-yl acetainide; N- (2-tert-butyl-5-{1-oxo-7- (quinolin-6-ylinethyl) -amino] 1,3-dihydro-isoindo1-2"yl)}phenyl) -2-piperidin-1-yl 25 acetamide; N- (2-tert-butyl-5-{1-oxo-7-[t(pyridin-4-ylinethyl) -amino] -1,3 dihydro-isoindol-2-yll-phenyl) -2-morpholin-4-yl acetainide; N- (2-tert-butyl-5-{1-oxo-7-[F(quinolin-6-ylmethyl) -amino] 30 l, 3 -dihydro-isoindol-2-yl}-phenyl) -2-morpholin-yl ace tamide; 7-[f(pyridin-4-ylmethyl) -amino] -2-m-tolyl-2, 3-dihydro isoindol-1-one; WO 2005/021532 PCTIUS2004/027595 - 190 2- (3-chloro-phenyl) -7- [ (pyridin-4-ylnethyl) -amino] -2,3 dihydro-isoindol-l-one; 7- [ (pyridin-4-ylmethyl) -amino] -2-p-tolyl-2,3-dihydro isoindol-1-one; 5 7-[(pyridin-4-ylmethyl)-amino]-2-(3 -trifluoromethyl-benzyl) *- 2 - 3 -- dihydro-isoindol-1-one; _ 2 - ( 4 -pentafluoroethyl-phenyl-)-7- [ (pyridin-4-ylmethyl) amino]-2, 3 -dihydro-isoindol-1-one; N- 2=tert-butyl-5-{l-oxo-7h-[(pyridin-4-ylmethyl)- -amino]-1,3 10 dihydro-isoindol-2-yl}-phenyl)-2 -dimethylamino-acetamide; 4,4-dimethyl-7-{7-{([1, 8 ]naphthryridin-.4-ylmethylene) amino]-l-oxo-1,3-dihydro-isoindol-2-yl}-3,4-dihydro-1H isoquinoline-2-carboxylic acid tert-butyl ester; 2-( 4 -tert-butyl-phenyl)-7-[(2 -chloro-pyridin-4-ylmethyl) 15 amino]-2, 3 -dihydro-isoindol-1-one; 2-( 4 , 4 -dimethyl-1,2,3,4-tetrahydro-isoquinoli.n-7-yl)-7 [(quinolin-6-ylmethyl)-amino]-2,3 -dihydro-isoindol-1-one; 2-(4-t-butylphenyl)-7-( 2 -pyridin-4-yl-vinyl)-2,3-dihydro isoindol-1-one; 20 2-( 4 -tert-butyl-phenyl)-7-(2-pyridin-2-yl-vinyl)-2,3 dihydro-isoindol-l-one; 2-(4-t-butyl-phenyl)-7-( 2 -pyridin-4-yl-ethyl)-2,3-dihydrol isoindol-1-one; 2-(4-t-butyl-phenyl)-7-(pyridin-4-ylmethoxy)-2,3-dihydro 25 isoindol-1-one; (S)-2-(4-t-butyl-phenyl)-7-(1-pyridin-4-yl-ethoxy)-2,3 dihydro-isoindol-1-one; (R)-2-( 4 -t-butyl-phenyl)-7-(l-pyridin-4-yl-ethoxy)-2,3 dihydro-isoindol-1-one; 30 2-( 4 -t-butyl-phenyl)-7-[( 2 -methylamino-pyrimidin-4 ylmethyl)-amino]-2, 3 -dihydro-isoindol-1-one; 2-(4-t -butyl-phenyl)-7-(pyridin-3-ylamino)-2,3-dihydro isoindol-l-one; WO 2005/021532 PCTIUS2004/027595 - 191 2- (4-t-butyl-phenyl) -7- (pyridin-4-ylamino) -2, 3-dihydro isoindol-1-one; 2- (4-t-butyl-phenyl) -7- (quinolin-5-ylamino) -2, 3-dihydro isoindol-1-one; 5 2-(4- 7 t-btyl-phenyl) -7- (quinolin-6-ylamino) -2, 3-dihydro iscindol-1-one; 2- (4- t-butyl-pheny-1-)--7---(-2-pyr idin-3 -yl-ethylamino) -2,3 - - -d-i-hydro--is-oindo-1==orre-; . (S)2(4bryp ny)7- (1-pyridin-4-yl-ethylamino) -2,3 10 dihydro-isoindol-1-one; (R) -2- (4-t-butyl-phenyl) -7- (1-pyridin-4-yl-ethylamino) -2,3 dihydro-isoindol-1-one; 2- (4-tert-butyl-phenyl) -1-hydroxy-4- [ (pyridin-4-ylmethyl) amino] -1, 2-dihydro-pyrrolo [3, 4-c]pyridin-3-one; 15 2- (4-tert-butyl-phenyl) -4- [ (pyridin-4-ylmethyl) -amino] -1,2 dihydro-pyrrolo [3, 4-c]pyridin-3-one; 2- (4- tert-Butyl-phenyl) -4- [ (2-methylamino-pyrimidin-4 ylmethyl)-amino]-1,2-dihydro-pyrrolo[3,4-clpyridin-3-one; 2- (4- tert-butyl-phenyl) -4- [ (2-methoxy-pyridin-4-ylmethyl) 20 amino] -1, 2-dihydro-pyrrolo [3, 4-c]pyridin-3-one; 4- [(2-amino-pyridin-4-ylmethyl) -amino ]-2- (4- tert-butyl phenyl)-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one; 2- (4- tert-butyl-phenyl) -4- (4-fluoro-benzylamino) -1,2 dihydro-pyrrolo[3,4-c]pyridin-3-one; 25 2- (4-tert-butyl-phenyl)-4- (1H-indazol-6-ylamino) -1,2 dihydro-pyrrolo[3,4-c]pyridin-3-one; 2- (4-tert-butyl-phenyl) -3-methyl-7- [ (pyridin-4-ylmethyl) amino ]-2, 3-dihydro-isoindol-1-one; 2-(4-tert-butyl-phenyl)-3-hydroxy-3-methyl-7-[(pyridin-4 30 ylmethyl) -amino] -2, 3-dihydro-isoindol-1-one; 7- (pyridin-4-ylamino) -2- [3- (tetrahydro-furan-3-yloxy) -5 trifluoromethyl-phenyl]-2,3-dihydro-isoindol-1-one; .2-biphenyl-4-yl-4-[(pyridin-4-ylmethyl)-amino]-1,2-dihydro pyrrolo [3, 4-c ]pyridin-3-one; WO 2005/021532 PCTIUS2004/027595 - 192 2- (4, 4-dimethyl-1, 2,3, 4-tetrahydro-isoquinolin-7-yl) -4 [(pyridin-4-ylmethyl) -amino -1, 2 -dihydro-pyrrolo [3,4 c]pyridin-3-one; 2-4-tert-butyl-phenyl) -4- [(pyridin-4-ylmethyl) -amino] -1,2 5 ~~~criydrdo--iazol~~3~~orie~T and 2-(-%ttbuthhl) -4- [ (pyridin-4-ylmethyl) -amino] - isoindole--1, 3-d-ione- - 4-9.--A-pharmaceuti-cal compsi-in~d6inpising -a 10 pharmaceutically-acceptable carrier and a compound as in any of Claims 1-48.
[26] 50. A method of treating cancer in a subject, said method comprising administering an effective amount of a 15 compound as in any of Claims 1-48.
[27] 51. The method of Claim 50 comprising a combination with a compound selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, 20 immunological agents, interferon-type agents and miscellaneous agents.
[28] 52. A method of treating angiogenesis in a subject, said method comprising administering an effective amount of 25 a compound as in any of Claims 1-48.
[29] 53. A method of treating proliferation-related disorders in a mammal, said method comprising administering an effective amount of a compound as in any of Claims 1-48. 30
[30] 54. The method of Claim 53 wherein the disorder is inflammation or an inflammation-related disorder. WO 2005/021532 PCTIUS2004/027595 - 193 55. A method of reducing blood flow in a tumor in a subject, said method comprising administering an effective amount of a compound as in any of Claims 1-48. 5 ~ 56. A method of reducing tumor size in a subject, said method comprising administering an effective amount of a compound as--in-any-of-&laims 1-48. 5' 7 A-5method-f -teating-diableticretinopathy- in a 10 subject, said method comprising administering an effective amount of a compound as in any of Claims 1-48.
[31] 58. A compound as in any of Claims 1-48 for use in a method of therapeutic treatment for the human or animal 15 body.
[32] 59. Use of a compound of any of Claims 1-48 for preparing a medicament for the treatment of cancer. 20
[33] 60. Use of a compound of any of Claims 1-48 for preparing a medicament for the treatment of angiogenesis.
[34] 61. Use of a compound of any of Claims 1-48 for preparing a medicament for the reduction of tumor size in a 25 subject.

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同族专利:

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AT453636T|2010-01-15|

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US7320992B2|2008-01-22|

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DE602004024900D1|2010-02-11|

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法律状态:
2011-03-24| MK4| Application lapsed section 142(2)(d) - no continuation fee paid for the application|

优先权:

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申请号 | 申请日 | 专利标题

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US49787803P| true| 2003-08-25|2003-08-25||

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US60/497,878||2003-08-25||

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US10/926,238|US7320992B2|2003-08-25|2004-08-24|Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use|

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US10/926,238||2004-08-24||

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PCT/US2004/027595|WO2005021532A1|2003-08-25|2004-08-25|Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use|

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