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Definitions

• the present invention is directed to novel compounds with multiple aromatic amino acids
• the present invention is also directed to methods of prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including but not limited to, cell growth disorders, metabolic disorders, blood vessel proliferative disorders, inflammatory disorders, neurodegenerative diseases and immune disorders.
• PTKs Protein tyrosine kinases
• Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular micro environment) .
• cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular micro environment) .
• tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
• SH2 src homology domains of signaling molecules.
• Several intracellular substrate proteins that associate with RTKs have been identified and are divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack a catalytic domain but serve as adapters and associate with catalytically active molecules.
• the RTKs comprise a large family of transmembrane receptors with diverse biological activities.
• the intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses.
• At present, at least nineteen distinct RTK subfamilies have been identified.
• One RTK subfamily, designated the HER subfamily is believed to be comprised of EGFR,
• Ligands to the HER subfamily of receptors include epithelial growth factor (EGF), TGF-a, amphiregulin, HB-EGF, betacellulin and heregulin.
• the second subfamily of RTKs, designated the insulin subfamily is comprised of the INS-R, the IGF-1R and the IR-R.
• the third RTK subfamily, the "PDGF" family includes the PDGF a and ⁇ receptors, CSFIR, c- kit and FLK-II.
• RTKs Another subfamily of RTKs, identified as the FLK family, is believed to be comprised of the kinase insert domain-receptor fetal liver kinase- 1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1). Each of these receptors was initially believed to be a receptor for hematopoietic growth factors.
• Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).
• the non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual nonreceptor tyrosine kinases, comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified.
• the Src subfamily of non- receptor tyrosine kinases is comprised of the largest number of PTKs, and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
• the Src subfamily of enzymes has been linked to oncogenesis. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993,
• PTKs protein tyrosine kinases
• RTKs protein tyrosine kinases
• RNA ligands (Jellinek, et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell 4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al, 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (U.S. Patent No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).
• the present invention is directed to compounds represented by Formula I capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction, and uses of the compounds and compositions incorporating the compounds for disease treatment and prevention.
• X is selected from the group consisting of NR , O, S(O) n ; n is 0 or an integer of from 1 to 2; R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 1 is selected from the group consisting of hydrogen, halogen, Ci to Cg alkyl, S(O) f R 4 , (CR 5 R 6 )dC(0)OR 4 , S(O) f (CR 5 R 6 )dC(0)OR 4 , (CR 5 R 6 ) d Ar, NR 4 (CR 5 R 6 ) d Ar, 0(CR 5 R 6 ) d Ar, S(O) f (CR 5 R 6 )dAr, (CR 5 R 6 ) d S(O) f R 4 , NR 4 (CR 5 R 6 ) d S(O) f R 4 , 0(CR 5 R 6 ) d S(O) f R 4 ,
• each R 4 is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -Cg alkyl, aryl, C 1 -Cg hydroxyalkyl, Ci-Cg alkoxyalkyl, (CR 5 R 6 )d and N(R 4 ) 2 may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N- methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpho
• hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR 5 R 6 may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or
• (CR 5 R 6 )d and (CR 5 R 6 ) e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, Ci-Cg alkyl, C 1 -Cs hydroxyalkyl, C 1 -Cs alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate; a is 0 or an integer of from 1 to 3; d is 0 or an integer of from 1 to 5; e is an integer of from 1 to 4; f is 0 or an integer of from 1 to 2;
• R is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy,
• R 2 R 3 carbonylalkenyl
• R 2 R 3 carbonylalkyl
• R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
• b is 0 or an integer of from 1 to 2;
• Y is selected from the group consisting of:
• g is 0 or an integer of from 1 to 3;
• h is 0 or an integer of from 1 to 3;
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl,
• alkylcarbonyl alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered cyclic ring;
• Ring A is selected from the group consisting of:
• Ring A can be illustrated but not limited to the following: wherein
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 111 represents optionally 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C5 alkoxy, hydroxy, amino, C1-C5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
• Z is selected from the group consisting of
• R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl.
• Ring B is selected from the group consisting of:
• Ring ⁇ can be illustrated but not limited to the following:
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and— NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
• a compound according to Formula I including any tautomer, stereoisomer,
• R 1 is selected from the group consisting of hydrogen, halogen, Ci to C 8 alkyl, (CR 5 R 6 ) d C(0)OR 4 , (CR 5 R 6 ) d Ar, NR 4 (CR 5 R 6 ) d Ar, (CR 5 R 6 ) d C(0)N(R 4 ) 2 , NR 4 (CR 5 R 6 ) d C(0)N(R 4 ) 2 ,
• hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR 5 R 6 may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR 5 R 6 ) d and (CR 5 R 6 ) e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, Ci-C 8 alkyl, Ci-C 8 hydroxyalkyl, C 1 -C 8 alkoxyalkyl,
• alkoxycarbonylalkyl alkoxycarbonyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate.
• W is C or N
• X is selected from the group consisting of NR 1 , O, and S(O) n ;
• n is 0 or an integer of from 1 to 2;
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, Ci- C8 alkyl, C 1 -Cs hydroxyalkyl, C 1 -Cs alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate;
• R n is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR 2 R 3 )alkoxy, (NR 2 R 3 )alkenyl, (NR 2 R 3 )alkyl, (NR 2 R 3 )carbonylalkenyl, and (NR 2 R 3 )carbonylalkyl, wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• b is 0 or an integer of from 1 to 2;
• Y is selected from the group consisting of:
• g is 0 or an integer of from 1 to 3;
• h is 0 or an integer of from 1 to 3;
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered cyclic ring;
• Ring A is selected from the group consisting of:
• Ring A can be illustrated but not limited to the following:
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,
• R 2 and R 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R in represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
• Z is selected from the group consisting of
• i 0 or 1 ;
• R 8 are independently selected from the nsisting of hydrogen and alkyl; s selected from the group consisting of:
• Ring B can be illustrated but not limited to the following:
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
• R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and— NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and any pharmaceutical acceptable salt or prodrug.
• the diseases or conditions are selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders.
• the diseases or conditions are selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast
• a pharmaceutical composition comprising a therapeutic effective amount of a
• paragraph 26 which are in the form selected from the group comprising of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, ophthalmic solutions, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts or depots.
• Fig. 1 shows a powder X-Ray Diffraction (XRPD) of Example 78;
• Fig 2 shows a powder X-Ray Diffraction (XRPD) of Example 69;
• Fig 3 shows a fluorescein angiography (blood-retinal barrier breakdown) of Example 121
• Example 84 Sodium, Example 83, Example 78, Example 75 Sodium, Example 69, and Example 66;
• Fig 4 shows a fundus photography (retinal vasodilation and vessel tortuosity) of Example 121, Example 84 Sodium, Example 83, Example 78, Example 75 Sodium, Example 69, and Example 66.
• the present invention is directed to a series of compounds with multiple aromatic components useful as protein tyrosine kinase inhibitors.
• the compounds of the present invention are useful for treating diseases related to unregulated tyrosine kinase signal transduction, for example, cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases.
• compounds of the present invention are useful for the treatment of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal
• neovascularization laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, transplant rejection, inflammation, neurodegenerative diseases and immune disorders.
• the compounds of the present invention can be represented by the general formula I:
• X is selected from the group consisting of NR 1 , O, and S(O) n ; n is 0 or an integer of from 1 to 2;
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,
• R 2 and R 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 1 is selected from the group consisting of hydrogen, halogen, Ci to Cg alkyl, S(O) f R 4 , (CR 5 R 6 )dC(0)OR 4 , S(O) f (CR 5 R 6 )dC(0)OR 4 , (CR 5 R 6 ) d Ar, NR 4 (CR 5 R 6 ) d Ar, 0(CR 5 R 6 ) d Ar, S(O) f (CR 5 R 6 )dAr, (CR 5 R 6 ) d S(O) f R 4 , NR 4 (CR 5 R 6 ) d S(O) f R 4 , 0(CR 5 R 6 ) d S(O) f R 4 ,
• each R 4 is independently selected from the group consisting of hydrogen, hydroxyl, Ci-Cg alkyl, aryl, Ci-Cg hydroxyalkyl, C 1 -Cg alkoxyalkyl, (CR 5 R 6 )d and N(R 4 ) 2 may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R 5 ; wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, hydroxyl
• R n is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR 2 R 3 )alkoxy, (NR 2 R 3 )alkenyl, (NR 2 R 3 )alkyl, (NR 2 R 3 )carbonylalkenyl, and (NR 2 R 3 )carbonylalkyl, wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; b is 0
• Y is selected from the group consisting of:
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,
• R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered cyclic ring;
• Ring A is selected from the group consisting of:
• Ring A can be illustrated but not limited to the following:
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 and R 3 may be taken together to form a 5-7 membered heterocyclic ring with N.
• R in represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
• Z is selected from the group consisting of
• R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl
• Ring B is selected from the group consisting of:
• Ring B can be illustrated but not limited to the following:
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R IV represents optionally 1-3 substituents, independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and— NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• the compounds of the present invention can be represented by the general formula II:
• W is C or N
• X is selected from the group consisting of NR 1 , O, and S(O) n ;
• n is 0 or an integer of from 1 to 2;
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
• R 2 andR 3 may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, Ci- C8 alkyl, C 1 -Cs hydroxyalkyl, C 1 -Cs alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, and sulfonate;
• R n is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR 2 R 3 )alkoxy, (NR 2 R 3 )alkenyl, (NR 2 R 3 )alkyl, (NR 2 R 3 )carbonylalkenyl, and (NR 2 R 3 )carbonylalkyl, wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; b is 0
• Y is selected from the group consisting of:
• g is 0 or an integer of from 1 to 3;
• h is 0 or an integer of from 1 to 3;
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
• R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered cyclic ring;
• Ring A is selected from the group consisting of:
• a 5 or 6 membered monocyclic heteroaryl group which have 1-5 heteroatoms independently selected from the group consisting of O, N and S;
• Ring A can be illustrated but not limited to the following:
• R is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
• R III represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
• Z is selected from the group consisting of
• i 0 or 1 ;
• j is O or l
• R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl.
• Ring B is selected from the group consisting of:
• Ring B can be illustrated but not limited to the following:
• R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 andR 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
• R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and— NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• reference to a compound should be construed broadly to include compounds, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, diastereoisomers, alternate solid forms, crystal forms, polymorphic forms, hydrates, solvates, metabolites, mixtures of stereoisomers, mixtures of crystal forms, non-covalent complexes, and combinations thereof, of a chemical entity of a depicted structure or a chemical name. Whenever there is a conflict between chemical name and its structure drawing, the structure drawing should be used to interpret the compound of the present invention.
• a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
• a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
• a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
• a “prodrug” is a compound, which when administered to the body of a subject (such as a mammal), breaks down in the subject's metabolic pathway to provide an active compound of Formula I. More specifically, a prodrug is an active or inactive "masked” compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject or patient.
• a prodrug is a masked carboxylic acid group.
• Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (19
• drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
• EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses
• Mannich-base hydroxamic acid prodrugs their preparation and use.For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group.
• Prodrug preparation is well known in the art. For example, "Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.
• Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion. Unless stereochemistry is explicitly and unambiguously depicted, a structure is intended to include every possible stereoisomer, both pure or in any possible mixture.
• Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
• alternate solid forms may be amorphous forms, crystal forms, polymorphs, and the mixtures thereof.
• Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
• the present invention is also directed to the use of the compounds as protein tyrosine kinase modulators and inhibitors. These compounds can be used to treat diseases related to unregulated tyrosine kinase signal transduction, for example, various cancers, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases.
• compounds of the present invention are useful for the treatment and/or prevention of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, transplant rejection, inflammation, neurodegenerative diseases and immune disorders in the human being.
• treat refers to the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition.
• the present invention is also directed to the preparation of a medicament for the treatment and prevention of diseases and conditions related with abnormal activities of tyrosine kinase receptors.
• the medicament contains a pharmaceutical acceptable composition, which comprises the therapeutic effective amount of the compounds of present invention, together with a pharmaceutical acceptable carrier.
• compositions contain therapeutic effective amount of the compounds of the present invention. These compositions can be used as a medicament and administered to a mammal, such as a person, in need thereof.
• suitable dosage forms and medicaments are well known in the art, and can be readily adapted for delivery of the compounds of the present invention, such as, but not limited to, systematic, parenteral, local and topical delivery.
• the dosage forms can be tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, ophthalmic solutions, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts or depots, nasal sprays and ointment, various rectal or vaginal preparations.
• the reaction vessel was sealed and the mixture stirred at 105°C for 18 h.
• the reaction vessel was cooled to rt and the mixture was filtered over celite, washing with EtOAc.
• the filtrate was concentrated to afford a dark oil, which was purified via column chromatography eluting with 30-50% EtOAc/hexanes to afford methyl 5-(4-(tert- butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate (2.98 g, 65% yield) as an orange oil.
• Methyl 5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate (0.40 g, 0.91 mmol) was taken up in toluene (38 mL) and Si0 2 (9.0 g) was added. The mixture stirred at reflux for 20 h. The mixture was cooled to rt and filtered over celite, washing with EtOAc. The filtrate was concentrated to a bright orange color. The solid was taken up in hexanes and filtered.
• Methyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.32 g, 3.9 mmol) was taken up in EtOAc/EtOH (1 : 1; 90 mL) and purged with N 2 . Pd/C (10%, 0.145 g) was added and the mixture was stirred under an atmosphere of H 2 at rt for 18 h. The mixture was filtered over celite, washing with EtOAc/EtOH. The filtrate was concentrated, taken back up in EtOAc and filtered over celite again to remove any residual catalyst. The filtrate was concentrated again and taken back up in EtOAc.
• the reaction vessel was sealed and the mixture stirred at 95°C for 16 h.
• the reaction vessel was cooled to room temperature and the mixture was poured into 100ml of water.
• the precipitates were filtered, washed with water and dried to give the crude, which was purified via column chromatography eluting with 30-40% EtOAc/hexanes to afford 5- ⁇ 4-[3-(2-Fluoro-5- methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl ⁇ -1H-pyrrole-3-carboxylic acid methyl ester (150mg, 58% yield).

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