# Patent

## Title
Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors

## Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. application Ser. No. 11/625,856, filed Jan. 23, 2007 which claims the benefit of U.S. Provisional Application No. 60/761,660, filed Jan. 24, 2006, which is expressly incorporated herein by reference in its entirety.


BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
2. Description of the Related Art
Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important role in the control of cell growth and differentiation.
For example, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. 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 microenvironment).
With respect to receptor tyrosine kinases, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Aberrant expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g. malignant tumor growth) or to defects in key developmental processes. Consequently, the biomedical community has expended significant resources to discover the specific biological role of members of the PTK family, their function in differentiation processes, their involvement in tumorigenesis and in other diseases, the biochemical mechanisms underlying their signal transduction pathways activated upon ligand stimulation and the development of novel drugs.
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
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 phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses.
At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Her subfamily of receptors include epithelial growth factor (EGF), TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin.
A second family of RTKs, designated the insulin subfamily, is comprised of the INS-R, the IGF-1R and the IR-R. A third family, the “PDGF” subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II. 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 receptors 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).
Because of the similarities between the PDGF and FLK subfamilies, the two subfamilies are often considered together. The known RTK subfamilies are identified in Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated herein by reference.
The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, 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, Oncogen 8: 2025-2031, which is incorporated herein by reference.
Many of the tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways leading to cellular signal cascades leading to pathogenic conditions, including cancer, psoriasis and hyper immune response.
In view of the surmised importance of PTKs to the control, regulation and modulation of cell proliferation the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosine kinase “inhibitors” using a variety of approaches, including the use of mutant ligands (U.S. Pat. No. 4,966,849), soluble receptors and antibodies (PCT Application No. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci 90: 10705-09; Kim, et al, 1993, Nature 362: 841-844), 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 (PCT Application Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).
More recently, attempts have been made to identify small molecules which act as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT Application No. WO 92/20642), vinylene-azaindole derivatives (PCT Application No. WO 94/14808) and 1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 A1), seleoindoles and selenides (PCT Application No. WO 94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO 92/21660) and benzylphosphonic acid compounds (PCT Application No. WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer.
The identification of effective small compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation is therefore desirable and one object of this invention.
In addition, certain small compounds are disclosed in U.S. Pat. Nos. 5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020 as useful for the treatment of diseases related to unregulated TKS transduction. See also U.S. patent application Ser. No. 10/256,381; WO 02/29630; U.S. Pat. No. 6,765,012, Ser. No. 10/886,213; U.S. Pat. Nos. 6,541,504 and 6,747,025. These patents are hereby incorporated by reference in its entirety for the purpose of disclosing starting materials and methods for the preparation thereof, screens and assays to determine a claimed compound's ability to modulate, regulate and/or inhibit cell proliferation, indications which are treatable with said compounds, formulations and routes of administration, effective dosages, etc.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. Such compounds are useful for the treatment of diseases related to unregulated TKS transduction, including cell proliferative diseases such as cancer, atherosclerosis, restenosis, metabolic diseases such as diabetes, inflammatory diseases such as psoriasis and chronic obstructive pulmonary disease, vascular proliferative disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity, autoimmune diseases and transplant rejection.
In one illustrative embodiment, the compounds of the present invention have the following general formulae:




wherein
X is O or S;
Y is selected from the group consisting of O, S, NR3 and CR3R4;
and wherein the ring system represented by A in formula V below, is a 5 or 6 membered aryl group, e.g. a carbocyclic aryl or a heterocyclic aryl




wherein said aryl group is selected from the group consisting of:








and wherein the ring system represented by B in formula VI, above, is a five membered unsaturated heterocyclic ring wherein said unsaturated heterocyclic ring is selected from the group consisting of:








wherein Z is selected from the group consisting of [C(R2)2]c, O, NR3 and S;





and wherein the ring system represented by C in formula VII, above, is a 5 or 6 membered aryl group e.g. a carbocyclic aryl or heterocyclic aryl, wherein said aryl group is selected from the group consisting of:





wherein R1 is —X′—B wherein X′ is selected from the group consisting of





and B is selected from a 5 to 6 membered carbocyclic aryl or heterocyclic aryl ring substituted with one or more of R;

R2 is selected from the group consisting of hydrogen, C1 to C8 alkyl, C1 to C8 alkenyl, C1 to C8 alkynyl, C1 to C4 alkylol, lower alkylphenyl, phenyl, (CR3R4)dAr, (CR3R4)dC(O)OR6, (CR3R4)dSO2R6, (CR3, R4)dOR6, (CR3, R4)dOSO2R6, (CR3R4)dP(O)(OR6)2, (CR3R4)dR6, (CR3R4)eN(R6)2 and (CR3R4)eNR6C(O)N(R6)2;

wherein N(R6)2 may form a 3-7 membered heterocyclic ring, for example, pyrrolidine, 3-fluoropyrrolidine, piperidine, 4-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be substituted with one or more of R3; and

[C(R2)2]c may form a 3-7 membered carbocyclic or heterocyclic ring;

R is selected from the group consisting of halogen, C1 to C8 alkyl, C2 to C8 conjugated alkenyl, (CR2═CR2)dCON(R2)2, CF3, OCF3, OCF2H, (CR3R4)dCN, NR2(CR3R4)eCN, O(CR3R4)eCN, S(O)fR2, (CR3R4)dC(O)OR2, NR2(CR3R4)dC(O)OR2, O(CR3R4)dC(O)OR2, S(O)f(CR3R4)dC(O)OR2, (CR3R4)dAr, NR2(CR3R4)dAr, O(CR3R4)dAr, S(O)f(CR3R4)dAr, (CR3R4)dSO2R2, NR2(CR3R4)dS(O)fR2,

O(CR3R4)dS(O)fR2, S(O)f(CR3R4)eS(O)fR2, (CR3R4)dC(O)N(R2)2, NR2(CR3R4)dC(O)N(R2)2, O(CR3R4)dC(O)N(R2)2, S(O)f(CR3R4)eC(O)N(R2)2, (CR3, R4)dOR2, NR2(CR3, R4)eOR2, O(CR3R4)eOR2, S(O)f(CR3, R4)dOR2, (CR3, R4)dOSO2R2, NR2(CR3, R4)eOSO2R2, O(CR3, R4)eOSO2R2, S(O)f(CR3, R4)eOSO2R2(CR3, R4)dP(O)(OR2)2, NR2(CR3, R4)dP(O)(OR2)2, O(CR3, R4)dP(O)(OR2)2, S(O)f(R3R4)eP(O)(OR2)2, C(O)(CR3R4)dR3, NR2C(O)(CR3R4)dR3, OC(O)(CR3R4)dN(R2)2, C(O)(CR3R4)dN(R2)2, NR2C(O)(CR3R4)dN(R2)2, OC(O)(CR3R4)dN(R2)2, (CR3R4)dR3, NR2(CR3R4)dR3, O(CR3R4)dR3, S(O)f(CR3R4)dR3, HNC(O)R2, HN—C(O)OR2, (CR3R4)dN(R2)2, NR2(CR3R4)eN(R2)2, O(CR3R4)eN(R2)2, S(O)f (CR3R4)dN(R2)2, OP(O)(OR2)2, OC(O)OR2, OCH2O, HN—CH═CH, —N(COR2)CH2CH2, HC═N—NH, N═CH—S, (CR3R4)dC═C(CR3R4)dR2, (CR3R4)dC═C(CR3R4)dOR2, (CR3R4)dC═C(CR3R4)dN(R2)2, (CR3R4)dCC(CR3R4)dR2, (CR3R4)dC═C(CR3R4)eOR2, (CR3R4)dC═C(CR3R4)eN(R2)2, (CR3R4)dC(O)(CR3R4)dR2, (CR3R4)dC(O)(CR3R4)dOR2 and (CR3R4)dC(O)(CR3R4)dN(R2)2;

R3 and R4 may be selected from the group consisting of H, F, hydroxy, and C1-C4 alkyl or CR3R4 may represent a carbocyclic or heterocyclic ring of from 3 to 6 carbons or alternatively, (CR3R4)d and (CR3R4)e may form a 3-7 membered carbocyclic or heterocyclic ring, preferably R3 and R4 are H, F, CH3 or hydroxy;

R5 is Ar—R1b, wherein Ar is 5-7 membered carbocyclic aryl or 5-7 membered heterocyclic aryl;

R6 is selected from the group consisting of hydrogen, C1-C8 alkyl, hydroxylmethyl and phenyl;

R7 is selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (R2CCR2)aCN and aryl;

a is 0 or an integer of from 1 to 3;

b is 0 or an integer of from 1 to 2;

c is an integer of from 1 to 2;

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;

g is an integer of from 2 to 5, and further provided said alkyl or aryl radicals may be substituted with one or two halo, hydroxy, lower alkyloxy, lower alkyl amino or cycloalkylamino radicals wherein the cycloalkyl ring can include an enchained oxygen, sulfur or additional nitrogen atom and may be substituted with one or two halo or lower alkyl radicals; and pharmaceutically acceptable salts thereof.




BRIEF DESCRIPTION OF THE DRAWING FIGURES
Illustrative routes to compounds of the present invention are illustrated in Schemes 1 through 11 set forth in the Drawing FIGS. 1-6 and are not intended to limit the scope of the invention.
FIG. 1 shows the schematics for the preparation of compounds of Formulae




(Tables 1 and 2), and





(Table 3).

FIG. 2 shows the schematics for the preparation of compounds of Formulae




(Table 4) and





(Table 5).

FIG. 3 shows the schematics for the preparation of compounds of Formulae




(Tables 6 and 9) and





(Table 6).

FIG. 4 shows the schematics for the preparation of compounds of the Formula




(Table 7).

FIG. 5 shows the schematics for the preparation of compounds of the Formulae




(Table 7) and





(Table 8).

FIG. 6 shows the schematics for the preparation of compounds of the Formulae




(Table 12).




DETAILED DESCRIPTION OF THE INVENTION
In particular, the compounds of the present invention may be selected from the group of compounds set forth in the Tables below.







TABLE 1







-3-[4-amino-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one derivatives










Example #
Chemical Structure
Chemical Name
FW













1




6-Fluoro-3-{4-[(2-methoxy-ethyl)- methyl- amino]-5H-furan-2-ylidene}- 1,3- dihydro-indol-2-one
304.319


 


2




6-Fluoro-3-[4-(4-methyl- piperazin-1- yl)-5H-furan-2-ylidene]-1,3- dihydro- indol-2-one
315.346


 


3




6-Fluoro-3-(4-{4-[2-(2-hydroxy- ethoxy)-ethyl]-piperazin-1-yl}-5H- furan-2-ylidene)-1,3-dihydro- indol-2-one
389.425


 


4




6-Fluoro-3-[4-(3-hydroxy- piperidin-1-yl)-5H-furan-2- ylidene]-1,3-dihydro-indol-2-one
316.33


 


5




6-Fluoro-3-[4-(4-hydroxy- piperidin-1-yl)-5H-furan-2- ylidene]-1,3-dihydro-indol-2-one
316.33


 


6




6-Fluoro-3-{4-[2-(2-hydroxy- ethoxy)-ethylamino]-5H-furan-2- ylidene}-1,3-dihydro-indol-2-one
320.318


 


7




3-[4-(3-Diethylamino- propylamino)-5H-furan-2- ylidene]-6-fluoro-1,3-dihydro- indol-2-one
345.416


 


8




6-Fluoro-3-[4-(2-morpholin-4-yl- ethylamino)-5H-furan-2-ylidene]- 1,3-dihydro-indol-2-one
345.372


 


9




6-Fluoro-3-(4-morpholin-4-yl-5H- furan-2-ylidene)-1,3-dihydro- indol-2-one
302.303


 


10




6-Fluoro-3-[4-(3-morpholin-4-yl- propylamino)-5H-furan-2- ylidene]-1,3-dihydro-indol-2-one
359.399
















TABLE 2







3-[4-amino-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one derivatives










Example #
Chemical Structure
Chemical Name
FW





11




3-{4-[4-(3-Diethylamino-propoxy)- 3-fluoro-phenylamino]-5H-furan-2- ylidene}-6-fluoro-1,3-dihydro-indol- 2-one
455.502


 


12




3-{4-[4-(2-Diethylamino-ethoxy)- phenylamino]-5H-furan-2-ylidene}-6- fluoro-1,3-dihydro-indol-2-one
423.485
















TABLE 3







3-[5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one derivatives










Example #
Chemical Structure
Chemical Name
FW













13




3-{3-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,5- dihydrofuran-3-yl]-1H-pyrrol-1- yl}propyl methanesulfonate
418.443 


 


14




(3E)-6-fluoro-3-{4-[1-(3-morpholin- 4-ylpropyl)-1H-pyrrol-3-yl]furan- 2(5H)-ylidene}-1,3-dihydro-2H- indol-2-one
409.459


 


15




(3E)-6-fluoro-3-{4-[1-(3- hydroxypropyl)-1H-pyrrol-3- yl]furan-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
340.352


 


16




(3E)-3-{4-[1-(3-{[tert- butyl(dimethyl)silyl]oxy}propyl)-1H- pyrrol-3-yl]furan-2(5H)-ylidene}-6- fluoro-1,3-dihydro-2H-indol-2-one
454.615


 


17




(3E)-3-[4-(1-benzothien-3-yl)furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
349.384


 


18




(3E)-6-fluoro-3-{4-[4-(3- hydroxypropyl)phenyl]furan-2(5H)- ylidene}-1,3-dihydro-2H-indol-2- one
351.375


 


19




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,5- dihydrofuran-3-yl]-N-methoxy-N- methylbenzamide
380.373


 


20




methyl 3-{4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H-indol-3- ylidene)-2,5-dihydrofuran-3- yl]phenyl}propanoate
379.385


 


21




(3E)-6-fluoro-3-{4-[4- (methoxymethyl)phenyl]furan- 2(5H)-ylidene}-1,3-dihydro-2H- indol-2-one
337.348


 


22




(3E)-6-fluoro-3-[4-(1-methyl-1H- indol-5-yl)furan-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
346.359


 


23




methyl (2E)-3-{4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H-indol-3- ylidene)-2,5-dihydrofuran-3- yl]phenyl}acrylate
377.369


 


24




N-{4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,5- dihydrofuran-3- yl]phenyl}methanesulfonamide
386.401


 


25




N-{4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,5- dihydrofuran-3- yl]phenyl}acetamide
350.348


 


26




(3E)-6-fluoro-3-[4-(1H-indol-5- yl)furan-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
332.333


 


27




(3E)-3-[4-(1,3-benzodioxol-5- yl)furan-2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol-2-one
337.305


 


28




N-{3-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,5- dihydrofuran-3- yl]phenyl}acetamide
350.348


 


29




(3E)-3-[4-(4-chlorophenyl)furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
327.741


 


30




(3E)-6-fluoro-3-[4-(4- fluorophenyl)furan-2(5H)-ylidene]- 1,3-dihydro-2H-indol-2-one
311.286


 


31




methyl 4-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,5-dihydrofuran-3-yl]-1H-pyrrole- 2-carboxylate
340.309


 


32




1-tert-butyl 2-methyl 4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro-3H-indol- 3-ylidene)-2,5-dihydrofuran-3-yl]- 1H-pyrrole-1,2-dicarboxylate
440.425


 


33




(3E)-3-(3,3′-bifuran-5(2H)- ylidene)-6-fluoro-1,3-dihydro-2H- indol-2-one
283.257


 


34




(3E)-6-fluoro-3-[4-(1H-pyrrol-3- yl)furan-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
282.273


 


35




(3E)-6-fluoro-3-{4-[1- (triisopropylsilyl)-1H-pyrrol-3- yl]furan-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
438.616


 


36




(3E)-6-fluoro-3-[4-(1H-pyrrol-2- yl)furan-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
282.273


 


37




tert-butyl 2-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,5-dihydrofuran-3-yl]-1H-pyrrole- 1-carboxylate
382.389


 


38




(3E)-6-fluoro-3-[4-(3-thienyl)furan- 2(5H)-ylidene]-1,3-dihydro-2H- indol-2-one
299.324


 


39




3-{4-[5-(6-Fluoro-2-oxo-1,2- dihydro- indol-3-ylidene)-2,5-dihydro- furan- 3-yl]-phenyl}-propionic acid
365.358


 


40




4-[5-(6-Fluoro-2-oxo-1,2-dihydro- indol-3-ylidene)-2,5-dihydro-furan-3- yl]-benzoic acid methyl ester
351.332


 


41




6-Fluoro-3-(4-styryl-5H-furan-2- ylidene)-1,3-dihydro-indol-2-one
319.334


 


42




3-[4-(4-Bromo-phenyl)-5H-furan-2- ylidene]-6-fluoro-1,3-dihydro-indol- 2-one
372.192


 


43




6-Fluoro-3-[4-(3-methoxy-phenyl)- 5H-furan-2-ylidene]-1,3-dihydro- indol-2-one
323.322


 


44




6-Fluoro-3-{4-[4-(2-morpholin-4-yl- ethoxy)-phenyl]-5H-furan-2- ylidene}- 1,3-dihydro-indol-2-one
422.454


 


45




3-[4-(4-Dimethylamino-phenyl)- 5H-furan-2-ylidene]-6-fluoro-1,3- dihydro-indol-2-one
336.364


 


46




6-Fluoro-3-[4-(4-methoxy-phenyl)- 5H-furan-2-ylidene]-1,3-dihydro- indol-2-one
323.322
















TABLE 4







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one derivatives










Example #
Chemical Structure
Chemical Name
FW













 47




(3E)-6-bromo-3-[5,5-dimethyl-4- (1H-pyrrol-3-yl)furan-2(5H)- ylidene]-1,3-dihydro-2H-indol-2- one
371.233


 


 48




(3E)-6-bromo-3-{5,5-dimethyl-4-[1- (triisopropylsilyl)-1H-pyrrol-3- yl]furan-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
527.576


 


 49




(3E)-6-fluoro-3-(2′,2′,5-trimethyl- 2,3′-bifuran-5′(2′H)-ylidene)-1,3- dihydro-2H-indol-2-one
325.337


 


 50




(3E)-3-[5,5-dimethyl-4-(4-methyl- 2-phenyl-1,3-thiazol-5-yl)furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
418.49


 


 51




(3E)-3-{5,5-dimethyl-4-[2-(4- methylpiperazin-1-yl)pyridin-4- yl]furan-2(5H)-ylidene}-6-fluoro- 1,3-dihydro-2H-indol-2-one
420.486


 


 52




(3E)-3-[4-(6-aminopyridin-3-yl)- 5,5-dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H-indol-2- one
337.352


 


 53




ethyl 5-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]nicotinate
394.4


 


 54




(3E)-6-fluoro-3-[4-(5- methoxypyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
352.363


 


 55




methyl 5-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]-1-benzothiophene-2- carboxylate
435.473


 


 56




N-[2-(dimethylamino)ethyl]-3- [(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]benzamide
435.496


 


 57




(3E)-3-[5,5-dimethyl-4-{4-[(4- methylpiperazin-1- yl)carbonyl]phenyl}furan-2(5H)- ylidene]-6-fluoro-1,3-dihydro-2H- indol-2-one
447.507


 


 58




(3E)-6-fluoro-3-[4-(3-fluoro-4- methoxyphenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro-2H- indol-2-one
369.365


 


 59




(3E)-3-[4-(1-benzothien-5-yl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
377.437


 


 60




(3E)-3-{5,5-dimethyl-4-[4- (morpholin-4- ylmethyl)phenyl]furan-2(5H)- ylidene}-6-fluoro-1,3-dihydro-2H- indol-2-one
420.482


 


 61




(3E)-3-[4-{4- [(dimethylamino)methyl]phenyl}- 5,5-dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H-indol-2- one
378.445


 


 62




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3-yl]-2- methoxyphenyl acetate
409.411


 


 63




(3E)-3-[5,5-dimethyl-4-(3- morpholin-4-ylphenyl)furan-2(5H)- ylidene]-6-fluoro-1,3-dihydro-2H- indol-2-one
406.455


 


 64




(3E)-6-fluoro-3-[4-(4-hydroxy-3- methoxyphenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro-2H- indol-2-one
367.374


 


 65




(3E)-6-fluoro-3-[4-(1H-indazol-5- yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H-indol-2- one
361.374


 


 66




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]benzamide
364.374


 


 67




(3E)-3-(2′,2′-dimethyl-2,3′-bifuran- 5′(2′H)-ylidene)-6-fluoro-1,3- dihydro-2H-indol-2-one
311.311


 


 68




(3E)-3-[4-(1-benzofuran-2-yl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
361.37


 


 69




(3E)-3-(2,2-dimethyl-3,3′-bifuran- 5(2H)-ylidene)-6-fluoro-1,3- dihydro-2H-indol-2-one
311.311


 


 70




(3E)-3-[4-(1-benzothien-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
377.437


 


 71




(3E)-3-[5,5-dimethyl-4-(3- thienyl)furan-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
327.378


 


 72




(3E)-3-[5,5-dimethyl-4-(5-phenyl- 2-thienyl)furan-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
403.475


 


 73




(3E)-3-[4-(5-acetyl-2-thienyl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
369.414


 


 74




(3E)-3-[4-(1-benzothien-2-yl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
377.437


 


 75




(3E)-3-[4-(5-chloro-2-thienyl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
361.823


 


 76




tert-butyl 2-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]-1H-pyrrole-1-carboxylate
410.443


 


 77




(3E)-3-[5,5-dimethyl-4-(1-methyl- 1H-indol-2-yl)furan-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H-indol-2- one
374.413


 


 78




(3E)-3-[5,5-dimethyl-4-{1-[(4- methylphenyl)sulfonyl]-1H-indol-3- yl}furan-2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol-2-one
514.575


 


 79




(3E)-6-fluoro-3-[4-(2-fluoropyridin- 4-yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H-indol-2- one
340.328


 


 80




(3E)-6-fluoro-3-[4-(3-fluoropyridin- 4-yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H-indol-2- one
340.328


 


 81




(3E)-3-[4-(2-chloropyridin-4-yl)- 5,5-dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H-indol-2- one
356.783


 


 82




(3E)-6-fluoro-3-[4-(2- fluoroquinolin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
390.387


 


 83




(3E)-6-fluoro-3-(4-isoquinolin-4-yl- 5,5-dimethylfuran-2(5H)-ylidene)- 1,3-dihydro-2H-indol-2-one
372.397


 


 84




(3E)-6-fluoro-3-[4-(2- methoxypyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
352.363


 


 85




(3E)-6-fluoro-3-[4-(6-fluoropyridin- 3-yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H-indol-2- one
340.328


 


 86




(3E)-6-fluoro-3-[4-(2-fluoropyridin- 3-yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H-indol-2- one
340.328


 


 87




(3E)-3-[4-(6-chloropyridin-3-yl)- 5,5-dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H-indol-2- one
356.783


 


 88




(3E)-3-(5,5-dimethyl-4-quinolin-3- ylfuran-2(5H)-ylidene)-6-fluoro- 1,3-dihydro-2H-indol-2-one
372.397


 


 89




(3E)-6-fluoro-3-[4-(6- methoxypyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
352.363


 


 90




(3E)-6-fluoro-3-[4-(4- methoxypyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
352.363


 


 91




(3E)-3-(5,5-dimethyl-4-pyridin-3- ylfuran-2(5H)-ylidene)-6-fluoro- 1,3-dihydro-2H-indol-2-one
322.337


 


 92




(3E)-3-[4-(4-benzoylphenyl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
425.457


 


 93




(2E)-3-{3-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]phenyl}acrylonitrile
372.397


 


 94




(3E)-6-fluoro-3-{4-[4-(3- hydroxypropyl)phenyl]-5,5- dimethylfuran-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
379.429


 


 95




(3E)-6-fluoro-3-[4-(1H-indazol-6- yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H-indol-2- one
361.374


 


 96




(3E)-3-[4-(3-amino-4- methoxyphenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
366.39


 


 97




methyl ({4-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]benzoyl}amino)acetate
436.437


 


 98




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3-yl]-N- methoxy-N-methylbenzamide
408.427


 


 99




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3-yl]-N- methoxybenzamide
394.4


 


100




ethyl 3-{4-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]phenyl}propanoate
421.466


 


101




methyl 3-{3-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]phenyl}propanoate
407.439


 


102




methyl 3-{4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]phenyl}propanoate
407.439


 


103




(3E)-3-(5,5-dimethyl-4-quinoxalin- 6-ylfuran-2(5H)-ylidene)-6-fluoro- 1,3-dihydro-2H-indol-2-one
373.385


 


104




(3E)-3-[4-(3-chloro-4- methoxyphenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
385.82


 


105




(3E)-3-[4-(1-benzofuran-5-yl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
361.37


 


106




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3-yl]-N- methylbenzamide
378.401


 


107




(3E)-6-fluoro-3-{4-[4- (methoxymethyl)phenyl]-5,5- dimethylfuran-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
365.402


 


108




methyl {4-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]phenyl}carbamate
394.4


 


109




5-{4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]phenyl}imidazolidine-2,4-dione
419.41


 


110




{4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2-  dimethyl-2,5-dihydrofuran-3- yl]phenyl}acetic acid
379.385


 


111




(3E)-3-[5,5-dimethyl-4-(1-methyl- 1H-indol-5-yl)furan-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H-indol-2- one
374.413


 


112




(3E)-3-{5,5-dimethyl-4-[4- (morpholin-4- ylcarbonyl)phenyl]furan-2(5H)- ylidene}-6-fluoro-1,3-dihydro-2H- indol-2-one
434.465


 


113




(3E)-3-{5,5-dimethyl-4-[4- (pyrrolidin-1- ylcarbonyl)phenyl]furan-2(5H)- ylidene}-6-fluoro-1,3-dihydro-2H- indol-2-one
418.466


 


114




2-fluoro-4-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]benzonitrile
364.35


 


115




2-fluoro-5-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]benzonitrile
364.35


 


116




(3E)-3-(5,5-dimethyl-4-quinolin-6- ylfuran-2(5H)-ylidene)-6-fluoro- 1,3-dihydro-2H-indol-2-one
372.397


 


117




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3-yl]- N,N-dimethylbenzamide
392.428


 


118




N-{3-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]phenyl}methanesulfonamide
414.455


 


119




methyl (2E)-3-{3-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]phenyl}acrylate
405.423


 


120




N-{4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]phenyl}methanesulfonamide
414.455


 


121




N-{4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]phenyl}acetamide
378.401


 


122




(3E)-3-{4-[3-(aminomethyl)phenyl]- 5,5-dimethylfuran-2(5H)-ylidene}- 6-fluoro-1,3-dihydro-2H-indol-2- one
350.391


 


123




methyl 3-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran-3- yl]benzoate
379.385


 


124




2-amino-3-{4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]phenyl}propanoic acid
408.427


 


125




(3E)-3-{4-[4-(aminomethyl)phenyl]- 5,5-dimethylfuran-2(5H)-ylidene}- 6-fluoro-1,3-dihydro-2H-indol-2- one
350.391


 


126




(3E)-3-{5,5-dimethyl-4-[4- (methylsulfonyl)phenyl]furan- 2(5H)-ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
399.44


 


127




(3E)-3-{5,5-dimethyl-4-[3- (methylthio)phenyl]furan-2(5H)- ylidene}-6-fluoro-1,3-dihydro-2H- indol-2-one
367.442


 


128




(3E)-6-fluoro-3-[4-(1H-indol-5-yl)- 5,5-dimethylfuran-2(5H)-ylidene]-  1,3-dihydro-2H-indol-2-one
360.386


 


129




(3E)-3-{4-[3- (dimethylamino)phenyl]-5,5- dimethylfuran-2(5H)-ylidene}-6-  fluoro-1,3-dihydro-2H-indol-2-one
364.418


 


130




4-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]benzonitrile
346.359


 


131




(3E)-6-fluoro-3-{4-[3- (hydroxymethyl)phenyl]-5,5- dimethylfuran-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
351.375


 


132




(3E)-3-[4-(3-acetylphenyI)-5,5- dimethylfuran-2(5H)-ylidene]-6-  fluoro-1,3-dihydro-2H-indol-2-one
363.386


 


133




(3E)-3-[4-(4-aminophenyl)-5,5- dimethylfuran-2(5H)-ylidene]-6-  fluoro-1,3-dihydro-2H-indol-2-one
336.364


 


134




(3E)-3-{5,5-dimethyl-4-[4- (trifluoromethoxy)phenyl]furan-  2(5H)-ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
405.345


 


135




(3E)-6-fluoro-3-[4-(3- hydroxyphenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro-2H- indol-2-one
337.348


 


136




(3E)-3-[4-(1,3-benzodioxol-5-yl)- 5,5-dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H-indol-2- one
365.358


 


137




(3E)-6-fluoro-3-{4-[4- (hydroxymethyl)phenyl]-5,5- dimethylfuran-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
351.375


 


138




(3E)-3-[5,5-dimethyl-4-(4- vinylphenyl)furan-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
347.387


 


139




(3E)-6-fluoro-3-[4-(3-fluorophenyl)- 5,5-dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol-2-one
339.34


 


140




N-{3-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]phenyl}acetamide
378.401


 


141




(3E)-3-[4-(3-chlorophenyl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
355.794


 


142




(3E)-3-{5,5-dimethyl-4-[4- (methylthio)phenyl]furan-2(5H)- ylidene}-6-fluoro-1,3-dihydro-2H- indol-2-one
367.442


 


143




(3E)-3-[4-(4-chlorophenyl)-5,5- dimethylfuran-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol-2-one
355.794


 


144




(3E)-6-fluoro-3-[4-(4-fluorophenyl)- 5,5-dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol-2-one
339.34


 


145




(3E)-3-[4-(1-benzothien-3-yl)furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
349.384


 


146




3-[5,5-Dimethyl-4-(6-morpholin-4- yl-pyridin-3-yl)-5H-furan-2-ylidene]- 6-fluoro-1,3-dihydro-indol-2-one
407.443


 


147




(3E)-3-[5,5-dimethyl-4-(1H-pyrrol- 3-yl)furan-2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol-2-one
310.327


 


148




(3E)-3-{5,5-dimethyl-4-[1- (triisopropylsilyl)-1H-pyrrol-3- yl]furan-2(5H)-ylidene}-6-fluoro- 1,3-dihydro-2H-indol-2-one
466.669


 


149




N-(2-Dimethylamino-ethyl)-4-[5-(6- fluoro-2-oxo-1,2-dihydro-indol-3- ylidene)-2,2-dimethyl-2,5-dihydro- furan-3-yl]-benzamide
435.496


 


150




3-{4-[5-(6-Fluoro-2-oxo-1,2- dihydro-indol-3-ylidene)-2,2- dimethyl-2,5-dihydro-furan-3-yl]- phenyl}-acrylic acid methyl ester
405.423


 


151




3-[4-(3-Amino-phenyl)-5,5- dimethyl-5H-furan-2-ylidene]-6- fluoro-1,3-dihydro-indol-2-one
336.364


 


152




3-(5,5-Dimethyl-4-pyridin-4-yl-5H- furan-2-ylidene)-6-fluoro-1,3- dihydro-indol-2-one
322.337


 


153




6-Fluoro-3-[4-(4-hydroxy-phenyl)- 5,5-dimethyl-5H-furan-2-ylidene]- 1,3-dihydro-indol-2-one
337.348


 


154




(3E)-6-(4-methoxyphenyl)-3-[4-(4- methoxyphenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro-2H- indol-2-one
439.509


 


155




(3E)-6-fluoro-3-{4-[(3- hydroxyphenyl)ethynyl]-5,5- dimethylfuran-2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
361.37


 


156




(3E)-3-{4-[4- (dimethylamino)phenyl]-5,5- dimethylfuran-2(5H)-ylidene}-6- fluoro-1,3-dihydro-2H-indol-2-one
364.418


 


157




(3E)-3-{4-[4- (dimethylamino)phenyl]-5,5- dimethylfuran-2(5H)-ylidene}-6- fluoro-1,3-dihydro-2H-indol-2-one
364.418


 


158




(3E)-6-fluoro-3-[4-(4- methoxyphenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro-2H- indol-2-one
351.375
















TABLE 5







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one benzamide derivatives










Example #
Chemical Structure
Chemical Name
FW













159




(3E)-6-fluoro-3-[4-{4- [(4-hydroxypiperidin-1- yl)carbonyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
448.4915


 


160




N-[2-(diethylamino)ethyl]- 4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]benzamide
463.55


 


161




(3E)-6-fluoro-3- {4-[4-({4-[2-(2- hydroxyethoxy)ethyl] piperazin-1- yl}carbonyl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
521.5858


 


162




(3E)-3-[4-(4-{[(2R,3R,4R)- 3,4-dihydroxy-2- (hydroxymethyl) pyrrolidin-1- yl]carbonyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
480.4895


 


163




(3E)-6-fluoro-3- [4-(4-{[4-(2- hydroxyethyl)piperazin-1- yl]carbonyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
477.5332


 


164




6-Fluoro-3-[4-[4-(3- hydroxy-pyrrolidine-1- carbonyl)-phenyl]-5,5- dimethyl-5H-furan-(2E)- ylidene]-1,3- dihydro-indol-2-one
434.4647


 


165




3-[5,5-Dimethyl-4-[4- ((3R,4R,5S)-3,4,5- trihydroxy-piperidine-1- carbonyl)-phenyl]-5H- furan-(2E)-ylidene]-6- fluoro-1,3-dihydro-indol- 2-one
480.4895


 


166




3-[5,5-Dimethyl-4-[4- ((2S,3R,4S,5R)-3,4,5- trihydroxy-2-methyl- piperidine-1-carbonyl)- phenyl]-5H-furan-(2E)- ylidene]-6-fluoro-1,3- dihydro-indol-2-one
494.5163


 


167




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]-N-(2-{2-[2-(2- hydroxyethoxy)ethoxy] ethoxy}ethyl)benzamide
540.5847


 


168




(3E)-5-fluoro-3- [4-(4-{[4-(2- hydroxyethyl)piperazin-1- yl]carbonyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
477.5332


 


169




(3E)-3-[4-(4-{[(3S,4S)-3,4- dihydroxypyrrolidin- 1-yl]carbonyl}phenyl)- 5,5-dimethylfuran- 2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol- 2-one
450.4637


 


170




(3E)-3-[4-(4-{[(3S,4S)-3,4- dihydroxypyrrolidin- 1-yl]carbonyl}phenyl)- 5,5-dimethylfuran- 2(5H)-ylidene]-5-fluoro- 1,3-dihydro-2H-indol- 2-one
450.4637


 


171




methyl (3E)-3-{5,5-dimethyl- 4-[4-(pyrrolidin-1- ylcarbonyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-5-carboxylate
458.5114


 


172




(3E)-3-{5,5-dimethyl- 4-[4-(pyrrolidin-1- ylcarbonyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-5- carboxylic acid
444.4846


 


173




methyl (3E)-3-{5,5-dimethyl- 4-[4-(pyrrolidin-1- ylcarbonyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-6- carboxylate
458.5114


 


174




(3E)-3-{5,5-dimethyl-4- [4-(pyrrolidin-1- ylcarbonyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-6- carboxylic acid
444.4846


 


175




methyl (3E)-3- [4-(4-{[4-(2- hydroxyethyl)piperazin- 1-yl]carbonyl}phenyl)- 5,5-dimethylfuran- 2(5H)-ylidene]-2- oxoindoline- 6-carboxylate
517.5789


 


176




(3E)-3-{5,5-dimethyl- 4-[4-(pyrrolidin-1- ylcarbonyl)phenyl]furan- 2(5H)-ylidene}-N- methyl-2-oxoindoline- 6-carboxamide
457.5273


 


177




methyl (3E)-3-{5,5-dimethyl- 4-[4-pyrrolidin-1- ylcarbonyl)phenyl]furan- 2(5H)-ylidene}-5- fluoro-2-oxoindoline- 6-carboxylate
476.5015


 


178




methyl (3E)-3- [4-(4-{[(2,3- dihydroxypropyl)(methyl) amino]carbonyl} phenyl)-5,5-dimethylfuran- 2(5H)-ylidene]-5-fluoro- 2-oxoindoline-6-carboxylate
510.5153


 


179




4-[(5E)-5-(5,6-difluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]-N-(2,3- dihydroxypropyl)-N- methylbenzamide
470.47


 


180




(3E)-5,6-difluoro-3- [4-(4-{[4-(2- hydroxyethyl)piperazin-1- yl]carbonyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
495.52


 


181




ethyl (2S)-2-({4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzoyl}amino)-4- (methylthio)butanoate
524.6101


 


182




4-[(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]-N- (2-morpholin-4- ylethyl)benzamide
477.5332


 


183




(3E)-6-fluoro-3- [4-(4-{[2- (hydroxymethyl) morpholin-4- yl]carbonyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
464.4905


 


184




(3E)-3-{5,5-dimethyl-4- [4-(thiomorpholin-4- ylcarbonyl)phenyl]furan- 2(5H)-ylidene}-6- fluoro-1,3-dihydro- 2H-indol-2-one
450.5317


 


185




N-(1,1-dioxidotetrahydro- 3-thienyl)-4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]- N-methylbenzamide
496.5565


 


186




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]- N-(2-piperidin-1- ylethyl)benzamide
475.561


 


187




(3E)-6-fluoro- 3-[4-(4-{[2- (hydroxymethyl) piperidin-1- yl]carbonyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
462.5183


 


188




(3E)-6-fluoro-3- [4-(4-{[3- (hydroxymethyl) piperidin-1- yl]carbonyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
462.5183


 


189




(3E)-6-fluoro-3-[4-{4-[(3- hydroxypiperidin-1- yl)carbonyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
448.4915


 


190




(3E)-6-fluoro-3- [4-(4-{[4- (hydroxymethyl) piperidin-1- yl]carbonyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
462.5183


 


191




(3E)-6-fluoro-3- [4-(4-{[3-(2- hydroxyethyl)piperidin-1- yl]carbonyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
476.5451


 


192




methyl 1-{4-[(5E)-5-(6- fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]benzoyl}-4- hydroxypyrrolidine-2- carboxylate
492.5005


 


193




ethyl 4-{4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzoyl}piperazine-1- carboxylate
505.5432


 


194




(3E)-3-[4-(4-{[4-(2- ethoxyethyl)piperazin-1- yl]carbonyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
505.5868


 


195




ethyl (4-{4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl] benzoyl}piperazin-1- yl)acetate
519.57


 


196




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3- yl]-N,N-bis(2- methoxyethyl)benzamide
480.5331


 


197




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]-N- (2-methoxyethyl)-N- methylbenzamide
436.4805


 


198




N-ethyl-4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]-N-(2- hydroxyethyl)benzamide
436.4805


 


199




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]- N-(2-pyrrolidin-1- ylethyl)benzamide
461.5342


 


200




N-{2-[bis(2-hydroxyethyl) amino]ethyl}-4-[(5E)- 5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3- yl]benzamide
495.548


 


201




N-{2-[4-(2-aminoethyl) piperazin-1-yl]ethyl}-4- [(5E)-5-(6-fluoro-2-oxo- 1,2-dihydro-3H-indol- 3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3- yl]benzamide
519.6176


 


202




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]-N-[2- (4-hydroxypiperidin-1- yl)ethyl]benzamide
491.56


 


203




tert-butyl 4-{4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]benzoyl}-3- (hydroxymethyl) piperazine-1-carboxylate
563.6226


 


204




methyl 4-{4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]benzoyl}piperazine-2- carboxylate
491.5164


 


205




(3E)-3-[4-(4-{[(2R,3R, 4R,5S)-3,4-dihydroxy- 2,5-bis(hydroxymethyl) pyrrolidin-1- yl]carbonyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
510.5153


 


206




methyl 1-({4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]benzoyl}amino) cyclopropanecarboxylate
462.4747


 


207




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]-N- (tetrahydro-2H-pyran-4- yl)benzamide
448.4915


 


208




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]-N- (tetrahydro-2H-pyran-4- ylmethyl)benzamide
462.5183


 


209




methyl (2R)-2-({4-[(5E)- 5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzoyl}amino)-3- hydroxypropanoate
466.4627


 


210




ethyl 3-({4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]benzoyl} amino)propanoate
464.4905


 


211




N-(2-amino-2-oxoethyl)- 4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]-N- methylbenzamide
435.4528


 


212




N-(2-amino-2-oxoethyl)- 4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]benzamide
421.426


 


213




methyl (2S)-2-({4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzoyl}amino)-3- hydroxypropanoate
466.4627


 


214




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]-N-(2- hydroxyethyl)benzamide
408.4269


 


215




N-(2,3-dihydroxypropyl)-4- [(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]-N- methylbenzamide
452.4795


 


216




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]- N-methyl-N- [(2S,3R,4S,5R)-2,3,4,5,6- pentahydroxyhexyl]benzamide
542.5569


 


217




methyl 1-{4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzoyl}piperidine-4- carboxylate
490.5283


 


218




N-{[(2R,3S,4S,5R)- 3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran- 2-yl]methyl}- 4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]benzamide
510.5153


 


219




N-[(1-ethylpyrrolidin-2- yl)methyl]-4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]benzamide
475.561


 


220




N-ethyl-4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]- N-(2-pyridin-2- ylethyl)benzamide
497.5672


 


221




ethyl 1-{4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzoyl}piperidine-4- carboxylate
504.5551


 


222




4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]-N- [2-(2-methylpiperidin-1- yl)ethyl]benzamide
489.5878
















TABLE 6







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one benzylmethyl amine derivatives










Example #
Chemical Structure
Chemical Name
FW













223




(3E)-6-fluoro-3- {4-[4-({4-[2-(2- hydroxyethoxy) ethyl]piperazin-1- yl}methyl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
507.6026


 


224




(3E)-6-fluoro-3-[4-{4- [(4-hydroxypiperidin-1- yl)methyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
434.5083


 


225




(3E)-1-acetyl-3-{5,5- dimethyl-4-[4-(morpholin- 4-ylmethyl)phenyl]furan- 2(5H)-ylidene}-6- fluoro-1,3-dihydro- 2H-indol-2-one
462.5183


 


226




(3E)-5-chloro-3- [4-(4-{[4-(2- hydroxyethyl)piperazin- 1-yl]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
480.005


 


227




methyl (3E)-3-{5,5-dimethyl- 4-[4-(morpholin- 4-ylmethyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-5-carboxylate
460.5272


 


228




(3E)-5-bromo-3-{5,5- dimethyl-4-[4- (morpholin-4-ylmethyl) phenyl]furan-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
481.3875


 


229




(3E)-3-{5,5-dimethyl-4- [4-(morpholin-4- ylmethyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-5-carbonitrile
427.5015


 


230




methyl (3E)-3-{5,5-dimethyl- 4-[4-(morpholin- 4-ylmethyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-6-carboxylate
460.5272


 


231




(3E)-3-{5,5-dimethyl-4- [4-(morpholin-4- ylmethyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-5- carboxylic acid
446.5004


 


232




(3E)-3-{5,5-dimethyl-4- [4-(morpholin-4- ylmethyl)phenyl]furan- 2(5H)-ylidene}-2- oxoindoline-6- carboxylic acid
446.5004


 


233




(3E)-3-[4-(4-{[4- (hydroxymethyl)piperidin-1- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-2-oxoindoline- 5-carboxylic acid
474.554


 


234




methyl 1-{4-[(5E)-5-(5,6- difluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl] benzyl}piperidine-4- carboxylate
494.54


 


235




1-{4-[(5E)-5-(5,6-difluoro- 2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzyl}piperidine-4- carboxylic acid
480.51


 


236




ethyl (2S)-2-({4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}amino)-4- (methylthio)butanoate
510.6269


 


237




2-({4-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzyl}amino)-4-(S- methylsulfonimidoyl) butanoic acid
513.5872


 


238




(3E)-3-[5,5-dimethyl-4- (4-{[(2-morpholin-4- ylethyl)amino]methyl} phenyl)furan-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
463.55


 


239




(3E)-6-fluoro- 3-[4-(4-{[2- (hydroxymethyl) morpholin-4- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
450.5073


 


240




(3E)-3-{5,5-dimethyl-4- [4-(thiomorpholin-4- ylmethyl)phenyl]furan- 2(5H)-ylidene}-6-fluoro- 1,3-dihydro-2H-indol-2-one
436.5485


 


241




(3E)-3-[4-(4-{[(1,1- dioxidotetrahydro-3- thienyl)(methyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
482.5733


 


242




(3E)-6-fluoro- 3-[4-(4-{[3- (hydroxymethyl)piperidin- 1-yl]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
448.5351


 


243




(3E)-6-fluoro-3-[4-{4-[(3- hydroxypiperidin-1- yl)methyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
434.5083


 


244




(3E)-6-fluoro- 3-[4-(4-{[4- (hydroxymethyl)piperidin- 1-yl]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
448.5351


 


245




(3E)-6-fluoro-3- [4-(4-{[3-(2- hydroxyethyl)piperidin-1- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
462.5619


 


246




(3E)-6-fluoro-3-[4-{4- [(3-fluoropiperidin-1- yl)methyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
436.4994


 


247




methyl 1-{4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}-4- hydroxypyrrolidine-2- carboxylate
478.5173


 


248




ethyl 4-{4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzyl}piperazine-1- carboxylate
491.56


 


249




(3E)-3-[5,5-dimethyl-4- {4-[(4-methylpiperazin- 1-yl)methyl]phenyl}furan- 2(5H)-ylidene]-6- fluoro-1,3-dihydro- 2H-indol-2-one
433.5242


 


250




(3E)-6-fluoro-3- [4-(4-{[4-(2- hydroxyethyl)piperazin- 1-yl]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
463.55


 


251




(3E)-3-[4-(4-{[4-(2- ethoxyethyl)piperazin-1- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
491.6036


 


252




(4-{4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]benzyl} piperazin-1-yl)acetic acid
477.5332


 


253




(3E)-3-[4-(4-{[ethyl (2-pyridin-2- ylethyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
483.584


 


254




(3E)-3-[4-(4-{[bis(2- methoxyethyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
466.5499


 


255




(3E)-6-fluoro- 3-[4-(4-{[(2- methoxyethyl)(methyl) amino]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
422.4973


 


256




(3E)-3-[4-(4-{[ethyl(2- hydroxyethyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
422.4973


 


257




(3E)-3-[4-{4-[({2-[4-(2- aminoethyl)piperazin-1- yl]ethyl}amino) methyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
505.6344


 


258




3-[2-({4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]benzyl} amino)ethyl]-1,3- thiazolidine-2,4-dione
493.5566


 


259




(3E)-6-fluoro-3-{4-[4-({[2- (4-hydroxypiperidin- 1-yl)ethyl]amino} methyl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro-2H- indol-2-one
477.5768


 


260




(3E)-3-{5,5-dimethyl- 4-[4-({[2-(2- oxoimidazolidin-1- yl)ethyl]amino}methyl) phenyl]furan-2(5H)- ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
462.5223


 


261




methyl ({4-[(5E)-5-(5- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzyl}amino)acetate
422.4537


 


262




methyl (2S,3R)-2-({4- [(5E)-5-(5-fluoro-2-oxo- 1,2-dihydro-3H-indol- 3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3- yl]benzyl}amino)-3- hydroxybutanoate
466.5063


 


263




(3E)-3-[5,5-dimethyl-4- (4-{[(2-morpholin-4- ylethyl)amino]methyl} phenyl)furan-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
463.55


 


264




(3E)-5-fluoro- 3-[4-(4-{[2- (hydroxymethyl) morpholin-4- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
450.5073


 


265




(3E)-3-{5,5-dimethyl- 4-[4-(morpholin-4- ylmethyl)phenyl]furan- 2(5H)-ylidene}-5-fluoro- 1,3-dihydro-2H-indol-2-one
420.4815


 


266




(3E)-3-[4-(4-{[(1,1- dioxidotetrahydro-3- thienyl)(methyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
482.5733


 


267




(3E)-3-[5,5-dimethyl- 4-(4-{[(2-piperidin-1- ylethyl)amino]methyl} phenyl)furan-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
461.5778


 


268




(3E)-5-fluoro- 3-[4-(4-{[3- (hydroxymethyl)piperidin- 1-yl]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
448.5351


 


269




(3E)-5-fluoro-3-[4-{4-[(3- hydroxypiperidin-1- yl)methyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
434.5083


 


270




(3E)-5-fluoro- 3-[4-(4-{[4- (hydroxymethyl)piperidin- 1-yl]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
448.5351


 


271




(3E)-5-fluoro-3- [4-(4-{[3-(2- hydroxyethyl)piperidin-1- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
462.5619


 


272




methyl (2S,4R)-1-{4- [(5E)-5-(5-fluoro-2-oxo- 1,2-dihydro-3H-indol-3- ylidene)-2,2-dimethyl- 2,5-dihydrofuran- 3-yl]benzyl}-4- hydroxypyrrolidine- 2-carboxylate
478.5173


 


273




(3E)-3-[5,5-dimethyl-4- {4-[(4-methylpiperazin- 1-yl)methyl]phenyl}furan- 2(5H)-ylidene]-5- fluoro-1,3-dihydro- 2H-indol-2-one
433.5242


 


274




(3E)-5-fluoro- 3-[4-(4-{[4-(2- hydroxyethyl)piperazin- 1-yl]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
463.55


 


275




(3E)-5-fluoro-3- {4-[4-({4-[2-(2- hydroxyethoxy) ethyl]piperazin-1- yl}methyl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
507.6026


 


276




(3E)-3-[4-(4-{[4-(2- ethoxyethyl)piperazin-1- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
491.6036


 


277




ethyl (4-{4-[(5E)-5- (5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}piperazin-1- yl)acetate
505.5868


 


278




(3E)-3-[4-(4-{[bis(2- methoxyethyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
466.5499


 


279




(3E)-5-fluoro- 3-[4-(4-{[(2- methoxyethyl)(methyl) amino]methyl}phenyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
422.4973


 


280




(3E)-3-[4-(4-{[ethyl(2- hydroxyethyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
422.4973


 


281




(3E)-3-[5,5-dimethyl-4- (4-{[(2-pyrrolidin-1- ylethyl)amino]methyl} phenyl)furan-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
447.551


 


282




(3E)-3-{4-[4-({[2- (diethylamino)ethyl]amino} methyl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-5-fluoro-1,3- dihydro-2H-indol-2-one
449.5668


 


283




(3E)-3-[4-{4-[({2-[bis(2- hydroxyethyl)amino] ethyl}amino)methyl] phenyl}-5,5-dimethylfuran- 2(5H)-ylidene]-5-fluoro- 1,3-dihydro-2H-indol-2-one
481.5648


 


284




(3E)-5-fluoro-3-{4-[4-({[2- (4-hydroxypiperidin- 1-yl)ethyl]amino} methyl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro-2H- indol-2-one
477.5768


 


285




tert-butyl 4-{4-[(5E)-5- (5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]benzyl}-3- (hydroxymethyl) piperazine-1-carboxylate
549.6394


 


286




(3E)-5-fluoro-3-[4-{4-[(3- hydroxypyrrolidin-1- yl)methyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
420.4815


 


287




(3E)-3-[4-(4-{[(2R,3R, 4R,5S)-3,4-dihydroxy- 2,5-bis(hydroxymethyl) pyrrolidin-1- yl]methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
496.5321


 


288




methyl 1-({4-[(5E)-5- (5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}amino) cyclopropanecarboxylate
448.4915


 


289




(3E)-3-[5,5-dimethyl-4- {4-[(tetrahydro-2H- pyran-4-ylamino)methyl] phenyl}furan-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
434.5083


 


290




(3E)-3-[5,5-dimethyl-4- (4-{[(tetrahydro-2H- pyran-4-ylmethyl)amino] methyl}phenyl)furan- 2(5H)-ylidene]-5-fluoro- 1,3-dihydro-2H-indol- 2-one
448.5351


 


291




methyl (2R)-2-({4-[(5E)- 5-(5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}amino)-3- hydroxypropanoate
452.4795


 


292




2-[{4-[(5E)-5-(5-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}(methyl) amino]acetamide
421.4696


 


293




2-({4-[(5E)-5-(5-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]benzyl} amino)acetamide
407.4428


 


294




methyl (2S)-2-({4-[(5E)- 5-(5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}amino)-3- hydroxypropanoate
452.4795


 


295




(3E)-5-fluoro-3-[4-(4-{[(2- hydroxyethyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
394.4437


 


296




(3E)-3-[4-(4-{[(2,3- dihydroxypropyl)(methyl) amino]methyl}phenyl)- 5,5-dimethylfuran- 2(5H)-ylidene]-5-fluoro- 1,3-dihydro-2H-indol-2-one
438.4963


 


297




(3E)-3-{5,5- dimethyl-4-[4- ({methyl[(2S,3R, 4S,5R)-2,3,4,5,6- pentahydroxyhexyl] amino}methyl)phenyl] furan-2(5H)-ylidene}-5- fluoro-1,3-dihydro-2H- indol-2-one
528.5737


 


298




(3E)-3-[4-{4-[({[(2R,3S, 4S,5R)-3,4-dihydroxy- 5-(hydroxymethyl) tetrahydrofuran-2- yl]methyl}amino) methyl]phenyl}-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
496.5321


 


299




(3E)-3-{4-[4-({[(1- ethylpyrrolidin-2- yl)methyl]amino} methyl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-5-fluoro-1,3- dihydro-2H-indol-2-one
461.5778


 


300




rel-(3E)-3-[5,5-dimethyl- 4-(4-{[(3R,4r,5S)- 3,4,5-trihydroxypiperidin-1- yl]methyl}phenyl) furan-2(5H)-ylidene]-5- fluoro-1,3-dihydro- 2H-indol-2-one
466.5063


 


301




ethyl (2S,4R)-1-{4-[(5E)- 5-(5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3- yl]benzyl}-4- hydroxypyrrolidine- 2-carboxylate
492.5441


 


302




ethyl 1-{4-[(5E)-5-(5-fluoro- 2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzyl}piperidine-4- carboxylate
490.5719


 


303




(3E)-3-{5,5-dimethyl- 4-[4-({[2-(2- methylpiperidin-1- yl)ethyl]amino}methyl) phenyl]furan-2(5H)- ylidene}-5-fluoro-1,3- dihydro-2H-indol-2-one
475.6046


 


304




(3E)-5-fluoro-3-[4-(4- {[(2-hydroxyethyl)(2- pyridin-4-ylethyl)amino] methyl}phenyl)-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
499.583


 


305




({[(2S,4R)-1-{4-[(5E)- 5-(5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]benzyl}- 4-hydroxypyrrolidin- 2-yl]carbonyl} amino)acetic acid
521.5422


 


306




(3E)-3-[5,5-dimethyl-4- (4-{[(2S,3R,4S,5R)- 3,4,5-trihydroxy-2- methylpiperidin-1- yl]methyl}phenyl) furan-2(5H)-ylidene]-5- fluoro-1,3-dihydro- 2H-indol-2-one
480.5331


 


307




(3E)-5-fluoro-3-{4-[4- (13-hydroxy-5,8,11- trioxa-2-azatridec- 1-yl)phenyl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro-2H- indol-2-one
526.6015


 


308




(3E)-3-{5,5-dimethyl- 4-[4-(pyrrolidin-1- ylmethyl)phenyl]furan- 2(5H)-ylidene}-5-fluoro- 1,3-dihydro-2H-indol-2-one
404.4825


 


309




1-{4-[(5E)-5-(5-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] benzyl}piperidine-4- carboxylic acid
462.5183


 


310




(3E)-3-{5,5-dimethyl- 4-[4-(piperidin-1- ylmethyl)phenyl]furan- 2(5H)-ylidene}-5-fluoro- 1,3-dihydro-2H-indol-2-one
418.5093
















TABLE 7







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one pyridin-3-yl derivatives










Example #
Chemical Structure
Chemical Name
FW













311




(3E)-3-{5,5-dimethyl- 4-[6-(2-morpholin-4- ylethyl)pyridin-3-yl] furan-2(5H)-ylidene}-6- fluoro-1,3-dihydro- 2H-indol-2-one
435.4964


 


312




(3E)-3-{5,5-dimethyl-4- [6′-(2-morpholin-4- ylethyl)-2,3′-bipyridin- 5-yl]furan-2(5H)- ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
512.5821


 


313




methyl [(2-{5-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl] pyridin-2-yl}ethyl) amino]acetate
437.4686


 


314




(3E)-3-[5,5-dimethyl-4- (6-{2-[(2-morpholin-4- ylethyl)amino]ethyl}pyridin- 3-yl)furan-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H-indol- 2-one
478.5649


 


315




3-{2-[(2-{5-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl] pyridin-2-yl}ethyl)amino] ethyl}-1,3-thiazolidine- 2,4-dione
508.5715


 


316




(3E)-6-fluoro-3-[4-(6-{2-[2- (hydroxymethyl)morpholin- 4-yl]ethyl}pyridin-3- yl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3- dihydro-2H-indol-2- one
465.5222


 


317




(3E)-6-fluoro-3-[4-(6-{2-[2- (hydroxymethyl)piperidin- 1-yl]ethyl}pyridin-3-yl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
463.55


 


318




(3E)-6-fluoro-3-[4-(6-{2-[3- (hydroxymethyl)piperidin- 1-yl]ethyl}pyridin-3- yl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
463.55


 


319




(3E)-6-fluoro-3-[4-{6-[2- (4-hydroxypiperidin-1- yl)ethyl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
449.5232


 


320




(3E)-6-fluoro-3-[4-{6- [2-(3-hydroxypiperidin-1- yl)ethyl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
449.5232


 


321




(3E)-6-fluoro-3-[4-(6- {2-[4-(hydroxymethyl) piperidin-1-yl]ethyl} pyridin-3-yl)-5,5-dimethyl- furan-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
463.55


 


322




(3E)-6-fluoro-3-[4-(6-{2- [3-(2-hydroxyethyl)piperidin- 1-yl]ethyl}pyridin-3-yl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
477.5768


 


323




(3E)-6-fluoro-3-[4-{6-[2- (3-fluoropiperidin-1- yl)ethyl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
451.5143


 


324




ethyl 4-(2-{5-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]pyridin- 2-yl}ethyl)piperazine] 1-carboxylate
506.5749


 


325




(3E)-3-[5,5-dimethyl-4- {6-[2-(4-methylpiperazin- 1-yl)ethyl]pyridin-3-yl}furan- 2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol- 2-one
448.5391


 


326




(3E)-6-fluoro-3-[4-(6-{2- [4-(2-hydroxyethyl)piperazin- 1-yl]ethyl}pyridin-3-yl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
478.5649


 


327




(3E)-6-fluoro-3-{4-[6-(2-{4- [2-(2-hydroxyethoxy)ethyl] piperazin-1-yl}ethyl)pyridin-3- yl]-5,5-dimethylfuran-2(5H)- ylidene}-1,3-dihydro-2H- indol-2-one
522.6175


 


328




(3E)-3-[4-(6-{2-[4-(2- ethoxyethyl)piperazin-1- yl]ethyl}pyridin-3-yl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
506.6185


 


329




(3E)-3-[4-(6-{2-[ethyl (2-pyridin-2-ylethyl)amino] ethyl}pyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro- 2H-indol-2-one
498.5989


 


330




(3E)-6-fluoro-3-[4-(6-{2-[(2- methoxyethyl)(methyl) amino]ethyl}pyridin-3- yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
437.5122


 


331




(3E)-3-[4-(6-{2-[ethyl(2- hydroxyethyl)amino]ethyl} pyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro- 2H-indol-2-one
437.5122


 


332




(3E)-6-fluoro-3-{4-[6-(4- hydroxypiperidin-1-yl)pyridin- 3-yl]-5,5-dimethylfuran-2(5H)- ylidene}-1,3-dihydro-2H-indol- 2-one
421.4696


 


333




(3E)-6-fluoro-3-[4-(6-{4- [2-(2-hydroxyethoxy)ethyl] piperazin-1-yl}pyridin-3- yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
494.5639


 


334




methyl ({5-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl} amino)acetate
409.415


 


335




methyl (2S,3R)-2-({5-[(5E)-5- (6-fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl}amino)- 3-hydroxybutanoate
453.4676


 


336




ethyl (2S)-2-({5-[(5E)-5- (6-fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]pyridin-2-yl}amino)-4- (methylthio)butanoate
497.5882


 


337




(2S)-2-({5-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H-indol- 3-ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]pyridin- 2-yl}amino)-3-(1,3- thiazol-4-yl)propanoic acid
492.5289


 


338




(3E)-3-[5,5-dimethyl-4-{6- [(2-morpholin-4-ylethyl)amino] pyridin-3-yl}furan-2(5H)- ylidene]-6-fluoro-1,3-dihydro- 2H-indol-2-one
450.5113


 


339




(3E)-6-fluoro-3-[4-{6-[2- (hydroxymethyl)morpholin-4- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
437.4686


 


340




(3E)-3-[5,5-dimethyl-4-(6- thiomorpholin-4-ylpyridin- 3-yl)furan-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H- indol-2-one
423.5098


 


341




(3E)-3-[4-{6-[(1,1- dioxidotetrahydro-3- thienyl)(methyl)amino] pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
469.5346


 


342




(3E)-3-[5,5-dimethyl-4-{6- [(2-piperidin-1-ylethyl)amino] pyridin-3-yl}furan-2(5H)- ylidene]-6-fluoro-1,3-dihydro- 2H-indol-2-one
448.5391


 


343




(3E)-6-fluoro-3-[4-{6-[2- (hydroxymethyl)piperidin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
435.4964


 


344




(3E)-6-fluoro-3-[4-{6-[3- (hydroxymethyl)piperidin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H- indol-2-one
435.4964


 


345




1-{5-[(5E)-5-(6-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}piperidine-4- sulfonic acid
485.5336


 


346




(3E)-6-fluoro-3-{4-[6-(3- hydroxypiperidin-1-yl) pyridin-3-yl]-5,5-dimethylfuran- 2(5H)-ylidene}-1,3-dihydro- 2H-indol-2-one
421.4696


 


347




(3E)-6-fluoro-3-[4-{6-[4- (hydroxymethyl)piperidin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
435.4964


 


348




(3E)-6-fluoro-3-[4-{6- [3-(2-hydroxyethyl) piperidin-1-yl]pyridin- 3-yl}-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
449.5232


 


349




(3E)-6-fluoro-3-{4-[6-(3- fluoropiperidin-1-yl)pyridin- 3-yl]-5,5-dimethylfuran- 2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
423.4607


 


350




methyl 1-{5-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl}-4- hydroxypyrrolidine-2- carboxylate
465.4786


 


351




(3E)-6-fluoro-3-[4-{6-[(2- hydroxyethyl)(2-pyridin-4- ylethyl)amino]pyridin-3-yl}- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
486.5443


 


352




ethyl 4-{5-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]pyridin-2-yl}piperazine- 1-carboxylate
478.5213


 


353




(3E)-3-{5,5-dimethyl-4-[6- (4-methylpiperazin-1-yl) pyridin-3-yl]furan-2(5H)- ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
420.4855


 


354




(3E)-6-fluoro-3-[4-{6- [4-(2-hydroxyethyl) piperazin-1-yl]pyridin- 3-yl}-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro- 2H-indol-2-one
450.5113


 


355




(3E)-3-[4-{6-[4-(2- ethoxyethyl)piperazin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
478.5649


 


356




(4-{5-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}piperazin-1- yl)acetic acid
464.4945


 


357




(3E)-3-[4-{6-[ethyl (2-pyridin-2-ylethyl)amino] pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H- indol-2-one
470.5453


 


358




(3E)-3-[4-{6-[bis(2- methoxyethyl)amino] pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
453.5112


 


359




(3E)-6-fluoro-3-[4-{6-[(2- methoxyethyl)(methyl) amino]pyridin-3-yl}- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
409.4586


 


360




(3E)-3-[4-{6-[ethyl(2- hydroxyethyl)amino] pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
409.4586


 


361




(3E)-3-[5,5-dimethyl-4- {6-[(tetrahydrofuran-2- ylmethyl)(2-thienylmethyl) amino]pyridin-3-yl}furan- 2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol- 2-one
517.6222


 


362




(3E)-3-[5,5-dimethyl-4- {6-[(2-pyrrolidin-1-ylethyl) amino]pyridin-3-yl}furan- 2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol- 2-one
434.5123


 


363




(3E)-3-[4-(6-{[2- (diethylamino)ethyl]amino} pyridin-3-yl)-5,5-dimethylfuran- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
436.5281


 


364




(3E)-3-{4-[6-({2-[bis(2- hydroxyethyl)amino]ethyl} amino)pyridin-3-yl]-5,5- dimethylfuran-2(5H)-ylidene}- 6-fluoro-1,3-dihydro- 2H-indol-2-one
468.5261


 


365




(3E)-3-[4-{6-[3-(2- aminoethyl)-2-oxoimidazolidin- 1-yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro- 2H-indol-2-one
449.4836


 


366




(3E)-3-{4-[6-({2-[4- (2-aminoethyl)piperazin- 1-yl]ethyl}amino)pyridin- 3-yl]-5,5-dimethylfuran- 2(5H)-ylidene}-6-fluoro- 1,3-dihydro-2H-indol- 2-one
492.5957


 


367




(3E)-6-fluoro-3-[4-(6-{[2- (4-hydroxypiperidin-1-yl) ethyl]amino}pyridin-3- yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
464.5381


 


368




(3E)-3-[5,5-dimethyl-4-(6- {[2-(2-methylpiperidin-1- yl)ethyl]amino}pyridin-3- yl)furan-2(5H)-ylidene]- 6-fluoro-1,3-dihydro- 2H-indol-2-one
462.5659


 


369




(3E)-6-fluoro-3-[4-(6-{[2- (1H-imidazol-1-yl)ethyl] amino}pyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol-2-one
431.4688


 


370




6-Fluoro-3-[4-{6-[(2- hydroxy-ethyl)-(2- pyridin-4-yl-ethyl)-amino]- pyridin-3-yl}-5,5-dimethyl- 5H-furan-(2E)-ylidene]- 1,3-dihydro-indol-2- one
486.5443


 


371




methyl ({5-[(5E)-5-(5-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}amino)acetate
409.415


 


372




methyl (2S,3R)-2-({5-[(5E)- 5-(5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}amino)-3- hydroxybutanoate
453.4676


 


373




(3E)-3-[5,5-dimethyl-4- {6-[(2-morpholin-4-ylethyl) amino]pyridin-3-yl}furan- 2(5H)-ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
450.5113


 


374




(3E)-5-fluoro-3-[4-{6-[2- (hydroxymethyl)morpholin- 4-yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
437.4686


 


375




(3E)-3-[5,5-dimethyl-4-{6- [(2-piperidin-1-ylethyl)amino] pyridin-3-yl}furan-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
448.5391


 


376




(3E)-5-fluoro-3-[4-{6-[2- (hydroxymethyl)piperidin- 1-yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
435.4964


 


377




(3E)-5-fluoro-3-[4-{6-[3- (hydroxymethyl)piperidin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
435.4964


 


378




(3E)-5-fluoro-3-{4-[6- (4-hydroxypiperidin-1- yl)pyridin-3-yl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
421.4696


 


379




1-{5-[(5E)-5-(5-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl]pyridin- 2-yl}piperidine-4- sulfonic acid
485.5336


 


380




(3E)-5-fluoro-3-{4-[6- (3-hydroxypiperidin-1- yl)pyridin-3-yl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
421.4696


 


381




(3E)-5-fluoro-3-[4-{6-[4- (hydroxymethyl)piperidin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
435.4964


 


382




(3E)-5-fluoro-3-[4-{6-[3-(2- hydroxyethyl)piperidin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
449.5232


 


383




methyl (2S,4R)-1-{5-[(5E)- 5-(5-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl}-4- hydroxypyrrolidine-2- carboxylate
465.4786


 


384




(3E)-5-fluoro-3-[4-{6- [4-(2-hydroxyethyl)piperazin- 1-yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
450.5113


 


385




(3E)-5-fluoro-3-[4-(6-{4- [2-(2-hydroxyethoxy)ethyl] piperazin-1-yl}pyridin-3- yl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3- dihydro-2H-indol-2- one
494.5639


 


386




(3E)-3-[4-{6-[4-(2- ethoxyethyl)piperazin-1- yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
478.5649


 


387




ethyl (4-{5-[(5E)-5-(5- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl}piperazin- 1-yl)acetate
492.5481


 


388




(3E)-3-[4-{6-[bis(2- methoxyethyl)amino] pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
453.5112


 


389




(3E)-5-fluoro-3-[4-{6-[(2- methoxyethyl)(methyl) amino]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
409.4586


 


390




(3E)-3-[4-{6-[ethyl(2- hydroxyethyl)amino] pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
409.4586


 


391




(3E)-3-[5,5-dimethyl-4- {6-[(2-pyrrolidin-1- ylethyl)amino]pyridin- 3-yl}furan-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
434.5123


 


392




(3E)-3-[4-(6-{[2- (diethylamino)ethyl]amino} pyridin-3-yl)-5,5- dimethylfuran-2(5H)-ylidene]- 5-fluoro-1,3-dihydro- 2H-indol-2-one
436.5281


 


393




(3E)-3-{4-[6-({2-[bis(2- hydroxyethyl)amino] ethyl}amino)pyridin-3-yl]- 5,5-dimethylfuran-2(5H)- ylidene}-5-fluoro-1,3- dihydro-2H-indol-2-one
468.5261


 


394




(3E)-5-fluoro-3-[4-(6-{[2- (4-hydroxypiperidin-1-yl) ethyl]amino}pyridin- 3-yl)-5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
464.5381


 


395




(3E)-3-{4-[6-({2-[4- (2-aminoethyl)piperazin-1- yl]ethyl}amino)pyridin- 3-yl]-5,5-dimethylfuran- 2(5H)-ylidene}-5-fluoro- 1,3-dihydro-2H-indol- 2-one
492.5957


 


396




tert-butyl 4-{5-[(5E)-5- (5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]pyridin- 2-yl}-3-(hydroxymethyl) piperazine-1-carboxylate
536.6007


 


397




methyl 4-{5-[(5E)-5-(5- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]pyridin-2-yl}piperazine- 2-carboxylate
464.4945


 


398




(3E)-5-fluoro-3-{4-[6-(3- hydroxypyrrolidin-1-yl) pyridin-3-yl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
407.4428


 


399




(3E)-3-[4-{6-[(2R,3R,4R,5S)- 3,4-dihydroxy-2,5-bis (hydroxymethyl)pyrrolidin- 1-yl]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
483.4934


 


400




methyl 1-({5-[(5E)-5-(5- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5- dihydrofuran-3-yl]  pyridin-2-yl}amino) cyclopropanecarboxylate
435.4528


 


401




(3E)-3-[5,5-dimethyl-4-{6- [(tetrahydro-2H-pyran-4- ylmethyl)amino]pyridin- 3-yl}furan-2(5H)-ylidene]- 5-fluoro-1,3-dihydro-2H- indol-2-one
435.4964


 


402




methyl (2R)-2-({5-[(5E)-5- (5-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl}amino)-3- hydroxypropanoate
439.4408


 


403




ethyl 3-({5-[(5E)-5-(5- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl] pyridin-2-yl}amino) propanoate
437.4686


 


404




2-[{5-[(5E)-5-(5-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl} (methyl)amino]acetamide
408.4309


 


405




2-({5-[(5E)-5-(5-fluoro- 2-oxo-1,2-dihydro-indol- 3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}amino) acetamide
394.4041


 


406




methyl (2S)-2-({5-[(5E)-5- (5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl]pyridin- 2-yl}amino)-3- hydroxypropanoate
439.4408


 


407




(3E)-5-fluoro-3-[4- {6-[(2-hydroxyethyl) amino]pyridin-3-yl}- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
381.405


 


408




(3E)-3-[4-{6-[(2,3- dihydroxypropyl)(methyl) amino]pyridin-3-yl}-5,5- dimethylfuran-2(5H)-ylidene]- 5-fluoro-1,3-dihydro-2H- indol-2-one
425.4576


 


409




(3E)-3-{4-[6- ({[(2R,3S,4S,5R)-3,4- dihydroxy-5- (hydroxymethyl)tetra- hydrofuran-2-yl]methyl} amino)pyridin-3-yl]-5,5- dimethylfuran-2(5H)-ylidene}- 5-fluoro-1,3-dihydro-2H- indol-2-one
483.4934


 


410




(3E)-3-[4-(6-{[(1- ethylpyrrolidin-2- yl)methyl]amino} pyridin-3-yl)-5,5- dimethylfuran-2(5H)- ylidene]-5-fluoro-1,3- dihydro-2H-indol-2-one
448.5391


 


411




ethyl (2S,4R)-1-{5-[(5E)- 5-(5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3- yl]pyridin-2-yl}-4- hydroxypyrrolidine- 2-carboxylate
479.5054


 


412




ethyl 1-{5-[(5E)-5-(5- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran-3- yl]pyridin-2-yl}piperidine-4- carboxylate
477.5332


 


413




(3E)-3-[5,5-dimethyl- 4-(6-{[2-(2-methylpiperidin- 1-yl)ethyl]amino}pyridin- 3-yl)furan-2(5H)-ylidene]- 5-fluoro-1,3-dihydro- 2H-indol-2-one
462.5659


 


414




({[(2S,4R)-1-{5-[(5E)-5- (5-fluoro-2-oxo-1,2- dihydro-3H-indol-3- ylidene)-2,2-dimethyl-2,5- dihydrofuran-3-yl] pyridin-2-yl}-4- hydroxypyrrolidin-2- yl]carbonyl}amino)acetic acid
508.5035


 


415




(3E)-5-fluoro-3-[4-{6- [(4-hydroxy-1,1- dioxidotetrahydro-3- thienyl)(3-hydroxypropyl) amino]pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
529.5862


 


416




(3E)-3-[5,5-dimethyl-4-(6- {[(2S)-pyrrolidin-2-ylmethyl] amino}pyridin-3-yl)furan- 2(5H)-ylidene]-5-fluoro- 1,3-dihydro-2H-indol-2-one
420.4855


 


417




(3E)-3-[5,5-dimethyl-4- {6-[(2S,3R,4S,5R)-3,4,5- trihydroxy-2-methylpiperidin- 1-yl]pyridin-3-yl} furan-2(5H)-ylidene]- 5-fluoro-1,3-dihydro- 2H-indol-2-one
467.4944


 


418




(3E)-5-fluoro-3-[4-{6- [(2-{2-[2-(2-hydroxyethoxy) ethoxy]ethoxy}ethyl)amino] pyridin-3-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
513.5628


 


419




1-{5-[(5E)-5-(5-fluoro-2- oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]pyridin-2-yl} piperidine-4- carboxylic acid
449.4796


 


420




(3E)-3-[5,5-dimethyl-4- (6-piperidin-1-ylpyridin- 3-yl)furan-2(5H)-ylidene]- 5-fluoro-1,3-dihydro- 2H-indol-2-one
405.4706


 


421




(3E)-3-[4-{6-[(2,3- dihydroxypropyl)(methyl) amino]pyridin-3-yl}- 5,5-dimethylfuran-2(5H)- ylidene]-5,6-difluoro- 1,3-dihydro-2H-indol- 2-one
443.4477
















TABLE 8







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one pyridin-4-yl derivatives










Example #
Chemical Structure
Chemical Name
FW





422




(3E)-6-fluoro-3-[4-(2-{4- [2-(2-hydroxyethoxy)ethyl] piperazin-1-yl}pyridin-4-yl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
494.5639


 


423




(3E)-6-fluoro-3-{4-[2- (4-hydroxypiperidin-1- yl)pyridin-4-yl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro-2H- indol-2-one
421.4696


 


424




ethyl (2S)-2-({4-[(5E)-5- (6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]pyridin- 2-yl}amino)-4- (methylthio)butanoate
497.5882


 


425




(3E)-3-[5,5-dimethyl-4-(2- {[2-(1,3-thiazol-4-yl)ethyl] amino}pyridin-4-yl)furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
448.5199


 


426




(3E)-3-[5,5-dimethyl-4-{2- [(2-morpholin-4-ylethyl) amino]pyridin-4-yl}furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
450.5113


 


427




(3E)-3-[5,5-dimethyl-4- {2-[(2-piperidin-1-ylethyl) amino]pyridin-4-yl}furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
448.5391


 


428




(3E)-3-[5,5-dimethyl-4-{2- [(2-pyrrolidin-1-ylethyl)amino] pyridin-4-yl}furan-2(5H)- ylidene]-6-fluoro-1,3-dihydro- 2H-indol-2-one
434.5123


 


429




(3E)-3-[4-(2-{[2- (diethylamino)ethyl]amino} pyridin-4-yl)-5,5- dimethylfuran-2(5H)-ylidene]- 6-fluoro-1,3-dihydro-2H- indol-2-one
436.5281


 


430




(3E)-3-{4-[2-({2-[bis(2- hydroxyethyl)amino]ethyl} amino)pyridin-4-yl]- 5,5-dimethylfuran-2(5H)- ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
468.5261


 


431




(3E)-3-[5,5-dimethyl-4- (2-{[2-(2-oxoimidazolidin-1- yl)ethyl]amino}pyridin-4- yl)furan-2(5H)-ylidene]- 6-fluoro-1,3-dihydro- 2H-indol-2-one
449.4836


 


432




(3E)-6-fluoro-3-[4-(2-{[2- (4-hydroxypiperidin-1-yl) ethyl]amino}pyridin-4-yl)-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
464.5381


 


433




(3E)-3-[5,5-dimethyl-4-(2- {[2-(2-methylpiperidin-1-yl) ethyl]amino}pyridin-4-yl)furan- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
462.5659


 


434




(3E)-6-fluoro-3-[4-(2- {[2-(1H-imidazol-1-yl)ethyl] amino}pyridin-4-yl)-5,5- dimethylfuran-2(5H)-ylidene]- 1,3-dihydro-2H-indol-2-one
431.4688


 


435




(3E)-6-fluoro-3-[4-{2-[2- (hydroxymethyl)morpholin- 4-yl]pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
437.4686


 


436




(3E)-3-[5,5-dimethyl-4- (2-morpholin-4-ylpyridin- 4-yl)furan-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H- indol-2-one
407.4428


 


437




(3E)-3-[5,5-dimethyl-4- (2-thiomorpholin-4- ylpyridin-4-yl)furan-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
423.5098


 


438




(3E)-6-fluoro-3-[4-{2-[2- (hydroxymethyl)piperidin- 1-yl]pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
435.4964


 


439




(3E)-6-fluoro-3-[4-{2-[3- (hydroxymethyl)piperidin- 1-yl]pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
435.4964


 


440




1-{4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}piperidine- 4-sulfonic acid
485.5336


 


441




(3E)-6-fluoro-3-{4-[2- (3-hydroxypiperidin-1- yl)pyridin-4-yl]-5,5- dimethylfuran-2(5H)- ylidene}-1,3-dihydro- 2H-indol-2-one
421.4696


 


442




(3E)-6-fluoro-3-[4-{2-[4- (hydroxymethyl)piperidin- 1-yl]pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
435.4964


 


443




(3E)-6-fluoro-3-[4-{2-[3-(2- hydroxyethyl)piperidin- 1-yl]pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
449.5232


 


444




(3E)-6-fluoro-3-{4-[2- (3-fluoropiperidin-1-yl)pyridin- 4-yl]-5,5-dimethylfuran-2(5H)- ylidene}-1,3-dihydro-2H- indol-2-one
423.4607


 


445




(3E)-6-fluoro-3-[4-{2- [(2-hydroxyethyl)(2- pyridin-4-ylethyl)amino] pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
486.5443


 


446




ethyl 4-{4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}piperazine- 1-carboxylate
478.5213


 


447




(3E )-6-fluoro-3-[4- {2-[4-(2-hydroxyethyl) piperazin-1-yl]pyridin- 4-yl}-5,5-dimethylfuran- 2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
450.5113


 


448




(3E)-3-[4-{2-[4-(2- ethoxyethyl)piperazin-1- yl]pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
478.5649


 


449




(4-{4-[(5E)-5-(6-fluoro- 2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl] pyridin-2-yl}piperazin-1- yl)acetic acid
464.4945


 


450




(3E)-3-[4-{2-[ethyl(2- pyridin-2-ylethyl)amino]  pyridin-4-yl}-5,5-dimethyl- furan-2(5H)-ylidene]- 6-fluoro-1,3-dihydro- 2H-indol-2-one
470.5453


 


451




(3E)-3-[4-{2-[bis(2- methoxyethyl)amino] pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol- 2-one
453.5112


 


452




(3E)-6-fluoro-3-[4- {2-[(2-methoxyethyl)(methyl) amino]pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
409.4586


 


453




(3E)-3-[4-{2-[ethyl(2- hydroxyethyl)amino] pyridin-4-yl}-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
409.4586


 


454




(3E)-3-[5,5-dimethyl-4- {2-[(tetrahydrofuran-2- ylmethyl)(2-thienylmethyl) amino]pyridin-4-yl}furan- 2(5H)-ylidene]-6-fluoro- 1,3-dihydro-2H-indol- 2-one
517.6222
















TABLE 9







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one thienylmethyl


derivatives










Example #
Chemical Structure
Chemical Name
FW





455




(3E)-6-fluoro-3-[4-{5- [(4-hydroxypiperidin-1-yl) methyl]-3-thienyl}-5,5-dimethyl- furan-2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
440.5365


 


456




(3E)-6-fluoro-3-{4-[5- ({4-[2-(2-hydroxyethoxy) ethyl]piperazin-1-yl}methyl)- 3-thienyl]-5,5-dimethylfuran- 2(5H)-ylidene}-1,3- dihydro-2H-indol-2-one
513.6308


 


457




methyl [({4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro-3H- indol-3-ylidene)-2,2-dimethyl- 2,5-dihydrofuran-3-yl]-2- thienyl}methyl)amino] acetate
428.4819


 


458




(3E)-6-fluoro-3-[4- (5-{[2-(hydroxymethyl) morpholin-4-yl]methyl}-3- thienyl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3- dihydro-2H-indol-2-one
456.5355


 


459




(3E)-3-{5,5-dimethyl-4- [5-(morpholin-4-ylmethyl)- 3-thienyl]furan-2(5H)- ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
426.5097


 


460




(3E)-3-[4-(5-{[(1,1- dioxidotetrahydro-3- thienyl)(methyl)amino] methyl}-3-thienyl)-5,5- dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
488.6015


 


461




(3E)-6-fluoro-3-[4-(5-{[3- (hydroxymethyl)piperidin- 1-yl]methyl}-3-thienyl)- 5,5-dimethylfuran- 2(5H)-ylidene]-1,3- dihydro-2H-indol- 2-one
454.5633


 


462




(3E)-6-fluoro-3-[4-{5- [(3-hydroxypiperidin-1- yl)methyl]-3-thienyl}-5,5- dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
440.5365


 


463




(3E)-6-fluoro-3-[4-(5-{[4- (hydroxymethyl)piperidin- 1-yl]methyl}-3-thienyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro-2H- indol-2-one
454.5633


 


464




(3E)-6-fluoro-3-[4-(5- {[3-(2-hydroxyethyl) piperidin-1-yl]methyl}- 3-thienyl)-5,5-dimethyl- furan-2(5H)-ylidene]- 1,3-dihydro-2H-indol- 2-one
468.5901


 


465




(3E)-6-fluoro-3-[4-{5- [(3-fluoropiperidin-1-yl)methyl]- 3-thienyl}-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro- 2H-indol-2-one
442.5276


 


466




methyl 1-({4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]-2-thienyl}methyl)-4- hydroxypyrrolidine-2- carboxylate
484.5455


 


467




ethyl 4-({4-[(5E)-5-(6- fluoro-2-oxo-1,2-dihydro- 3H-indol-3-ylidene)-2,2- dimethyl-2,5-dihydrofuran- 3-yl]-2-thienyl}methyl) piperazine-1-carboxylate
497.5882


 


468




(3E)-6-fluoro-3-[4- (5-{[4-(2-hydroxyethyl) piperazin-1-yl]methyl}-3- thienyl)-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro- 2H-indol-2-one
469.5782


 


469




(3E)-3-[4-(5-{[ethyl (2-pyridin-2-ylethyl) amino]methyl}-3-thienyl)- 5,5-dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
489.6122


 


470




(3E)-3-[4-(5-{[bis(2- methoxyethyl)amino]methyl}- 3-thienyl)-5,5-dimethylfuran- 2(5H)-ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
472.5781


 


471




(3E)-6-fluoro-3-[4-(5-{[(2- methoxyethyl)(methyl) amino]methyl}-3-thienyl)- 5,5-dimethylfuran-2(5H)- ylidene]-1,3-dihydro- 2H-indol-2-one
428.5255


 


472




(3E)-3-[4-(5-{[ethyl(2- hydroxyethyl)amino]methyl}- 3-thienyl)-5,5-dimethyl- furan-2(5H)-ylidene]- 6-fluoro-1,3-dihydro- 2H-indol-2-one
428.5255


 


473




(3E)-3-[4-{5-[({2- [4-(2-aminoethyl) piperazin-1-yl]ethyl} amino)methyl]-3-thienyl}- 5,5-dimethylfuran-2(5H)- ylidene]-6-fluoro-1,3- dihydro-2H-indol-2-one
511.6626


 


474




(3E)-6-fluoro-3-{4-[5- ({[2-(4-hydroxypiperidin- 1-yl)ethyl]amino}methyl)- 3-thienyl]-5,5-dimethylfuran- 2(5H)-ylidene}-1,3-dihydro- 2H-indol-2-one
483.605 


 


475




(3E)-3-{5,5-dimethyl-4- [5-({[2-(2-oxoimidazolidin- 1-yl)ethyl]amino}methyl)-3- thienyl]furan-2(5H)- ylidene}-6-fluoro-1,3- dihydro-2H-indol-2-one
468.5505
















TABLE 10







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one amine derivatives










Example #
Chemical Structure
Chemical Name
FW













476




(3E)-6-fluoro-3-{4-[4-(2- hydroxyethyl)piperazin-1-yl]-5,5- dimethylfuran-2(5H)-ylidene}-1, 3-dihydro-2H- indol-2-one
373.4256


 


477




(3E)-3-{4-[(2,4- dimethoxybenzyl) amino]-5,5-dimethylfuran- 2(5H)-ylidene}- 6-fluoro-1,3-dihydro- 2H-indol-2-one
410.4427


 


478




N-[(5E)-5-(6-fluoro-2-oxo-1,2- dihydro-3H-indol-3-ylidene)- 2,2-dimethyl-2,5- dihydrofuran-3-yl]-6-[4-(2- hydroxyethyl)piperazin-1- yl]nicotinamide
493.5362


 


479




(3E)-6-bromo-3-(5,5-dimethyl- 4-morpholin-4-ylfuran-2(5H)- ylidene)-1,3-dihydro-2H-indol-2- one
391.2631


 


480




(3E)-3-(5,5-dimethyl-4- morpholin-4-ylfuran- 2(5H)-ylidene)-6-iodo- 1,3-dihydro-2H-indol-2- one
438.26
















TABLE 11







[5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one carbonyl derivatives










Example #
Structure
Chemical Name
FW





481




(3E)-3-[5,5-dimethyl-4- (morpholin-4-ylcarbonyl) furan-2(5H)-ylidene]-6- fluoro-1,3-dihydro-2H- indol-2-one
358.3671


 


482




(3E)-6-fluoro-3-[4-{[4-(2- hydroxyethyl)piperazin-1- yl]carbonyl}-5,5-dimethylfuran- 2(5H)-ylidene]-1,3-dihydro- 2H-indol-2-one
401.4356
















TABLE 12







[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-


indol-6-yl] derivatives










Example #
Chemical Structure
Chemical Name
FW





483




methyl 2-{[(3E)-3-(5,5- dimethyl-4-morpholin- 4-ylfuran-2(5H)-ylidene)- 2-oxo-2,3-dihydro- 1H-indol-6-yl]thio} benzoate
478.5664


 


484




2-{[(3E)-3-(5,5-dimethyl- 4-morpholin-4-ylfuran- 2(5H)-ylidene)-2-oxo-2,3- dihydro-1H-indol-6-yl] thio}benzoic acid
464.5396


 


485




2-{[(3E)-3-(5,5-dimethyl- 4-morpholin-4-ylfuran- 2(5H)-ylidene)-2-oxo-2,3- dihydro-1H-indol-6-yl] thio}-N-methyl- benzamide
477.5823


 


486




N-(3-{[(3E)-3-(5,5-dimethyl- 4-morpholin-4-ylfuran- 2(5H)-ylidene)-2-oxo-2,3- dihydro-1H-indol-6-yl] amino}phenyl)acetamide
460.5312









The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient. Such a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of
catalytic activity, affinity to ATP or ability to interact with a substrate.
More particularly, the compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy. Examples of fibrotic disorders include hepatic cirrhosis and athelosclerosis. Examples of metabolic disorders include psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases.
Additional disorders that can be treated by the compounds/compositions of the present invention include: blood vessel proliferative disorder (such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis and restenosis); and mesangial cell proliferative disorder (such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies).
The following defined terms are used throughout this specification:
“Me” refers to methyl.
“Et” refers to ethyl.
“tBu” refers to t-butyl.
“iPr” refers to i-propyl.
“Ph” refers to phenyl.
“Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
“Alkyl” refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. The alkyl group may be optionally substituted with one or more substituents are selected from the group consisting of hydroxyl, cyano, alkoxy, ═O, ═S, NO2, halogen, dimethyl amino, and SH.
“Alkenyl” refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Preferably, the alkenyl group has 2 to 12 carbons. More preferably it is a lower alkenyl of from 2 to 7 carbons, most preferably 2 to 4 carbons. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, ═O, ═S, NO2, halogen, dimethyl amino, and SH.
“Alkynyl” refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Preferably, the alkynyl group has 2 to 12 carbons. More preferably it is a lower alkynyl of from 2 to 7 carbons, most preferably 2 to 4 carbons. The alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, ═O, ═S, NO2, halogen, dimethyl amino, and SH.
“Alkoxyl” refers to an “O-alkyl” group.
“Aryl” refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO2, amine, thioether, cyano, alkoxy, alkyl, and amino.
“Alkaryl” refers to an alkyl that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl.
“Carbocyclic aryl” refers to an aryl group wherein the ring atoms are carbon.
“Carbocyclic ring” refers to a cyclic aliphatic ring or an aryl ring wherein the ring atoms are carbon.
“Heterocyclic aryl” refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
“Heterocyclic ring” refers to an aliphatic ring or heterocyclic aryl wherein one or more of the ring atoms are heteroatoms.
“Hydrocarbyl” refers to a hydrocarbon radical having only carbon and hydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
“Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
“Amide” refers to —C(O)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
“Thioamide” refers to —C(S)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
“Amine” refers to a —N(R′′)R′′′ group, wherein R′′ and R′′′ are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
“Thioether” refers to —S—R′′, wherein R′′ is alkyl, aryl, or alkylaryl.
“Sulfonyl” refers to —S(O)2—R′′′′, where R′′′′ is aryl, C(CN)═C-aryl, CH2CN, alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.
The present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. 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 effects and responses to the extracellular microenvironment).
It has been shown that tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Tyrosine kinase signal transduction results in, among other responses, cell proliferation, differentiation and metabolism. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis, e.g. macular degeneration).
This invention is therefore directed to compounds which regulate, modulate and/or inhibit tyrosine kinase signal transduction by affecting the enzymatic activity of the RTKs and/or the non-receptor tyrosine kinases and interfering with the signal transduced such proteins. More particularly, the present invention is directed to compounds which regulate, modulate and/or inhibit the RTK and/or non-receptor tyrosine kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
The invention is further illustrated by the following non-limiting examples.
Preparation of 6-Fluoro-3-(4-methoxy-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one




To a stirred solution of 6-fluorooxindole (2.6 g, 17.5 mmol) in anhydrous THF (30 mL) under nitrogen was added 1.0M LiHMDS/THF solution (35 mL, 35 mmol). The mixture was stirred at room temperature for 10 minutes. Methyl tetronate (1.0 g, 8.8 mmol) was added as one portion. After stirring at room temperature for 1 hour, the reaction was cooled to 0° C., and quenched with 2M HCl until pH=3. The mixture was stirred at room temperature for 2 more hours, and poured into 250 mL of water. The resulting precipitates were filtered, rinsed with water and dried in vacuum to give 6-fluoro-3-(4-methoxy-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one as off-white solid. Yield: 840 mg, 38%.
1H NMR (500 MHz, DMSO-d6) δ ppm 3.99 (s, 3H) 5.22 (s, 2H) 6.59 (dd, J=9.52, 2.20 Hz, 1H) 6.63 (s, 1H) 6.66-6.72 (m, 1H) 7.43 (dd, J=8.06, 5.61 Hz, 1H) 10.32 (s, 1H)
Preparation of 3-(4-Methoxy-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one




1H NMR (500 MHz, DMSO-d6) δ ppm 3.99 (s, 3H) 5.22 (s, 2H) 6.67 (s, 1H) 6.78 (d, J=7.32 Hz, 1H) 6.88 (t, J=7.32 Hz, 1H) 6.99 (t, J=7.57 Hz, 1H) 7.47 (d, J=7.81 Hz, 1H) 10.17 (s, 1H)
Example 1




6-Fluoro-3-{4-[(2-methoxy-ethyl)-methyl-amino]-5H-furan-2-ylidene}-1,3-dihydro-indol-2-one
HR MS (ES+): 305.0476 (MH+)

    
    
        (ES−): 303.1947 (M−H)
    
    


Example 2




6-Fluoro-3-[4-(4-methyl-piperazin-1-yl)-5H-furan-2-ylidene]-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 2.22 (s, 3H) 2.40 (t, J=4.88 Hz, 4H) 3.32 (br.s., 4H) 5.33 (s, 2H) 6.21 (s, 1H) 6.52 (dd, J=9.76, 2.44 Hz, 1H) 6.57-6.64 (m, 1H) 7.33 (dd, J=8.30, 5.86 Hz, 1H) 10.05 (s, 1H)
HR MS (ES+): 316.3362 (MH+)
Example 3




6-Fluoro-3-(4-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (br. s., 6H) 3.32 (br.s., 4H) 3.41 (t, J=5.37 Hz, 2H) 3.49 (q, J=4.88 Hz, 2H) 3.54 (t, J=5.61 Hz, 2H) 4.59 (t, J=5.13 Hz, 1H) 5.32 (s, 2H) 6.20 (s, 1H) 6.52 (d, J=9.28 Hz, 1H) 6.60 (t, J=9.52 Hz, 1H) 7.33 (dd, J=8.06, 6.10 Hz, 1H) 10.05 (s, 1H)
Example 4




6-Fluoro-3-[4-(3-hydroxy-piperidin-1-yl)-5H-furan-2-ylidene]-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 1.50 (br. s., 2H) 1.82 (br. s., 2H) 3.03 (dd, J=12.69, 7.32 Hz, 1H) 3.10-3.55 (m, 3H) 3.67 (br. s., 1H) 4.99 (br. s., 1H) 5.31 (s, 2H) 6.18 (s, 1H) 6.52 (dd, J=9.76, 2.44 Hz, 1H) 6.56-6.64 (m, 1H) 7.32 (dd, J=8.30, 5.86 Hz, 1H) 10.03 (s, 1H)
Example 5




6-Fluoro-3-[4-(4-hydroxy-piperidin-1-yl)-5H-furan-2-ylidene]-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 1.41-1.53 (m, 2H) 1.77-1.87 (m, 2H) 3.18 (t, J=7.32 Hz, 2H) 3.49 (br. s., 2H) 3.71-3.80 (m, 1H) 4.84 (d, J=3.91 Hz, 1H) 5.32 (s, 2H) 6.18 (s, 1H) 6.52 (dd, J=9.76, 2.44 Hz, 1H) 6.56-6.63 (m, 1H) 7.32 (dd, J=8.30, 5.86 Hz, 1H) 10.03 (s, 1H)
HR MS (ES+): 317.1436 (MH+)
Example 6




6-Fluoro-3-{4-[2-(2-hydroxy-ethoxy)-ethylamino]-5H-furan-2-ylidene}-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 3.34 (br. s, 2H) 3.46-3.50 (m, 2H) 3.53 (q, J=5.21 Hz, 2H) 3.61 (br. s., 2H) 4.60 (t, J=5.61 Hz, 1H) 5.13 (s, 2H) 6.15 (s, 1H) 6.53 (dd, J=9.52, 2.20 Hz, 1H) 6.57-6.67 (m, 1H) 7.34 (dd, J=7.81, 5.86 Hz, 1H) 7.92 (s, 1H) 10.05 (s, 1H)
Example 7




3-[4-(3-Diethylamino-propylamino)-5H-furan-2-ylidene]-6-fluoro-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.08 Hz, 6H) 1.63-1.73 (m, 2H) 2.41-2.49 (m, 6H) 3.19 (br. s., 2H) 5.13 (s, 2H) 6.11 (s, 1H) 6.53 (dd, J=9.52, 2.20 Hz, 1H) 6.57-6.65 (m, 1H) 7.34 (dd, J=8.30, 5.86 Hz, 1H) 7.86 (s, 1H) 10.04 (s, 1H).
Example 8




6-Fluoro-3-[4-(2-morpholin-4-yl-ethylamino)-5H-furan-2-ylidene]-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 2.43 (br. s., 4H) 2.53 (t, J=5.86 Hz, 2H) 3.29 (br. s, 2H) 3.60 (t, J=4.39 Hz, 4H) 5.13 (s, 2H) 6.14 (s, 1H) 6.53 (dd, J=9.52, 2.20 Hz, 1H) 6.57-6.64 (m, 1H) 7.34 (dd, J=8.30, 5.86 Hz, 1H) 7.80 (s, 1H) 10.04 (s, 1H)
Example 9




6-Fluoro-3-(4-morpholin-4-yl-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one
A mixture of 6-fluoro-3-(4-methoxy-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.40 mmol) and morpholine (0.5 mL, 5.7 mmol) in 20 mL of EtOH was heated at reflux for 16 hours. The mixture was cooled to room temperature. The precipitates were filtered, rinsed with EtOH and dried in vacuum to give 6-fluoro-3-(4-morpholin-4-yl-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one as a pale yellow powder. Yield: 55 mg, 45%.
1H NMR (500 MHz, DMSO-d6) δ ppm 3.34 (br. s., 4H) 3.70 (t, J=4.88 Hz, 4H) 5.35 (s, 2H) 6.25 (s, 1H) 6.54 (dd, J=9.28, 2.44 Hz, 1H) 6.59-6.65 (m, 1H) 7.35 (dd, J=8.54, 5.61 Hz, 1H) 10.07 (s, 1H)
Example 10




6-Fluoro-3-[4-(3-morpholin-4-yl-propylamino)-5H-furan-2-ylidene]-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 1.68-1.77 (m, 2H) 2.35 (t, J=6.59 Hz, 6H) 3.22 (br. s., 2H) 3.59 (t, J=4.39 Hz, 4H) 5.13 (s, 2H) 6.13 (s, 1H) 6.53 (dd, J=9.52, 1.71 Hz, 1H) 6.58-6.64 (m, 1H) 7.34 (dd, J=7.81, 5.86 Hz, 1H) 7.86 (s, 1H) 10.04 (s, 1H).
Example 11




3-{4-[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-5H-furan-2-ylidene}-6-fluoro-1,3-dihydro-indol-2-one
HR MS (ES+): 456.1934 (MH+)

    
    
        (ES−): 454.2536 (M−H)
    
    


Example 12




3-{4-[4-(2-Diethylamino-ethoxy)-phenylamino]-5H-furan-2-ylidene}-6-fluoro-1,3-dihydro-indol-2-one
HR MS (ES+): 424.2889 (MH+)

    
    
        (ES−): 422.2836 (M−H)
    
    


Preparation of 4-Bromo-5H-furan-2-one




To a stirred suspension of tetronic acid (5.0 g, 50 mmol) in 100 mL of anhydrous CH2Cl2, was added 5 mL of anhydrous DMF, and cooled with ice bath. Oxalyl bromide (5.6 mL, 60 mmol) was added slowly over 50 minutes. The mixture was stirred at 0° C. for 30 minutes and then room temp for 2 hours. Water (100 mL) was added and the mixture separated into two layers. The aqueous layer was extracted with Et2O (2×100 mL). All the organic layers were combined, washed with water (100 mL), saturated NaHCO3 (2×100 mL) and brine (100 mL), dried over Na2SO4, and evaporated to dryness to give 4-bromo-5H-furan-2-one as a light brown solids. Yield: 5.6 g, 69%.
1H NMR (500 MHz, CDCl3) δ ppm 4.87-4.89 (m, 2H) 6.36-6.38 (m, 1H)
Preparation of 3-(4-Bromo-5H-furan-2-ylidene)-6-fluoro-1,3-dihydro-indol-2-one




To a 0° C. stirred solution of 6-fluorooxindole (370 mg, 2.45 mmol) in anhydrous THF (10 mL) was added 1M LiHMDS/THF solution (4.9 mL, 4.9 mmol). The mixture was stirred at 0° C. for 10 minutes. 4-Bromo-5H-furan-2-one (200 mg, 1.23) was added as a solution in 2 mL of THF. The resulting mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour and quenched with 10 mL of 2M HCl. Methanol (5 mL) was added and the mixture was stirred at 50° C. for 0.5 hour. The mixture was poured into 150 mL of water and then stirred for 30 minutes. The precipitates were filtered, washed with water, and dried in vacuum to give 3-(4-bromo-5H-furan-2-ylidene)-6-fluoro-1,3-dihydro-indol-2-one as a yellow solid. Yield: 228 mg, 63%.
1H NMR (500 MHz, DMSO-d6) δ ppm 5.44 (s, 2H) 6.62 (dd, J=9.28, 2.44 Hz, 1H) 6.70-6.76 (m, 1H) 7.47 (dd, J=8.30, 5.37 Hz, 1H) 7.67 (t, J=1.71 Hz, 1H) 10.48 (s, 1H)
Example 40




4-[5-(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-2,5-dihydro-furan-3-yl]-benzoic acid methyl ester
To a 1:1 mixture of toluene/water (10 mL), were added the bromide (40 mg, 0.14 mmol), 4-methoxycarbonylphenylboronic acid (49 mg, 0.27 mmol), PdCl2(PPh3)2 (17 mg, 0.024 mmol), 2M KF aqueous solution (0.35 mL, 0.7 mmol), benzyltriethylammonium chloride (3 mg, 0.013 mmol). The mixture was heated at 80° C. under N2 for 16 hours, cooled to room temperature and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with saturated NaHCO3 
(50 mL) and brine (50 mL), dried over Na2SO4. Purification through silica gel column with 10-25% MeOH/CHCl3 led to the product as a brown solid. Yield: 29 mg, 62%.
1H NMR (500 MHz, DMSO-d6) δ ppm 3.88 (s, 3H) 5.83 (s, 2H) 6.63 (dd, J=9.28, 2.44 Hz, 1H) 6.70-6.79 (m, 1H) 7.55 (dd, J=8.30, 5.86 Hz, 1H) 7.86 (d, J=8.30 Hz, 2H) 7.98 (s, 1H) 8.04 (d, J=8.30 Hz, 2H) 10.48 (s, 1H)
The Examples 13 through 46 were prepared using the experiment procedure described in Example 40, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation
Example 34




(3E)-6-fluoro-3-[4-(1H-pyrrol-3-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
A solution of (3E)-6-fluoro-3-{4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]furan-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one (Example 33; 90 mg) in a mixture of trifluoroacetic acid (7 mL) and CH2Cl2 (7 mL) was stirred at room temperature for 3 days. The mixture was evaporated to dryness, and re-dissolved in 1:1 THF/MeOH (6 mL). The solution was slowly added into diluted NaHCO3 solution (100 mL) with stirring. The precipitates were filtered, washed with water, and dried in vacuum to give (3E)-6-fluoro-3-[4-(1H-pyrrol-3-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as brown solid. Yield: 40 mg.
1H NMR (500 MHz, DMSO-d6) δ ppm 5.60 (s, 2H) 6.49 (s, 1H) 6.59 (dd, J=9.28, 1.95 Hz, 1H) 6.66-6.74 (m, 1H) 6.92 (s, 1H) 7.38 (d, J=5.86 Hz, 2H) 7.49 (dd, J=7.81, 5.86 Hz, 1H) 10.32 (s, 1H) 11.43 (s, 1H)
Example 35




(3E)-6-fluoro-3-{4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]furan-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 (d, J=7.81 Hz, 18H) 1.51-1.61 (m, 3H) 5.62 (s, 2H) 6.59 (dd, J=9.28, 2.44 Hz, 1H) 6.63 (d, J=1.95 Hz, 1H) 6.67-6.74 (m, 1H) 6.97 (s, 1H) 7.44-7.53 (m, 3H) 10.33 (s, 1H)
LR MS (EI): 438 (M+)
Example 36




(3E)-6-fluoro-3-[4-(1H-pyrrol-2-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
A solution of tert-butyl 2-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,5-dihydrofuran-3-yl]-1H-pyrrole-1-carboxylate (Example 37; 30 mg) in a mixture of trifluoroacetic acid (2 mL) and CH2Cl2 (10 mL) was stirred at room temperature for 16 hours. The mixture was evaporated to dryness, and re-dissolved in 1:1 THF/MeOH (4 mL). The solution was slowly added into diluted NaHCO3 solution (100 mL) with stirring. The precipitates were filtered, washed with water, and dried in vacuum to give (3E)-6-fluoro-3-[4-(1H-pyrrol-2-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as brown solid. Yield: 15 mg.
1H NMR (500 MHz, DMSO-d6) δ ppm 5.62 (s, 2H) 6.21-6.25 (m, 1H) 6.57-6.62 (m, 2H) 6.67-6.73 (m, 1H) 7.13 (s, 1H) 7.49 (dd, J=8.06, 5.61 Hz, 1H) 7.61 (s, 1H) 10.32 (s, 1H) 11.95 (s, 1H)
LR MS (EI): 282 (M+)
Example 37




tert-butyl 2-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,5-dihydrofuran-3-yl]-1H-pyrrole-1-carboxylate
1H NMR (500 MHz, DMSO-d6) δ ppm 1.59 (s, 9H) 5.66 (s, 2H) 6.40 (t, J=3.42 Hz, 1H) 6.61 (dd, J=9.76, 2.44 Hz, 1H) 6.69-6.75 (m, 1H) 6.82 (dd, J=3.42, 1.46 Hz, 1H) 7.50 (dd, J=8.30, 5.37 Hz, 1H) 7.59 (dd, J=3.42, 1.46 Hz, 1H) 7.70 (s, 1H) 10.35 (s, 1H)
LR MS (EI): 382 (M+)
Example 38




(3E)-6-fluoro-3-[4-(3-thienyl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 5.71 (s, 2H) 6.61 (dd, J=9.52, 2.20 Hz, 1H) 6.70-6.76 (m, 1H) 7.53 (dd, J=8.30, 5.86 Hz, 1H) 7.60 (d, J=5.37 Hz, 1H) 7.68 (s, 1H) 7.72 (dd, J=5.13, 2.69 Hz, 1H) 8.06 (d, J=2.44 Hz, 1H) 10.42 (s, 1H)
LR MS (EI): 299 (M+)
Example 39




3-{4-[5-(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-2,5-dihydro-furan-3-yl]-phenyl}-propionic acid
HR MS (ES−): 364.0864 (M−H)
Example 43




6-Fluoro-3-[4-(3-methoxy-phenyl)-5H-furan-2-ylidene]-1,3-dihydro-indol-2-one
HR MS (ES+): 324.2709 (MH+)
Example 44




6-Fluoro-3-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-5H-furan-2-ylidene}-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 2.47 (br.s., 4H) 2.70 (t, J=5.61 Hz, 2H) 3.57 (t, J=4.88 Hz, 4H) 4.17 (t, J=5.61 Hz, 2H) 5.76 (s, 2H) 6.61 (dd, J=9.28, 2.44 Hz, 1H) 6.68-6.76 (m, 1H) 7.07 (d, J=8.79 Hz, 2H) 7.52 (dd, J=8.30, 5.86 Hz, 1H) 7.66 (d, J=8.79 Hz, 2H) 7.72 (s, 1H) 10.40 (s, 1H)
Example 45




3-[4-(4-Dimethylamino-phenyl)-5H-furan-2-ylidene]-6-fluoro-1,3-dihydro-indol-2-one
HR MS (ES+): 337.1384 (MH+)
Example 46




6-Fluoro-3-[4-(4-methoxy-phenyl)-5H-furan-2-ylidene]-1,3-dihydro-indol-2-one
1H NMR (500 MHz, DMSO-d6) δ ppm 3.83 (s, 3H) 5.77 (s, 2H) 6.61 (dd, J=9.28, 2.44 Hz, 1H) 6.69-6.77 (m, 1H) 7.06 (d, J=8.79 Hz, 2H) 7.52 (dd, J=8.30, 5.86 Hz, 1H) 7.67 (d, J=8.79 Hz, 2H) 7.72 (s, 1H) 10.40 (s, 1H)
Preparation of 4-pyrrolidin-1-ylfuran-2(5H)-one




A mixture of methyl tetronate (2.0 g, 17.5 mmol) and pyrrolidine (4.0 mL, 48 mmol) in EtOH (20 mL) was heated at reflux for 2 hours. The mixture was cooled to room temperature, and evaporated to dryness. The resulting solid was recrystallized with benzene/hexanes to give 4-pyrrolidin-1-ylfuran-2(5H)-one as white crystals. Yield: 2.60 g, 96%.
1H NMR (500 MHz, CDCl3) δ ppm 2.01-2.05 (m, 4H) 3.28 (t, J=6.83 Hz, 4H) 4.53 (s, 1H) 4.67 (s, 2H)
Preparation of 5,5-dimethyl-4-pyrrolidin-1-ylfuran-2(5H)-one




To a −78° C. stirred suspension of 4-pyrrolidin-1-ylfuran-2(5H)-one (1.0 g, 6.5 mmol) in 20 mL of anhydrous THF, was slowly added 1M LiHMDS/THF solution (14.4 mL, 14.4 mmol). The mixture was stirred at −78° C. under nitrogen for 30 minutes, and methyl iodide (3 mL, 24 mmol) was added. The mixture was stirred at −78° C. for 1 hour, then allowed to warm up to room temp. The reaction was quenched with AcOH (3 mL) and water (10 mL), concentrated to about 15 mL, and extracted with CHCl3 (3×50 mL). The organic layers were combined, washed with 0.5M HCl (2×50 mL), brine (50 mL), dried over Na2SO4, and evaporated to give 5,5-dimethyl-4-pyrrolidin-1-ylfuran-2(5H)-one as a brown solid. Yield: 1.08 g, 92%.
1H NMR (500 MHz, CDCl3) δ ppm 1.54 (s, 6H) 1.89-1.99 (m, 4H) 3.32 (br. s., 4H) 4.33 (s, 1H)
Preparation of 4-Hydroxy-5,5-dimethyl-5H-furan-2-one




A suspension of 5,5-dimethyl-4-pyrrolidin-1-ylfuran-2(5H)-one (535 mg) in a mixture of MeOH (2 mL) and 5M HCl (8 mL) was heated at 88° C. for 2 hours. The mixture was cooled to room temp., extracted with CHCl3 (10×15 mL), combined, dried over Na2SO4, and evaporated to dryness to give 4-hydroxy-5,5-dimethyl-5H-furan-2-one as light brown solid. Yield: 359 mg, 95%.
1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (s, 6H) 4.78 (s, 1H) 12.64 (s, 1H)
Preparation of 2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate




To a −78° C. stirred solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (250 mg, 1.95 mmol) in 18 mL of anhydrous CH2Cl2, was added triethylamine (0.40 mL, 2.9 mmol) and Tf2O (0.49 mL, 2.9 mmol). The reaction was stirred at −78° C. for 30 minutes, and quenched with saturated NH4Cl solution (10 mL). The mixture was warmed up to room temperature and separated. The aqueous layer was extracted with CH2Cl2 (2×20 mL). All organic layers were combined, dried over Na2SO4 and evaporated to brown oil, which was purified by plugging through a short pad of silica gel column with EtOAc/hexanes (1/3). Evaporation of solvents gave 2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate as a light brown oil (450 mg, 89%).
Preparation of 4-(4-methoxyphenyl)-5,5-dimethylfuran-2(5H)-one




To a 1:1 mixture of toluene/water (20 mL), were added 2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (100 mg, 0.38 mmol), 4-methoxyphenylboronic acid (87 mg, 0.57 mmol), PdCl2(PPh3)2 (27 mg, 0.038 mmol), 2M KF aqueous solution (0.95 mL, 1.9 mmol), benzyltriethylammonium chloride (8.7 mg, 0.038 mmol). The mixture was heated at 50° C. under N2 for 30 minutes, cooled to room temperature and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4. Purification through silica gel column with 10-30% EtOAc/hexanes led to the product as yellow solid. Yield: 33 mg, 40%.
1H NMR (500 MHz, CDCl3) δ ppm 1.70 (s, 6H) 3.87 (s, 3H) 6.14 (s, 1H) 6.97 (d, J=8.79 Hz, 2H) 7.53 (d, J=8.79 Hz, 2H)
Example 158




(3E)-6-fluoro-3-[4-(4-methoxyphenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
To a 0° C. stirred solution of 6-fluorooxindole (45 mg, 0.3 mmol) in anhydrous THF (5 mL) was added 1M LiHMDS/THF solution (0.6 mL, 0.6 mmol). The mixture was stirred at 0° C. for 10 minutes. 4-(4-methoxyphenyl)-5,5-dimethylfuran-2(5H)-one (33 mg, 0.15 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour and quenched with 2 mL of 2M HCl. The mixture was stirred at room temperature for 16 hours and poured into 100 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give 3(3E)-6-fluoro-3-[4-(4-methoxyphenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as yellow solids. Yield: 228 mg, 63%.
1H NMR (500 MHz, DMSO-d6) δ ppm 1.76 (s, 6H) 3.83 (s, 3H) 6.60 (dd, J=9.28, 2.44 Hz, 1H) 6.69-6.78 (m, 1H) 7.05 (d, J=9.28 Hz, 2H) 7.53 (dd, J=8.30, 5.86 Hz, 1H) 7.66 (s, 1H) 7.76 (d, J=8.79 Hz, 2H) 10.38 (s, 1H)
Preparation of 4-Bromo-5,5-dimethyl-5H-furan-2-one




To a solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (2.1 g, 16.4 mmol) in DCE (40 mL) and DMF (1.5 mL) at 0° C. was added dropwise oxalyl bromide (3.0 mL, 32 mmol, 2 equiv). The mixture was stirred at room temperature for 4-5 h, and then put in an ice bath. Ice water (100 mL) was added slowly. The mixture was extracted with CH2Cl2 (100 mL). The organic phase was washed with 10% NaHCO3 and again with water, dried over sodium sulfate and evaporated to give the title compound 2.7 g (86% yield).
1H NMR (300 MHz, CDCl3) δ 6.17 (s, 1H), 1.54 (s, 6H), ESI-MS m/z 251.9 (M+H)+
Preparation of 3-[4-Bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1.3-dihydro-indol-2-one




To a solution of 6-fluorooxindole (3 g, 20 mmol) in THF (50 mL) at 0° C., was added 40 mL of 1M LHMDS in THF. The reaction mixture was stirred at 0° C. for 15 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (5) (1.91 g, 10 mmol) in 5 mL of THF was added to the above reaction mixture. The reaction was stirred at 0° C. for further 30 minutes and then at room temperature for 2.5 hrs. To the reaction, 80 mL of 2M HCl was added. The resulting mixture was stirred at 50-55° C. for one hour, cooled down to room temperature, poured to 1000 mL of water and was stirred at room temperature for one hour. The precipitates formed were collected and washed with water, dried in vacuum to give the title compound as a yellow solid product (2.4 g, yield: 74%).
1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.54 (s, 1H), 7.49 (dd, J=8.7, 5.4 Hz, 1H), 6.73 (ddd, J=10.8, 8.1, 2.4 Hz, 1H), 6.61 (dd, J=9.3, 2.7 Hz, 1H). 1.57 (s, 6H). ESI-MS m/z 324.3 M+
Preparation of Examples 46-158 (FIG. 3)
Each of the examples was synthesized in 40 mL vial. To each reaction vial, 3-[4-Bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1.3-dihydro-indol-2-one (55 mg, 0.17 mmol), boronic acid (0.4 mmol), THF (4 mL), 1M of potassium carbonate water solution (1.5 mL) and tetrakis(triphenylphosphine) palladium(0) (18 mg) were added. The reaction was heated at 60° C. overnight under nitrogen atmosphere. After cooling down to room temperature, 10 mL of ethyl acetate and 8 mL of water were added. The organic layer was evaporated to give the crude product that was subjected to QC and purification. The library compounds were purified by high throughput RP-HPLC. Each compound was re-analyzed by LCMS after purification.
Preparation of methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate




To 30 mL of 1,4-dioxane, was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (500 mg, 1.54 mmol), 4-methoxycarbonylphenylboronic acid (333 mg, 1.85 mmol), PdCl2(PPh3)2 (54 mg, 0.077 mmol), 1M Na2CO3 aqueous solution (6.2 mL, 6.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 200 mL of water. The brown precipitates were filtered, washed with water and dried to give the crude product. Purification through silica gel column with 1-5% MeOH/CHCl3 led to methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate as orange/red solid. Yield: 500 mg, 86%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.79 (s, 6H) 3.89 (s, 3H) 6.63 (d, J=8.79 Hz, 1H) 6.77 (t, J=8.30 Hz, 1H) 7.57 (dd, J=7.57, 5.61 Hz, 1H) 7.89 (s, 1H) 7.96 (d, J=8.30 Hz, 2H) 8.05 (d, J=8.30 Hz, 2H) 10.47 (s, 1H)
Preparation of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid




Methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate (500 mg, 1.32 mmol) was added to a mixture of 1M NaOH (4 mL, 4 mmol), THF (8 mL) and MeOH (20 mL). The mixture was heated at 58° C. for 5 hours, cooled to room temp., and poured into 200 mL of water. 2M HCl was added to bring pH down to 3. The precipitates were filtered, washed with water and dried in vacuo to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid as an orange/red solid. Yield: 480 mg, quantitative.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.77 (s, 6H) 6.61 (dd, J=9.38, 2.35 Hz, 1H) 6.71-6.78 (m, 1H) 7.55 (dd, J=8.50, 5.57 Hz, 1H) 7.86 (s, 1H) 7.90 (d, J=8.50 Hz, 2H) 8.02 (d, J=8.50 Hz, 2H) 10.44 (s, 1H) 13.16 (br s, 1H)
LR MS (ES−): 364 (M−1)
Example 159




(3E)-6-Fluoro-3-[4-{4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.137 mmol), 4-hydroxypiperidine (15 mg, 0.15 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (57 mg, 0.15 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in 3 mL of anhydrous DMF was stirred at room temperature. The mixture was poured into 75 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-fluoro-3-[4-{4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as orange solid. Yield: 52 mg, 85%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.30-1.43 (m, 2H) 1.68-1.83 (m, 2H) 1.79 (s, 6H) 3.12-3.28 (m, 2H) 3.51 (br s, 1H) 3.72-3.78 (m, 1H) 4.02 (br s, 1H) 4.80 (d, J=3.91 Hz, 1H) 6.63 (dd, J=9.28, 2.44 Hz, 1H) 6.73-6.79 (m, 1H) 7.49 (d, J=8.30 Hz, 2H) 7.56 (dd, J=8.30, 5.86 Hz, 1H) 7.83 (s, 1H) 7.86 (d, J=8.30 Hz, 2H) 10.44 (s, 1H)
LR MS (ES+): 449 (M+1)
The following examples 160 through 178 were prepared using the experiment procedure described in Example 159, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
Example 160




N-[2-(diethylamino)ethyl]-4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzamide
1H NMR (500 MHz, d6-DMSO) δ ppm 0.98 (t, J=7.08 Hz, 6H) 1.79 (s, 6H) 2.53 (q, J=7.32 Hz, 4H) 2.58 (t, J=6.83 Hz, 2H) 3.28-3.38 (m, 2H) 6.63 (dd, J=9.28, 2.44 Hz, 1H) 6.74-6.79 (m, 1H) 7.57 (dd, J=8.30, 5.86 Hz, 1H) 7.85 (s, 1H) 7.89 (d, J=8.79 Hz, 2H) 7.94 (d, J=8.79 Hz, 2H) 8.54 (t, J=5.86 Hz, 1H) 10.46 (s, 1H)
Example 161




(3E)-6-fluoro-3-{4-[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}carbonyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
1H NMR (500 MHz, d6-DMSO) δ ppm 1.79 (s, 6H) 2.40-2.50 (br, 6H) 3.34-3.37 (m, 2H) 3.40 (t, J=5.13 Hz, 2H) 3.48 (q, J=5.21 Hz, 2H) 3.53 (t, J=5.86 Hz, 2H) 3.63 (br s, 2H) 4.61 (t, J=5.61 Hz, 1H) 6.64 (dd, J=9.76, 2.44 Hz, 1H) 6.74-6.80 (m, 1H) 7.51 (d, J=8.30 Hz, 2H) 7.57 (dd, J=8.30, 5.86 Hz, 1H) 7.83 (s, 1H) 7.87 (d, J=8.30 Hz, 2H) 10.45 (s, 1H)
LR MS (ES+): 522 (M+1)
Example 162




(3E)-3-[4-(4-{[(2R,3R,4R)-3,4-Dihydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one
1H NMR (500 MHz, d6-DMSO) δ ppm 1.80 (s, 6H) 3.26-3.30 (m, 1H) 3.54 (dd, J=10.74, 5.86 Hz, 1H) 3.64-3.71 (m, 1H) 3.78-3.83 (m, 1H) 3.86-3.89 (m, 2H) 4.04-4.07 (m, 1H) 4.98 (t, J=5.37 Hz, 1H) 5.23 (d, J=4.39 Hz, 1H) 5.30 (d, J=4.39 Hz, 1H) 6.63 (dd, J=9.76, 2.44 Hz, 1H) 6.74-6.79 (m, 1H) 7.54-7.61 (m, 3H) 7.84 (s, 1H) 7.87 (d, J=8.30 Hz, 2H) 10.45 (s, 1H)
LR MS (ES+): 481 (M+1)
Example 163




(3E)-6-fluoro-3-[4-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
1H NMR (300 MHz, d6-DMSO) δ ppm 1.77 (s, 6H) 2.39-2.45 (m, 6H) 3.34 (br s, 2H) 3.49 (q, J=5.96 Hz, 2H) 3.60 (br s, 2H) 4.41 (t, J=5.28 Hz, 1H) 6.61 (dd, J=9.53, 2.49 Hz, 1H) 6.71-6.78 (m, 1H) 7.48 (d, J=8.21 Hz, 2H) 7.54 (dd, J=8.35, 5.72 Hz, 1H) 7.81 (s, 1H) 7.84 (d, J=8.50 Hz, 2H) 10.42 (s, 1H)
LR MS (ES+): 478 (M+1)
Example 164




5-Fluoro-3-[4-[4-(3-hydroxy-pyrrolidine-1-carbonyl)-phenyl]-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one
LR MS (ES−): 433 (M−1)
Example 165




3-[5,5-Dimethyl-4-[4-((3R,4R,5S)-3,4,5-trihydroxy-piperidine-1-carbonyl)-phenyl]-5H-furan-(2E)-ylidene]-6-fluoro-1,3-dihydro-indol-2-one
1H NMR (300 MHz, d6-DMSO) δ ppm 1.78 (s, 6H) 2.71 (br, 1H) 2.90 (br, 1H) 3.09-3.16 (m, 2H) 3.21 (br, 1H) 3.49 (br, 1H) 4.28 (br, 1H) 5.00 (d, J=3.81 Hz, 2H) 5.15 (br, 1H) 6.61 (dd, J=9.38, 2.35 Hz, 1H) 6.71-6.78 (m, 1H) 7.49 (d, J=8.50 Hz, 2H) 7.54 (dd, J=8.21, 5.86 Hz, 1H) 7.82 (s, 1H) 7.86 (d, J=8.50 Hz, 2H) 10.42 (s, 1H)
LR MS (ES−): 479 (M−1)
Example 166




3-[5,5-Dimethyl-4-[4-((2S,3R,4S,5R)-3,4,5-trihydroxy-2-methyl-piperidine-1-carbonyl)-phenyl]-5H-furan-(2E)-ylidene]-6-fluoro-1,3-dihydro-indol-2-one
LR MS (ES−): 493 (M−1)
Example 167




4-[(5E)-5-(6-Fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)benzamide
1H NMR (300 MHz, d6-DMSO) δ ppm 1.77 (s, 6H) 3.35-3.55 (m, 16H) 4.53 (t, J=5.42 Hz, 1H) 6.61 (dd, J=9.38, 2.35 Hz, 1H) 6.71-6.78 (m, 1H) 7.55 (dd, J=8.35, 5.72 Hz, 1H) 7.83 (s, 1H) 7.87 (d, J=8.79 Hz, 2H) 7.94 (d, J=8.50 Hz, 2H) 8.65 (t, J=5.42 Hz, 1H) 10.43 (s, 1H)
LR MS (ES+): 563 (M+Na+)
Example 168




(3E)-5-Fluoro-3-[4-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
1H NMR (500 MHz, d6-DMSO) δ ppm 1.81 (s, 6H) 2.36-2.48 (m, 6H) 3.34 (br s, 2H) 3.49-3.53 (m, 2H) 3.63 (br s, 2H) 4.43 (t, J=5.13 Hz, 1H) 6.78 (dd, J=8.54, 4.64 Hz, 1H) 6.85-6.92 (m, 1H) 7.35 (dd, J=8.79, 2.44 Hz, 1H) 7.51 (d, J=8.30 Hz, 2H) 7.85 (s, 1H) 7.88 (d, J=8.30 Hz, 2H) 10.30 (s, 1H)
Example 169




(3E)-3-[4-(4-{[(3S,4S)-3,4-Dihydroxypyrrolidin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one
1H NMR (300 MHz, d6-DMSO) δ ppm 1.78 (s, 6H) 3.19 (d, J=10.85 Hz, 1H) 3.34 (d, J=12.90 Hz, 1H) 3.63-3.73 (m, 2H) 3.90 (br s, 1H) 3.97 (br s, 1H) 5.10 (d, J=3.22 Hz, 1H) 5.21 (d, J=3.52 Hz, 1H) 6.61 (dd, J=9.38, 2.35 Hz, 1H) 6.71-6.78 (m, 1H) 7.54 (dd, J=8.35, 5.72 Hz, 1H) 7.61 (d, J=8.50 Hz, 2H) 7.82 (s, 1H) 7.84 (d, J=8.50 Hz, 2H) 10.42 (s, 1H)
LR MS (ES−): 449 (M−1)
Example 170




(3E)-3-[4-(4-{[(3S,4S)-3,4-Dihydroxypyrrolidin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-5-fluoro-1,3-dihydro-2H-indol-2-one
1H NMR (300 MHz, d6-DMSO) δ ppm 1.80 (s, 6H) 3.19 (d, J=10.85 Hz, 1H) 3.34 (d, J=12.90 Hz, 1H) 3.63-3.73 (m, 2H) 3.90 (br s, 1H) 3.97 (br s, 1H) 5.10 (d, J=3.22 Hz, 1H) 5.21 (d, J=3.22 Hz, 1H) 6.76 (dd, J=8.50, 4.69 Hz, 1H) 6.84-6.91 (m, 1H) 7.33 (dd, J=8.79, 2.35 Hz, 1H) 7.61 (d, J=8.21 Hz, 2H) 7.84 (s, 1H) 7.86 (d, J=8.50 Hz, 2H) 10.28 (s, 1H)
LR MS (ES−): 449 (M−1)
Example 171




Methyl (3E)-3-{5,5-dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylate
1H NMR (300 MHz, d6-DMSO) δ ppm 1.83 (s, 6H) 1.79-1.89 (m, 4H) 3.42 (t, J=6.30 Hz, 2H) 3.49 (t, J=6.45 Hz, 2H) 3.84 (s, 3H) 6.92 (d, J=7.92 Hz, 1H) 7.65 (d, J=8.21 Hz, 2H) 7.77 (dd, J=8.06, 1.61 Hz, 1H) 7.88 (d, J=8.50 Hz, 2H) 7.90 (s, 1H) 8.16 (d, J=1.17 Hz, 1H) 10.73 (s, 1H)
Example 172




(3E)-3-{5,5-Dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylic acid
1H NMR (500 MHz, d6-DMSO) δ ppm 1.83 (s, 6H) 1.82-1.92 (m, 4H) 3.42 (t, J=6.35 Hz, 2H) 3.49 (t, J=6.83 Hz, 2H) 6.89 (d, J=8.30 Hz, 1H) 7.64 (d, J=8.30 Hz, 2H) 7.75 (dd, J=8.06, 1.71 Hz, 1H) 7.88 (d, J=8.30 Hz, 2H) 7.91 (s, 1H) 8.15 (d, J=1.95 Hz, 1H) 10.70 (s, 1H) 12.58 (s, 1H)
LR MS (ES−): 443 (M−1)
Example 173




Methyl (3E)-3-{5,5-dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-6-carboxylate
1H NMR (300 MHz, d6-DMSO) δ ppm 1.83 (s, 6H) 1.79-1.91 (m, 4H) 3.41 (t, J=6.01 Hz, 2H) 3.49 (t, J=6.74 Hz, 2H) 3.84 (s, 3H) 7.37 (s, 1H) 7.60-7.70 (m, 4H) 7.88-7.91 (m, 3H) 10.52 (s, 1H)
Example 174




(3E)-3-{5,5-Dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-6-carboxylic acid
1H NMR (300 MHz, d6-DMSO) ppm 1.80 (s, 6H) 1.79-1.86 (m, 4H) 3.40 (t, J=6.01 Hz, 2H) 3.47 (t, J=6.74 Hz, 2H) 7.34 (s, 1H) 7.56-7.67 (m, 4H) 7.83-7.92 (m, 3H) 10.46 (s, 1H) 12.69 (s, 1H)
LR MS (ES−): 443 (M−1)
Example 175




Methyl (3E)-3-[4-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-2-oxoindoline-6-carboxylate
1H NMR (300 MHz, d6-DMSO) δ ppm 1.81 (s, 6H) 2.41 (t, J=5.86 Hz, 6H) 3.34 (br s, 2H) 3.49 (q, J=5.28 Hz, 2H) 3.61 (br s, 2H) 3.82 (s, 3H) 4.42 (t, J=5.57 Hz, 1H) 7.35 (d, J=1.17 Hz, 1H) 7.50 (d, J=8.21 Hz, 2H) 7.60 (dd, J=7.62, 1.47 Hz, 1H) 7.67 (d, J=7.92 Hz, 1H) 7.88 (d, J=8.21 Hz, 2H) 7.89 (s, 1H) 10.50 (s, 1H)
LR MS (ES+): 539 (M+Na+)
LR MS (ES−): 516 (M−1)
Example 176




(3E)-3-{5,5-Dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-N-methyl-2-oxoindoline-6-carboxamide
LR MS (ES−): 456 (M−1)
Example 177




Methyl (3E)-3-{5,5-dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-5-fluoro-2-oxoindoline-6-carboxylate
LR MS (ES+): 499 (M+Na+)
LR MS (ES−): 475 (M−1)
Example 178




Methyl (3E)-3-[4-(4-{[(2,3-dihydroxypropyl)(methyl)amino]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-5-fluoro-2-oxoindoline-6-carboxylate
LR MS (ES−): 509 (M−1)
Preparation of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one




To a solution of 5,6-difluorooxindole (450 mg, 2.66 mmol) in THF (20 mL) at 0° C., was added 1 M LiHMDS in THF (5.3 mL, 5.3 mmol). The reaction mixture was stirred at 0° C. for 10 minutes. 4-bromo-5,5-dimethyl-5H-furan-2-one (340 mg, 1.78 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 min., and then at room temperature for an additional 30 min and quenched with 2.5M aqueous H2SO4 (3 mL). The resulting mixture was stirred at room temperature for 16 hours and poured into water (100 mL). The precipitates were filtered, washed with water and dried in vacuo to yield (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 547 mg, 90%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.58 (s, 6H) 6.81 (dd, J=10.55, 6.74 Hz, 1H) 7.45 (dd, J=10.55, 8.21 Hz, 1H) 7.54 (s, 1H) 10.44 (s, 1H)
Preparation of methyl 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate




To 10 mL of 1,4-dioxane, was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (250 mg, 0.73 mmol), 4-methoxycarbonylphenylboronic acid (158 mg, 0.88 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), 2M Na2CO3 aqueous solution (1.5 mL, 3.0 mmol). The mixture was heated at 86° C. under N2 for 2 hours, cooled to room temperature and poured into 100 mL of water. The brown precipitates were filtered, washed with water and dried to give the crude product. Purification through silica gel column with 1-2% MeOH/CHCl3 led to methyl 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate as orange/red solid. Yield: 112 mg, 39%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.79 (s, 6H) 3.87 (s, 3H) 6.81 (dd, J=10.85, 7.04 Hz, 1H) 7.50 (dd, J=10.55, 8.21 Hz, 1H) 7.85 (s, 1H) 7.95 (d, J=8.50 Hz, 2H) 8.04 (d, J=8.50 Hz, 2H) 10.43 (s, 1H)
LR MS (ES−): 396 (M−1)
Preparation of 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid




To a solution of methyl 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate (100 mg, 0.25 mmol) in a 1:1 mixture of THF/MeOH (5 mL/5 mL), was added 1M NaOH (2 mL). The mixture was heated in 60° C. bath for 1.5 hours, poured into 100 mL of water and acidified with 2M HCl (2 mL). The precipitates were filtered, washed with water, and dried in vacuum to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid as yellow solid. Yield: 90 mg, 93%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.79 (s, 6H) 6.81 (dd, J=10.85, 6.74 Hz, 1H) 7.49 (dd, J=10.41, 8.35 Hz, 1H) 7.84 (s, 1H) 7.92 (d, J=8.50 Hz, 2H) 8.02 (d, J=8.50 Hz, 2H) 10.42 (s, 1H) 13.17 (s, 1H)
LR MS (ES−): 382 (M−1)
Example 179




4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-(2,3-dihydroxypropyl)-N-methylbenzamide
A mixture of 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.13 mmol), 3-methylamino-1,2-propanediol (40 mg, 0.38 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 61 mg, 0.16 mmol) and diisopropylethylamine (37 mg, 0.29 mmol) in 6 mL of anhydrous DMF was stirred at room temperature for 10 minutes. The mixture was poured into 100 mL of water. The precipitates were filtered, washed with water, and dried in vacuum to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-(2,3-dihydroxypropyl)-N-methylbenzamide as yellow solid. Yield: 47 mg, 81%.
LR MS (ES−): 469 (M−1)
Example 180




(3E)-5,6-Difluoro-3-[4-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
Similar procedure as Example 179.
LR MS (ES−): 494 (M−1)
Preparation of Examples 181-222 (FIG. 4)
Each of the examples was prepared through the library synthesis as follows:
To an 8-mL screw cap vial was added 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (58.5 mg, 0.16 mmol), amine (0.24 mmol, 1.5 eq.), DMF (1 mL), and DIPEA (0.06 mL, 0.35 mmol, 2.2 eq.), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (91 mg, 0.24 mmol, 1.5 eq). The reaction mixture was shaken at room temperature for 24 hours. The resulting clear reaction mixture was submitted for preparative RP-HPLC purification without workup. The library compounds were purified by high throughput RP-HPLC. Each compound was re-analyzed by LCMS after purification.
Example 97 is the compound example for the library synthesis (FIG. 4).




Methyl ({4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoyl}amino)acetate
1H NMR (300 MHz, DMSO-d6) δ ppm 10.45 (s, 1H), 9.11 (t, J=5.7 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.85 (s, 1H), 7.55 (dd, J=8.4, 5.7 Hz, 1H), 6.75 (ddd, J=2.4, 8.4, 10.5 Hz, 1H), 6.62 (dd, J=2.4, 9.3 Hz, 1H), 4.03 (d, J=5.7 Hz, 2H), 3.66 (s, 3H), 1.79 (s, 6H).
ESI-MS m/z 437.4 (M+H)+.
Preparation of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde




Method A: To 10 mL of 1,4-dioxane was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (100 mg, 0.31 mmol), 4-formylphenylboronic acid (56 mg, 0.37 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (1.2 mL, 1.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 100 mL of water. The mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as orange/red solid. Yield: 100 mg, 93%.
Method B: To a mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (2.0 g, 6.17 mmol), 4-formyl phenylboronic acid (1.85 g, 12.3 mmol), aqueous potassium carbonate (1 M, 31 mL, 31 mmol) in THF (120 mL) under a nitrogen atmosphere, was added palladium(0) tetrakis(triphenylphosphine) (356 mg, 0.3 mmol, 5 mol %). The mixture was heated at 65° C. overnight (20 h). The reaction was cooled to room temperature and ethyl acetate (500 mL) was added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5% CH3OH/CH2Cl2 elution). Trituration of the product obtained from the column chromatography with ethyl acetate/hexane (1/1), followed by isolation of the precipitate by filtration, provided 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as a red orange solid (1.1 g, yield 51%).
1H NMR (300 MHz, DMSO-d6) δ ppm 10.47 (s, 1H), 10.05 (s, 1H), 8.0 (m, 4H), 7.91 (s, 1H), 7.55 (dd, J=8.4, 6.0 Hz, 1H), 6.75 (ddd, J=10.5, 8.4, 2.4 Hz, 1H), 6.60 (dd, J=9.3, 2.4 Hz, 1H), 1.80 (s, 6H).
ESI-MS m/z 350.1 (M+1)+.
Example 223




(3E)-6-Fluoro-3-{4-[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]methyl)phenyl}-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (55 mg, 0.16 mmol), 2-(2-(piperazin-1-yl)ethoxy)ethanol (56 mg, 0.32 mmol) and 4 Å molecular sieves (100 mg) in anhydrous DMF (3 mL) was stirred at room temp for 16 hours. To this stirred mixture was added AcOH (10 mg), 1M sodium cyanoborohydride in THF solution (0.32 mL, 0.32 mmol) and 3 mL of anhydrous methanol. The reaction mixture was stirred at room temp for 5 hours and poured into 100 mL of water. Saturated NaHCO3 solution was then added until pH=9. The precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 5-10% MeOH/CHCl3 to give (3E)-6-fluoro-3-{4-[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]methyl)phenyl}-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 45 mg, 56%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.78 (s, 6H) 2.36-2.51 (m, 10H) 3.40 (t, J=5.13 Hz, 2H) 3.46-3.52 (m, 6H) 4.61 (s, 1H) 6.62 (dd, J=9.28, 2.44 Hz, 1H) 6.73-6.77 (m, 1H) 7.43 (d, J=8.30 Hz, 2H) 7.55 (dd, J=8.30, 5.86 Hz, 1H) 7.76 (t, J=4.15 Hz, 3H) 10.42 (s, 1H)
LR MS (ES+): 508 (M+1)
The following examples 224-226 were prepared using the experiment procedure described in Example 223, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
Example 224




(3E)-6-Fluoro-3-[4-{4-[(4-hydroxypiperidin-1-yl)methyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
1H NMR (500 MHz, d6-DMSO) δ ppm 1.41 (br s, 2H) 1.71 (br s, 2H) 1.78 (s, 6H) 2.07 (br s, 2H) 2.68 (br s, 2H) 3.49 (br s, 3H) 4.55 (br s, 1H) 6.62 (dd, J=9.28, 1.95 Hz, 1H) 6.73-6.77 (m, 1H) 7.43 (d, J=6.83 Hz, 2H) 7.55 (dd, J=8.30, 5.86 Hz, 1H) 7.76 (br s, 3H) 10.42 (s, 1H)
LR MS (ES+): 435 (M+1)
Example 225




(3E)-1-Acetyl-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one
1H NMR (500 MHz, d6-DMSO) ppm 1.83 (s, 6H) 2.39 (br s, 4H) 2.65 (s, 3H) 3.54 (br s, 2H) 3.59 (s, 4H) 7.07-7.11 (m, 1H) 7.48 (d, J=7.81 Hz, 2H) 7.78 (dd, J=8.30, 5.86 Hz, 1H) 7.84 (s, 1H) 7.85 (d, J=7.81 Hz, 2H) 7.92 (dd, J=10.74, 2.44 Hz, 1H)
LR MS (ES+): 463 (M+1)
Example 226




(3E)-5-Chloro-3-[4-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
1H NMR (300 MHz, d6-DMSO) δ ppm 1.79 (s, 6H) 2.34-2.44 (m, 10H) 3.46 (q, J=5.28 Hz, 2H) 3.49 (s, 2H) 4.33 (t, J=4.84 Hz, 1H) 6.78 (d, J=8.21 Hz, 1H) 7.07 (dd, J=8.35, 2.20 Hz, 1H) 7.42 (d, J=8.50 Hz, 2H) 7.50 (d, J=2.05 Hz, 1H) 7.76 (d, J=8.50 Hz, 2H) 7.77 (s, 1H) 10.38 (s, 1H)
LR MS (ES+): 480 (M+1)
Preparation of methyl (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-2-oxoindoline-5-carboxylate




To a 0° C. stirred solution of methyl oxindole-5-carboxylate (421 mg, 2.2 mmol) and 4-bromo-5,5-dimethylfuran-2(5H)-one (382 mg, 2.0 mmol) in THF (10 mL), was added 1M LiHMDS/THF solution (4.4 mL, 4.4 mmol) under nitrogen. The mixture was stirred at 0° C. for 80 min, quenched with 2.5M H2SO4 (3 mL), and poured into 100 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give methyl (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-2-oxoindoline-5-carboxylate as yellow solid. Yield: 408 mg, 56%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.61 (s, 6H) 3.83 (s, 3H) 6.91 (d, J=8.21 Hz, 1H) 7.64 (s, 1H) 7.78 (dd, J=8.21, 1.76 Hz, 1H) 8.09 (d, J=1.47 Hz, 1H) 10.76 (s, 1H)
Example 227




Methyl (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylate
A mixture of methyl (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-2-oxoindoline-5-carboxylate (90 mg, 0.25 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine hydrochloride (92 mg, 0.27 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with CH2Cl2, 20 mg, 0.027 mmol) and 2M Na2CO3 (0.5 mL, 1.0 mmol) in 8 mL of DMF was heated in 85° C. bath under nitrogen for 90 minutes. The mixture was cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give methyl (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylate as yellow solid. Yield: 20 mg, 18%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.82 (s, 6H) 2.38 (t, J=4.69 Hz, 4H) 3.53 (s, 2H) 3.59 (t, J=4.69, 4H) 3.84 (s, 3H) 6.91 (d, J=8.21 Hz, 1H) 7.47 (d, J=8.21 Hz, 2H) 7.75 (dd, J=8.21, 1.76 Hz, 1H) 7.80 (d, J=8.50 Hz, 2H) 7.84 (s, 1H) 8.15 (d, J=1.17 Hz, 1H) 10.71 (s, 1H)
The following examples 228 through 235 were prepared using the experiment procedure described in Example 227, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
Example 228




(3E)-5-bromo-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
1H NMR (300 MHz, d6-DMSO) δ ppm 1.81 (s, 6H) 2.38 (br s, 4H) 3.52 (br s, 2H) 3.59 (br s, 4H) 6.77 (d, J=8.21 Hz, 1H) 7.22 (dd, J=8.21, 2.05 Hz, 1H) 7.46 (d, J=8.21 Hz, 2H) 7.64 (d, J=1.76 Hz, 1H) 7.79 (d, J=8.21 Hz, 2H) 7.80 (s, 1H) 10.42 (s, 1H)
Example 229




(3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carbonitrile
LR MS (ES+): 428 (M+1)
Example 230




Methyl (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-6-carboxylate
1H NMR (300 MHz, d6-DMSO) δ ppm 1.82 (s, 6H) 2.38 (br s, 4H) 3.53 (br s, 2H) 3.59 (br s, 4H) 3.84 (s, 3H) 7.36 (s, 1H) 7.47 (d, J=8.50 Hz, 2H) 7.61 (d, J=7.33 Hz, 1H) 7.68 (d, J=7.92 Hz, 1H) 7.81 (d, J=8.21 Hz, 2H) 7.85 (s, 1H) 10.50 (s, 1H)
LR MS (ES−): 459 (M−1)
Example 231




(3E)-3-{5,5-Dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylic acid
To a stirred solution of methyl (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylate (18 mg, 0.039 mmol) in MeOH (1 mL) was added 1M NaOH solution (1 mL, 1 mmol). The mixture was heated in 50° C. bath under nitrogen for 4 hours, cooled to room temp, and neutralized with 1M HCl to about pH 7. The mixture was extracted with 10% MeOH/CHCl3 solution (3×30 mL). The organic layers were combined, dried over Na2SO4, and evaporated to dryness to give (3E)-3-{5,5-dimethyl-4[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylic acid as yellow solid. Yield: 15 mg, 88%.
LR MS (ES−): 445 (M−1)
The following examples 232 through 233 were prepared using the experiment procedure described in Example 231, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
Example 232




(3E)-3-{5,5-Dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-6-carboxylic acid
LR MS (ES−): 445 (M−1)
Example 233




(3E)-3-[4-(4-{[4-(Hydroxymethyl)piperidin-1-yl]methyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-2-oxoindoline-5-carboxylic acid
LR MS (ES+): 475 (M+1)
LR MS (ES−): 473 (M−1)
Preparation of 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde




To 10 mL of 1,4-dioxane was added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (85 mg, 0.25 mmol), 4-formylphenylboronic acid (45 mg, 0.30 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol), 2M Na2CO3 aqueous solution (0.5 mL, 1.0 mmol).
The mixture was heated at 80° C. under N2 for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (80 mL). The EtOAc solution was washed with brine (2×50 mL), dried over Na2SO4, and concentrated to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as the crude product, which was used in the next step without further purification.
Example 234




Methyl 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylate
A mixture of 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (60 mg, 0.16 mmol), methyl isonipecotate (50 mg, 0.35 mmol), and 100 mg of 4 Å molecular sieves in 5 mL of anhydrous DMF was stirred under nitrogen for 16 hours. Acetic acid (20 mg) and 1M sodium cyanoborohydride/THF solution (0.35 mL, 0.35 mmol) were then added. The mixture was diluted with 5 mL of anhydrous methanol, stirred at room temperature for 1 hour, and poured into 100 mL of water with stirring. The resulting precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give methyl 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylate as yellow solid. Yield: 50 mg, 62%.
LR MS (ES−): 493 (M−1)
Example 235




1-{4-[(5E)-5-(5,6-Difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylic acid
To a suspension of methyl 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylate (50 mg, 0.10 mmol) in MeOH (5 mL), was added 1M NaOH (1 mL). The mixture was heated in 50° C. bath for 1 hour, poured into 50 mL of water and neutralized with 0.5M HCl to pH 7. The precipitates were filtered, washed with water, and dried in vacuo to give 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylic acid as a yellow solid. Yield: 9 mg, 19%.
LR MS (ES−): 479 (M−1)
Preparation of Examples 236-260 (FIG. 5)
Each of the examples was prepared through the library synthesis as follows:
To each 8-mL reaction vial was added 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (25 mg, 0.07 mmol), amine (0.105 mmol, 1.5 eq), 5% HOAc/DMF (v/v) (1 mL), and NaBH(OAc)3 (45 mg, 0.21 mmol, 3 eq.). The reaction was shaken at room temperature for 20 hours. It was then quenched with water (0.1 mL). The solvents were evaporated in a SpeedVac and the residue was dissolved in DMSO (1 mL). The DMSO solution was submitted for preparative RP-HPLC purification. Each compound was re-analyzed by LCMS after purification.
Preparation of 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one




To a solution of 5-fluorooxindole (7.5 g, 49 mmol) in THF (80 mL) at 0° C., was added 1 M LHMDS in THF (100 mL, 100 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (6.4 g, 33 mmol) in THF (20 mL) was added to the reaction mixture. The reaction was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature over 5 hours. To the reaction mixture was added aqueous 2 M HCl (100 mL). The resulting mixture was stirred at 60-65° C. for 1 hour, cooled to room temperature, poured into water (3000 mL) and stirred at room temperature for 2 hours. The precipitates separated and were collected, washed with water, and dried in vacuo to provide 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (8.7 g, yield 80%), which was used for the next reaction without further purification.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.26 (s, 1H), 7.50 (s, 1H), 7.22 (dd, J=9.0, 2.7 Hz, 1H), 6.84 (ddd, J=11.1, 8.7, 2.7 Hz, 1H), 6.69 (dd, J=8.7, 4.5 Hz, 1H). 1.53 (s, 6H).
ESI-MS m/z 324.0 M+.
Preparation of 4-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-2,2-dimethyl-2,5-dihydro-furan-3-yl}-benzaldehyde




To a mixture of 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (6.5 g, 20 mmol), 4-formyl phenyl boronic acid (3.6 g, 24 mmol) in THF (250 mL), was added a solution of potassium carbonate (27.6 g, 200 mmol) in water (25 mL). The resulting mixture was deoxygenated with nitrogen, and palladium(0) tetrakis(triphenylphosphine) (1.15 g, 1.0 mmol, 5 mol %) then added. The reaction mixture was heated at 65° C. for 20 hours and then it was allowed to cool to room temperature. Ethyl acetate (800 mL) was added. The organic phase was washed with water (200 mL×2), dried over sodium sulfate and evaporated to give crude product. The purification first by column (SiO2) chromatography (5% CH3OH/CH2Cl2) and then by titration with ethyl acetate led to 4-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-2,2-dimethyl-2,5-dihydro-furan-3-yl}-benzaldehyde as a deep red solid (3.6 g, yield 51.5%).
1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 10.05 (s, 1H), 8.01 (m, 4H), 7.92 (s, 1H), 7.34 (dd, J=9.0, 2.7 Hz, 1H), 6.90 (ddd, J=9.9, 8.4, 2.7 Hz, 1H), 6.77 (dd, J=8.4, 4.5 Hz, 1H), 1.82 (s, 6H).
ESI-MS m/z 350.1 (M+1)+.
Preparation of Examples 261-310 (FIG. 6)
Each of the examples was prepared through the library synthesis as follows:
To each 8-mL reaction vial was added 4-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3E)-ylidene]-2,2-dimethyl-2,5-dihydro-furan-3-yl}-benzaldehyde (55 mg, 0.16 mmol), amine (0.24 mmol, 1.5 eq.), 5% HOAc/DMF (v/v) (1 mL), and NaBH(OAc)3 (62 mg, 0.29 mmol, 1.8 eq.) were added. The reaction was shaken at room temperature overnight. The reaction was quenched with water (0.1 mL), the solvents were evaporated in a SpeedVac, and the residue was dissolved in DMSO (1 mL). The DMSO solution was submitted for preparative RP-HPLC purification. Each compound was re-analyzed by LCMS after purification.
Preparation of 3-[4-(6-chloro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1,3-dihydro-indol-2-one




To 240 mL of 1,4-dioxane, were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (3.0 g, 9.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with CH2Cl2, 360 mg, 0.49 mmol), 1M KF aqueous solution (37.5 mL, 37.5 mmol). The resulting mixture was heated at 70° C. under Ar and then 2-chloro-5-pyridineboronic acid (1.57 g, 10.0 mmol) was added in several portions. The reaction was heated at 70° C. under Ar for 22 hours. LC-MS indicated that no starting material molecular peak left; the major peak at 2.59 min with MH+=357.0 was assigned to the product, 3-[4-(6-chloro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1,3-dihydro-indol-2-one (yield>60%).
1H NMR (500 MHz, d6-DMSO) δ ppm 1.76 (s, 6H) 6.63 (dd, J=9.28, 2.44 Hz, 1H) 6.73-6.80 (m, 1H) 7.57 (dd, J=8.54, 5.61 Hz, 1H) 7.63 (d, J=8.79 Hz, 1H) 7.88 (s, 1H) 8.28 (dd, J=8.54, 2.68 Hz, 1H) 8.83 (d, J=2.44 Hz, 1H) 10.47 (s, 1H).
Preparation of (3E)-3-[4-(6′-chloro-2,3′-bipyridin-5-yl)-5,5-dimethylfuran-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one




A minor product in a similar procedure as 3-[4-(6-chloro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1.3-dihydro-indol-2-one.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.82 (s, 6H) 6.63 (dd, J=9.28, 2.44 Hz, 1H) 6.74-6.80 (m, 1H) 7.58 (dd, J=8.30, 5.37 Hz, 1H) 7.70 (d, J=8.30 Hz, 1H) 7.94 (s, 1H) 8.21 (d, J=8.79 Hz, 1H) 8.37 (dd, J=8.30, 2.44 Hz, 1H) 8.59 (dd, J=8.30, 2.44 Hz, 1H) 9.12 (d, J=1.95 Hz, 1H) 9.19 (d, J=2.44 Hz, 1H) 10.47 (s, 1H)
Preparation of (3E)-3-[5,5-Dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one




Method A: A mixture of 3-[4-(6-chloro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1.3-dihydro-indol-2-one (60 mg, 0.17 mmol), potassium vinyltrifluoroborate (40 mg, 0.30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with CH2Cl2, 10 mg, 0.012 mmol) and triethylamine (60 mg, 0.59 mmol) in isopropanol/water (10 mL/5 mL) solution was heated at 76° C. under nitrogen for 2.5 hours. The reaction was cooled to room temperature and poured into 100 mL of water. The resulting precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 50 mg, 85%.
Method B: To a solution of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (3.0 g, 9.3 mmol, 1 eq.) in 1,4-dioxane (240 mL) were added Pd(dppf)Cl2 (0.36 g, 0.49 mmol, 0.05 eq.) and 1 M KF aqueous solution (37.5 mL, 37.5 mmol, 4 eq.). The reaction mixture was first heated at 70° C. under Ar and was then added 2-chloro-5-pyridineboronic acid (1.57 g, 10.0 mmol, 1.08 eq.) in several portions in 15 minutes. The reaction mixture was continuously heated at 70° C. under Ar for another 22 hours. LC-MS analysis confirmed that (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one had completely disappeared and 3-[4-(6-chloro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1,3-dihydro-indol-2-one was produced (ESI-MS m/z 357.0 (M+H)+).
To the above reaction mixture under Ar were added Potassium vinyltrifluoroborate (4.98 g, 37.2 mmol, 4 eq.) and extra Pd(dppf)Cl2 (0.36 g, 0.49 mmol, 0.05 eq.). The mixture was heated at 70° C. for 6 hours, cooled to room temperature, and poured into water (300 mL) with stirring. The precipitates were collected by filtration, washed with water (50 mL×2) and dried in vacuo to provide (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one as a brown solid (1.94 g, 60% yield for two steps; >90% purity by ELS).
ESI-MS m/z 349.2 (M+H)+.
Preparation of (3E)-3-[5,5-Dimethyl-4-(6′-vinyl-2,3′-bipyridin-5-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one




Similar procedure as (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one by Method A.
Example 311




(3E)-3-{5,5-Dimethyl-4-[6-(2-morpholin-4-ylethyl)pyridin-3-yl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one
A mixture of (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one (50 mg, 0.14 mmol) and morpholine (0.2 mL, 2.3 mmol) in 5 mL of DMF was heated in 96° C. bath under nitrogen for 3 hours. The mixture was cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-{5,5-dimethyl-4-[6-(2-morpholin-4-ylethyl)pyridin-3-yl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 40 mg, 64%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.75 (s, 6H) 2.50 (br s, 4H) 2.72 (br s, 2H) 2.96 (t, J=7.92 Hz, 2H) 3.56 (br s, 4H) 6.61 (d, J=9.67 Hz, 1H) 6.74 (t, J=9.53 Hz, 1H) 7.42 (d, J=8.21 Hz, 1H) 7.54 (dd, J=7.77, 6.01 Hz, 1H) 7.80 (s, 1H) 8.11 (br s, 1H) 8.86 (d, J=1.17 Hz, 1H) 10.42 (s, 1H)
LR MS (ES+): 436 (M+1)
Example 312




(3E)-3-{5,5-dimethyl-4-[6′-(2-morpholin-4-ylethyl)-2,3′-bipyridin-5-yl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one
Similar procedure as Example 311.
LR MS (ES+): 513 (M+1)
Preparation of Examples 314-331 (FIG. 7)
Each of the examples was prepared through the library synthesis as follows:
To each reaction vial were added (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one (70 mg, 0.20 mmol, 1 eq.), amine (0.40 mmol, 2 eq.) and DMSO (1 mL). The resulting reaction mixtures were heated at 75° C. for either 20 hours or 45 hours (for the reaction mixtures with the less reactive amine). Representative examples of the reactions were monitored by LCMS. After cooling to room temperature, the DMSO solutions were then submitted for preparative RP-HPLC purification. Each compound was re-analyzed by LCMS after purification.
Example 314 is the compound example for the library synthesis (FIG. 7).




(3E)-3-[5,5-Dimethyl-4-(6-{2-[(2-morpholin-4-ylethyl)amino]ethyl}pyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one
To a 8-mL vial were added 3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one (32 mg, 0.095 mmol, 1 eq.), 4-(2-aminoethyl)morpholine (62 mg, 0.48 mmol, 5 eq.) and DMSO (2.5 mL). The reaction was heated at 75° C. for 20 hour. After cooling to room temperature, the DMSO solution was then submitted for preparative RP-HPLC purification to provide (E)-3-(5,5-dimethyl-4-(6-(2-(2-morpholinoethylamino)-ethyl)pyridin-3-yl)furan-2(5H)-ylidene)-6-fluoroindolin-2-one (8.0 mg, 18% yield) as a brown solid.
ESI-MS m/z 479.1 (M+H)+.
Preparation of (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one




To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (200 mg, 0.62 mmol), 6-fluoropyridin-3-ylboronic acid (104 mg, 0.74 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (2.5 mL, 2.5 mmol). The mixture was heated at 88° C. under N2 for 2 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-5% MeOH/CHCl3 afforded (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 100 mg, 47%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.75 (s, 6H) 6.61 (dd, J=9.38, 2.64 Hz, 1H) 6.70-6.77 (m, 1H) 7.30 (dd, J=8.65, 3.08 Hz, 1H) 7.54 (dd, J=8.35, 5.72 Hz, 1H) 7.81 (s, 1H) 8.39-8.45 (m, 1H) 8.65 (d, J=2.64 Hz, 1H) 10.43 (s, 1H)
LR MS (ES−): 339 (M−1)
Example 332




(3E)-6-Fluoro-3-{4-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
A mixture of (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 4-hydroxypiperidine (50 mg, 0.49 mL) in anhydrous DMSO (3 mL) was heated at 100° C. under nitrogen for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-{4-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 55 mg, 89%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.33-1.40 (m, 2H) 1.76 (s, 6H) 1.75-1.82 (m, 2H) 3.25-3.30 (m, 2H) 3.73-3.79 (m, 1H) 4.08-4.13 (m, 2H) 4.74 (d, J=4.39 Hz, 1H) 6.60 (dd, J=9.76, 2.44 Hz, 1H) 6.70-6.75 (m, 1H) 6.95 (d, J=8.79 Hz, 1H) 7.53 (dd, J=8.30, 5.86 Hz, 1H) 7.58 (s, 1H) 7.93 (dd, J=9.03, 2.68 Hz, 1H) 8.51 (d, J=2.44 Hz, 1H) 10.35 (s, 1H)
LR MS (ES+): 422 (M+1)
Example 333




(3E)-6-Fluoro-3-[4-(6-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
Similar procedure as Example 332.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.76 (s, 6H) 2.50-2.54 (m, 6H) 3.42 (t, J=5.13 Hz, 2H) 3.50 (q, J=5.21 Hz, 2H) 3.56 (t, J=5.86 Hz, 2H) 3.63 (t, J=5.37 Hz, 4H) 4.61 (t, J=5.37 Hz, 1H) 6.60 (dd, J=9.52, 2.20 Hz, 1H) 6.71-6.75 (m, 1H) 6.94 (d, J=9.28 Hz, 1H) 7.53 (dd, J=8.30, 5.86 Hz, 1H) 7.60 (s, 1H) 7.95 (dd, J=9.28, 2.44 Hz, 1H) 8.53 (d, J=2.44 Hz, 1H) 10.36 (s, 1H)
LR MS (ES+): 495 (M+1)
Preparation of Examples 334-369 (FIG. 8)
Each of the examples was prepared through the library synthesis as follows:
To each 8-mL screw cap reaction vial were added (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (40 mg, 0.11 mmol), amine (0.25 mmol, 2.3 eq.), DMSO (1 mL), and DIPEA (0.1 mL, 5 eq.). The vial was flushed with nitrogen, capped, and heated at 115-120° C. for 18 hours. After cooling to room temperature, the reaction mixtures were filtered through a plug of cotton and the resulting DMSO solutions were submitted for preparative RP-HPLC purification. Each compound was re-analyzed by LCMS after purification.
Example 338 is the compound example for the library synthesis (FIG. 8):




(3E)-3-[5,5-Dimethyl-4-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3-yl}furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one
32.6 mg, yield 65.7%.
1H NMR (300 MHz, DMSO-d6) δ ppm 10.32 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.80 dd, J=9.0, 2.4 Hz, 1H), 7.52 (s, 1H), 7.50 (dd, J=8.4, 6.3 Hz, 1H), 7.25 (m, 1H), 6.71 (ddd, J=10.5, 8.4, 2.7 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.60 (dd, J=9.0, 2.4 Hz, 1H), 3.57 (t, J=5.4 Hz, 4H), 3.45 (m, 2H), 2.45-2.55 (m, 4H), 2.38-2.44 (m, 2H), 1.75 (s, 6H). ESI-MS m/z 450.6 (M)+.
Preparation of 5-fluoro-3-[4-(6-fluoro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one




to a mixture or 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (3.24 g, 10.0 mmol), 6-fluoropyridin-3-ylboronic acid (1.8 g, 12 mmol) in THF (150 mL), was added a solution of potassium carbonate (13.8 g, 100 mmol) in water (20 mL). The resulting mixture was deoxygenated by bubbling nitrogen through the reaction mixture for 3 minutes and palladium(0) tetrakis(triphenylphosphine) (578 mg, 5 mol %) was then added. The reaction mixture was heated at 65° C. for 18 hours. The reaction was cooled to room temperature and ethyl acetate (500 mL) added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated to give the crude product, which was purified first by silica gel column chromatography (5% CH3OH/CH2Cl2 elution) and then by titration with ethyl acetate. The resulting product was isolated by filtration and dried under vacuum to provide 5-fluoro-3-[4-(6-fluoro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (1.6 g, yield 48%).
1H NMR (300 MHz, DMSO-d6) δ ppm 10.31 (s, 1H), 8.67 (d, J=2.7 Hz, 1H), 8.44 (ddd, J=8.4, 7.5, 2.7 Hz, 1H), 7.84 (s, 1H), 7.33 (m, 2H), 6.89 (ddd, J=9.6, 8.4, 2.7 Hz, 1H), 6.76 (dd, J=8.4, 4.5 Hz, 1H), 1.79 (s, 6H).
ESI-MS m/z 341.3 (M+1)+
Preparation of Examples 370-420 (FIG. 8)
Each of the examples was prepared through the library synthesis as follows:
To each 8-mL screw cap reaction vial were added 5-fluoro-3-[4-(6-fluoro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one (55 mg, 0.16 mmol), amine (0.24 mmol, 1.5 eq.), DIPEA (0.1 mL, 0.57 mmol, 3.6 eq.) and DMSO (1.0 mL). The reaction vial was capped and heated at 110° C. for 20 h. After cooling to room temperature, the resulting solution was submitted for preparative RP-HPLC purification. Each compound was re-analyzed by LCMS after purification.
Preparation of (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one




To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (150 mg, 0.44 mmol), 6-fluoropyridin-3-ylboronic acid (74 mg, 0.53 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 2M Na2CO3 aqueous solution (0.6 mL, 1.2 mmol). The mixture was heated at 78° C. under N2 for 3 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-3% MeOH/CHCl3 gave (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid (yield: 60 mg, 38%).
1H NMR (300 MHz, d6-DMSO) δ ppm 1.77 (s, 6H) 6.80 (dd, J=10.70, 6.89 Hz, 1H) 7.31 (dd, J=8.79, 2.93 Hz, 1H) 7.49 (dd, J=10.55, 8.21 Hz, 1H) 7.80 (s, 1H) 8.40-8.47 (m, 1H) 8.67 (d, J=2.64 Hz, 1H) 10.41 (s, 1H)
Example 421




(3E)-3-[4-{6-[(2,3-Dihydroxypropyl)(methyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-5,6-difluoro-1,3-dihydro-2H-indol-2-one
A mixture of (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.14 mmol) and 3-methylamino-1,2-propanediol (50 mg, 0.48 mmol) in 5 mL of DMF was heated in 100° C. bath under nitrogen for 16 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-[4-{6-[(2,3-dihydroxypropyl)(methyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-5,6-difluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 51 mg, 82%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.76 (s, 6H) 3.14 (s, 3H) 3.31-3.37 (m, 2H) 3.44 (dd, J=13.78, 7.04 Hz, 1H) 3.67-3.79 (m, 2H) 4.65 (t, J=5.57 Hz, 1H) 4.82 (d, J=4.98 Hz, 1H) 6.73-6.80 (m, 2H) 7.44 (dd, J=10.70, 8.06 Hz, 1H) 7.53 (s, 1H) 7.91 (dd, J=9.09, 2.64 Hz, 1H) 8.50 (d, J=2.34 Hz, 1H) 10.29 (s, 1H)
LR MS (ES−): 442 (M−1)
Preparation of (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one




Method A: To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (200 mg, 0.62 mmol), 2-fluoropyridin-4-ylboronic acid (104 mg, 0.74 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mol), 1M Na2CO3 aqueous solution (2.5 mL, 2.5 mmol). The mixture was heated at 96° C. under N2 for 4 hours, cooled to room temperature and poured into 150 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-5% MeOH/CHCl3 led to (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 100 mg, 48%.
Method B: To a mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (2.0 g, 6.1 mmol), 2-fluoropyridine-4-boronic acid (1.1 g, 8.0 mmol), potassium fluoride (1.8 g, 5 eq.) in dioxane (50 mL) and water (5 mL) under a nitrogen atmosphere, was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250 mg, 5%). The mixture was heated at 80° C. for 20 hour. The reaction was allowed to cool to room temperature and ethyl acetate (350 mL) was added. The organic phase was washed with water (100 mL×2) and evaporated to provide the crude product. The crude product was purified by column chromatography (silica gel, 5% CH3OH/CH2Cl2 elution) and then recrystallized from ethyl acetate/hexanes (80/20) to provide (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow-orange solid (1.2 g, yield 57%).
1H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 7.99 (s, 1H), 7.55 (dd, J=8.4, 6.0 Hz, 1H), 7.71 (d, J=5.7 Hz, 1H), 7.50-7.58 (m, 2H), 6.73 (dt, J=10.2, 2.4 Hz, 1H), 6.62 (dd, J=15.6, 5.4 Hz, 1H), 1.77 (s, 6H).
ESI-MS m/z 341.1 (M+1)+.
Example 422




(3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
A mixture of (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 2-(2-(piperazin-1-yl)ethoxy)ethanol (50 mg, 0.29 mmol) in 2 mL of DMSO was heated in 105° C. bath for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 64 mg, 89%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.72 (s, 6H) 2.48-2.53 (m, 6H) 3.38-3.56 (m, 10H) 4.61 (br s, 1H) 6.60 (dd, J=9.38, 2.35 Hz, 1H) 6.70-6.77 (m, 1H) 6.89 (d, J=5.28 Hz, 1H) 6.92 (s, 1H) 7.54 (dd, J=8.35, 5.72 Hz, 1H) 7.80 (s, 1H) 8.19 (d, J=5.28 Hz, 1H) 10.45 (s, 1H)
LR MS (EI+): 495 (MH+)
Example 423




(3E)-6-Fluoro-3-{4-[2-(4-hydroxypiperidin-1-yl)pyridin-4-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
Similar procedure as Example 422.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.30-1.42 (m, 2H) 1.72 (s, 6H) 1.73-1.82 (m, 2H) 3.08-3.17 (m, 2H) 3.65-3.74 (m, 1H) 4.02-4.10 (m, 2H) 4.67 (d, J=4.10 Hz, 1H) 6.61 (dd, J=9.38, 2.64 Hz, 1H) 6.70-6.77 (m, 1H) 6.83 (dd, J=5.28, 1.17 Hz, 1H) 6.91 (s, 1H) 7.54 (dd, J=8.35, 5.72 Hz, 1H) 7.79 (s, 1H) 8.18 (d, J=5.28 Hz, 1H) 10.44 (s, 1H)
LR MS (EI+): 422 (MH+)
Preparation of Examples 424-454 (FIG. 9)
Each of the examples was prepared through the library synthesis as follows:
To each 8-mL screw cap reaction vial were added (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (40 mg, 0.11 mmol), amine (0.25 mmol, 2.3 eq.), DMSO (1 mL), and DIPEA (0.1 mL, 5 eq.). The reaction was heated at 115-120° C. for 1-4 days and monitored by LCMS. After cooling to room temperature, the reaction mixtures were filtered through a plug of cotton and the resulting DMSO solutions were submitted for preparative RP-HPLC purification. Each compound was re-analyzed by LCMS after purification.
Example 426 is the compound example for the library synthesis (FIG. 9).




(3E)-3-[5,5-dimethyl-4-{2-[(2-morpholin-4-ylethyl)amino]pyridin-4-yl}furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one
25.2 mg, yield 51%.
1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.04 (d, J=5.7 Hz, 1H), 7.78 (s, 1H), 7.53 (dd, J=8.4, 5.7 Hz, 1H), 6.86 (s, 1H), 6.70-6.80 (m, 2H), 6.60-6.65 (m, 2H), 3.06 (m, 4H), 2.38-3.44 (m, 2H), 2.45-2.5 (m, 2H), 2.38-2.44 (m, 4H), 1.74 (s, 6H).
ESI-MS m/z 450.9 (M+H)+.
Preparation of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde




To 30 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (600 mg, 1.85 mmol), 5-formylthiophene-3-boronic acid (348 mg, 2.23 mmol), PdCl2(PPh3)2 (60 mg, 0.085 mmol), 1M Na2CO3 aqueous solution (7.4 mL, 7.4 mmol). The mixture was heated at 80° C. under N2 for 3.5 hours, cooled to room temperature and poured into 200 mL of water. The mixture was extracted with EtOAc (3×80 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde as brown solid. Yield: 458 mg, 70%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.78 (s, 6H) 6.62 (dd, J=9.52, 2.20 Hz, 1H) 6.74-6.78 (m, 1H) 7.56 (dd, J=5.37, 2.93 Hz, 1H) 7.77 (s, 1H) 8.65 (d, J=1.46 Hz, 1H) 8.70 (t, J=1.46 Hz, 1H) 10.02 (s, 1H) 10.44 (s, 1H)
Example 455




(3E)-6-Fluoro-3-[4-{5-[(4-hydroxypiperidin-1-yl)methyl]-3-thienyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde (120 mg, 0.34 mmol), 4-hydroxypiperidine (69 mg, 0.68 mmol) and 100 mg of 4 Å molecular sieves in 5 mL of anhydrous DMF was stirred under nitrogen for 16 hours. Acetic acid (20 mg) and 1M sodium cyanoborohydride (0.68 mL, 0.68 mmol) were then added. The mixture was diluted with 5 mL of anhydrous methanol and stirred at room temperature for 3 hours. The mixture was poured into 100 mL of water with stirring, and basified to about pH 8 with saturated NaHCO3 solution. The resulting precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 10-20% MeOH/CHCl3 to give (3E)-6-fluoro-3-[4-{5-[(4-hydroxypiperidin-1-yl)methyl]-3-thienyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as yellow powder. Yield: 38 mg, 26%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.32-1.43 (m, 2H) 1.66-1.72 (m, 2H) 1.73 (s, 6H) 2.09 (t, J=9.67 Hz, 2H) 2.67-2.74 (m, 2H) 3.40-3.49 (m, 1H) 3.66 (s, 2H) 4.52 (d, J=4.40 Hz, 1H) 6.59 (dd, J=9.38, 2.35 Hz, 1H) 6.68-6.75 (m, 1H) 7.42 (s, 1H) 7.49-7.53 (m, 2H) 8.04 (d, J=1.47 Hz, 1H) 10.37 (s, 1H)
LR MS (ES−): 439 (M−1)
Example 456




(3E)-6-Fluoro-3-{4-[5-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]methyl)-3-thienyl}-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
Similar procedure as Example 455.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.73 (s, 6H) 2.38-2.47 (m, J=6.16 Hz, 10H) 3.37 (t, J=4.98 Hz, 2H) 3.46 (q, J=6.16 Hz, 4H) 3.68 (s, 2H) 6.59 (dd, J=9.38, 2.05 Hz, 1H) 6.68-6.75 (m, 1H) 7.44 (s, 1H) 7.49-7.54 (m, 2H) 8.05 (d, J=1.17 Hz, 1H) 10.38 (s, 1H)
LR MS (ES+): 514 (M+1)
Preparation of Examples 457-475 (FIG. 5)
Each of the examples was prepared through the library synthesis as follows:
To each 8-mL reaction vial were added 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde (25 mg, 0.07 mmol), amine (0.105 mmol, 1.5 eq), 5% HOAc/DMF (v/v) (1 mL), and NaBH(OAc)3 (45 mg, 0.21 mmol, 3 eq.). The resulting reaction mixture was shaken at room temperature for 20 hours. It was then quenched by the addition of water (0.1 mL). The solvents were evaporated in a SpeedVac and the residue was dissolved in DMSO (1 mL). The DMSO solutions were submitted for preparative RP-HPLC purification. Each compound was re-analyzed by LCMS after purification.
Example 476




(3E)-6-Fluoro-3-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one
A mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (95 mg, 0.29 mmol) and 1-(2-hydroxyethyl)piperazine (0.40 mL, 3.3 mmol) in 6 mL of DMF was heated in 100° C. bath for 2 hours. The mixture was cooled, diluted with ethyl acetate (60 mL), washed with brine (3×50 mL), and concentrated to give the crude product, which was purified by silica gel chromatography with 5-20% methanol in chloroform to give (3E)-6-fluoro-3-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a grey solid. Yield: 73 mg, 67%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.64 (s, 6H) 2.42 (t, J=6.16 Hz, 2H) 2.51 (br s, 4H) 3.41 (br s, 4H) 3.51 (q, J=5.96 Hz, 2H) 4.44 (t, J=5.28 Hz, 1H) 6.10 (s, 1H) 6.50 (dd, J=9.53, 2.49 Hz, 1H) 6.56-6.63 (m, 1H) 7.33 (dd, J=8.35, 5.72 Hz, 1H) 10.02 (s, 1H)
LR MS (ES−): 372 (M−1)
Example 477




(3E)-3-{4-[(2,4-Dimethoxybenzyl)amino]-5,5-dimethylfuran-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one
Similar procedure as Example 476.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.56 (s, 6H) 3.75 (s, 3H) 3.83 (s, 3H) 4.25 (d, J=5.37 Hz, 2H) 5.96 (s, 1H) 6.49-6.54 (m, 2H) 6.58-6.62 (m, 2H) 7.11 (d, J=8.30 Hz, 1H) 7.34 (dd, J=8.30, 5.86 Hz, 1H) 8.00 (t, J=5.61 Hz, 1H) 9.98 (s, 1H)
LR MS (ES+): 411 (M+1)
LR MS (ES−): 409 (M−1)
Preparation of 6-fluoro-N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]nicotinamide




To a stirred solution of (3E)-3-{4-[(2,4-dimethoxybenzyl)amino]-5,5-dimethylfuran-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one (370 mg, 0.90 mmol) in 5 mL of methylene chloride was added 5 mL of TFA. The mixture was stirred at room temperature for 1 hour and evaporated to dryness. The residue was re-dissolved in ethyl acetate (80 mL), washed with saturated NaHCO3 solution (2×30 mL) and brine (30 mL), dried over Na2SO4, and evaporated to dryness to afford the enamine intermediate as a light yellow solid. The enamine was dissolved in 10 mL of dry THF, and then cooled to 0° C. Pyridine (0.5 mL, 6.2 mmol) and 6-fluoronicotinoyl chloride (180 mg, 1.13 mmol) were then added. The mixture was allowed to warm up to room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate (80 mL), washed with 0.1M HCl (2×30 mL), saturated NaHCO3 (30 mL) and brine (30 mL), concentrated, and purified by silica gel chromatography to give 6-fluoro-N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]nicotinamide as a yellow solid. Yield: 150 mg, 43%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.51 (s, 6H) 6.02 (s, 1H) 6.49 (dd, J=9.53, 2.49 Hz, 1H) 6.53-6.61 (m, 1H) 7.29-7.36 (m, 2H) 7.38 (br s, 1H) 8.42-8.49 (m, 1H) 8.78 (d, J=1.76 Hz, 1H) 9.90 (s, 1H)
LR MS (ES−): 382 (M−1)
Example 478




N-[(5E)-5-(6-Fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-6-[4-(2-hydroxyethyl)piperazin-1-yl]nicotinamide
To a stirred solution of 6-fluoro-N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]nicotinamide (75 mg, 0.20 mmol) in DMF (3 mL) was added 1-(2-hydroxyethyl)piperazine (70 mg, 0.54 mmol). The reaction mixture was heated in 66° C. bath for 30 minutes, cooled to room temperature, and diluted with ethyl acetate (80 mL). The ethyl acetate solution was washed with brine (4×20 mL), dried over Na2SO4, and concentrated to give the crude product. Purification of the crude product by silica gel chromatography with a gradient of methanol in chloroform (5-20%) gave N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-6-[4-(2-hydroxyethyl)piperazin-1-yl]nicotinamide as a yellow solid. Yield: 42 mg, 43%.
LR MS (ES+): 494 (M+1)
LR MS (ES−): 492 (M−1)
Example 479




(3E)-6-Bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one
A mixture of (3E)-6-bromo-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (2.3 g, 6.0 mmol) and morpholine (1.0 mL, 11.4 mmol) in 10 mL of DMF was heated in 96 C bath for 3 hours. The mixture was cooled to room temperature and poured into 200 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 2.1 g, 89%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.68 (s, 6H) 3.45 (br s, 4H) 3.70 (br s, 4H) 6.18 (s, 1H) 6.85 (s, 1H) 6.98 (d, J=7.81 Hz, 1H) 7.32 (d, J=7.32 Hz, 1H) 10.05 (s, 1H)
Example 480




(3E)-3-(5,5-Dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one
To a heavy-wall pressure tube were added (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (1.6 g, 4.09 mmol), copper (I) iodide (39 mg, 0.20 mmol), sodium iodide (1.23 g, 8.18 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (58 mg, 0.41 mmol), and 20 mL of anhydrous 1,4-dioxane. The mixture was purged with nitrogen, sealed and heated in 110° C. bath for 3 days. The mixture was poured into 200 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude product, (3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one, as a brown solid. Yield: 2.1 g. This crude material was used in the next step without further purification.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.67 (s, 6H) 3.45 (t, J=4.88 Hz, 4H) 3.69 (t, J=4.88 Hz, 4H) 6.18 (s, 1H) 7.01 (d, J=1.46 Hz, 1H) 7.14 (dd, J=7.81, 1.46 Hz, 1H) 7.21 (d, J=7.81 Hz, 1H) 10.01 (s, 1H)
LR MS (ES+): 439 (M+1)
Example 481




(3E)-3-[5,5-Dimethyl-4-(morpholin-4-ylcarbonyl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one
A pressure tube was charged with (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (60 mg, 0.19 mmol), morpholine (48 mg, 0.56 mmol), Mo(CO)6 (49 mg, 0.19 mmol), palladium(II) acetate (4.0 mg, 0.018 mmol), DBU (85 mg, 0.56 mmol) and anhydrous THF (3 mL). The tube was immediately capped under nitrogen and heated in 108° C. bath for 1 hour. After cooling, the reaction mixture was filtered through a short celite pad. The filtrate was concentrated and purified by silica gel flash chromatography (5-10% MeOH in CHCl3) to give (3E)-3-[5,5-dimethyl-4-(morpholin-4-ylcarbonyl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 39 mg, 55%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.61 (s, 6H) 3.53-3.65 (m, 8H) 6.62 (dd, J=9.28, 2.44 Hz, 1H) 6.74-6.78 (m, 1H) 7.36 (s, 1H) 7.52 (dd, J=8.30, 5.86 Hz, 1H) 10.46 (s, 1H)
LR MS (ES−): 357 (M−1)
Example 482




(3E)-6-Fluoro-3-[4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one
Similar procedure as Example 481.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.67 (s, 6H) 2.44 (t, J=6.10 Hz, 2H) 2.53 (t, J=4.88 Hz, 4H) 3.43 (t, J=4.88 Hz, 4H) 3.53 (q, J=5.37 Hz, 2H) 4.46 (t, J=5.37 Hz, 1H) 6.12 (s, 1H) 6.52 (dd, J=9.28, 2.44 Hz, 1H) 6.60-6.64 (m, 1H) 7.35 (dd, J=8.30, 5.37 Hz, 1H) 10.04 (s, 1H)
LR MS (ES+): 402 (M+1)
Example 483




Methyl 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate
A 25 mL reaction vessel was charged with (3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one (100 mg, 0.23 mmol), methyl thiosalicylate (77 mg, 0.46 mmol), PdCl2(dppf).CH2Cl2 (19 mg, 0.023 mmol), cesium carbonate (225 mg, 0.69 mmol) and 8 mL of anhydrous DMF. The mixture was purged with nitrogen and heated in 90° C. bath for 2.5 hours. The mixture was cooled to room temperature, diluted with 50 mL of water and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated NaHCO3 (50 mL), brine (2×50 mL), dried over Na2SO4, and concentrated to give a brown oil. Purification of the oily mixture by silica gel chromatography eluted with 1-10% MeOH/CHCl3 provided methyl 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate as a brown solid. Yield: 60 mg, 55%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.70 (s, 6H) 3.48 (br s, 4H) 3.71 (br s, 4H) 3.87 (s, 3H) 6.23 (s, 1H) 6.77 (d, J=8.30 Hz, 1H) 6.83 (d, J=1.46 Hz, 1H) 7.03 (dd, J=7.81, 1.46 Hz, 1H) 7.16-7.19 (m, 1H) 7.35-7.38 (m, 1H) 7.52 (d, J=7.81 Hz, 1H) 7.89 (d, J=7.81 Hz, 1H) 10.08 (s, 1H)
LR MS (ES+): 479 (M+1)
Example 484




2-{[(3E)-3-(5,5-Dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoic acid
A mixture of methyl 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate (50 mg) and 1M NaOH (3 mL) in 20 mL of MeOH was heated in 66° C. bath for 2 hours. The mixture was cooled to room temp, poured into 100 mL of water, and acidified to about pH 3. The precipitates were filtered, washed with water and dried in vacuo to give 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoic acid as a brown solid. Yield: 50 mg, 97%.
LR MS (ES−): 463 (M−1)
Example 485




2-{[(3E)-3-(5,5-Dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}-N-methylbenzamide
To a stirred solution of 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoic acid in 5 mL of anhydrous DMF, were added 2M methylamine in THF solution (0.066 mL, 0.13 mmol), HBTU (49 mg, 0.13 mmol) and DIPEA (31 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 15 minutes and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product as a brown solid. Purification of the crude product by silica gel chromatography eluted with a gradient of 5-15% MeOH in CHCl3 afforded 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}-N-methylbenzamide as brown solid. Yield: 6 mg, 12%.
1H NMR (300 MHz, d6-DMSO) δ ppm 1.70 (s, 6H) 2.78 (d, J=4.69 Hz, 3H) 3.47 (br s, 4H) 3.71 (br s, 4H) 6.22 (s, 1H) 6.79-6.84 (m, 2H) 6.99 (dd, J=7.92, 1.47 Hz, 1H) 7.11-7.16 (m, 1H) 7.20-7.27 (m, 1H) 7.41 (dd, J=7.33, 1.47 Hz, 1H) 7.48 (d, J=7.92 Hz, 1H) 8.32 (br s, 1H) 10.05 (s, 1H)
LR MS (ES−): 476 (M−1)
Example 486




N-(3-{[(3E)-3-(5,5-Dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]amino}phenyl)acetamide
A 25 mL reaction flask was charged with (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (100 mg, 0.26 mmol), N-(4-aminophenyl)acetamide (46 mg, 0.31 mmol), dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (4.9 mg, 0.012 mmol), Pd2(dba)3 (4.8 mg, 0.0052 mmol), 1M LiHMDS in THF (0.83 mL, 0.83 mmol) and dry THF (10 mL). The mixture was purged with nitrogen and heated in 62° C. bath under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was quenched with 0.5 mL of 2M HCl, and diluted with ethyl acetate (100 mL). The solution was washed with saturated NaHCO3 (2×50 mL), brine (50 mL), and concentrated to give the crude product. Purification of the crude product by silica gel chromatography with a gradient of methanol in chloroform (5-10%) led to N-(3-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]amino}phenyl)acetamide as a yellow solid. Yield: 20 mg, 17%.
1H NMR (500 MHz, d6-DMSO) δ ppm 1.66 (s, 6H) 2.00 (s, 3H) 3.39 (t, J=4.39 Hz, 4H) 3.69 (t, J=4.39 Hz, 4H) 6.15 (s, 1H) 6.53 (s, 1H) 6.63 (t, J=7.57 Hz, 2H) 6.94 (d, J=8.30 Hz, 1H) 7.05 (t, J=8.06 Hz, 1H) 7.29 (d, J=7.81 Hz, 1H) 7.34 (s, 1H) 7.91 (s, 1H) 9.73 (s, 1H) 9.81 (s, 1H)
LR MS (ES−): 459 (M−1)
The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention only. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. For example novel compounds of formula VIII, below may be utilized in the method of treating diseases described above.




wherein D is a 5-membered unsaturated heterocyclic group, R8, R9 and R10 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl.

Such modifications are intended to fall within the scope of the appended claims.
All references cited herein are hereby incorporated by reference in their entirety.
The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the appended claims.

## Claims

1. A method of treating a disease selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, transplant rejection glomerulopathies, psoriasis, diabetes mellitus, wound healing, and inflammation, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula IA:



or a pharmaceutically acceptable salt thereof;
wherein:
X is O;
Y is O;
the ring system represented by A in formula V, below, is a 6 membered aryl group,





wherein said aryl group is:




and wherein the ring system represented by B in formula VI




is a five membered unsaturated heterocyclic ring having the formula:




wherein Z is [C(R2)2]c;
wherein R1 is —X′-D wherein X′ is selected from the group consisting of




and D is a 6 membered carbocyclic aryl ring substituted with one or more substituents selected from the group consisting of (CR3aR4a)d′C(O)OR2, (CR3aR4a)d′C(O)N(R2)2, and NR2C(O)(CR3aR4a)d′R3a; wherein each R2 independently is selected from the group consisting of hydrogen, and C1-C8 alkyl;
R in variable Ra is (CR3R4)d′′R8 wherein (CR3R4)d′′ is morpholine, and R8 is selected from the group consisting of H, F, C1-C4 alkyl and hydroxy;
R3a and R4a are independently H or C1-C4 alkyl;
R6a is hydrogen;
R7 is selected from the group consisting of hydrogen, and C1-C8 alkyl;
a in variable Ra is 1;
b in the variable —(C═X)b— is 0;
b in variable R1b is 1;
c in the variable [C(R2)2]c is an integer of from 1 to 2;
d is 0;
d′ is 0; and
f in —S(O)f— in the definition of X′ above is 0.

2. A method of treating a disease selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, transplant rejection glomerulopathies, psoriasis, diabetes mellitus, wound healing, and inflammation, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of at least one compound selected from the group consisting of
Methyl 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate, and
2-{[(3E)-3-(5,5-Dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}-N-methylbenzamide; or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein said disease is age-related macular degeneration.

4. The method of claim 2, wherein said disease is age-related macular degeneration.