Novel compounds useful as poly(ADP-ribose) polymerase (PARP) inhibitors

Abstract

The present invention provides novel poly(ADP-ribose) polymerase (PARP) inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods for using them to treat, prevent, and / or ameliorate PARP-mediated diseases or disorders. In particular, the compounds described herein are useful for the treatment of breast cancer, ovarian cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, and gastric cancer.

Description

[Technical Field]

[0001] This invention claims the benefit of Indian Patent Nos. 202041018149, filed April 28, 2020, and 202041047713, filed November 2, 2020, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention relates to compounds useful as poly(ADP-ribose) polymerase (PARP) inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods for treating, preventing, and / or ameliorating diseases or disorders in which PARP is involved. [Background technology]

[0003] Poly(ADP-ribose) polymerases (PARPs) define a family of 17 enzymes that cleave NAD+ into nicotinamide and ADP-ribose, forming long, branched (ADP-ribose) polymers on glutamate residues of many target proteins, including PARP itself. The addition of the negatively charged polymer significantly alters the properties and function of the acceptor protein. Poly(ADP-ribosyl)ation is involved in the regulation of many cellular processes, including DNA repair, gene transcription, cell cycle progression, cell death, chromatin function, and genome stability. These functions are primarily attributed to PARP-1, which is considered the best-characterized member of the PARP family. However, the identification of novel genes encoding PARPs, along with the characterization of their structure and subcellular localization, has revealed distinct roles for poly(ADP-ribosyl)ation in the cell, including telomere replication and cellular trafficking.

[0004] Recently, poly(ADP-ribose) binding sites have been identified in many DNA damage checkpoint proteins, such as the tumor suppressor p53 and the cyclin-dependent kinase inhibitor p21. Cip1 / waf1PARP-1 has been identified as a DNA damage recognition factor (i.e., nucleotide excision repair xeroderma pigmentosum group A complementing protein and mismatch repair protein MSH6), base excision repair (BER) proteins (i.e., DNA ligase III, X-ray repair cross-complementing 1, and XRCC1), DNA-dependent protein kinase (DNA-PK), and cell death and survival regulators (i.e., NF-kB, inducible nitric oxide synthase, and telomerase). These findings suggest that different members of the PARP family may participate in DNA damage signaling networks and thus regulate protein-protein and protein-DNA interactions, thereby regulating various types of cellular responses to genotoxic stress. In addition to its involvement in BER and single-strand break (SSB) repair, PARP-1 appears to support the nonhomologous end joining (NHEJ) and homologous recombination (HR) pathways of double-strand break (DSB) repair. (See Lucio Tentori et al., Pharmacological Research, Vol. 45, No. 2, 2002, pp. 73-85.)

[0005] PARP inhibition may be a useful therapeutic strategy not only for the treatment of BRCA mutations but also for a wider range of tumors with various defects in the HR pathway. Furthermore, existing clinical data (e.g., Csaba Szabo et al., British Journal of Pharmacology (2018) 175:192-222) have shown that stroke, traumatic brain injury, circulatory shock, and acute myocardial infarction are also some of the indications, demonstrating that PARP activation contributes to tissue necrosis and inflammatory responses.

[0006] Currently, four PARP inhibitors, namely olaparib, talazoparib, niraparib, and rucaparib, have been approved for human use by regulatory agencies worldwide.

[0007] Patent documents related to PARP inhibitors include International Publication Nos. 2000 / 42040, 2001 / 016136, 2002 / 036576, 2002 / 090334, 2003 / 093261, 2003 / 106430, 2004 / 080976, 2004 / 087713, and 200 5 / 012305, 2005 / 012524, 2005 / 012305, 2005 / 012524, 2005 / 053662, 200 6 / 033003, 2006 / 033007, 2006 / 033006, 2006 / 021801, 2006 / 067472, 2007 / 144637, 2007 / 144639, 2007 / 144652, 2008 / 047082, 2008 / 114114, 2009 / 050469, 2011 / 098971, 2015 / 108986, 2016 / 028689, 2016 / 165650, 2017 Nos. 2017 / 153958, 2017 / 191562, 2017 / 123156, 2017 / 140283, 2018 / 197463, 2018 / 038680, and 2018 / 108152, each of which is incorporated by reference in its entirety for all purposes. Summary of the Invention [Problem to be solved by the invention]

[0008] There remains an unmet need for new PARP inhibitors for the treatment of various diseases and disorders associated with cell proliferation, such as cancer.

[0009] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, processes for preparing them, and methods of treatment using them. In particular, the compounds of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment, prevention, and / or amelioration of diseases or disorders involving PARP.

[0010] In one aspect, the present invention provides a compound of formula (I):

[0011] [ka] [In the formula, R a , R b , R c and R d is hydrogen, halogen, substituted or unsubstituted C 1~3 Alkyl (e.g., C 1~3 haloalkyl), X is CR x or N, Y is CR y or N, Z is CR Z or N, R x , R y and R z are the same or different and are each independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl; G is

[0012] [ka] (In the formula, R e and R f are the same or different and include hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl (e.g., haloalkyl), substituted or unsubstituted alkoxy, and -OR g or R directly bonded to a common atom e and R f Both are combined to form C 3~6 may form a cycloalkyl or heterocyclic ring (e.g., a 3- to 7-membered heterocyclic ring), R g is hydrogen, substituted or unsubstituted C 1~3 Alkyl, and -(CO)R h is selected from R h is selected from hydrogen and substituted or unsubstituted alkyl; R 1 , R 2 , R 3and R 4 are each independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl (e.g., haloalkyl)), or a tautomer, prodrug, N-oxide, stereoisomer, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present invention provides a compound of formula (I):

[0014] [ka] [In the formula, R a , R b , R c and R d is hydrogen, halogen, substituted or unsubstituted C 1~3 are each independently selected from alkyl, X is CR x or N, Y is CR y or N, Z is CR Z or N, R x , R y and R z may be the same or different and are hydrogen, halogen, substituted or unsubstituted C 1~3 are each independently selected from alkyl, G is

[0015] [ka] (In the formula, R e and R f may be the same or different and may be hydrogen, halogen, hydroxy, substituted or unsubstituted Cd 1~3 Alkyl (e.g., C 1~3 haloalkyl), substituted or unsubstituted C 1~3 Alkoxy and -O(CO)R h are each independently selected from R gis hydrogen, substituted or unsubstituted C 1~3 Alkyl, and -(CO)R h is selected from R h is selected from hydrogen and substituted or unsubstituted alkyl; R 1 , R 2 , R 3 and R 4 is hydrogen, halogen, and substituted or unsubstituted C 1~3 Alkyl (e.g., C 1~3 or a tautomer thereof, a prodrug thereof, an N-oxide thereof, a stereoisomer thereof, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, the present invention provides a compound of formula (IA) or (IB):

[0017] [ka] [wherein the variable R a , R b , R c , R d , X, Y, Z, R e , R f , R 1 , R 2 , R 3 and R 4 is as defined above for compounds of formula (I), or a tautomer, a prodrug, an N-oxide, a stereoisomer, a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof.

[0018] One particular embodiment is a compound of formula (I), (IA) or (IB), wherein R a , R b , R c and R d wherein any one or more of is a halogen.

[0019] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R a , R b , R c and R d wherein any one or more of is hydrogen.

[0020] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R a , R c and R d is hydrogen and R b is a halogen.

[0021] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R b is fluorine or chlorine.

[0022] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R a , R b and R d is hydrogen and R c is a halogen.

[0023] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R c is fluorine or chlorine.

[0024] Another embodiment is a compound of formula (I), (IA) or (IB) wherein X, Y and Z are each independently CH or N.

[0025] Another embodiment is a compound of formula (I), (IA) or (IB) where X is CH or N.

[0026] Another embodiment is a compound of formula (I), (IA) or (IB) where Y is CH or N.

[0027] Another embodiment is a compound of formula (I), (IA) or (IB) where Z is CH or N.

[0028] Another embodiment is a compound of formula (I), (IA) or (IB) where X is N.

[0029] Another embodiment is a compound of formula (I), (IA) or (IB) where Y is N.

[0030] Another embodiment is a compound of formula (I), (IA) or (IB) where Z is N.

[0031] Another embodiment is a compound of formula (I), (IA) or (IB) where Y and Z are CH and X is N.

[0032] Another embodiment is a compound of formula (I), (IA) or (IB) where X and Z are CH and Y is N.

[0033] Another embodiment is a compound of formula (I), (IA) or (IB) where X and Y are CH and Z is N.

[0034] Another embodiment is a compound of formula (I), (IA) or (IB) wherein Y is CH and Z is CR Z (In the formula, R z is defined as above).

[0035] Another embodiment is a compound of formula (I), (IA) or (IB) wherein X and Y are CH and Z is CR Z (In the formula, R z is a halogen).

[0036] Another embodiment is a compound of formula (I), (IA) or (IB) wherein X and Y are CH and Z is CR Z (In the formula, R z is a fluorine compound.

[0037] Another embodiment is a compound of formula (I), (IA) or (IB) where Z is CH.

[0038] Another embodiment is a compound of formula (I), (IA) or (IB) where X, Y and Z are CH.

[0039] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R e and R f is hydrogen, hydroxy, substituted or unsubstituted C 1~3 Alkyl (e.g., C 1~3 haloalkyl), substituted or unsubstituted C 1~3 and each independently selected from alkoxy and acetyloxy.

[0040] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R e is hydroxy, substituted or unsubstituted C 1~3 alkoxy or acetyloxy.

[0041] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R e is hydroxy].

[0042] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R f is a substituted or unsubstituted C 1~3 Alkyl (e.g., C 1~3 haloalkyl).

[0043] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R f is a substituted or unsubstituted C 1~3 It is a compound of the formula:

[0044] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R e is hydroxy and R f is a substituted or unsubstituted C 1~3 It is a compound of the formula:

[0045] Another embodiment is a compound of formula (I), (IA) or (IB), wherein: (i)R e and R f are both hydrogen or (ii)R e and R f is substituted or unsubstituted C 1~3 alkyl; (iii) R directly attached to a common atom e and R f Both are combined to form C 3~6 forming a cycloalkyl or heterocyclic ring (for example, a 3- to 7-membered heterocyclic ring).

[0046] Another embodiment is a compound of formula (I), (IA) or (IB), wherein: (i)R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen or halogen; (ii)R 1 , R 2 , R 3 and R 4 is hydrogen or (iii)R 1 , R 2 , R 3 and R 4 is a halogen or (iv)R 1 , R 3 and R 4 is hydrogen and R 2 is a halogen, or (v)R 1 , R 2 and R 4 is hydrogen and R 3 is a halogen.

[0047] Another embodiment is a compound of formula (I), (IA) or (IB), wherein: (i)R 1 , R 2 , R 3 and R 4 one or more of the following is fluorine or chlorine; (ii)R 1 , R3 and R 4 is hydrogen and R 2 is fluorine, or (iii)R 1 , R 2 and R 4 is hydrogen and R 3 is a fluorine compound.

[0048] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R e and R f is a compound of the formula:

[0049] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R e and R f is methyl].

[0050] Another embodiment is a compound of formula (I), (IA) or (IB) wherein R e and R f Both are combined to form C 3~6 forming a cycloalkyl ring or a heterocyclic ring (for example, a 3- to 7-membered heterocyclic ring).

[0051] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 2 , R 3 and R 4 wherein any one or more of is selected from hydrogen and halogen.

[0052] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 2 , R 3 and R 4 wherein any one or more of is hydrogen.

[0053] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 2 , R 3 and R 4wherein any one or more of is a halogen.

[0054] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 2 , R 3 and R 4 wherein any one or more of is fluorine or chlorine.

[0055] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 3 and R 4 is hydrogen and R 2 is a halogen.

[0056] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 3 and R 4 is hydrogen and R 2 is a fluorine compound.

[0057] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 2 and R 4 is hydrogen and R 3 is a halogen.

[0058] Another embodiment is a compound of formula (I), (IA) or (IB), wherein R 1 , R 2 and R 4 is hydrogen and R 3 is a fluorine compound.

[0059] Another embodiment is a compound of formula (I) wherein G is selected from:

[0060] [ka]

[0061] Another embodiment is a compound of formula (I) wherein G is selected from:

[0062] [ka]

[0063] Representative compounds of the present invention include the compounds specified below and pharmaceutically acceptable salts thereof, but the present invention should not be construed as being limited to these specific compounds.

[0064] In one embodiment, the present invention relates to a compound selected from: 1. 4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 2. (R)-(+)-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 3. (S)-(-)-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4. 4-(4-fluoro-3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 5. 4-((5-(3-ethyl-3-hydroxy-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 6. 7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 7. (+)-7-Fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 8. (-)-7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 9. 6-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 10. 7-fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 11. (+)-7-Fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 12. (-)-7-fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 13. 4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 14. (+)-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 15. (-)-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 16. 7-fluoro-4-((5-(6-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 17. 7-fluoro-4-((5-(6-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 18. 4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 19. (-)-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 20. (+)-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 21. 7-fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 22. (-)-7-Fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 23. (+)-7-Fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 24. 7-fluoro-4-((2-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 25. 4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 26. (+)-4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 27. (-)-4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 28. 4-(3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 29. 7-Fluoro-4-(4-fluoro-3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 30. 4-((5-(3-methoxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 31. 4-(3-(3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)benzyl)phthalazin-1(2H)-one; 32. 3-methyl-2-oxo-1-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)pyridin-3-yl)indolin-3-yl acetate; 33. 4-(4-fluoro-3-(2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 34. 4-(3-(3,3-dimethyl-2-oxoindolin-1-yl)-4-fluorobenzyl)phthalazin-1(2H)-one; 35. 4-((5-(3,3-dimethyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 36. 4-((5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 37. 4-(3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-fluorobenzyl)phthalazin-1(2H)-one; 38. 1'-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one; and pharmaceutically acceptable salts thereof.

[0065] [Table 1-1]

[0066] [Table 1-2]

[0067] Yet another embodiment of the present invention is a method of inhibiting PARP in a patient (such as a patient in need thereof) by administering to the patient an effective amount of at least one compound of the present invention (e.g., a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof).

[0068] Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune, or proliferative disease (e.g., via inhibition of PARP) by administering to a patient (such as a patient in need thereof) an effective amount of at least one compound of the present invention.

[0069] In one embodiment, the compounds of the invention inhibit PARP (i.e., an effective amount of the compound is administered to inhibit PARP), hi one embodiment, the compounds of the invention inhibit PARP1 and / or PARP2 (i.e., an effective amount of the compound is administered to inhibit PARP1 and / or PARP2).

[0070] Yet another embodiment of the present invention is a method of treating an inflammatory, autoimmune, or proliferative disease (e.g., via inhibition of PARP) by administering to a patient (such as a patient in need thereof) an effective amount of at least one compound of the present invention in combination (simultaneously or sequentially) with at least one other anti-inflammatory, immunomodulatory, and / or anti-cancer agent.

[0071] The compounds of formula (I), and their pharmaceutically acceptable esters and salts, can be administered for the treatment, prevention, and / or amelioration of diseases or disorders associated with PARP, particularly for the amelioration of diseases or disorders mediated by PARP, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, and cancer and other proliferative diseases or disorders.

[0072] The compounds of the present invention are useful in the treatment of a variety of cancers, including, but not limited to: · Cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); Hematopoietic malignancies of the lymphoid system, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; Myeloid hematopoietic malignancies, including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; Tumors of the central and peripheral nervous system, including astrocytomas, neuroblastomas, gliomas, and schwannomas; and Other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0073] The compounds of the present invention as modulators of apoptosis may be useful in the treatment of cancer (including, but not limited to, those types described herein above), viral infections (including, but not limited to, herpesviruses, poxviruses, Epstein-Barr virus, Sindbis virus, and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus, lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS-associated dementia, and pancreatic cancer), and the prevention of AIDS-associated diseases (including, but not limited to, pulmonary tuberculosis, pulmonary tuberculosis, and pancreatic cancer). The compounds are useful in the treatment of diseases such as Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration, myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, cardiac arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver disease, blood disorders (including but not limited to chronic anemia, aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

[0074] The compounds of the present invention can modulate the level of cellular RNA and DNA synthesis. Thus, the compounds described herein are useful in the treatment of viral infections, including but not limited to HIV, human papillomavirus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus, and adenovirus.

[0075] The compounds of the present invention are useful for the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by preventing the initiation of mutagenic events, or by preventing the progression of already damaged premalignant cells, or by inhibiting tumor recurrence. The compounds described herein are also useful for inhibiting tumor angiogenesis and metastasis. One embodiment of the present invention is a method of inhibiting tumor angiogenesis or metastasis in a patient (e.g., a patient in need thereof) by administering an effective amount of one or more compounds of the present invention.

[0076] Another embodiment of the invention is a method of treating an immune system-related disease (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, and disorders of the immune system), cancer or other proliferative disease, a liver disease or disorder, or a kidney disease or disorder. The method comprises administering to a patient (e.g., a patient in need thereof) an effective amount of one or more compounds of the invention.

[0077] Examples of immune disorders include, but are not limited to, psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle diseases, allergic diseases (e.g., allergic rhinitis), vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allo- or xenotransplant (organ, bone marrow, stem cell, and other cell and tissue) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0078] In one embodiment, the compounds described herein are used as immunosuppressants to prevent transplant rejection, allo- or xenograft rejection (organ, bone marrow, stem cells, other cells and tissues), and graft-versus-host disease. In another embodiment, the transplant rejection results from tissue or organ transplantation. In a further embodiment, the graft-versus-host disease results from bone marrow or stem cell transplantation. One embodiment is a method of preventing or reducing the risk of transplant rejection, allo- or xenograft rejection (organ, bone marrow, stem cells, other cells and tissues), or graft-versus-host disease by administering to a patient (e.g., a patient in need thereof) an effective amount of one or more compounds of the invention.

[0079] The compounds of the present invention may also be used in combination with known anti-cancer treatments, for example, but not limited to, radiation therapy, or in combination with cytostatic, cytotoxic or anti-cancer agents, for example, but not limited to, DNA interacting agents such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents such as paclitaxel, docetaxel, or epothilones (e.g., ixabepilone), either of natural origin or synthetic; hormones such as tamoxifen; and antimetabolites such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; HDAC inhibitors, SRC inhibitors; c-Kit inhibitors; Her1 / 2 inhibitors and monoclonal antibodies against growth factor receptors such as Erbitux (EGF) and Harceptin (Her2), as well as other protein kinase modulators or any combination of the above.

[0080] The compounds of the invention are also useful in combination (administered together or sequentially) with one or more steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or immunoselective anti-inflammatory derivatives (ImSAIDs).

[0081] In another aspect, the present invention further provides pharmaceutical compositions comprising one or more compounds of the present invention (e.g., compounds of Formula (I) or pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable carriers. The pharmaceutical compositions may further comprise one or more additional active ingredients identified herein, such as other anti-cancer agents.

[0082] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0083] Yet another embodiment is a method of treating cancer in a patient (e.g., a patient in need thereof) by administering a therapeutically effective amount of a compound of the invention. For example, the compounds of the invention are effective in treating lymphoid hematopoietic malignancies, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; myeloid hematopoietic malignancies, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia. The compounds of the present invention are also effective in treating bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, neurilemmoma, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0084] Yet another embodiment is a method of treating leukemia in a patient (e.g., a patient in need thereof) by administering a therapeutically effective amount of a compound of the invention. For example, the compounds of the invention are effective in treating breast cancer, ovarian cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, or gastric cancer. DETAILED DESCRIPTION OF THE INVENTION

[0085] As used herein, the following definitions shall apply unless otherwise indicated. Furthermore, many of the groups defined herein can be optionally substituted. The list of substituents in the definitions is exemplary and should not be construed as limiting the substituents defined elsewhere herein.

[0086] The term "alkyl," unless otherwise specified, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). 1~6 The term "alkyl" refers to an alkyl group as defined above having up to 6 carbon atoms. 1~4 The term "alkyl" refers to an alkyl group, as defined above, having up to four carbon atoms. In appropriate circumstances, the term "alkyl" refers to a hydrocarbon chain group, as defined above, that is divalent.

[0087] The term "alkenyl," unless otherwise specified, refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched or unbranched, having from about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. 2~6 The term "alkenyl" refers to alkenyl groups as defined above having up to 6 carbon atoms.

[0088] The term "alkynyl," unless otherwise specified, refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond and in the range of 2 to 12 carbon atoms, with groups having in the range of 2 to 10 carbon atoms being currently preferred, such as ethynyl, propynyl, and butynyl. 2~6 The term "alkynyl" refers to alkynyl groups as defined above having up to 6 carbon atoms.

[0089] The term "alkoxy," unless otherwise specified, refers to an alkyl, cycloalkyl, or cycloalkylalkyl group, as defined above, attached to the remainder of the molecule through an oxygen linkage. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (i.e., -O-(substituted alkyl)), and the term "substituted alkyl" is the same as defined above for "alkyl." For example, "alkoxy" refers to an -O-alkyl group containing from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof, attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.

[0090] The term "cycloalkyl," unless otherwise specified, refers to a non-aromatic monocyclic or polycyclic ring system having about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl, and norbornyl groups, bridged cyclic groups, and spiro bicyclic groups such as sprio(4,4)non-2-yl. 3~8 The term "cycloalkyl" refers to a cycloalkyl group as defined above having up to 8 carbon atoms.

[0091] The term "cycloalkylalkyl," unless otherwise specified, refers to a cyclic ring-containing group containing in the range of about 3 to 8 carbon atoms directly bonded to an alkyl group, which carbon atom can be further attached to the main structure at any carbon from the alkyl group resulting in the creation of a stable structure, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

[0092] The term "cycloalkenyl," unless otherwise specified, refers to cyclic ring-containing groups containing in the range of about 3 to 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl group directly attached to an alkyl group, further attached to the main structure at any carbon from the alkyl group that results in the creation of a stable structure.

[0093] The term "aryl," unless otherwise specified, refers to aromatic groups having in the range of 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0094] The term "arylalkyl", unless otherwise specified, refers to an aryl group as defined above directly bonded to an alkyl group as defined above, for example, -CH2C6H5 and -C2H5C6H5.

[0095] The term "heterocycle," unless otherwise specified, refers to a non-aromatic 3- to 15-membered ring group consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen, and sulfur. For purposes of this invention, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused, bridged, or spirocyclic ring systems, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic group can be optionally oxidized to various oxidation states. Furthermore, the nitrogen atom can be optionally quaternized. The heterocyclic group can be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0096] The term "heterocyclyl," unless otherwise specified, refers to a heterocylic ring radical, as defined above. The heterocyclyl ring radical can be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0097] The term "heterocyclylalkyl," unless otherwise specified, refers to a heterocyclyl ring group, as defined above, directly attached to an alkyl group. The heterocyclylalkyl group can be attached to the main structure at a carbon atom of the alkyl group, which results in the creation of a stable structure. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0098] The term "heteroaryl," unless otherwise specified, refers to an optionally substituted 5- to 14-membered aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms. Heteroaryl can be a monocyclic, bicyclic, or tricyclic ring system. Examples of such "heterocycle" or "heteroaryl" groups include oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, Examples of heteroaryl groups include, but are not limited to, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "substituted heteroaryl" also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.

[0099] The term "heteroarylalkyl," unless otherwise specified, refers to a heteroaryl ring group, as defined above, directly attached to an alkyl group. The heteroarylalkyl group can be attached to the main structure at any carbon atom from the alkyl group that results in the creation of a stable structure.

[0100] The term "cyclic ring" refers to a cyclic ring containing from 3 to 10 carbon atoms.

[0101] The term "substituted," unless otherwise specified, refers to substitution with any one or any combination of the following substituents, which may be the same or different: hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocycle, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -COOR t , -C(O)R v , -C(S)R V , -C(O)NR t R u , -C(O)ONR t R u , -NR t R u , -NR t CONR u R v , -N(R t )SOR u , -N(R t )SO2R u , -(=NN(R t )R u ), -NR t C(O)OR u , -NR t Ru , -NR t C(O)R u -, -NR t C(S)R u -NR t C(S)NR t R u , -SONR t R u -,-SO2NR t R u -, -OR t , -OR t C(O)NR u R v , -OR t C(O)OR u -, -OC(O)R t , -OC(O)NR t R u , -R t NR u C(O)R v , -R t OR u , -R t C(O)OR u , -R t C(O)NR u R v , -R t C(O)R u , -R t OC(O)R u , -SR t , -SOR t , -SO2R t and -ONO2, and R in each of the above groups is independently selected from t , R u and R v may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocycle, or substituted heterocyclylalkyl ring, or R t , Ru and R v any two of these may be bonded to form a substituted or unsubstituted, saturated or unsaturated 3- to 10-membered ring, and the 3- to 10-membered ring may be the same or different; O, NR q (R q is hydrogen or C 1~6 The substituents may optionally contain a heteroatom selected from S, which may be alkyl, or S. Substituents or combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound or structure that does not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and incorporation into pharmaceutical compositions. Substituents of the aforementioned "substituted" groups cannot be further substituted. For example, if a substituent on a "substituted alkyl" is a "substituted aryl," the substituent on the "substituted aryl" cannot be a "substituted alkenyl."

[0102] The terms "halo," "halide," or alternatively, "halogen" mean fluoro, chloro, bromo, or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures that are substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[0103] The term "protecting group" or "PG" refers to a substituent used to block or protect a particular functional group. Other functional groups on a compound can remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl. A "carboxy-protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CHCHSOPh, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0104] Certain compounds described herein may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical compounds, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Non-limiting examples of intermediate mixtures include mixtures of isomers in ratios of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers can be prepared using chiral synthesizers or chiral reagents or resolved using conventional techniques. Where a compound described herein contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, the compound is intended to include both E- and Z-geometric isomers.

[0105] As used herein, the term "tautomer" refers to a compound characterized by relatively easy interconversion of isomeric forms at equilibrium. These isomers are intended to be encompassed by the present invention. "Tautomers" are structurally distinct isomers that interconvert via tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton shift tautomerization, which are considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of a proton with a change in bond order, often the swapping of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0106] A "leaving group or atom" is any group or atom that splits off from the starting material under reaction conditions, thus facilitating reaction at a particular site. Unless otherwise specified, suitable examples of such groups include halogen atoms and mesyloxy, p-nitrobenzenesulfonyloxy, and tosyloxy groups.

[0107] The term "prodrug" refers to an inactive precursor of a compound that is converted to an active form in the body through normal metabolic processes. Prodrug design is generally discussed in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). By way of illustration, prodrugs can be converted to their pharmacologically active form by hydrolysis of an ester bond, amide bond, or the like, thereby introducing or exposing a functional group in the reaction product. Prodrugs can be designed to react with endogenous compounds to form water-soluble conjugates that further enhance the pharmacological properties of the compounds (e.g., increase circulatory half-life). Alternatively, prodrugs can be designed to undergo covalent modification at functional groups, for example, with glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugates may be inactivated and excreted in the urine, or may be more potent than the parent compound. Also, high molecular weight conjugates can be excreted in the bile, undergo enzymatic cleavage, and be released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound.

[0108] The term "ester" refers to a compound formed by reacting an acid with an alcohol with the elimination of water. Esters can be represented by the general formula RCOOR'.

[0109] These prodrugs and esters are intended to be included within the scope of the present invention.

[0110] Furthermore, the present invention provides a method for the replacement of hydrogen with deuterium or tritium, or for the replacement of carbon with 13C -or 14C - also includes compounds that differ only in the presence of one or more isotopically enriched atoms, such as by substitution with an -enriched carbon.

[0111] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon 14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0112] Pharmaceutically acceptable salts that form part of the invention include, for example, salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamines, and thiamine; chiral bases such as alkylphenylamines, glycinol, and phenylglycinol; salts of glycine, alanine, valine, leucine, isoleucine, norleucine, Salts include salts of natural amino acids such as tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, and serine; quaternary ammonium salts of the compounds of the present invention with alkyl halides and alkyl sulfates, such as MeI and (Me)SO; unnatural amino acids, such as D-isomers or substituted amino acids; guanidine; and substituted guanidines, where the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium, or substituted ammonium and aluminum salts. Salts may optionally include acid addition salts such as sulfate, nitrate, phosphate, perchlorate, borate, hydrogen halide (e.g., hydrochloride), acetate, tartrate, maleate, citrate, fumarate, succinate, palmoate, methanesulfonate, benzoate, salicylate, benzenesulfonate, ascorbate, glycerophosphate, and ketoglutarate.

[0113] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" means that the stated number or numerical range is an approximation within experimental variation (or statistical experimental error), and thus means that the number or numerical range may vary, for example, by 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments that "consist of" or "consist essentially of" the described features, e.g., any material, composition, method, or process.

[0114] The following abbreviations and terms have the indicated meanings throughout: AIDS = Acquired Immune Deficiency Syndrome; HIV = Human Immunodeficiency Virus. The abbreviations used herein have their conventional meanings within the chemical and biological arts.

[0115] The term "cell proliferation" refers to a change in cell number as a result of division. The term also encompasses cell growth in which cell morphology changes (e.g., increased size) in response to proliferation signals.

[0116] As used herein, the terms "co-administration," "administered in combination," and their grammatical equivalents include administration of two or more agents to an animal such that both agents and / or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0117] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to achieve its intended use, including, but not limited to, disease treatment, as defined below. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo) or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that elicits a specific response in target cells, such as reduced platelet adhesion and / or cell migration. Specific doses vary depending on the compound selected, the dosing regimen to be pursued, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered. In one embodiment, the amount of compound administered ranges from about 0.1 mg to 5 g, about 1 mg to 2.0 g, about 100 mg to 1.5 g, about 200 mg to 1.5 g, about 400 mg to 1.5 g, and about 400 mg to 1.0 g.

[0118] As used herein, the terms "treatment," "treat," and "ameliorate" are used interchangeably. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or preventative benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient, even though the patient may still be afflicted by the underlying disease. For preventative benefit, the compositions may be administered to patients at risk of developing a particular disease or to patients who report one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0119] As used herein, the term "therapeutic benefit" encompasses therapeutic benefit and / or prophylactic benefit as described above. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0120] The term "subject" or "patient" refers to an animal, such as a mammal, e.g., a human. The methods described herein can be useful in both human therapy and veterinary applications (e.g., dogs, cats, cows, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese).

[0121] In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.

[0122] As used herein, "radiation therapy" means exposing a patient to radiation emitters such as alpha particle-emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation (including, but not limited to, X-rays, gamma rays, and neutrons) using conventional methods and compositions known to physicians.

[0123] As used herein, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled-release matrices, colorants / flavoring agents, carriers, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0124] Any of the methods of the present invention described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as within an animal or human or subject's body. In this context, the methods of the present invention can be used therapeutically or prophylactically within an individual. "Ex vivo" or "in vitro" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including, but not limited to, bodily fluid or tissue samples obtained from an individual. Such samples can be obtained by methods known in the art. Examples of biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Examples of tissue samples include tumors and their biopsies. In this context, the present invention can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present invention can be used ex vivo or in vitro to determine optimal dosing schedules and / or dosages of PARP inhibitors for a given indication, cell type, individual, and other parameters. Information obtained from such use may be used for experimental or diagnostic purposes, or to design in vivo treatment protocols in the clinic. Other ex vivo uses for which the present invention may be suitable are described below or will become apparent to those skilled in the art.

[0125] Pharmaceutical Composition The present invention provides pharmaceutical compositions comprising one or more compounds of the present invention.The pharmaceutical compositions may comprise one or more additional active ingredients as described herein.The pharmaceutical compositions can be administered for any of the disorders described herein.

[0126] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the compound of the present invention as an active ingredient. Optionally, the pharmaceutical compositions contain the compound of the present invention as an active ingredient and one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.

[0127] The pharmaceutical composition can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of a pharmaceutical composition. If desired, the subject compound and the other drug(s) can be mixed in a preparation, or both components can be formulated into separate preparations and used separately or in combination at the same time.

[0128] The methods include administering a compound of the present invention, alone or in combination as described herein, in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants / flavors, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.

[0129] The preparation of various pharmaceutical compositions is known in the art. For example, Anderson, Philip O. Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw. See Hill, 2003; Goodman and Gilman, eds., the Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed. Lippincott Williams & Wilkins., 2000; Martindale, the Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). all of which are incorporated herein by reference in their entirety.

[0130] The compounds or pharmaceutical compositions of the present invention can be administered by any route that allows delivery of the compound to the site of action, for example, oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g., transdermal administration), rectal administration, via local delivery by catheter or stent, or by inhalation, etc. The compounds can also be administered intraadiposally or intrathecally.

[0131] The composition can be administered in solid, semi-solid, liquid, or gaseous form, or in dry powder form, such as lyophilized form.The pharmaceutical composition can be packaged in a form convenient for delivery, including solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, capsules, suppositories, pellets, pills, troches, and lozenges.The type of packaging generally depends on the desired route of administration.Such as transdermal formulations, implantable sustained-release formulations are also contemplated.

[0132] Treatment method The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease states, including, but not limited to, diseases associated with overexpression of PARP and / or diseases resulting from an excess of PARP.

[0133] The therapeutic methods provided herein comprise administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention provides a method for treating inflammatory disorders, including autoimmune diseases, in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention.

[0134] It will be understood that the therapeutic methods of the present invention described herein are useful in the fields of human medicine and veterinary medicine. Thus, the individual to be treated can be a mammal, preferably a human, or other animal. For veterinary purposes, individuals include, but are not limited to, livestock including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and / or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.

[0135] The present invention also relates to a method for treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention. In some embodiments, the method relates to the treatment of cancer, such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharynx, bladder, gastric, stomach, pancreas, bladder, breast, cervix, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g., lymphoma, Kaposi's sarcoma), or virus-induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0136] The present invention also relates to a method of treating a disease associated with angiogenesis or neovascularization in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention. In some embodiments, the method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid carcinoma.

[0137] Patients who can be treated with the compounds of the invention according to the methods of the invention include, for example, those suffering from psoriasis; restenosis; atherosclerosis; BPH; breast cancer, e.g., ductal carcinoma arising in the ductal tissue of the mammary gland, medullary carcinoma, colloid carcinoma, tubular carcinoma, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors, e.g., adenocarcinoma of the ovary and adenocarcinoma that has spread from the ovary to the peritoneal cavity; uterine cancer; cervical cancer, e.g., adenocarcinoma of the cervical epithelium, including squamous cell carcinoma and adenocarcinoma; prostate cancer, e.g., prostate cancer selected from the following: adenocarcinoma or adenocarcinoma that has spread to the bone; pancreatic cancer. bladder cancers, such as transitional cell carcinoma in the bladder, urothelial carcinoma (transitional cell carcinoma), tumors of the urothelial cells lining the bladder, squamous cell carcinoma, adenocarcinoma, and small cell carcinoma; leukemias, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), M), and myelodysplastic syndromes (MDS); bone cancer; lung cancer, such as non-small cell lung cancer (NSCLC), which is classified as squamous cell carcinoma, adenocarcinoma, and undifferentiated large cell carcinoma, and small cell lung cancer; skin cancer, such as basal cell carcinoma, melanoma, squamous cell carcinoma, and actinic keratosis, a skin condition that can progress to squamous cell carcinoma; ocular retinoblastoma; cutaneous melanoma or intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer, such as papillary carcinoma, follicular carcinoma, medullary carcinoma, and undifferentiated carcinoma; AIDS-related lymphoma, such as diffuse large B-cell lymphoma , B-cell immunoblastic lymphoma, and small non-divided cell lymphoma; Kaposi's sarcoma; virally induced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus type 1 (HTLV-I) and adult T-cell leukemia / lymphoma; and human papillomavirus (HPV) and cervical cancer; central nervous system cancers (CNS), such as primary brain tumors including glioma (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), oligodendroglioma, ependymoma, meningioma, lymphoma, schwannoma, and medulloblastoma;Included are patients diagnosed with peripheral nervous system (PNS) cancers, such as acoustic neuroma and malignant peripheral nerve sheath tumors (MPNSTs), including neurofibromas and schwannomas, malignant fibrous cell tumors, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Mullerian tumors; oral cavity and oropharyngeal cancers, such as hypopharyngeal carcinoma, laryngeal carcinoma, nasopharyngeal carcinoma, and oropharyngeal carcinoma; gastric cancers, such as lymphoma, gastric stromal tumor, and carcinoid tumor; testicular tumors, such as germ cell tumors (GCTs), including seminomas and non-seminomas, and gonadal stromal tumors, including Leydig cell tumors and Sertoli cell tumors; thymic cancers, such as thymoma, thymic carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma carcinoid, or carcinoid tumor; rectal cancer; and colon cancer.

[0138] In another aspect of the present invention, there is provided a method for treating an ocular disease by administering to the eye of a subject one or more of the compounds or pharmaceutical compositions described herein.

[0139] The present invention further provides methods for inhibiting PARP enzyme activity by contacting PARP with a compound of the present invention in an amount sufficient to inhibit the activity of the PARP enzyme. In some embodiments, the present invention provides methods for inhibiting PARP enzyme activity by contacting a PARP enzyme with a compound of the present invention in an amount sufficient to inhibit the activity of the PARP enzyme. In some embodiments, the present invention provides methods for inhibiting PARP enzyme activity. Such inhibition can occur in solution, in cells expressing one or more PARP enzymes, in tissues containing cells expressing PARP, or in organisms expressing PARP. In some embodiments, the present invention provides methods for inhibiting PARP activity in an animal (including a mammal, such as a human) by contacting the animal with a compound of the present invention in an amount sufficient to inhibit the activity of the PARP enzyme in the animal.

[0140] The following general methodologies described herein provide methods and processes for making and using the compounds of the present invention and are exemplary rather than limiting. Further modifications of the provided methodologies and even new methods may be devised to achieve and accomplish the objectives of the present invention. It is therefore to be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined by the specification herein.

[0141] General Preparation Method The compounds of the present invention can be prepared by the following process: Unless otherwise indicated, the variables (e.g., X, Y, Z, G, R) when used in the formulas below are a , R b , R c , R d , R e , R f , R 1 , R 2 , R 3 and R 4 ) shall be understood to represent those groups described above with respect to compounds of formula (I), (IA) and (IB). These methods can be applied equally to other compounds of formula as provided herein above, with or without modification.

[0142] [ka]

[0143] The aldehyde compound of formula (1) can be protected with a protecting group (PG), such as by reaction with 1,2-ethanediol, to give acetal (2). Compounds of formula (3) (GH) can be N-arylated with acetal (2) using Buchwald-type reaction conditions to give compounds of formula (4). The acetal of formula (4) can be deprotected with a suitable acid, such as hydrochloric acid, to give aldehydes of formula (5). The aldehyde of formula (5) can be reacted with a Wittig salt of formula (6) to give olefins of formula (7). The olefin of formula (7) can be reacted with hydrazine hydrate to form compounds of formula (I). Compounds of formula (6) can be prepared by brominating compound (Int-1) with, for example, N-bromosuccinimide to form compound (Int-2), which can then be reacted with triphenylphosphine. Compounds of formula (I) can be converted into salts by methods known in the art, which are illustrated below as Scheme 1A, Scheme 1 and Scheme 2.

[0144] [ka]

[0145] In Scheme 1A, an aldehyde compound of formula (1), where X, Y, and Z are independently selected from CH or N, can be protected, such as by reaction with 1,2-ethanediol, to provide an acetal (2). e is selected from hydrogen, methyl, ethyl, or trifluoromethyl; R f is selected from hydroxy, acetyloxy, or methoxy; R 1 ~R 4 A compound of formula (4a) can be N-arylated with acetal (2) using Buchwald-type reaction conditions to give a compound of formula (4a). The acetal of formula (4a) can be deprotected using a suitable acid, such as hydrochloric acid, to give an aldehyde of formula (5a). The aldehyde of formula (5a) can be converted to a compound of formula (6), where R a , Rb , R c and R d is independently selected from hydrogen or a halogen to provide an olefin of formula (7a). The olefin of formula (7a) can be reacted with hydrazine hydrate to form a compound of formula (I).

[0146] Similarly, a compound of formula (b), (c), (d) or (e) can be substituted for a compound of formula (a) in Scheme 1A to prepare a compound of formula (I), as depicted in Scheme 1 below.

[0147] [ka]

[0148] Similar methodologies, with certain modifications known to those skilled in the art, can be used to synthesize compounds of formula (I) using appropriate intermediates and reagents, where all variables are understood to represent the groups described above.

[0149] Yet another method for preparing compounds of formula (I) is provided below as Scheme 2.

[0150] [ka]

[0151] A compound of formula (1) can be reacted with a Wittig salt of formula (6) to give an olefin of formula (8). The olefin of formula (8) can be reacted with hydrazine hydrate to form a compound of formula (9), which can then undergo N-arylation with a compound of formula (3) using Buchwald-type reaction conditions to give a compound of formula (I). The compound of formula (I) can be converted to a salt by methods known in the art.

[0152] Experimental data General procedure for Buchwald coupling reaction - 1: Aryl halide (1 equiv.), oxindole (2-hydroxyindole) and related derivatives or NH-containing heterocycles (1 equiv.), trans-4-hydroxy-L-proline (0.4 equiv.), and potassium carbonate (1 equiv.) were dissolved in DMSO (6 volumes) and degassed with nitrogen for 15 minutes. Copper(I) iodide (0.2 equiv.) was added to the above mixture, and the mixture was degassed again for 15 minutes. After degassing, the reaction mixture was heated to 130 °C and stirred at the same temperature for 4 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with MeOH:DCM (1:9) to obtain the crude product. The crude product was purified by column chromatography to obtain the N-arylated product.

[0153] General procedure-2 for Wittig reaction: An aldehyde (1 equivalent) and a Wittig salt (1 equivalent) were dissolved in dichloromethane (100 volumes). To this mixture, triethylamine (2 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with water and the organic layer was separated. Evaporation of the organic layer on a rotary evaporator provided the olefin, which was used in the next step without further purification.

[0154] General procedure-3 for phthalazinone formation: Olefin (1 equiv.) and hydrazine hydrate (1.2 equiv.) were dissolved in THF (15 vol.). The mixture was stirred at room temperature for 1 h. After 1 h, acetic acid (0.5 equiv.) was added and the reaction mixture was refluxed at 80 °C. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with a mixture of MeOH and DCM (1:9). The organic layer was dried over anhydrous Na2SO4 and distilled to obtain the crude product. The crude product was purified by CombiFlash or column chromatography using an appropriate mixture of MeOH and DCM.

[0155] General Procedure-4 for Chiral Separation of Racemic Intermediates and Examples: Chiral intermediates and examples obtained synthetically in racemic form can be separated into pure enantiomers by using the following preparative chiral separation by appropriate HPLC methods. Using the following method, Examples 2, 3, 7, 8, 11, 12, 14, 15, 19, 20, 22 and 23 can be resolved into pure enantiomers.

[0156] [Table 2-1]

[0157] [Table 2-2]

[0158] Intermediate 1: 2-(4-fluoro-3-iodophenyl)-1,3-dioxolane: 4-Fluoro-3-iodobenzaldehyde (5 g, 19.99 mmol) was suspended in toluene (22 mL). To this mixture, camphorsulfonic acid (23 mg, 0.1 mmol) and ethylene glycol (1.61 mL, 29.99 mmol) were added, and the mixture was refluxed for 4 hours under a Dean-Stark condenser. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous Na2SO4. The organic layer was evaporated under vacuum to give the title compound (5.88 g) as a brown liquid. 1 H-NMR (δ ppm, CDCl3, 400MHz): 7.88 (d, J4.2, 1H), 7.42 (t, J6, 1H), 7.05 (t, J8.1, 1H), 5.74 (s, 1H), 4.17-3.98 (m, 4H).

[0159] Intermediate 2: 3-Bromoisobenzofuran-1(3H)-one: Phthalide (100 g, 0.745 mol) was suspended in carbon tetrachloride (500 mL), and N-bromosuccinimide (146 g, 0.82 mol) was added to the mixture. The reaction mixture was heated to 85° C., and azobisisobutyronitrile (AIBN) (6.12 g, 37.2 mmol) was added to the reaction mixture in lots (10 lots). After 4 hours, the reaction mixture was cooled to room temperature. The reaction mixture was quenched with water, and the organic layer was separated. The aqueous layer was extracted with DCM, and the combined organic layer was dried over anhydrous Na2SO4. The organic layer was evaporated on a rotary evaporator to give a crude solid. The crude solid was suspended in petroleum ether (300 mL) and stirred for 15 minutes to give a solid. The solid was filtered and washed with petroleum ether (100 mL). The solid was dried under vacuum for 1 hour to give the title compound (145 g) as a brown solid. Yield: 91.39%. 1 H-NMR (δ ppm, CDCl3, 400MHz): 7.94 (d, J8, 1H), 7.79 (t, J7.6, 1H), 7.64 (d, J7.6, 2H), 7.40 (s, 1H).

[0160] Intermediate 3: (3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosphonium bromide: Intermediate 2 (50 g, 0.234 mol) was suspended in acetonitrile (180 mL) and triphenylphosphine (61.54 g, 0.234 mol) was added. The mixture was heated to 90° C. and stirred for 2.5 hours. The reaction mixture was cooled to room temperature to obtain a solid. The solid was filtered and washed with diethyl ether (125 mL). The solid was dried under vacuum for 30 minutes to obtain the title compound as a white solid (94 g). Yield: 84%. 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):8.61(s,1H),8.00-7.93(m,3H),7.86-7.70(m,15H),6.95(d,J7.6,1H).

[0161] Intermediate 4: 3-bromo-5-(1,3-dioxolan-2-yl)pyridine: 5-Bromonicotinaldehyde (35 g, 0.19 mol) was suspended in toluene (500 mL), and camphorsulfonic acid (350 mg, 0.15 mmol) and ethylene glycol (15.23 mL, 0.28 mol) were added. The mixture was refluxed under a Dean-Stark condenser for 4 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous Na2SO4. The organic layer was evaporated under vacuum to give the title compound (5.88 g) as a brown liquid. Yield: 100%. 1 H-NMR (δ ppm, CDCl3, 400MHz): 7.88 (d, J4.2, 1H), 7.42 (t, J6, 1H), 7.05 (t, J8.1, 1H), 5.74 (s, 1H), 4.17-3.98 (m, 4H).

[0162] Intermediate 5: 3-hydroxy-3-methylindolin-2-one: Isatin (3 g, 20.39 mmol) was dissolved in THF (50 mL) under a nitrogen atmosphere and cooled to -10 °C. 3 M methylmagnesium chloride in THF (20.39 mL, 61.1 mmol) was added dropwise to the above mixture, and the reaction mixture was stirred at -10 °C for 2 h. After 2 h, the reaction mixture was quenched with aqueous ammonium chloride solution and extracted with MeOH and DCM (1:9) (3 × 150 mL). The combined organic layers were washed with water (100 mL) and dried over anhydrous NaSO. The organic layer was distilled to give the crude product. The crude product was suspended in diethyl ether (50 mL) and stirred for 15 min to give a solid. The solid was filtered and washed with diethyl ether (10 mL). The solid was dried under vacuum for 30 min to give the title compound (2.35 g) as a yellow solid. Yield: 71%. 1 H-NMR (δ ppm, DMSO-d 6,400 MHz): 10.18 (s, 1H), 7.26 (d, J7.6, 1H), 7.17 (t, J7.6, 1H), 6.94 (t, J7.6, 1H), 6.78 (d, J7.6, 1H), 5.82 (s, 1H), 1.33 (s, 3H). MS (m / z): 162.2 ([MH]-). Racemic 3-hydroxy-3-methylindolin-2-one can be separated into the (+) and (-) enantiomers according to one of the preparation methods described in General Procedure 4 and used as needed.

[0163] (R)-(+)-3-hydroxy-3-methylindolin-2-one: 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):10.19(s,1H),7.26(d,J7.6,1H),7.17(t,J7.6,1H),6.94(t,J7.6,1H),6.78(d,J7.6,1H),5.82(s,1H),1.33(s,3H). [α] D 25 :+45.90° (MeOH;c 1.0)

[0164] (S)-(-)-3-hydroxy-3-methylindolin-2-one: 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):10.19(s,1H),7.26(d,J7.6,1H),7.17(t,J7.6,1H),6.94(t,J7.6,1H),6.78(d,J7.6,1H),5.83(s,1H),1.33(s,3H). [α] D 25 :-45.94° (MeOH;c 1.0).

[0165] Intermediate 6: 1-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized from Intermediate 1 (1.63 g, 5.54 mmol) and Intermediate 5 (0.9 g, 5.54 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (2.1:97.9) as eluents. The combined pure fractions from Combiflash were distilled to give the title compound (740 mg) as a brown gel. Yield: 40.88%. 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):7.66-7.58(m,1.5H),7.56-7.41(m,2.5H)7.28-7.21(m,1H),7.16-7.08(m,1H),6.55(t,J8.2,1H) 6.28(s,0.45H),6.16(s,0.55H)5.81(s,0.55H),5.78(s,0.45H),4.10-4.03(m,2H),3.98-3.93(m,2H),1.53(s,1.35H),1.49(s,1.65H).

[0166] Intermediate 7: 4-fluoro-3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzaldehyde: Intermediate 6 (700 mg, 2.13 mmol) was dissolved in THF (10 mL) and 6N hydrochloric acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mass was cooled to 0°C and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give the title compound (605 mg) as a brown gel. Yield: 100%. 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):10.04(s,0.55H),10.01(s,0.45H),8.19-8.02(m,2H),7.74(t,J9.5,1H),7.50-7.43(m,1H),7.30-7.22 (m,1H),7.18-7.10(m,1H),6.70-6.62(m,1H),6.32(s,0.45H),6.21(s,0.55H),1.55(s,1.35H),1.50(s,1.65H).

[0167] Intermediate 8: 1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenyl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized as a pale yellow gel (840 mg) from Intermediate 7 (600 mg, 2.1 mmol) and Intermediate 3 (1.79 g, 3.8 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0168] Intermediate 9: 1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized from Intermediate 4 (2 g, 8.68 mmol) and Intermediate 5 (1.4 g, 8.68 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (3.1:96.9) as eluents. The combined pure fractions from Combiflash were distilled to give the title compound (865 mg) as a pale yellow gel. Yield: 31.9%. 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):8.71(bs,2H),7.92(s,1H),7.46(d,J7.3,1H),7.27(t,J7.6,1H),7.13(t,J7.4,1H),6 .75(d,J7.8,1H),6.15(s,1H),5.93(s,1H),4.15-4.09(m,2H),4.02-3.95(m,2H),1.52(s,3H). MS(m / z):312.8([M+H] + ).

[0169] Intermediate 10: 5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)nicotinaldehyde: Intermediate 9 (850 mg, 2.72 mmol) was dissolved in THF (10 mL) and concentrated hydrochloric acid (2.5 mL) was added. The mixture was refluxed at 70° C. for 1 h. After 1 h, the reaction mixture was cooled to 0° C. and the pH of the reaction mixture was adjusted to about 7 with saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (2×100 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give the title compound (729 mg) as a pale yellow gel. Yield: 100%. 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):10.18(s,1H),9.13(d,J1.2,1H),8.96(d,J2.4,1H),8.34(t,J2,1H),7.48(d,J7. 2,1H),7.28(td,J8,1.2,1H),7.16(t,J7.2,1H),6.89(d,J8,1H),6.19(s,1H),1.53(s,3H). MS(m / z):268.8([M+H] + ).

[0170] Intermediate 11: 3-hydroxy-3-methyl-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-2-one: Following general procedure 2, the title compound was synthesized from Intermediate 10 (720 mg, 2.7 mmol) and Intermediate 3 (2.29 g, 4.8 mmol) as a yellow gel (1.03 g). Yield: 100%. MS (m / z): 384.8 ([M+H] + ).

[0171] Intermediate 12: 2-bromo-4-(1,3-dioxolan-2-yl)pyridine: 2-Bromoisonicotinaldehyde (5 g, 26.9 mmol) was suspended in toluene (40 mL). Camphorsulfonic acid (20 mg, 0.09 mmol) and ethylene glycol (2.25 mL, 0.28 mol) were added to the mixture, and the mixture was refluxed for 15 hours under a Dean-Stark condenser. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous Na2SO4 and distilled to give the title compound (6 g) as a brown liquid. Yield: 97% 1 H-NMR (δ ppm, CDCl3, 400MHz): 8.39 (d, J4.9, 1H), 7.60 (s, 1H), 7.35 (d, J4.9, 1H), 5.80 (s, 1H), 4.06 (s, 4H).

[0172] Intermediate 13: 1-(4-(1,3-dioxolan-2-yl)pyridin-2-yl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized from Intermediate 12 (4.3 g, 18.69 mmol) and Intermediate 5 (3 g, 18.69 mmol) according to general procedure 1. The crude product obtained after workup was used in the next step without further purification (900 mg). Yield: 17%. The compound was carried forward without any characterization.

[0173] Intermediate 14: 2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)isonicotinaldehyde: Intermediate 13 (900 mg, 2.88 mmol) was dissolved in THF (10 mL) and concentrated hydrochloric acid (0.9 mL) was added. The mixture was refluxed at 80° C. for 1 h. After 1 h, the reaction mass was cooled to 0° C. and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (2×100 mL). The organic layer was dried over anhydrous NaSO and evaporated on a rotary evaporator to give the title compound (700 mg) as a pale yellow gel. Yield: 100%. The compound was carried forward without any characterization.

[0174] Intermediate 15: 3-hydroxy-3-methyl-1-(4-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-2-yl)indolin-2-one: The title compound was synthesized as a yellow gel (500 mg) from Intermediate 14 (350 mg, 1.30 mmol) and Intermediate 3 (1.1 g, 2.35 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0175] Intermediate 16: 3-ethyl-3-hydroxyindolin-2-one: This compound was prepared as follows: Magnesium turnings (2.48 g, 0.101 mol) and iodine (2 mg) were placed in diethyl ether (50 mL) under a nitrogen atmosphere. To this mixture was added bromoethane (7.57 mL, 0.101 mol) dropwise over 20 minutes, and the reaction mixture was stirred at room temperature for 2 hours to give ethylmagnesium bromide.

[0176] Isatin (5 g, 0.033 mol) was dissolved in THF (50 mL) under a nitrogen atmosphere and cooled to -15 °C. Ethyl magnesium bromide in diethyl ether from the above reaction was added dropwise to the reaction mixture at -15 °C and stirred at the same temperature for 2 h. After 2 h, the reaction mixture was quenched with aqueous ammonium chloride solution (200 mL) and extracted with MeOH and DCM (1:9) (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO and distilled to obtain the crude product. The crude product was purified by Combiflash using MeOH and DCM (3:97) as the eluent. The pure fractions from Combiflash were distilled to give the title compound (1.24 g) as a brown solid. Yield: 21%. 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):10.19(s,1H),7.22(d,J7.31,1H),7.18(t,J7.7,1H),6.95(t,J 7.4,1H),6.78(d,J7.7,1H),5.79(s,1H),1.75(m,2H),0.59(t,J7.4,3H). MS(m / z):176.1([MH]-).

[0177] Intermediate 17: 1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-ethyl-3-hydroxyindolin-2-one: The title compound was synthesized from Intermediate 4 (1.43 g, 6.2 mmol) and Intermediate 16 (1.1 g, 6.2 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (2.5:97.5) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound (800 mg) as a pale yellow gel. Yield: 39%. 1 H-NMR (δ ppm, DMSO-d 6, 400MHz):8.71(s,1H),8.67(s,1H),7.88(d,J1.9,1H),7.429d,J7.3,1H),7.28(td,J7.1,1,1H),7.15(t,J7.4,1H),6. 76(d,J7.8,1H),6.15(s,1H),5.93(s,1H),4.12-4.06(m,2H),4.01-3.96(m,2H),1.97-1.88(m,2H),0.72(t,J7.4,3H).

[0178] Intermediate 18: 5-(3-ethyl-3-hydroxy-2-oxoindolin-1-yl)nicotinaldehyde: Intermediate 17 (800 mg, 2.45 mmol) was dissolved in THF (20 mL) and concentrated hydrochloric acid (2 mL) was added. The mixture was refluxed at 80° C. for 2 hours. After 2 hours, the reaction mass was cooled to 0° C. and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (3×50 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give the title compound (700 mg) as a brown liquid. Yield: 100%. The compound was carried forward without any characterization.

[0179] Intermediate 19: 3-ethyl-3-hydroxy-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-2-one: The title compound was synthesized as a pale yellow gel (987 mg) from Intermediate 18 (700 mg, 2.48 mmol) and Intermediate 3 (2.12 g, 4.46 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0180] Intermediate 20: (2-bromo-4-fluorophenyl)methanol: This compound was prepared as follows: 2-Bromo-4-fluorobenzaldehyde (12 g, 59.11 mmol) was suspended in MeOH (120 mL) and cooled to 0° C. Sodium borohydride (4.47 g, 118.2 mmol) was added in lots to the above mixture and stirred at 0° C. for 1 hour. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (150 mL). The reaction mixture was evaporated to remove MeOH, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined ethyl acetate layers were dried over anhydrous NaSO and evaporated to give the title compound as an off-white solid (11.6 g). Yield: 95.71% 1 H-NMR (δppm, CDCl3,400MHz):7.46(dd,J8.4,6.1,1H),7.31(dd,J8.2,2.5,1H),7.05(dd,J8.3,5.9,1H),4.72(d,J5.1,2H),1.96(t,J5.7,1H).

[0181] Intermediate 21: 6-Fluoroisobenzofuran-1(3H)-one: This compound was prepared as follows: Intermediate 20 (11.5 g, 56.1 mmol) was dissolved in DMF (50 mL) under a nitrogen atmosphere. To this was added copper cyanide (10.04 g, 112.2 mmol), and the reaction mixture was heated to 180° C. for 2.5 hours. After 2.5 hours, the reaction mixture was cooled to 100° C., and water was added to the reaction mixture. The reaction was continued at 100° C. for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (250 mL). The reaction mixture was filtered through a plug of Celite, and the Celite bed was washed with ethyl acetate (100 mL). The combined ethyl acetate filtrate was washed with water (200 mL), brine solution (200 mL), and saturated aqueous lithium chloride solution (200 mL). The organic layer was dried over anhydrous NaSO and evaporated to give the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (16:84) as the eluent. The combined pure fractions from the column were evaporated to give the title compound as a brown solid (3 g). Yield: 36%. 1 H-NMR (δ ppm, CDCl 3, 400MHz):7.59(dd,J7.2,2,1H),7.48(dd,J8.3,4.3,1H),7.41(td,J8.5,2.2,1H),5.31(s,2H).

[0182] Intermediate 22: 3-Bromo-6-fluoroisobenzofuran-1(3H)-one: Intermediate 21 (1.5 g, 9.86 mmol) was suspended in carbon tetrachloride (20 mL) and N-bromosuccinimide (1.93 g, 10.84 mmol) was added. The reaction mixture was heated to 85° C., and azobisisobutyronitrile AIBN (80 mg, 0.49 mmol) was added to the reaction mixture in lots (2 lots). After 4 hours, the reaction mixture was cooled to room temperature. The reaction mixture was quenched with water, and the organic layer was separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried over anhydrous NaSO. The organic layer was evaporated to give the title compound (2.27 g) as a brown gel. Yield: 100%. 1H-NMR (δ ppm, CDCl3, 400MHz): 7.62 (dd, J8.4, 4.2, 1H), 7.57 (dd, J6.8, 2.2, 1H), 7.50 (td, J8.5, 2.3, 1H), 7.83 (s, 1H).

[0183] Intermediate 23: (5-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosphonium bromide: Intermediate 22 (5 g, 21.6 mmol) was suspended in acetonitrile (20 mL), and triphenylphosphine (5.67 g, 21.6 mmol) was added. The mixture was heated to 90° C. and stirred at the same temperature for 2.5 hours. The reaction mixture was cooled to room temperature to obtain a solid. The solid was filtered and washed with diethyl ether (20 mL). The solid was dried under vacuum for 1 hour to obtain the crude product (8.2 g). The crude compound was mixed with ethanol (25 mL) and refluxed at 90° C. for 1 hour. After 1 hour, the heterogeneous mixture was stirred at room temperature for 15 hours. The solid was filtered and washed with ethanol (5 mL). The solid was dried under vacuum to obtain the title compound (6 g) as an off-white solid. Yield: 56%. 1 H-NMR (δppm, DMSO-d6, 400MHz): 8.75 (s, 1H), 8.02-7.94 (m, 3H), 7.84-7.67 (m, 14H), 7.00-6.94 (m, 1H).

[0184] Intermediate 24: 3-hydroxy-3-methyl-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-2-one: The title compound was synthesized as a pale yellow gel (674 mg) from Intermediate 10 (450 mg, 1.68 mmol) and Intermediate 23 (1.48 g, 3.01 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0185] Intermediate 25: 5-Fluoroisobenzofuran-1(3H)-one: This compound was prepared as follows: (2-Bromo-5-fluorophenyl)methanol (10 g, 48.8 mmol) was dissolved in DMF (50 mL) under a nitrogen atmosphere. To this was added copper cyanide (8.74 g, 97.54 mmol), and the reaction mixture was heated to 180° C. for 3 hours. After 3 hours, the reaction mixture was cooled to 100° C., and water was added to the reaction mixture. The reaction was continued at 100° C. for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (250 mL). The reaction mixture was filtered through a plug of Celite, and the Celite bed was washed with ethyl acetate (100 mL). The combined ethyl acetate filtrate was washed with water (200 mL), brine solution (200 mL), and saturated aqueous lithium chloride solution (200 mL). The organic layer was dried over anhydrous NaSO and evaporated to give the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (16:84) as the eluent. The combined pure fractions from the Combiflash were evaporated to give the title compound as a brown solid (4.2 g). Yield: 57%. 1 H-NMR (δ ppm, CDCl3, 400MHz): 7.93 (dd, J8.5, 5, 1H), 7.24 (td, J8.4, 1.8, 1H), 7.18 (dd, J7.8, 1.4, 1H), 5.30 (s, 2H).

[0186] Intermediate 26: 3-Bromo-5-fluoroisobenzofuran-1(3H)-one: Intermediate 25 (3 g, 19.72 mmol) was suspended in carbon tetrachloride (40 mL) and N-bromosuccinimide (3.86 g, 21.69 mmol) was added. The reaction mixture was heated to 85° C., and azobisisobutyronitrile AIBN (161 mg, 0.98 mmol) was added to the reaction mixture in batches (3 batches). After 4 hours, the reaction mixture was cooled to room temperature. The reaction mixture was quenched with water, and the organic layer was separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried over anhydrous NaSO. The organic layer was evaporated on a rotary evaporator to give the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (11:89) as the eluent. The combined pure fractions from Combiflash were distilled to give the title compound (3.96 g) as a brown liquid. Yield: 87%. 1 H-NMR (δ ppm, CDCl3, 400MHz): 7.94 (dd, J8.3, 4.7, 1H), 7.38-7.29 (m, 3H).

[0187] Intermediate 27: (6-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosphonium bromide: Intermediate 26 (3.46 g, 14.98 mmol) was suspended in acetonitrile (10 mL), and triphenylphosphine (3.92 g, 14.98 mmol) was added. The mixture was heated to 90° C. and stirred at the same temperature for 2.5 hours. The reaction mixture was cooled to room temperature to give a solid. The solid was filtered and washed with diethyl ether (50 mL). The solid was dried under vacuum for 1 hour to give the crude product (6.2 g). The crude compound was suspended in ethanol (30 mL) and refluxed at 90° C. for 1 hour. After 1 hour, the heterogeneous mixture was stirred at room temperature for 18 hours, filtered, and washed with ethanol (5 mL). The solid was dried under vacuum to give the title compound (2.7 g) as an off-white solid. Yield: 37%. 1 H-NMR (δ ppm, DMSO-d6, 400MHz): 8.58 (s, 1H), 8.02-7.90 (m, 4H), 7.77-7.65 (m, 12H), 7.61 (t, J8.8, 1H), 6.65 (d, J7.9, 1H).

[0188] Intermediate 28: 1-(5-((6-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized as a pale yellow gel (674 mg) from Intermediate 10 (450 mg, 1.68 mmol) and Intermediate 27 (1.48 g, 3.01 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0189] Intermediate 29: 5-Fluoro-3-hydroxy-3-methylindolin-2-one: 5-Fluoroisatin (10 g, 60.56 mmol) was suspended in THF (150 mL) under a nitrogen atmosphere and cooled to -10 °C. 3 M methylmagnesium chloride in THF (60.56 mL, 181.69 mmol) was added dropwise to the above mixture, and the reaction mixture was stirred at -10 °C for 3 hours. After 3 hours, the reaction mixture was quenched with aqueous ammonium chloride (250 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with water (300 mL) and dried over anhydrous NaSO. The organic layers were distilled to give the crude product (10 g). The crude product was suspended in diethyl ether (50 mL) and stirred for 15 minutes to give a solid. The solid was filtered and washed with diethyl ether (2 × 25 mL). The solid was dried under vacuum for 30 minutes to give the title compound (8 g) as a brown solid. Yield: 72%. 1 H-NMR (δ ppm, DMSO-d6, 400MHz): 10.22 (s, 1H), 7.15 (dd, J8.1, 2.6, 1H), 7.04-6.98 (m, 1H), 6.78 (dd, J8.4, 4.3, 1H), 5.95 (s, 1H), 1.34 (s, 3H).

[0190] Intermediate 30: 1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-5-fluoro-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized from Intermediate 4 (1.5 g, 6.51 mmol) and Intermediate 29 (1.18 g, 6.51 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (2.5:97.5) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound as a pale yellow solid (650 mg). Yield: 30%. 1 H-NMR(δ ppm,DMSO-d6,400MHz):8.76(bs,2H),7.92(s,1H),7.38(dd,J7.9,2.5,1H),7.10(td,J9.2,2.5,1H),6 .77(dd,J8.6,4.1,1H),6.27,(s,1H),5.93(s,1H),4.12-4.05(m,2H),4.01-3.95(m,2H),1.53(s,3H).

[0191] Intermediate 31: 5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)nicotinaldehyde: Intermediate 30 (650 mg, 1.97 mmol) was dissolved in THF (20 mL) and concentrated hydrochloric acid (2 ml) was added. The mixture was refluxed at 80° C. for 2.5 hours. After 2.5 hours, the reaction mass was cooled to room temperature and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (3×50 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give the title compound (700 mg) as a brown liquid. Yield: 100%. The compound was carried forward without any characterization.

[0192] Intermediate 32: 5-fluoro-3-hydroxy-3-methyl-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-2-one: The title compound was synthesized as a pale yellow gel (351 mg) from Intermediate 31 (250 mg, 0.87 mmol) and Intermediate 3 (746 mg, 1.57 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0193] Intermediate 33: 5-fluoro-1-(5-((5-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized as a pale yellow gel (366 mg) from Intermediate 31 (250 mg, 0.87 mmol) and Intermediate 23 (0.77 g, 1.57 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0194] Intermediate 34: 6-Fluoro-3-hydroxy-3-methylindolin-2-one: 6-Fluoroisatin (5 g, 30.28 mmol) was suspended in THF (75 mL) under a nitrogen atmosphere and cooled to -10 °C. 3 M methylmagnesium chloride in THF (60.56 mL, 181.69 mmol) was added dropwise to the above mixture, and the reaction mixture was stirred at -10 °C for 2 hours. After 2 hours, the reaction mixture was quenched with aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO, and the organic layer was distilled to give the crude product (6.2 g). The crude product was suspended in diethyl ether (100 mL) and stirred for 15 minutes to give a solid. The solid was filtered and washed with diethyl ether (50 mL). The solid was dried under vacuum for 3 hours to give the title compound (4 g) as a brown solid. Yield: 73%. 1 H-NMR (δ ppm, DMSO-d6,400MHz): 10.34(s,1H),7.28(dd,J8.1,5.7,1H),6.73(td,J8.2,2.4,1H),6.60(dd,J9.3,2.3,1H),5.87(s,1H),1.33(s,3H).

[0195] Intermediate 35: 1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-6-fluoro-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized from Intermediate 4 (1.5 g, 6.51 mmol) and Intermediate 34 (1.18 g, 6.51 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (2.5:97.5) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound as a pale yellow solid (650 mg). Yield: 30%. 1 H-NMR(δ ppm,DMSO-d6,400MHz):8.72(s,1H),8.69(s,1H),7.92(s,1H),7.48(dd,J8.2,5.6,1H),6,94(td,J8.4,2.2 ,1H),6.63(dd,J9.4,2.2,1H),6.18(s,1H),5.94(s,1H),4.11-4.05(m,2H),4.01-3.95(m,2H),1.52(s,3H).

[0196] Intermediate 36: 5-(6-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)nicotinaldehyde: Intermediate 35 (730 mg, 2.21 mmol) was dissolved in THF (20 mL) and concentrated hydrochloric acid (3.5 mL) was added. The mixture was refluxed at 80° C. for 3 hours. After 3 hours, the reaction mixture was cooled to 0° C., and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (2×200 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give the title compound (632 mg) as a brown liquid. Yield: 100%. The compound was carried forward without any characterization.

[0197] Intermediate 37: 6-Fluoro-3-hydroxy-3-methyl-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-2-one: The title compound was synthesized as a yellow solid (420 mg) from Intermediate 36 (300 mg, 1.04 mmol) and Intermediate 3 (895 mg, 1.88 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0198] Intermediate 38: 6-fluoro-1-(5-((5-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized as a yellow gel (440 mg) from Intermediate 36 (300 mg, 1.04 mmol) and Intermediate 23 (929 mg, 1.88 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0199] Intermediate 39: 1-(4-((5-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-2-yl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized as a dark brown gel (800 mg) from Intermediate 14 (350 mg, 1.30 mmol) and Intermediate 23 (1.15 g, 1.8 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0200] Intermediate 40: 1-(4-(1,3-dioxolan-2-yl)pyridin-2-yl)-5-fluoro-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized from Intermediate 12 (2 g, 8.7 mmol) and Intermediate 29 (1.57 g, 8.7 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (5:95) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound as a brown solid (900 mg). Yield: 31%. 1 H-NMR(δ ppm,DMSO-d6,400MHz):8.61(d,J4.8,1H),7.81(s,1H),7.64(dd,J8.8,4.4,1H),7.42(dd,J5.2,1.2,1H), 7.35(dd,J8,2.8,1H),7.14(td,J9.2,2.8,1H),6.33(s,1H),5.89(s,1H),4.05-3.98(m,4H),1.51(s,3H).

[0201] Intermediate 41: 2-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)isonicotinaldehyde: Intermediate 40 (765 mg, 2.31 mmol) was dissolved in THF (8 mL) and concentrated hydrochloric acid (3 mL) was added. The mixture was refluxed at 80° C. for 3 hours. After 3 hours, the reaction mass was cooled to 0° C. and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (2×50 mL). The combined organic layers were dried over anhydrous NaSO and evaporated on a rotary evaporator to give the title compound (662 mg) as a brown liquid. Yield: 100%. The compound was carried forward without any characterization.

[0202] Intermediate 42: 5-fluoro-1-(4-((5-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-2-yl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized as a dark brown gel (930 mg) from Intermediate 41 (662 mg, 2.31 mmol) and Intermediate 23 (2.05 g, 4.16 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0203] Intermediate 43: 3-hydroxy-3-(trifluoromethyl)indolin-2-one: This compound was prepared following a reported procedure (Chen Zang et.al. Organic & Biomolecular Chemistry, 2013, 11, 5621-5633). Aniline (6 g, 64.4 mmol) and ethyl 3,3,3-trifluoro-2-oxopropanoate (13.1 g, 77.3 mmol) were placed in a microwave vial. 1,2-Dichlorobenzene (17.16 mL) was added to the vial and heated in a microwave oven at 150 °C for 20 minutes. The reaction mass was diluted with water (150 mL) and brine (150 mL). The aqueous layer was extracted with EtOAc to obtain the crude product. The crude product was purified by column chromatography to obtain the title compound as an off-white solid (4.9 g). Yield: 35%. 1 H-NMR (δ ppm, DMSO-d6, 400MHz): 10.80 (s, 1H), 7.59 (s, 1H), 7.42-7.33 (m, 2H), 7.05 (t, J7.6, 1H), 6.89 (d, J8, 1H). MS(m / z):216.21([MH] + ).

[0204] Intermediate 44: 1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-hydroxy-3-(trifluoromethyl)indolin-2-one: The title compound was synthesized from Intermediate 4 (2.64 g, 11.5 mmol) and Intermediate 43 (2.49 g, 11.5 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (2.4:97.6) as eluents. The combined pure fractions from Combiflash were distilled to give the title compound (700 mg) as a brown solid. Yield: 17%. 1 H-NMR(δ ppm,DMSO-d6,400MHz):8.77(s,1H),8.70(d,J16,1H),7.94(s,1H),7.91(s,1H),7.59(d,J7.2,1H),7. 45(t,J7.6,1H),7.25(t,J7.6,1H),6.85(d,J8,1H),5.95(s,1H),4.12-4.07(m,2H),4.04-3.95(m,2H). MS(m / z):367.34([M+H] +).

[0205] Intermediate 45: 5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)nicotinaldehyde: Intermediate 44 (680 mg, 1.9 mmol) was dissolved in a mixture of water (17 mL) and acetone (17 mL). Oxalic acid hydrate (2.34 g, 18.6 mmol) was added to the mixture and stirred at 70° C. for 16 hours. The acetone was evaporated from the reaction mixture and the mixture was basified with 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined DCM layers were distilled to obtain the crude product. The crude product was triturated with diethyl ether to obtain the title compound (490 mg) as a brown solid. Yield: 82%. 1 H-NMR(δ ppm,DMSO-d6,400MHz):10.19(s,1H),9.18(d,J1.7,1H),8.96(d,J2.4,1H),8.36(t,J2 ,1H),7.60(t,J7.5,1H),7.47(td,J7.8,1.1,1H),7.28(t,J7.5,1H),7.00(d,J7.9,1H). MS(m / z):323.0([M+H] + ).

[0206] Intermediate 46: 3-hydroxy-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)-3-(trifluoromethyl)indolin-2-one: The title compound was synthesized as a yellow solid (660 mg) from Intermediate 45 (490 mg, 1.5 mmol) and Intermediate 3 (800 mg, 1.7 mmol) following general procedure 2. MS (m / z): 437.36 ([MH]-).

[0207] Intermediate 47: 2-(3-iodophenyl)-1,3-dioxolane: 3-Iodobenzaldehyde (14.5 g, 62.5 mmol) was suspended in toluene (145 mL). To this mixture, p-toluenesulfonic acid monohydrate (594 mg, 3.12 mmol) and ethylene glycol (4.65 g, 75 mmol) were added and refluxed for 7 hours under a Dean-Stark condenser. After 7 hours, the reaction mixture was cooled to room temperature, diluted with toluene (29 mL), and washed with saturated aqueous sodium bicarbonate (75 mL). The organic layer was washed with water (2 × 75 mL) and dried over anhydrous Na2SO4. The organic layer was evaporated under vacuum to give the title compound (15 g) as a yellow liquid. Yield: 87%. 1 H-NMR(δ ppm, CDCl3,400MHz):7.86(d,J1.6,1H),7.73(dd,J7.6,1.2,1H),7.45(d,J7. 2,1H),7.14(td,J7.6,1H),5.78(s,1H),4.17-4.10(m,2H),4.08-4.01(m,2H). MS(m / z):276.98([M+H] + ).

[0208] Intermediate 48: 1-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized from Intermediate 47 (12 g, 52.39 mmol) and Intermediate 5 (8.55 g, 52.39 mmol) according to general procedure 1. The crude was purified by Combiflash using ethyl acetate and petroleum ether (1:1) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound as a black gel (7.8 g). Yield: 48%. 1 H-NMR(δ ppm,DMSO-d6,400MHz):7.59(t,J7.2,1H),7.51(d,J7.6,1H),7.48-7.40(m,3H),7.24(t,J7.2,1H),7.10(t ,J7.2,1H),6.68(d,J7.6,1H),6.11(s,1H),5.80(s,1H),4.09-4.03(m,2H),3.99-3.92(m,2H),1.49(s,3H).

[0209] Intermediate 49: 3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzaldehyde: Intermediate 48 (7.7 g, 25 mmol) was dissolved in a mixture of water (60 ml) and acetone (60 mL). Oxalic acid hydrate (8 g, 125 mmol) was added to the mixture and stirred at 55° C. for 3 hours. The reaction mixture was evaporated to remove acetone and basified with 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (3×100 mL), and the combined DCM layers were distilled to give the title compound (6 g) as a brown solid, which was used in the next step without further purification. Yield: 91%. 1 H-NMR(δppm,DMSO-d6,400MHz):10.07(s,1H),8.01-7.94(m,2H),7.85-7.75(m,2H),7.46(d, J6.8,1H),7.26(t,J7.2,1H),7.13(t,J7.2,1H),6.80(d,J7.6,1H),6.16(s,1H),1.52(s,3H).

[0210] Intermediate 50: 3-hydroxy-3-methyl-1-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenyl)indolin-2-one: The title compound was synthesized as a black gel (7.9 g) from Intermediate 49 (5.5 g, 20.6 mmol) and Intermediate 3 (10.8 g, 22.6 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0211] Intermediate 51: 1-(2-fluoro-5-((5-fluoro-3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenyl)-3-hydroxy-3-methylindolin-2-one: The title compound was synthesized as a black gel (3.1 g) from Intermediate 7 (2 g, 7 mmol) and Intermediate 23 (4 g, 8 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0212] Intermediate 52: 4-((5-(3-chloro-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: 4-((5-(3-Hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 1) (8 g, 20.1 mmol) and thionyl chloride (33.9 g, 285 mmol) were mixed at 0° C. and refluxed at 90° C. for 1 hour. Thionyl chloride was distilled off from the reaction mixture to give a solid. The solid was suspended in water and basified with aqueous sodium bicarbonate. The solid was filtered and washed with a mixture of EtOAc and diethyl ether (1:1) to give the title compound (7.7 g) as a white solid. Yield: 92%. 1 H-NMR(δ ppm,DMSO-d6,400MHz):12.58(s,1H),8.68(d,J1.2,1H),8.59(d,J3.2,1H),8.26(d,J7.2,1H),8.06(d,J8.4,1H),7.97-7.91(m,2 H),7.85(t,J7.2,1H),7.66(d,J6.4,1H),7.32(td,J8.0,1.2,1H),7.20(t,J7.2,1H),6.76(d,J7.6,1H)4.47(s,2H),1.96(s,3H). MS(m / z):417.29([M+H] + ).

[0213] Intermediate 53: tert-butyl pyridin-3-ylcarbamate: 3-Aminopyridine (45 g, 0.478 mol) was dissolved in 2-propanol (150 mL) and water (29 mL) and cooled to 0 °C. Boc anhydride (119 g, 0.545 mol) was dissolved in 2-propanol (75 mL) and added to the above mixture at 0 °C. The mixture was stirred at room temperature for 18 hours. After 18 hours, 2-propanol was distilled off from the reaction mixture to obtain a residue. Water (100 mL) was added to the residue, and the mixture was extracted with MTBE (2 × 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. The organic layers were distilled under vacuum to obtain a crude product. The crude product was purified by column chromatography using EtOAc and petroleum ether (3:7) as the eluent to yield the title compound (74 g) as a white solid. Yield: 80%. 1 H-NMR (δ ppm, DMSO-d6, 400MHz): 7.77 (s, 1H), 7.36 (d, J4, 1H), 7.17 (d, J7.6, 1H), 6.55 (dd, J7.6, 4, 1H), 0.74 (s, 9H). MS(m / z):194.93([M+H] + ).

[0214] Intermediate 54: Ethyl 2-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-oxoacetate: Intermediate 53 (17 g, 87.5 mmol) was dissolved in THF (400 mL). N,N,N,N-Tetramethylethylenediamine (25.33 g, 218 mmol) was added to this mixture and cooled to -78 °C. t-BuLi (14.02 g, 219 mmol) was added dropwise to the above mixture over 45 minutes. The reaction mixture was warmed to -10 to -20 °C and stirred for 2 hours. After 2 hours, the reaction mixture was cooled again to -60 °C, and diethyl oxalate (38.4 g, 262.6 mmol) was added. The reaction mixture was warmed to 0 °C and stirred at 0 °C for 3 hours. After 3 hours, the reaction mixture was quenched with aqueous NH4Cl at 0 °C. The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (200 mL) and dried over anhydrous Na2SO4. The organic layer was distilled under vacuum to give the crude product, which was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (2:8) as eluent to afford the title compound as a brown oil (25 g). Yield: 25%. 1 H-NMR(δppm,DMSO-d6,400MHz):10.34(s,1H),8.51(d,J2.4,1H),8.41(dd,J4.8,2. 4,1H),7.46(dd,J4.8,2.4,1H),4.24(q,J7.2,2H),1.41(s,9H),1.26(t,J7.2,3H).

[0215] Intermediate 55: 1H-pyrrolo[2,3-c]pyridine-2,3-dione: Intermediate 54 (1.7 g, 5.77 mmol) was heated to 180° C. under high vacuum for 7 minutes. After 7 minutes, the reaction mixture was cooled to room temperature. The reaction on the above scale was repeated six more times. The combined residues were purified by Combiflash using ethyl acetate as the eluent to give the title compound as a yellow solid (2.23 g). Yield: 37%. 1 H-NMR (δppm, DMSO-d6, 400MHz): 11.20 (s, 1H), 8.44 (t, J5.2, 1H), 8.33 (d, J5.2, 1H), 7.41 (t, J5.2, 1H). MS(m / z):147.20([MH] - ).

[0216] Intermediate 56: 3-hydroxy-3-methyl-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one: Intermediate 55 (2.1 g, 14 mmol) was dissolved in THF (5 mL) under nitrogen atmosphere and cooled to -5 °C. 3 M methylmagnesium chloride in THF (14 mL, 43 mmol) was added dropwise to the above mixture. The reaction mixture was stirred at 0-5 °C for 2 h. After 2 h, the reaction mixture was quenched with aqueous ammonium chloride (50 mL) and extracted with MeOH and DCM (1:9) (6 × 50 mL). The combined organic layers were dried over anhydrous NaSO. The organic layer was distilled to give the crude product. The crude product was purified by Combiflash using MeOH and DCM (8:92) as eluent to give the title compound (1.2 g) as a brown solid. Yield: 52%. 1 H-NMR (δppm, DMSO-d6, 400MHz): 10.45 (s, 1H), 8.30 (d, J4.8, 1H), 8.15 (d, J4.8, 1H), 7.36 (d, J4.8, 1H), 6.16 (s, 1H), 1.38 (s, 3H). MS(m / z):165.05([M+H] + ).

[0217] Intermediate 56: 1-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-3-methyl-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one: The title compound was synthesized from intermediate 47 (680 mg, 2.5 mmol) and intermediate 56 (400 mg, 2.5 mmol) according to general procedure 1. The crude was purified by combiflash using MeOH and DCM (4:96) as eluent. The combined pure fractions from combiflash were distilled to give the title compound (300 mg) as a black gel. Yield: 32%. 1H-NMR(δppm,DMSO-d6,400MHz):8.44(bs,1H),8.06(bs,1H),7.60(t,J7.9,1H),7.55-7. 49(m,4H),6.36(s,1H),5.82(s,1H),4.09-4.00(m,2H),3.99-3.91(m,2H),1.52(s,3H). MS(m / z):313.29([M+H] + ).

[0218] Intermediate 57: 3-(3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)benzaldehyde: Intermediate 56 (280 mg, 0.5 mmol) was dissolved in a mixture of water (4 mL) and acetone (4 mL). To this mixture was added oxalic acid hydrate (570 mg, 4.5 mmol), and the mixture was stirred at 55° C. for 4 hours. The acetone was evaporated from the reaction mixture, and the mixture was basified with 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (3×100 mL), and the combined DCM layers were distilled to give the title compound as a brown solid (160 g). It was used in the next step without further purification. Yield: 67%. MS (m / z): 269.22 ([M+H] + ).

[0219] Intermediate 58: 3-hydroxy-3-methyl-1-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one: The title compound was synthesized as a black gel (210 mg) from Intermediate 57 (150 mg, 0.56 mmol) and Intermediate 3 (290 mg, 0.62 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization. MS (m / z): 383.61 ([M−H] - ).

[0220] Intermediate 59: 1-(naphthalen-1-ylmethyl)indoline-2,3-dione: Indoline-2,3-dione (37 g, 0.25 mol) was dissolved in DMF (740 mL) and cooled to 0 °C. Sodium hydride was added portionwise to the above mixture at 0 °C and stirred at the same temperature for 10 minutes. 1-(Chloromethyl)naphthalene was added to the above reaction mixture at 0 °C and stirred at 0 °C for 30 minutes and at room temperature for 12 hours. After 12 hours, the reaction mixture was quenched with saturated NH4Cl (1 L) to give a solid. The solid was filtered and washed with water (500 mL). The solid was dissolved in a 1:9 mixture of MeOH and DCM (2 L) and dried over anhydrous Na2SO4. The solution was distilled to give the crude product. The crude product was purified by column chromatography on 60-120 mesh silica gel using DCM as the eluent. The combined pure fractions from the column were distilled to give the title compound (43.8 g) as a brown solid. Yield: 61%. 1 H-NMR(δppm,DMSO-d6,400MHz):8.20(d,J8.4,1H),7.99(d,J8.4,1H),7.88(d,J8,4,1H ),7.68-7.50(m,5H),7.42(t,J8,1H),7.12(t,J7.6,1H),6.90(d,J8,1H),5.39(s,2H).

[0221] Intermediate 60: (R)-3-methyl-1-(naphthalen-1-ylmethyl)-2-oxoindolin-3-yl acetate: (R)-N-(4-chlorobenzyl)-2-hydroxy-2-phenylacetamide (3.148 g, 12.03 mmol) was dissolved in DCM (1200 mL) and stirred under a nitrogen atmosphere. To this mixture, 2 M dimethylzinc (60.14 mL, 120.3 mmol) was added and stirred at room temperature for 30 minutes. Intermediate 59 (17.28 g, 60.14 mmol) was dissolved in DCM (600 mL) and added dropwise to the above reaction mixture over 1 hour. The reaction mixture was further stirred at room temperature for 1 hour.

[0222] The reaction mixture was cooled to 0°C, and acetic anhydride (22.7 mL, 240 mmol) was added dropwise to the reaction mixture. After the addition of acetic anhydride, the reaction mixture was warmed to room temperature and stirred for 1 hour. At this stage, pyridine (19.03 mL, 240 mmol) and DMAP (733 mg, 6 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After 1 hour, pyridine (9.52 mL, 120 mmol), DMAP (733 mg, 6 mmol), and acetic anhydride (11.37 mL, 120 mmol) were added again, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride (75 g in 750 mL of water). The organic and aqueous layers were separated. The aqueous layer was extracted with DCM (2 x 350 mL). The combined DCM layers were washed with water (700 mL) and brine (700 ml). The organic layer was distilled to give a crude solid (22 g). The crude solid (22 g) was suspended in a mixture of EtOAc (12 mL) and hexane (108 mL) and stirred for 2 hours. The solid was filtered and washed with hexane (35 mL). The solid was dried under vacuum to give the title compound (17 g) as an off-white solid. Yield: 82%. Chiral HPLC purity: 90.45%, retention time: 22.92 min. 1 H-NMR(δppm,DMSO-d6,400MHz):8.18(d,J8,1H),7.97(d,J8,1H),7.85(d,J8,1H),7.58(Quintet,J7.2,2H),7.45(d,J6.8,1H),7.41(d,J8,1H) ),7.37(d,J7.2,1H),7.18(t,J8,1H),7.02(t,J7.6,1H),6.75(d,J8,1 H),5.44(d,J16.8,1H),5.32(d,J16.8,1H),2.07(s,3H),1.59(s,3H).

[0223] Intermediate 61: (R)-3-methyl-2-oxoindolin-3-yl acetate: Intermediate 60 (1.25 g, 3.62 mmol) was suspended in chlorobenzene (70 mL), and N-bromosuccinimide (772 mg, 4.34 mmol) and AIBN (118 mg, 0.723 mmol) were added. The mixture was refluxed at 130° C. for 3 hours. After 3 hours, chlorobenzene was distilled from the reaction mixture to obtain a crude product. The crude product was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous NaSO and distilled to obtain a crude product. The crude product was purified by Combiflash using EtOAc and petroleum ether (2:8) as the eluent to obtain the title compound (360 mg) as a light brown solid. Yield: 48%. Chiral HPLC purity: 89.85%, retention time: 5.18 min. 1 H-NMR(δppm,DMSO-d6,400MHz):10.52(s,1H),7.24(d,J7.2,1H),7.22(td,J7. 6,1.2,1H),6.95(td,J7.6,1.2,1H),6.82(d,J8,1H),2.00(s,3H),1.47(s,3H).

[0224] Intermediate 62: (R)-(+)-3-hydroxy-3-methylindolin-2-one: Intermediate 61 (300 mg, 1.46 mmol) and LiOH (135 mg, 2.2 mmol) were suspended in MeOH (1.5 mL) and THF (1.5 mL). The mixture was stirred at room temperature for 3 h. After 3 h, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous NaSO and distilled to give the title compound (150 mg) as a light brown solid. Yield: 48%. Chiral HPLC purity: 82.81%, retention time: 3.01 min. 1 H-NMR(δppm,DMSO-d6,400MHz):10.19(s,1H),7.26(d,J7.2,1H),7.17(td,J7.6 ,1.2,1H),6.94(td,J7.6,1.2,1H),6.78(d,J7.6,1H),5.82(s,1H),1.33(s,3H).

[0225] Intermediate 63: 1-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)indolin-2-one: According to the general procedure 1, the title compound was synthesized as a brown liquid (700 mg) from Intermediate 1 (10 g, 34.00 mmol) and oxindole (4.53 g, 34.00 mmol). Yield: 6%. The compound was carried to the next step without any characterization.

[0226] Intermediate 64: 4-fluoro-3-(2-oxoindolin-1-yl)benzaldehyde: Intermediate 63 (350 mg, 1.17 mmol) was dissolved in THF (5 ml) and 6N hydrochloric acid (4 mL) was added. The mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mass was cooled to 0°C and the pH was adjusted to approximately 7 using saturated aqueous sodium bicarbonate (50 mL). The aqueous reaction mixture was extracted with MeOH:DCM (1:9) and the organic layer was evaporated on a rotary evaporator to afford the crude product. The crude product was purified by Combiflash using MeOH and DCM (1:9) as eluents. The combined pure fractions from Combiflash were distilled on a rotary evaporator to give the title compound (160 mg) as a brown gel. Yield: 53.69%. The compound was carried forward without any characterization.

[0227] Intermediate 65: 1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenyl)indolin-2-one: The title compound was synthesized as a yellow gel (240 mg) from Intermediate 64 (150 mg, 0.58 mmol) and Intermediate 3 (500 mg, 1.06) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0228] Intermediate 66: tert-butyl 2-oxoindoline-1-carboxylate: Oxindole (16 g, 0.12 mol) was dissolved in THF (382 mL) and cooled to 0° C. To this mixture, sodium carbonate (101.89 g, 0.96 mol) and Boc anhydride (41.4 mL, 0.18 mol) were added at 0° C. The reaction mixture was heated to 70° C. and stirred at the same temperature for 24 hours. The reaction mixture was cooled to room temperature, and the insoluble solid was filtered from the reaction mixture. The filtered solid was stirred with ethyl acetate (200 mL) and filtered. The combined filtrate was distilled to obtain the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (2:98) as the eluent. The combined pure fractions from Combiflash were distilled to obtain the title compound as a white solid (5.5 g). Yield: 19.6%. 1 H-NMR (δppm, CDCl3, 400MHz): 7.78 (d, J8.2, 1H), 7.30 (t, J7.8, 1H), 7.24 (d, J7.8, 1H), 7.13 (t, J7.4, 1H), 3.65 (s, 2H), 1.64 (s, 9H).

[0229] Intermediate 67: tert-butyl 3,3-dimethyl-2-oxoindoline-1-carboxylate: Intermediate 66 (5.5 g, 23.6 mmol) and methyl iodide (4.42 mL, 70.77 mmol) were dissolved in THF (45 mL) and cooled to 0° C. To this mixture was added sodium hydride (60%) (2.06 g, 51.9 mmol) in lots at the same temperature. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 0° C. and quenched with water (100 mL). The aqueous reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was distilled to give the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (15:85) as the eluent. The combined pure fractions from Combiflash were distilled to give the title compound (2.4 g) as an off-white solid. Yield: 39%. 1 H-NMR (δppm, CDCl3, 400MHz): 7.84 (d, J8.1, 1H), 7.29 (d, J7.2, 1H), 7.24-7.13 (m, 2H), 1.65 (s, 9H), 1.42 (s, 6H).

[0230] Intermediate 68: 3,3-dimethylindolin-2-one: This intermediate was prepared according to literature reports (Reference: Li, Honghe; et al. Angewandte Chemie, International Edition (2019), 58(20), 6732-6736). Intermediate 67 (2 g, 7.65 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Trifluoroacetic acid (5.9 mL, 76.5 mmol) was added to the above reaction mixture and stirred at 0 °C for 30 minutes. The pH of the reaction mixture was adjusted to approximately 7 using saturated aqueous sodium bicarbonate. The aqueous layer was extracted with MeOH:DCM (1:9), and the organic layer was evaporated to give the crude product. The crude product was suspended in diethyl ether (20 mL) and stirred to give a solid. The solid was filtered and dried under vacuum to give the title compound (1.25 g) as a brown solid. Yield: 100%. 1 H-NMR (δppm, DMSO-d6, 400MHz): 10.29 (s, 1H), 7.25 (d, J7.2, 1H), 7.14 (t, J7.6, 1H), 6.94 (t, J7.5, 1H), 6.82 (d, J7.6, 1H), 1.22 (s, 6H).

[0231] Intermediate 69: 1-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-3,3-dimethylindolin-2-one: The title compound was synthesized from Intermediate 1 (1.64 g, 5.58 mmol) and Intermediate 68 (0.9 g, 5.58) according to general procedure 1. The crude was purified by Combiflash using ethyl acetate and petroleum ether (20:80) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound as a brown solid. Yield: 32%. 1H-NMR(δppm,DMSO-d6,400MHz):7.63-7.60(m,2H),7.50(t,J9.5,1H),7.45(d,J7.1,1H),7.21(t,J7.7,1H),7.1 0(t,J7.2,1H),6.56(d,J7.7,1H),5.79(s,1H),4.10-4.03(m,2H),3.97-3.90(m,2H),1.41(s,3H),1.37(s,3H).

[0232] Intermediate 70: 3-(3,3-dimethyl-2-oxoindolin-1-yl)-4-fluorobenzaldehyde: Intermediate 69 (600 mg, 1.84 mmol) was dissolved in THF (6 ml) and 6N hydrochloric acid (2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After 30 minutes, the reaction mass was cooled to 0°C and the pH was adjusted to about 7 using saturated aqueous sodium bicarbonate solution (50 mL). The aqueous reaction mixture was extracted with a mixture of dichloromethane and MeOH (1:9). The organic layer was dried over anhydrous Na2SO4 and evaporated to give the crude product. The crude product was stirred with petroleum ether (3 mL) to give a solid, which was filtered. The solid was dried under vacuum to give the title compound (450 mg) as a brown solid. Yield: 86%. 1 H-NMR(δppm,DMSO-d6,400MHz):10.02(s,1H),8.17(d,J7.2,1H),8.14-8.11(m,1H),7.73(t,J9.4,1H ),7.48(d,J7,1H),7.22(t,J6.8,1H),7.13(t,J7.4,1H),6.67(d,J7.8,1H),1.43(s,3H),1.39(s,3H).

[0233] Intermediate 71: 1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenyl)-3,3-dimethylindolin-2-one: The title compound was synthesized as a yellow solid from Intermediate 70 (450 mg, 1.58 mmol) and Intermediate 3 (1.36 g, 2.86 mmol) following general procedure 2. Yield: 100%.

[0234] Intermediate 72: 1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3,3-dimethylindolin-2-one: The title compound was synthesized from Intermediate 4 (1.28 g, 5.58 mmol) and Intermediate 68 (899 mg, 5.58) according to general procedure 1. The crude was purified by Combiflash using ethyl acetate and petroleum ether (20:80) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound as a brown solid (800 mg). Yield: 46%. 1 H-NMR(δppm,DMSO-d6,400MHz):8.70(d,J6.5,2H),7.96(s,1H),7.46(d,J7.7,1H),7.22(t,J7.7,1H), 7.12(t,J7.4,1H),6.75(d,J7.7,1H),5.92(s,1H),4.12-4.07(m,2H),4.01-3.95(m,2H),1.40(s,6H).

[0235] Intermediate 73: 5-(3,3-dimethyl-2-oxoindolin-1-yl)nicotinaldehyde: Intermediate 72 (800 mg, 2.6 mmol) was dissolved in THF (15 ml) and concentrated hydrochloric acid (2.5 mL) was added. The mixture was stirred at 80° C. for 2 hours. After 2 hours, the reaction mass was cooled to room temperature and water (50 mL) was added. The pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4 and evaporated to give the title compound (600 mg) as a brown solid. Yield: 87%. 1 H-NMR(δppm,DMSO-d6,400MHz):10.17(s,1H),9.12(s,1H),8.99(s,1H),8.40(s,1H),7 .48(d,J7.2,1H),7.24(t,J7.4,1H),7.14(t,J7.3,1H),6.89(d,J7.7,1H),1.42(s,6H).

[0236] Intermediate 74: 3,3-dimethyl-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-2-one: The title compound was synthesized as a yellow solid (620 mg) from Intermediate 73 (550 mg, 2.7 mmol) and Intermediate 3 (1.76 g, 3.71 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0237] Intermediate 75: Diethyl 2-(3-nitropyridin-2-yl)malonate: Sodium hydride (60%) (18.22 g, 0.46 mol) was suspended in DMSO (360 mL) under a nitrogen atmosphere and cooled to 0°C. Diethyl malonate (69.18 mL, 0.46 mol) was added to the above mixture, warmed to room temperature, and stirred for 30 minutes. 2-Chloro-3-nitropyridine (31 g, 0.195 mol) was added to the above reaction mixture and heated to 100°C for 15 minutes. After 15 minutes, the reaction mixture was cooled to 0°C and quenched with aqueous ammonium chloride solution. The aqueous reaction mixture was extracted with ethyl acetate (2 x 250 mL), and the ethyl acetate layer was washed with water (2 x 500 mL). The organic layer was distilled under vacuum to give the title compound (55.2 g) as a brown gel. Yield: 100%. 1 H-NMR(δppm,DMSO-d6,400MHz):8.88(dd,J4.6,1.3,1H),8.61(dd,J8.4,1.4,1 H),7.75(dd,J8.3,4.7,1H),5.59(s,1H),4.20-4.14(m,4H),1.17(t,J7.1,6H).

[0238] Intermediate 76: Ethyl 2-(3-nitropyridin-2-yl)acetate: A mixture of intermediate 75 (55 g, 0.282 mol), lithium chloride (20.65 g, 0.487 mol), DMSO (550 mL), and water (3.5 mL, 0.194 mol) was heated to 100° C. for 16 h. The reaction mixture was cooled to room temperature and quenched with brine solution (500 mL). The aqueous reaction mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (5×200 mL) and dried over anhydrous NaSO. The organic layer was distilled to give the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (15:85) as eluent. The pure fractions from Combiflash were distilled to give the title compound (35.9 g) as a brown gel. Yield: 88%. 1 H-NMR (δppm, DMSO-d6,400MHz): 8.84(d,J3.5,1H) 8.54(d,J8.3,1H),7.68(dd,J8.2,4.8,1H),4.23(s,2H),4.08(q,J7.1,2H),1.15(t,J7.1,3H).

[0239] Intermediate 77: Ethyl 2-methyl-2-(3-nitropyridin-2-yl)propanoate: Intermediate 76 (3.8 g, 18 mmol) was dissolved in DMF (30 mL) under a nitrogen atmosphere. Methyl iodide (3.3 mL, 54 mmol) and 18-Crown-6 (0.48 g, 1.8 mmol) were added to the solution and cooled to 0 °C. Sodium hydride (60%) (1.59 g, 39.8 mmol) was added in batches to the reaction mixture and stirred at 0 °C for 1 h. The reaction mixture was quenched with water at 0 °C and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (5 × 100 mL) and evaporated on a rotary evaporator to give the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (8:92) as the eluent. The pure fractions from Combiflash were combined and distilled to give the title compound (3 g) as a brown gel. Yield: 70%. 1H-NMR (δ ppm, CDCl3, 400MHz): 8.79 (d, J4.5, 1H), 8.24 (d, J8.1, 1H), 7.40 (dd, J8.1, 4.6, 1H), 4.12 (q, J7.1, 2H), 1.71 (s, 6H), 1.20 (t, J7.1, 3H).

[0240] Intermediate 78: 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one: Intermediate 77 (3 g, 12 mmol) was suspended in ethanol (25 mL), and ammonium formate (3.17 g, 50.37 mmol) and 10% Pd / C (300 mg) were added. The mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered over a bed of celite, and the bed of celite was washed with MeOH and DCM (1:9) (250 mL). The combined filtrate was distilled on a rotary evaporator to give a residue. The residue was dissolved in a mixture of MeOH and DCM (1:9) (250 ml) and washed with water (2×100 mL). The organic layer was dried over anhydrous NaSO and distilled to give the title compound (1.45 g) as a brown solid. Yield: 71%. 1 H-NMR (δppm, DMSO-d6, 400MHz): 10.51 (s, 1H), 8.07 (d, J4.4, 1H), 7.20-7.11 (m, 2H), 1.23 (s, 6H).

[0241] Intermediate 79: 1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one: The title compound was synthesized from Intermediate 4 (1.5 g, 6.5 mmol) and Intermediate 78 (1.06 g, 6.5 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (3:97) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound (1.2 g) as a pale yellow gel. Yield: 59%. 1H-NMR(δppm,DMSO-d6,400MHz):8.75(s,1H),8.70(s,1H),8.24(d,J4.8,1H),8.01(s,1H),7.27-7.21(m,1H),7.18(d,J8,1H),5.92 9s, 1H), 4.11-4.05(m, 2H), 4.01-3.96(m, 2H), 1.14(s, 6H).

[0242] Intermediate 80: 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)nicotinaldehyde: Intermediate 79 (620 mg, 2 mmol) was dissolved in THF (5 ml) and concentrated hydrochloric acid (1.5 mL) was added. The mixture was stirred at 80° C. for 3 hours. After 3 hours, the reaction mass was cooled to 0° C. and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (2×100 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give the title compound (532 mg) as a pale yellow gel. Yield: 100%. 1 H-NMR(δppm,DMSO-d6,400MHz):10.18(s,1H),9.13(s,1H),9.02(s,1H),8.4 3(s,1H),8.26(d,J4.2,1H),7.32(d,J8,1H),7.29-7.22(m,1H),1.43(s,6H).

[0243] Intermediate 81: 3,3-dimethyl-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one: The title compound was synthesized as a yellow solid (762 mg) from Intermediate 80 (532 mg, 2 mmol) and Intermediate 3 (1.70 g, 4 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0244] Intermediate 82: 1-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one: The title compound was synthesized from Intermediate 1 (730 mg, 2.48 mmol) and Intermediate 78 (402 mg, 2.48 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using MeOH and DCM (2.5:97.5) as eluents. The combined pure fractions from Combiflash were distilled to give the title compound (460 mg) as a brown gel. Yield: 57%. 1 H-NMR(δppm,DMSO-d6,400MHz):8.23(d,J5,1H),7.67(dd,J7.2,2,1H),7.65-7.60(m,1H),7.51(t,J9.9,1H),7. 23(dd,J8,5,1H),6.99(d,J8,1H),5.79(s,1H),4.10-4.03(m,2H),3.97-3.91(m,2H),1.43(s,3H),1.38(s,3H).

[0245] Intermediate 83: 3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-fluorobenzaldehyde: Intermediate 82 (440 mg, 1.34 mmol) was dissolved in THF (10 mL) and concentrated hydrochloric acid (2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After 30 minutes, the reaction mass was cooled to 0°C and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9). The organic layer was dried over anhydrous Na2SO4 and evaporated to give the title compound (380 mg) as a pale yellow gel. Yield: 100%. 1 H-NMR(δppm,DMSO-d6,400MHz):10,02(s,1H),8.25(dd,J5,1.2,1H),8.23(dd,J6.8,4.8,1H),8.1 6-8.10(m,1H),7.74(t,J9.6,1H),7.25(dd,J8,5,1H),7.13(d,J8,1H),1.45(s,3H),1.40(s,3H).

[0246] Intermediate 84: 1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one: The title compound was synthesized as a yellow gel (404 mg) from Intermediate 83 (380 mg, 1.33 mmol) and Intermediate 3 (1.70 g, 4 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0247] Intermediate 85: tert-butyl 2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate: Intermediate 66 (2.5 g, 10.72 mmol) was dissolved in DMF (25 mL) under a nitrogen atmosphere. To this solution, 1,2-dibromoethane (2.77 mL, 32.16 mmol) and 18-Crown-6 (0.28 g, 1.072 mmol) were added and cooled to 0 °C. To this mixture, sodium hydride (60%) (943 mg, 23.6 mmol) was added in batches at 0 °C. The reaction mixture was stirred at room temperature for 3 h and at 70 °C for 3 h. The reaction mixture was quenched with water at 0 °C and extracted with MeOH and DCM (1:9) (3 × 200 mL). The combined organic layers were washed with water (3 × 250 mL) and evaporated to give the crude product. The crude product was purified by Combiflash using ethyl acetate and petroleum ether (4:96) as eluents. The pure fractions from Combiflash were combined and distilled to give the title compound as a white solid (1.1 g). Yield: 40%. 1 H-NMR(δ ppm, CDCl3,400MHz):7.90(d,J8.2,1H),7.30-7.22(m,1H),7.12(t,J7.5, 1H), 6.81 (d, J7.4, 1H), 1.82 (q, J4.2, 2H), 1.65 (s, 9H), 1.54 (q, J3.9, 2H).

[0248] Intermediate 86: Spiro[cyclopropane-1,3-indolin]-2'-one: Intermediate 85 (1.1 g, 4.24 mmol) was dissolved in dichloromethane (40 mL) and cooled to 0° C. Trifluoroacetic acid (3.27 mL, 42.4 mmol) was added to the mixture and stirred at 0° C. for 30 minutes. The pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate. The aqueous layer was extracted with MeOH:DCM (1:9) (4×100 mL) and the organic layer was evaporated to give the title compound as a brown solid (650 mg). Yield: 96%. 1 H-NMR (δppm, DMSO-d6, 400MHz): 10.52 (s, 1H), 7.13 (td, J7.6, 1.7, 1H), 6.97-6.85 (m, 3H), 1.56-1.50 (m, 2H), 1.46-1.41 (m, 2H).

[0249] Intermediate 87: 1'-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)spiro[cyclopropane-1,-3'-indolin]-2'-one: The title compound was synthesized from Intermediate 4 (940 mg, 4.08 mmol) and Intermediate 86 (649 mg, 4.08 mmol) according to general procedure 1. The resulting crude was purified by Combiflash using ethyl acetate and petroleum ether (35:65) as eluent. The combined pure fractions from Combiflash were distilled to give the title compound (501 mg) as a brown gel. Yield: 40%. 1 H-NMR(δppm,DMSO-d6,400MHz):8.74(d,J2.3,1H),8.70(d,J1.7,1H),7.97(d,J2.1,1H),7.25-7.19(m,1H),7.15-7.0 6(m,2H),6.84(d,J7.8,1H),5.92(s,1H),4.11-4.03(m,2H),4.01-3.93(m,2H),1.78-1.72(m,2H),1.67-1.62(m,2H).

[0250] Intermediate 88: 5-(2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)nicotinaldehyde: Intermediate 87 (480 mg, 1.56 mmol) was dissolved in THF (15 mL) and concentrated hydrochloric acid (2 mL) was added. The mixture was refluxed at 80 °C for 3.5 h. After 3.5 h, the reaction mass was cooled to 0 °C and the pH of the reaction mixture was adjusted to about 7 using saturated aqueous sodium bicarbonate solution. The aqueous reaction mixture was extracted with MeOH and DCM (1:9) (2 × 150 mL). The organic layer was dried over anhydrous NaSO and evaporated to give the title compound (411 mg) as a yellow gel. Yield: 100%. The compound was carried forward without any characterization.

[0251] Intermediate 89: 1'-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one: The title compound was synthesized as a yellow gel (411 mg) from Intermediate 88 (411 mg, 1.56 mmol) and Intermediate 3 (1.33 g, 2.8 mmol) according to general procedure 2. Yield: 100%. The compound was carried forward without any characterization.

[0252] Example 1 4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 11 (1 g, 2.6 mmol), hydrazine hydrate (156 mg, 3.12 mmol), and acetic acid (78 mg, 1.3 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 5.3:94.7. Appearance: off-white solid. Yield: 236 mg. Yield: 23%. MP: 110-113 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.59(s,1H),8.65(s,1H),8.52(s,1H),8 .26(d,J7.8,1H),8.06(d,J8.1,1H),7.93(t,J8,1H),7.85(t,J8,1H),7.7 9(s,1H),7.43(d,J7.2,1H),7.21(t,J7.6,1H),7.11(t,J7.2,1H),6.69(d ,J7.7,1H),6.12(s,1H),4.46(s,2H),1.48(s,3H)MS(m / z):399.29([M+H] + ).

[0253] Example 2 (R)-(+)-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: Method-1: The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 1) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.16, retention time: 11.48 min. MP: 97-100°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.58(s,1H),8.65(d,J1.7,1H),8.52(d ,J2.2,1H),8.26(d,J7.4,1H),8.06(d,J8.0,1H),7.93(t,J7.8,1H),7.85 (t,J7.8,1H),7.79(t,J2.0,1H),7.43(d,J6.9,1H),7.22(t,J7.8,1H),7. 11(t,7.6,1H),6.69(d,J7.6,1H),6.12(s,1H),4.47(s,2H),1.48(s,3H). MS(m / z):399.39([M+H] + ). [α] D 25 :+30.36° [MeOH:chloroform (1:9);c 1.0]

[0254] Method-2: 5-Bromonicotinaldehyde was converted to an acetal by treatment with ethylene glycol. The acetal was reacted with (R)-(+)-3-methyl-2-oxoindolin-3-yl acetate under Buchwald conditions to give (R)-(+)-1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-methyl-2-oxoindolin-3-yl acetate. (R)-(+)-1-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-methyl-2-oxoindolin-3-yl was deprotected under acidic conditions to give (R)-(+)-1-(5-formylpyridin-3-yl)-3-methyl-2-oxoindolin-3-yl acetate. The (R)-(+)-1-(5-formylpyridin-3-yl)-3-methyl-2-oxoindolin-3-yl acetate thus obtained was reacted with (3-oxo-1,3-dihydroisobenzofuran-1-yl)triphenylphosphonium bromide under Wittig reaction conditions to give (R)-(+)-3-methyl-2-oxo-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-3-yl acetate. (R)-(+)-3-Methyl-2-oxo-1-(5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)pyridin-3-yl)indolin-3-yl acetate was reacted with hydrazine hydrate to give (R)-(+)-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one.

[0255] Method-3: Following the similar procedure described in Example-1, the title compound was also synthesized using chiral intermediate-5(R)-(+)-3-hydroxy-3-methylindolin-2-one.

[0256] Example 3 (S)-(-)-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 1) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.82, retention time: 13.61 min. MP: 94-97°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.59(s,1H),8.65(d,J1.7,1H),8.52(d ,J2.2,1H),8.26(d,J7.8,1H),8.06(d,J7.9,1H),7.93(t,J7.6,1H),7.85 (t,J8.0,1H),7.79(t,J2,1H),7.43(d,J7.2,1H),7.21(t,J7.8,1H),7.1 1(t,J7.8,1H),6.69(d,J7.8,1H),6.12(s,1H),4.46(s,2H),1.48(s,3H). MS(m / z):399.41([M+H] + ). [α] D 25 :-26.44° [MeOH:chloroform (1:9);c 1.0]

[0257] Example 4 4-(4-fluoro-3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 8 (800 mg, 1.99 mmol), hydrazine hydrate (119 mg, 2.4 mmol), and acetic acid (59 mg, 1 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 3:97. Appearance: off-white solid. Yield: 240 mg. Yield: 29%. MP: 131-134 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.60(s,1H),8.25(d,J7.7,1H),7.99(d,J7. 9,1H),7.90(t,J7.3,1H),7.81(t,7.3,1H),7.54-7.49(m,1H),7.47-7.35(m, 3H),7.24-7.17(m,1H),7.09(t,J7.3,1H),6.46(d,J7.7,1H),6.25(s,0.4H), 6.13(s,0.6H),4.39(s,1.2H),4.36(s,0.8H),1.50(s,1.8H),1.45(s,1.2H). MS(m / z): 416.1 ([M+H] + ).

[0258] Example 5 4-((5-(3-ethyl-3-hydroxy-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 19 (900 mg, 2.26 mmol), hydrazine hydrate (135 mg, 2.71 mmol), and acetic acid (67 mg, 1.13 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 5:95. Appearance: off-white solid. Yield: 200 mg. Yield: 21%. MP: 117-120 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.58(s,1H),8.65(d,J1.4,H),8.50(d,J2. 1,1H),8.26(d,J7.7,1H),8.07(d,J8,1H),7.94(t,J7,1H),7.85(t,J7.2,1H) ,7.79(s,1H),7.40(d,J7.2,1H),7.23(t,J7.1,1H),7.12(t,J7.5,1H),6.70( d, J7.8, 1H), 6.12 (s, 1H), 4.47 (s, 2H), 1.94-1.83 (m, 2H), 0.68 (t, J7.4, 3H). MS(m / z): 413.43 ([M+H] + ).

[0259] Example 6 7-Fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 24 (650 mg, 1.61 mmol), hydrazine hydrate (97 mg, 1.94 mmol), and acetic acid (48 mg, 0.81 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 4:96. Appearance: off-white solid. Yield: 110 mg. Yield: 16%. MP: 133-136 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),8.65(d,J1.5,1H),8.53(d,J2.1,1H),8.19(dd,J8.9,5.0,1H),7.94(dd,J8.8,2.7,1H),7.84(td,J 8.8,2.7,1H),7.81(t,J2.7,1H),7.44(d,J7,1H),7.23(t,J7.7,1H),7.1 1(t,J7.4,1H),6.71(d,J7.8,1H),6.13(s,1H),4.47(s,2H),1.48(s,3H). MS(m / z):417.47([MH]-).

[0260] Example 7 (+)-7-Fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was resolved as a pure enantiomer from the racemic mixture of 7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 6) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.54, retention time: 5.86 min. MP: 148-151°C. 1H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),8.65(d,J1.6,1H),8.53(d,J2.0,1H),8.19(dd,J9.2,5.2,1H),7.94(dd,J8.8,2.7,1H),7.84(td,J 8.8,2.7,1H),7.80(t,J2.7,1H),7.44(d,J7,1H),7.23(t,J7.6,1H),7.1 2(t,J7.6,1H),6.71(d,J7.6,1H),6.13(s,1H),4.47(s,2H),1.48(s,3H). MS(m / z):417.32([M+H] + ). [α] D 25 :+ 23.51° [MeOH:chloroform (1:9)];c 0.5]

[0261] Example 8 (-)-7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was resolved as a pure enantiomer from the racemic mixture of 7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 6) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.64%, retention time: 6.75 min. MP: 138-141°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),8.65(d,J1.5,1H),8.53(d,J2.1,1H),8.19(dd,J8.9,5,1H),7.94(dd,J8.8,2.7,1H),7.84(t,J8.8 ,2.7,1H),7.80(t,J2.7,1H),7.44(d,J7.6,1H),7.23(t,J7.6,1H),7.12 (t,J7.6,1H),6.71(d,J7.6,1H),6.13(s,1H),4.47(s,2H),1.48(s,3H). MS(m / z):417.28([M+H] + ). [α] D 25:-27.74° [MeOH:chloroform (1:9); c 0.5]

[0262] Example 9 6-Fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 28 (650 mg, 1.61 mmol), hydrazine hydrate (97 mg, 1.94 mmol), and acetic acid (48 mg, 0.80 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 4.1:95.9. Appearance: pale yellow solid. Yield: 210 mg. Yield: 31%. MP: 132-135 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.66(s,1H),8.65(d,J1.6,1H),8.53(d,J2.2,1H),8.33(dd,J8.8,5.7,1H),7.93(dd,J9.8,2.2,1H),7.83 (s,1H),7.72(t,J8.8,1H),7.44(d,J7,1H),7.23(t,J7.7,1H),7.12(t ,J7.1,1H),6.73(d,J7.8,1H),6.14(s,1H),4.44(s,2H),1.49(s,3H). MS(m / z):417.43([M+H] + ).

[0263] Example 10 7-Fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 33 (350 mg, 0.83 mmol), hydrazine hydrate (49 mg, 1 mmol), and acetic acid (24 mg, 0.42 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 4.2:95.8. Appearance: off-white solid. Yield: 140 mg. Yield: 38%. MP: 157-160 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.68(s,1H),8.64(d,J2,1H),8.52(d,J2,1H),8.19(dd,J8.8,5,1H),7.94(dd,J8.8,2.6,1H),7.84(td,J8.8 ,2.6,1H),7.81(t,J2,1H),7.35(dd,J7.8,2.4,1H),7.07(td,J8.8,2. 5,1H),6.75(dd,J8.8,4.0,1H),6.25(s,1H),4.46(s,2H),1.50(s,3H). MS(m / z):435.32([M+H] + ).

[0264] Example 11 (+)-7-Fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was resolved as a pure enantiomer from the racemic mixture of 7-fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 10) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.90%, retention time: 5.88 min. MP: 148-151°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),8.64(d,J2,1H),8.52(d,J2,1H),8.19(dd,J8.8,5,1H),7.94(dd,J8.4,2.4,1H),7.84(td,J8. 8,2.4,1H),7.81(t,J2,1H),7.35(dd,J8,2.8,1H),7.08(td,J8.8,2.4 ,1H),6.75(dd,J8.4,4.0,1H),6.26(s,1H),4.46(s,2H),1.50(s,3H). MS(m / z):435.39([M+H] + ). [α] D 25 :+17.79°[MeOH:chloroform (1:9); c 0.5]

[0265] Example 12 (-)-7-Fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was resolved as a pure enantiomer from the racemic mixture of 7-fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 10) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.28%, retention time: 6.92 min. MP: 154-157°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.69(s,1H),8.64(d,J2,1H),8.52(d,1H),8.19(dd,J8.8,5,1H),7.94(dd,J8.4,2.4,1H),7.84(td,J8.4, 2.4,1H),7.81(t,J2,1H),7.36(dd,J7.6,2.4,1H),7.08(td,J9.2,2.8 ,1H),6.75(dd,J8.4,4.0,1H),6.26(s,1H),4.46(s,2H),1.50(s,3H). MS(m / z):435.33([M+H] + ). [α] D 25 :-25.52° [MeOH:chloroform (1:9); c 0.5]

[0266] Example 13 4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 32 (351 mg, 0.87 mmol), hydrazine hydrate (52 mg, 1.05 mmol), and acetic acid (26 mg, 0.44 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 5.1:94.9. Appearance: off-brown solid. Yield: 90 mg. Yield: 25%. MP: 116-120 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.58(s,1H),8.65(d,J2,1H),8.52(d,J2,1H),8.26(d,J7.4 1H), 8.06(d,J7.9,1H),7.93(t,J8.4,1H),7.85(t,J7.4,1H),7.80(t,J2,1H),7.35(dd,J7.9,2.6, 1H), 7.06 (td, J8.8, 2.7, 1H), 6.72 (dd, J8.6, 4.1, 1H), 6.24 (s, 1H), 4.46 (s, 2H), 1.49 (s, 3H). MS(m / z):417.35([M+H] + ).

[0267] Example 14 (+)-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 13) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.65%, retention time: 6.05 min. MP: 198-201 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.59(s,1H),8.65(d,J2.5,1H),8.52(d,J1.2,1H),8.26(d,J8,1H),8.06(d,J8,1H),7.94(t,J7.6,1H),7.8 5(t,J7.4,1H),7.80(t,J2,1H),7.35(dd,J8,2.4,1H),7.06(td,J8.8, 2.8,1H),6.72(dd,J8.8,4,1H),6.25(s,1H),4.46(s,2H),1.49(s,3H). MS(m / z):417.33([M+H] + ). [α] D 25 :+23.63° [MeOH:chloroform (1:9);c 0.5]

[0268] Example 15 (-)-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 13) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 98.81%, retention time: 7.61 min, MP: 197-200°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.59(s,1H),8.65(d,J2.5,1H),8.52(d,J2,1H),8.26(d,J8,1H),8.06(d,J8,1H),7.94(t,J7.6,1H),7.85( t,J7.4,1H),7.80(t,J2,1H),7.35(dd,J8,2.6,1H),7.06(td,J8.8,2. 8,1H),6.72(dd,J8.8,4.2,1H),6.25(s,1H),4.46(s,2H),1.49(s,3H). MS(m / z):417.34([M+H] + ). [α] D 25 :-28.17° [MeOH:chloroform (1:9); c 0.5]

[0269] Example 16 7-Fluoro-4-((5-(6-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was synthesized from Intermediate 37 (400 mg, 1 mmol), hydrazine hydrate (59 mg, 1.19 mmol), and acetic acid (29 mg, 0.5 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 4.7:95.3. Appearance: off-white solid. Yield: 150 mg. Yield: 36%. MP: 125-128 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.57(s,1H),8.66(s,1H),8,52(s,1H),8.26(d,J7.3,1H),8.06(d,J8,1H),7.92(t,J7,1H),7.84(t ,J7.2,1H),7.80(s,1H),7.46(dd,J8.1,5.6,1H),6.93-6.88(m,1H),6.54(dd,J9.4,2.1,1H),6.15(s,1H),4.47(s,2H),1.48(s,3H). MS(m / z):417.33([M+H] + ).

[0270] Example 17 7-Fluoro-4-((5-(6-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 38 (400 mg, 0.95 mmol), hydrazine hydrate (72 mg, 1.56 mmol), and acetic acid (39 mg, 0.47 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 3.8:96.2. Appearance: pale yellow solid. Yield: 90 mg. Yield: 22%. MP: 219-221 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.68(s,1H)8.66(d,J7.1,1H),8.529d,J2.2,1H),8.17(dd,J9,5.04,1H),7.93(dd,J 8.8,2.7,1H),7.87-7.76(m,2H),7.45(dd,J8.2,5.7,1H),6.91(t,J10.1,1H),6.15(s,1H),4.47(s,2H),1.48(s,3H). MS(m / z):435.32([M+H] + ).

[0271] Example 18 4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 15 (500 mg, 1.3 mmol), hydrazine hydrate (78 mg, 1.56 mmol), and acetic acid (39 mg, 0.65 mmol) according to general procedure 3. Purification: Column chromatography on 100-200 mesh silica gel. Eluent: MeOH and DCM: 1.5:98.5. Appearance: Off-white solid. Yield: 35 mg. Yield: 6.7% MP: 203-205 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.63(s,1H),8.51(d,J5.2,1H),8.28(d, J6.8,1H),7.99(d,J8,1H),7.91(td,J7.2,1.2,1H),7.84(t,J7.2,1H),7. 69(s,1H),7.49(d,J8,1H)7.44(d,J6.8,1H),7.39(d,J5.2,1H),7.26(td, J7.6,1.2,1H),7.14(t,J7.6,1H),6.15(s,1H),4.46(s,2H),1.48(s,3H). MS(m / z):399.11([M+H] + ).

[0272] Example 19 (-)-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one: The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one (Example 18) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.54%, retention time: 9.19 min. MP: 207-210°C. 1H-NMR(δppm,DMSO-d6,400MHz):12.63(s,1H),8.49(d,J5.2,1H),8.26(d,J7.6,1H),7. 98(d,J8,1H),7.90(td,J7.2,1.2,1H),7.83(t,J7.2,1H),7.69(s,1H),7.48(d,J8,1H) 7.42(d,J7.2,1H),7.37(d,J5.0,1H),7.26(td,J7.6,1.6,1H),7.12(t,J7.6,1H),6.15(s,1H),4.45(s,2H),1.48(s,3H). MS(m / z): 399.29 ([M+H] + ). [α] D 25 :-33.01° [MeOH:chloroform (1:9); c 0.5]

[0273] Example 20 (+)-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one (Example 18) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.11, retention time: 11.22 min. MP: 205-208°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.63(s,1H),8.49(d,J5.2,1H),8.26(d, J7.6,1H),7.98(d,J8,1H),7.90(td,J7.2,1.2,1H),7.83(t,J7.2,1H),7. 68(s,1H),7.48(d,J8,1H)7.44(d,J6.8,1H),7.37(d,J5.0,1H),7.26(td, J7.6,1.2,1H),7.12(t,J7.6,1H),6.15(s,1H),4.45(s,2H),1.47(s,3H). MS(m / z):399.29([M+H] + ). [α] D 25:+29.62° [MeOH chloroform (1:9);c 0.5]

[0274] Example 21 7-Fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 39 (640 mg, 1.3 mmol), hydrazine hydrate (32 mg, 0.65 mmol), and acetic acid (16 mg, 0.27 mmol) according to general procedure 3. Purification: Column chromatography on 60-120 mesh silica gel: 3.8:96.2. Appearance: Off-white solid. Yield: 23 mg. Yield: 5.2%. MP: 187-189 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.74(s,1H),8.50(d,J5.2,1H),8.10(dd,J9.0,5,1H),7.94(dd,J8.8,2.4 1H),7.80(td,J8.8,2.8,1H),7.67(s,1H),7.48(d,J8,1H),7.42(d,J7.6,1H),7.36(d,J 5.2,1H),7.26(td,J8,1,1H),7.13(t,J7.2,1H),6.16(s,1H),4.46(s,2H),1.48(s,3H). MS(m / z):417.16([M+H] + ).

[0275] Example 22 (-)-7-fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one: The title compound was resolved as a pure enantiomer from the racemic mixture of 7-fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one (Example 21) using the preparation method reported in General Procedure 4. Chiral HPLC purity: 99.95%, retention time: 8.23 ​​min. MP: 165-168 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.74(s,1H),8.50(d,J5.2,1H),8.10(dd,J9.0,5.2,1H),7.94(dd,J8.8,2.4 1H),7.80(td,J8.8,2.8,1H),7.67(s,1H),7.48(d,J8,1H),7.42(d,J7.6,1H),7.36(d,J 5.2,1H),7.26(td,J8,1,1H),7.13(t,J7.2,1H),6.16(s,1H),4.46(s,2H),1.47(s,3H). MS(m / z):417.28([M+H] + ). [α] D 25 :-29.17° [MeOH:chloroform (1:9); c 0.5]

[0276] Example 23 (+)-7-Fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one: The title compound was resolved as a pure enantiomer from the racemic mixture of 7-fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one (Example 21) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.23, retention time: 10.79 min. MP: 167-170°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.74(s,1H),8.50(d,J5.2,1H),8.10(dd,J8.8,4.8,1H),7.95(dd,J8.8,2.4,1H),7.80(td,J8.8,2.8,1H),7. 67(s,1H),7.48(d,J8,1H),7.42(d,J7.2,1H),7.36(d,J5.2,1H),7.26( d, J7.6, 1H), 7.13 (t, J7.2, 1H), 6.15 (s, 1H), 4.46 (s, 2H), 1.47 (s, 3H). MS(m / z):417.30([M+H] + ). [α] D 25:+24.29° [MeOH:chloroform (1:9);c 0.5]

[0277] Example 24 7-Fluoro-4-((2-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one: The title compound was synthesized from Intermediate 42 (508 mg, 1.2 mmol), hydrazine hydrate (72 mg, 1.45 mmol), and acetic acid (36 mg, 0.6 mmol) according to general procedure 3. Purification: Column chromatography on 100-200 mesh silica gel: 2:98. Appearance: Off-white solid. Yield: 80 mg. Yield: 15.2%. MP: 225-228 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.73(s,1H),8.49(d,J4.8,1H),8.10(dd,J8.8,4.8,1H),7.95(dd,J8.8,2.8, 1H),7.81(td,J8.4,2.8,1H),7.72(s,1H),7.61(dd,J9.2,4.8,1H),7.37(dd,J4.8,1.5,1H),7.33(dd,J8.02.8 1H), 7.12 (td, J9.2, 2.8, 1H), 6.28 (s, 1H), 4.46 (s, 2H), 1.49 (s, 3H). MS(m / z):435.14([M+H] + ).

[0278] Example 25 4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was synthesized from Intermediate 45 (670 mg, 1.5 mmol), hydrazine hydrate (100 mg, 2 mmol), and acetic acid (41 mg, 0.69 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 2:98. Appearance: off-white solid. Yield: 360 mg. Yield: 52%. MP: 258-260 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.57(s,1H),8.70(d,J2,1H),8.52(d,J2,1H),8.26(d,J7.6,1H),8.08(d,J8,1H),7.94(t,J8 .4,1H),7.93(s,1H),7.89-7.82(m,2H),7.57(d,J7.6,1H),7.42(t,J7.6,1H),7.23(t,J7.6,1H),6.81(d,J8,1H),4.49(s,2H). MS(m / z):453.1([M+H] + ).

[0279] Example 26 (+)-4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 25) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.5, retention time: 4.2 min. MP: 170-174°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.60(s,1H),8.71(d,J1.6,1H),8.54(d,J2.4,1H),8.29(dd,J8.0,1.2,1H),8.10(d,J8.0,1H),7.98(dt,J7.2) ,1.2,1H),7.94(s,1H),7.89-7.83(m,2H),7.59(d,J7.6,1H),7.46(dt, J7.6,1.2,1H),7.27(dt,J8.0,0.8,1H),6.83(d,J8.0,1H),4.50(s,2H). MS(m / z):453.33([M+H] + ). [α] D 25 :+46.33° [chloroform; c 0.15],

[0280] Example 27 (-)-4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was resolved as a pure enantiomer from the racemic mixture of 4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one (Example 25) using the preparative method reported in General Procedure 4. Chiral HPLC purity: 99.9, retention time: 7.3 min. MP: 210-214°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.60(s,1H),8.71(d,J2.0,1H),8.54(d,J2.4,1H),8.29(dd,J8.0,0.8,1H),8.11(d,J8.0,1H),7.98(dt,J7.6) ,1.6,1H),7.94(s,1H),7.89-7.83(m,2H),7.59(d,J7.2,1H),7.46(dt, J8.0,1.2,1H),7.27(dt,J7.6,0.8,1H),6.83(d,J8.4,1H),4.50(s,2H). MS(m / z):453.33([M+H] + ). [α] D 25 :-41.50° [chloroform; c 0.15],

[0281] Example 28 4-(3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one Intermediate 49 (7.5 g, 19.6 mmol), hydrazine hydrate (1.26 g, 25.2 mmol), and 2-propanol (150 ml) were mixed and refluxed at 100° C. for 3 hours. After 3 hours, the reaction mixture was cooled to room temperature and stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture. The aqueous layer was extracted with MeOH and DCM (1:9) (3×150 mL). The combined organic layers were dried over anhydrous NaSO and distilled to give a solid. Purification: CombiFlash. Eluent: MeOH and DCM: 4:96. Appearance: off-white solid. Yield: 4.7 g. Yield: 60%. MP: 240-243° C.1 H-NMR(δppm,DMSO-d6,400MHz):12.61(s,1H),8,26(d,J8,1H),8.00(d,J8,1H),7.90(t,J7.6,1H),7.83(t,J7.6,1H),7.49(t,J7.6,1H),7.4 1(t,J6.2,2H),7.35(s,1H),7.26(d,J7.6,1H),7.18(t,J8,1H),7.08( t,J7.6,1H),6.60(d,J7.6,1H),6.09(s,1H),4.40(,2H),1.47(s,3H). MS(m / z):398.27([M+H] + ).

[0282] Example 29 7-Fluoro-4-(4-fluoro-3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one Intermediate 51 (3 g, 7 mmol), hydrazine hydrate (500 mg, 9 mmol), and 2-propanol (60 mL) were mixed and refluxed at 100°C for 3 hours. After 3 hours, the reaction mixture was cooled to room temperature and stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction mixture. The aqueous layer was extracted with MeOH and DCM (1:9) (2 x 25 mL). The combined organic layers were dried over anhydrous NaSO and distilled to give a solid. Purification: Combi-flash. Eluent: MeOH and DCM: 3:97. Appearance: Light brown solid. Yield: 1.3 g. Yield: 40%. MP: 207-210°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.72(s,1H),8.16-8.09(m,1H),7.94(d,J7.6,1H),7.81(t,J8,1H),7.51(d,J5. 2,1H),7.44(d,J6.8,2H),7.39(d,J6.4,1H),7.22(t,J7.6,1H),7.11(t,J7.2,1H),6.50(d,J5.6,1H),6.27(s,0.4 H),6.15(s,0.6 H),4.41(s,1.2 H)4.38(s,0.8 H),1.51(s,1.2 H),1.47(s,1.8 H). MS(m / z): 434.26 ([M+H] + ).

[0283] Example 30 4-((5-(3-methoxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one Intermediate 52 (1.25 g, 3 mmol) was suspended in MeOH (5 mL) and cooled to 0 °C. To this mixture was added sodium methoxide (972 mg, 4.5 mmol). The reaction mixture was warmed to room temperature and stirred at room temperature for 2 h. After 2 h, the reaction mixture was quenched with water (250 mL), and the aqueous layer was extracted with a mixture of DCM and MeOH (9:1) (2 × 50 mL). The combined organic layers were washed with water (50 mL) and 5% aqueous citric acid (50 mL). The organic layer was dried over anhydrous NaSO and distilled under vacuum to give the crude product. The crude product was purified by column chromatography using EtOAc as the eluent to give the title compound as a white solid. Yield: 65 mg. Yield: 5.3%. MP: 207-210 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.59(s,1H),8.65(s,1H),8.57(d,J2,1H),8.28(d,J8,1H),8.08(d,J7.6,1H),7.95(t ,J7.6,1H),7.90(s,1H),7.86(t,J7.6,1H),7.45(d,J7.6,1H),7.31(t,J7.6,1H),7.19(t,J7.6,1H),6.75(d,J7.6,1H) 4.47(s,2H),2.97(s,3H),1.54(s,3H). MS(m / z):413.34([M+H] + ).

[0284] Example 31 4-(3-(3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)benzyl)phthalazin-1(2H)-one Intermediate 58 (210 mg, 0.55 mmol), hydrazine hydrate (35 mg, 0.7 mmol), and 2-propanol (5.2 ml) were mixed and refluxed at 100°C for 3 hours. After 3 hours, the reaction mixture was cooled to room temperature and stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction mixture. The aqueous layer was extracted with MeOH and DCM (1:9) (2 x 50 mL). The combined organic layers were dried over anhydrous NaSO and distilled to give a solid. Purification: CombiFlash. Eluent: MeOH and DCM: 5:95. Appearance: pale yellow solid. Yield: 30 mg. Yield: 14%. MP: 133-136°C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.60(s,1H),8.39(d,J4.4,1H),8.27(dd,J8,1.2,1H),8.02(d,J8,1H),7.99(s,1H),7.90(td,J 8,1.2,1H),7.83(td,J8,1.2,1H),7.53-7.48(m,2H),7.47-7.40(m,2H),7.32(d,J8,1H),6.34(s,1H),4.41(s,2H),1.50(s,3H). MS(m / z):399.40([M+H] + ).

[0285] Example 32 3-Methyl-2-oxo-1-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)pyridin-3-yl)indolin-3-yl acetate Intermediate 52 (5 g, 12 mmol) was dissolved in DMF (60 mL), and 18-Crown-6 (3.17 g, 12 mmol) and cesium acetate (9.21 g, 48 mmol) were added. The mixture was stirred at 80°C for 1.5 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM (3 x 100 mL). The combined organic layer was distilled to obtain the crude product. Purification: Column chromatography on 60-120 mesh silica gel. Eluent: MeOH and DCM: 4:96. Appearance: Off-white solid. Yield: 1.2 g. Yield: 22.7%. MP: 237-239°C. 1H-NMR(δppm,DMSO-d6,400MHz):12.58(s,1H),8.67(s,1H),8.49(d,J2,1H),8.27(d,J8,1H),8.07(d,J8,1H),7.94(t,J7.2,1H),7.85(t, J8,1H),7.79(s,1H),7.43(d,J7.6,1H),7.26(t,J7.6,1H),7.12(t,J7.6,1H),6.69(d,J7.6,1H),4.48(s,2H),2.03(s,3H),1.63(s,3H). MS(m / z):441.3([M+H] + ).

[0286] Example 33 4-(4-fluoro-3-(2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one The title compound was synthesized from Intermediate 65 (200 mg, 0.54 mmol), hydrazine hydrate (32 mg, 0.65 mmol), and acetic acid (16 mg, 0.27 mmol) according to general procedure 3. Purification: Combi-Flash. Eluent: MeOH and DCM: 2.7:97.3. Appearance: off-white solid. Yield: 12 mg. Yield: 5.8%. MP: 232-235 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.59(s,1H),8.25(d,J7.8,1H),7.99(d,J7.8,1H),7.94-7.88(m,1H),7.87-7.80(m,1H),7 .50-7.37(m,3H),7.32(d,J7.2,1H),7.14(t,J7.6,1H),7.06(t,J7.2,1H),6.44(d,J7.6,1H),4.37(s,2H),3.76(d,J5,2H). MS(m / z):386.0([M+H] + ).

[0287] Example 34 4-(3-(3,3-dimethyl-2-oxoindolin-1-yl)-4-fluorobenzyl)phthalazin-1(2H)-one The title compound was synthesized from Intermediate 71 (600 mg, 1.5 mmol), hydrazine hydrate (90 mg, 1.8 mmol), and acetic acid (45 mg, 0.75 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 2:98. Appearance: off-white solid. Yield: 340 mg. Yield: 54%. MP: 129-132 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.59(s,1H),8.25(d,J7.7,1H),8.00(d,J7.8,1H),7.90(t,J7,1H),7.87-7.80(m,1H),7.52(d ,J6.2,1H),7.48-7.35(m,3H),7.15(t,J7.5,1H),7.09(t,J7.2,1H),6.48(d,J7.7,1H),4.37(s,2H),1.38(s,3H),1.35(s,3H). MS(m / z):414.45([M+H].

[0288] Example 35 4-((5-(3,3-dimethyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was synthesized from Intermediate 74 (600 mg, 1.57 mmol), hydrazine hydrate (94 mg, 1.88 mmol), and acetic acid (47 mg, 0.78 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 3:97. Appearance: off-white solid. Yield: 260 mg. Yield: 41%. MP: 221-224 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.58(s,1H),8.63(s,1H),8.54(s,1H),8.26(d,J7.8,1H),8.06(d,J7.8,1H),7.93(t,J7.8, 1H),7.88-7.80(m,2H),7.43(d,J7.2,1H),7.18(t,J7.6,1H),7.10(t,J7.3,1H),6.70(d,J7.7,1H),4.45(s,2H),1.37(s,6H). MS(m / z):397.47([M+H] + ).

[0289] Example 36 4-((5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one The title compound was synthesized from Intermediate 81 (762 mg, 1.99 mmol), hydrazine hydrate (119 mg, 2.38 mmol), and acetic acid (59 mg, 0.99 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 5.2:94.8. Appearance: off-white solid. Yield: 300 mg. Yield: 38%. MP: 242-245 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.58(s,1H),8.64(s,1H),8.58(s,1H),8.26(d,J7.8,1H),8.22(d,J4.6,1H),8.05(d,J8 ,1H),7.93(t,J7.6,1H),7.89(s,1H),7.84(t,J7.4,1H),7.24-7.18(m,1H),7.12(d,J7.8,1H),4.45(s,2H),1.38(s,6H). MS(m / z):398.1([M+H] + ).

[0290] Example 37 4-(3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-fluorobenzyl)phthalazin-1(2H)-one The title compound was synthesized from Intermediate 84 (390 mg, 0.97 mmol), hydrazine hydrate (49 mg, 1.17 mmol), and acetic acid (29 mg, 0.49 mmol) according to general procedure 3. Purification: Combi-Flash eluent: MeOH and DCM: 3.2:96.8. Appearance: off-white solid. Yield: 168 mg. Yield: 42%. MP: 114-117 °C. 1H-NMR(δppm,DMSO-d6,400MHz):12.59(S,1H),8.25(d,J7.8,1H),8.23-8. 21(m,1H),7.99(d,J8,1H),7.90(t,J7,1H),7.85-7.81(m.1H),7.60-7.53( m,1H),7.50-7.45(m,1H),7.44-7.38(m,1H),7.20(dd,J8,5.04,1H),6.91 (d,J7.9,1H),4.37(s,2H),1.40(s,3H),1.36(s,3H)MS(m / z):415.2([M+H] + ).

[0291] Example 38 1'-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one The title compound was synthesized from Intermediate 89 (591 mg, 1.55 mmol), hydrazine hydrate (93 mg, 1.86 mmol), and acetic acid (46 mg, 0.78 mmol) according to general procedure 3. Purification: Combi-Flash. Eluent: MeOH and DCM: 3.1:96.9. Appearance: pale yellow solid. Yield: 160 mg. Yield: 26%. MP: 219-222 °C. 1 H-NMR(δppm,DMSO-d6,400MHz):12.57(s,1H),8.63(d,J1.7,1H),8.57(d,J2.3,1H),8.26(d,J7.8,1H),8.07(d,J8,1H),7.93(t,J7, 1H),7.90-7.81(m,2H),7.20-7.16(m,1H),7.12-7.04(m,2H),6.79(d,J7.8,1H),4.46(s,2H),1.76-1.70(m,2H),1.65-1.60(m,2H). MS(m / z):395.35([M+H] + ).

[0292] Biological assays The pharmacological properties of the compounds of the present invention can be confirmed by a number of pharmacological assays. Suitable pharmacological assays that can be performed to evaluate the compounds described herein are set out below.

[0293] Example 1 GI of compounds of formula (I) in HCT-116 and UWB1.289 cell lines 50 Cell proliferation assay (MTT assay) to determine Assay Protocol: On day "0," test cells were seeded in triplicate in 96-well plates at 100 μL / well in complete medium, and the plates were incubated at 37°C and 5% CO2. On day 1, 10 μL of MTT (5 mg / ml) was added to the column designated for day "0." The column was mixed well and incubated at 37°C and 5% CO2 for 3.5 hours. The cells were pelleted at 4000 rpm for 10 minutes. The medium was aspirated, and 150 μL of DMSO was added to the cells and mixed by pipetting to dissolve the crystals. The plates were read at A560nm and A640nm. DMSO dilutions of inhibitors were diluted in growth medium to three times the required concentration. Each well of cells was treated with 50 μL of complete medium containing inhibitor. The DMSO concentration in the well was 0.1%. The plates were incubated at 37°C and 5% CO2 for 144 hours as needed. 15 μL of MTT (5 mg / mL) was added to each well. The plate was incubated at 37°C, 5% CO2 for 3.5 hours. After incubation, the cells were pelleted at 4000 rpm for 10 minutes. The medium was aspirated, and 150 μL of DMSO was added per well to dissolve the formazan crystals. The plate was read at A560 nm and A640 nm.

[0294] Results: For the compounds of the present invention, GI 50 The value was calculated. 50 The values ​​are shown in Table 2 below:

[0295] Example 2 IC of the compound of formula (1) 50 PARP enzyme assay for determining Assay Protocol Step 1 - Coating: 1) Coating 25 μL of histone solution onto a 384-well plate as described below: Dilute the 5x histone mixture 1:5 with PBS. Add 25 μL of diluted histone solution to each well and incubate overnight at 4°C. Wash the plate three times with 100 μL per well of PBST buffer (1x PBS containing 0.05% Tween 20). Tap the plate on a clean paper towel to remove any liquid. Add 100 μL of Blocking Buffer 3 to each well to block the wells. Incubate at room temperature for 1 hour and 15 minutes. Wash the plate three times with 100 μL of PBST buffer as above. Tap the plate on a clean paper towel to remove any liquid.

[0296] Step 2: Ribosylation reaction: 1) Preparation of 1x PARP buffer: Prepare 1x PARP buffer by adding 1 part 10x PARP buffer to 9 parts distilled water (v / v). To prepare 500µL of 1x PARP buffer, add 50µL of 10x PARP Assay Buffer to 450µL of H2O and mix thoroughly. 2) Preparation of ribosylation master mix: N wells x (1.25 μL 10x PARP buffer + 1.25 μL 10x PARP assay mix + 2.5 μL activated DNA + 7.5 μL distilled water). Add 12.5 μL to all wells. 3) Preparation of inhibitor solutions: A 10 mM stock solution of inhibitor was prepared in DMSO. From the 10 mM stock solution, a 250x concentrated inhibitor was made in DMSO. The 250x DMSO inhibitor was further diluted to 10x concentration in 1x kinase buffer. 2.5 μL (10x concentrated) kinase buffer containing inhibitor was added to each well. For the "positive control" and "blank", 2.5 μL of kinase buffer containing DMSO (4%) was added. The final DMSO concentration in the wells was 0.4%. 4) Preparation of enzyme solution: Thaw PARP1 enzyme on ice. During the initial thaw, briefly spin the tube containing the enzyme to recover the entire volume. Calculate the amount of PARP1 required for the assay and dilute the enzyme to 2.0 ng / μL in 1x PARP buffer. · Initiate the reaction by adding 10 μL of diluted PARP1 enzyme to wells designated as "positive control" and "test inhibitor." Add 10 μL of 1x PARP buffer to wells designated as "blank." Centrifuge the plate at 1000 RPM for 30 seconds and incubate at room temperature for 60 minutes. After 1 hour, discard the reaction mixture, wash the plate three times with 100 μL of PBST buffer, and pat the plate on a clean paper towel as before.

[0297] Step 3: Detection 1) Preparation of Streptavidin-HRP: Dilute streptavidin-HRP 1:50 in blocking buffer. Add 25 μL of diluted streptavidin-HRP to each well. Incubate at room temperature for 30 minutes. Wash three times with 100 μL of PBST buffer and dab the plate on a clean paper towel as above. 2) Preparation of ECL substrate: Immediately before use, mix equal volumes of ELISA ECL Substrate A and ELISA ECL Substrate B on ice and add 50 μL to each well. Immediately read the plate using the chemiluminescence setting on your microtiter plate. The "blank" value is subtracted from all other values.

[0298] Results: Inhibition rate and IC 50 The values ​​are shown in Table 2 below.

[0299] Example 3 UWB1.289 cells were seeded at a predetermined density in 6-well plates in their respective media, and the plates were incubated overnight at 37°C, 5% CO. After overnight incubation, the plates were treated with desired concentrations of compounds or DMSO, and the plates were incubated for 24 hours at 37°C, 5% CO, as needed.

[0300] After the 24-hour incubation was completed, whole cell lysates were prepared from the treated samples.

[0301] Lysates were analyzed by Western blot analysis and probed with a human PAR-specific monoclonal antibody or a human-specific beta-actin monoclonal antibody (loading control).

[0302] The Western blot images were exposed to a chemiluminescent substrate, developed, and captured using an imaging system.

[0303] Target-specific and loading-specific bands were measured by densitometry analysis. Densitometry values ​​of target-specific bands were normalized to the loading control values. Percent inhibition of PAR was calculated relative to the DMSO-treated sample.

[0304] Results: The inhibition rates are shown in Table 2 below:

[0305] [Table 3] Inhibition rate: A represents more than 75% to 100%; B represents more than 50% to 75% or less; C represents more than 25% to 50% or less, and D represents 25% or less. IC50: + represents 10nM or less, ++ represents 10nM or more; GI50: A1 represents 2500nM or less; B1 represents 2500nM to 5000nM or less; C1 represents 5000nM to 7500nM or less; D1 represents 7500nM to 10000nM or less; E1 represents more than 10000nM.

[0306] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the invention. It is therefore to be understood that numerous modifications can be made to the exemplary embodiments and that other arrangements can be devised without departing from the spirit and scope of the invention as set forth above. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0307] All publications, patents, and / or patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R ａ , R ｂ , R ｃ and R ｄ are each hydrogen, halogen, substituted or unsubstituted C １～３ Alkyl, and C １～３ haloalkyl; X is CR ｘ or N, Y is CR ｙ or N, Z is CR Ｚ or N, R ｘ , R ｙ and R ｚ are each hydrogen, halogen, and substituted or unsubstituted C １～３ independently selected from alkyl, G is, 【Chemistry 2】 (In the formula, R ｅ and R ｆ are each hydrogen, halogen, hydroxy, alkyl, haloalkyl, alkoxy, and —OR ｇ or R directly bonded to a common atom ｅ and R ｆ Both are combined to form C ３～６ may form a cycloalkyl, R ｇ is hydrogen, substituted or unsubstituted C １～３ Alkyl, and —(CO)R ｈ is selected from R ｈ is selected from hydrogen and alkyl; R １ , R ２ , R ３ and R ４ are each independently selected from hydrogen, halogen, haloalkyl, and substituted or unsubstituted alkyl. Selected from or a tautomer, an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof.

2. The compound has the formula (I): 【Chemistry 1】 [In the formula, R ａ , R ｂ , R ｃ and R ｄ are each hydrogen, halogen, and substituted or unsubstituted C １～３ independently selected from alkyl, X is CR ｘ or N, Y is CR ｙ or N, Z is CR Ｚ or N, R ｘ , R ｙ and R ｚ are each hydrogen, halogen, and substituted or unsubstituted C １～３ independently selected from alkyl, G, 【Transformation 3】 (In the formula, R ｅ and R ｆ are hydrogen, halogen, hydroxy, and C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy and —O(CO)R ｈ are independently selected from R ｇ is hydrogen, substituted or unsubstituted C １～３ Alkyl, and —(CO)R ｈ is selected from R ｈ is selected from hydrogen and alkyl, and R １ , R ２ , R ３ and R ４ are hydrogen, halogen, and C, respectively. １～３ haloalkyl, and substituted or unsubstituted C １～３ alkyl) Selected from 2. The compound of claim 1, having the formula:

3. The compound has formula (IA) or (IB): 【Chemistry 4】 (In the formula, R ａ , R ｂ , R ｃ , R ｄ , X, Y, Z, R ｅ , R ｆ , R １ , R ２ , R ３ and R ４ is as defined above for compounds of formula (I).

2. The compound of claim 1, having the formula:

4. (i) R ａ , R ｂ , R ｃ and R ｄ are each independently selected from hydrogen and halogen; (ii) R ａ , R ｃ and R ｄ is hydrogen and R ｂ is a halogen, or (iii) R ａ , R ｂ and R ｄ is hydrogen and R ｃ The compound according to any one of claims 1 to 3, wherein is a halogen.

5. R ｂ The compound of claim 4, wherein is fluorine or chlorine.

6. R ｃ The compound of claim 4, wherein is fluorine or chlorine.

7. The compound of any one of claims 1 to 6, wherein X, Y and Z are each independently selected from CH and N.

8. (i) Y and Z are CH and X is N; (ii) X and Z are CH and Y is N; or (iii) The compound of claim 7, wherein X and Y are CH and Z is N.

9. X and Y are CH and Z is CR Ｚ The compound according to any one of claims 1 to 8, wherein

10. R ｚ The compound of claim 9 , wherein is hydrogen or halogen.

11. R ｚ The compound of claim 10, wherein is fluorine.

12. R ｅ and R ｆ are hydrogen, hydroxy, and C, respectively. １～３ Alkyl, C １～３ Haloalkyl, C １～３ The compound of any one of claims 1 to 11, independently selected from alkoxy and acetyloxy.

13. R ｅ But hydroxy, C １～３ 13. The compound of claim 12, which is alkoxy or acetyloxy.

14. R ｅ The compound of claim 13, wherein is hydroxy.

15. R ｆ is C １～３ Alkyl or C １～３ The compound of claim 12 which is a haloalkyl.

16. R ｆ is methyl, ethyl or CF ３ 16. The compound of claim 15, wherein:

17. R ｅ is hydroxy, and R ｆ is C １～３ The compound of claim 12, wherein the compound is alkyl.

18. (i) R ｅ and R ｆ is hydrogen or (ii) R ｅ and R ｆ are respectively, C １～３ independently selected from alkyl, or (iii) R directly bonded to a common atom ｅ and R ｆ are bonded to form C ３～６ forming a cycloalkyl, The compound of claim 1.

19. R ｅ and R ｆ 19. The compound of claim 18, wherein is hydrogen.

20. R ｅ and R ｆ 19. The compound of claim 18, wherein is methyl.

21. R directly bonded to a common atom ｅ and R ｆ are bonded to form C ３～６ 20. The compound of claim 18, which forms a cycloalkyl.

22. (i) R １ , R ２ , R ３ and R ４ are each independently selected from hydrogen or halogen; (ii) R １ , R ２ , R ３ and R ４ is hydrogen, or (iii) R １ , R ２ , R ３ and R ４ are each independently selected from halogen; (iv) R １ , R ３ and R ４ is hydrogen and R ２ is a halogen, or (v) R １ , R ２ and R ４ is hydrogen and R ３ The compound of any one of claims 1 to 21, wherein is halogen.

23. (i) R １ , R ２ , R ３ and R ４ any one or more of (ii) R １ , R ３ and R ４ is hydrogen and R ２ is fluorine, or (iii) R １ , R ２ and R ４ is hydrogen and R ３ The compound of claim 1 , wherein is fluorine.

24. 24. The compound of any one of claims 1 to 23, wherein G is selected from: 【Transformation 5】

25. 25. The compound of claim 24, wherein G is selected from the following: 【Transformation 6】

26. 4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (R)-(+)-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (S)-(-)-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4-(4-fluoro-3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 4-((5-(3-ethyl-3-hydroxy-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (+)-7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (-)-7-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 6-fluoro-4-((5-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 7-fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (+)-7-fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (-)-7-fluoro-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (+)-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (-)-4-((5-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 7-fluoro-4-((5-(6-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 7-fluoro-4-((5-(6-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; (-)-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; (+)-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 7-fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; (-)-7-fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; (+)-7-fluoro-4-((2-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 7-fluoro-4-((2-(5-fluoro-3-hydroxy-3-methyl-2-oxoindolin-1-yl)pyridin-4-yl)methyl)phthalazin-1(2H)-one; 4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (+)-4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; (-)-4-((5-(3-hydroxy-2-oxo-3-(trifluoromethyl)indolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4-(3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 7-fluoro-4-(4-fluoro-3-(3-hydroxy-3-methyl-2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 4-((5-(3-methoxy-3-methyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4-(3-(3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)benzyl)phthalazin-1(2H)-one; 3-methyl-2-oxo-1-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)pyridin-3-yl)indolin-3-yl acetate; 4-(4-fluoro-3-(2-oxoindolin-1-yl)benzyl)phthalazin-1(2H)-one; 4-(3-(3,3-dimethyl-2-oxoindolin-1-yl)-4-fluorobenzyl)phthalazin-1(2H)-one; 4-((5-(3,3-dimethyl-2-oxoindolin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4-((5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-3-yl)methyl)phthalazin-1(2H)-one; 4-(3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-fluorobenzyl)phthalazin-1(2H)-one; 1'-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one; and pharmaceutically acceptable salts thereof A compound selected from:

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier.

28. 28. The pharmaceutical composition of claim 27, further comprising one or more additional therapeutic agents and combinations thereof.

29. 29. The pharmaceutical composition of claim 28, wherein the one or more additional therapeutic agents are an anti-cancer agent, an anti-inflammatory agent, an immunosuppressant, a steroid, a non-steroidal anti-inflammatory agent, an antihistamine, an analgesic, or a combination of any of the foregoing.

30. 27. Use of a compound according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of a disease, disorder or condition that benefits from the inhibition of the catalytic activity of an enzyme.

31. 31. The use of a compound according to claim 30, wherein the enzyme is PARP.

32. A medicament for use in treating a PARP-related disease or disorder in a subject in need thereof, comprising a compound according to any one of claims 1 to 26.

33. 33. The pharmaceutical of claim 32, wherein the use of the pharmaceutical further comprises the step of simultaneously or sequentially administering to the subject at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressant, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or any combination of any of the foregoing.

34. The pharmaceutical of claim 32 or 33, wherein the PARP-related disease, disorder or condition is an immune system-related disease, a disease or disorder involving inflammation, cancer or other proliferative disease, a liver disease or disorder, or a kidney disease or disorder.

35. The PARP-related disease, disorder, or condition is selected from the group consisting of inflammation, glomerulonephritis, uveitis, liver disease or disorder, kidney disease or disorder, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allo- or xenotransplantation, graft rejection, graft-versus-host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic recurrent hepatitis, primary pulmonary arthritis, and the like. biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjögren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barré syndrome, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, antiphospholipid syndrome, vasculitis, Behçet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, type 1 or immune-mediated diabetes mellitus, Graves' disease, pontine thrombocytopenia ... pontine thrombocytopenia, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine thrombocytopenia, pontine Thyroiditis, autoimmune oophoritis and orchitis, autoimmune diseases of the adrenal glands, systemic lupus erythematosus, polymyositis, dermatomyositis, ankylosing spondylitis, transplant rejection, skin graft rejection, arthritis, bone diseases associated with increased bone resorption, ileitis, Barrett's syndrome, adult respiratory distress syndrome, chronic obstructive airway disease, corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmia, endophthalmitis, gingivitis, periodontitis, tuberculosis, leprosy, uremic complications, nephrosis, sclerodermatitis, psoriasis, chronic diseases of the nervous system 34. The pharmaceutical of claim 32 or 33, wherein the therapeutic agent is selected from demyelinating diseases, AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, viral or autoimmune encephalitis, autoimmune diseases, immune complex vasculitis, systemic lupus and erythematosus, systemic lupus erythematosus (SLE), cardiomyopathy, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, chronic liver failure, brain and spinal cord injury, and cancer.

36. The PARP-related disease, disorder or condition is selected from the group consisting of lymphoid hematopoietic tumors, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma, myeloid hematopoietic tumors, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic leukemia, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, and the like. The pharmaceutical composition of claim 32 or 33, wherein the cancer is selected from cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, neurilemmoma, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular carcinoma, and Kaposi's sarcoma.

37. The pharmaceutical composition of claim 32 or 33, wherein the PARP-related disease, disorder or condition is selected from breast cancer, ovarian cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, and gastric cancer.

38. The method of claim 32 or 33, wherein the PARP-related disease, disorder or condition is selected from breast cancer and ovarian cancer.

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