Indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell prolif

专利摘要:
The present invention relates to an indazole compound that modulates or inhibits cell proliferation due to the activity of protein kinases. The indazole compound and pharmaceutical composition can modulate kinase-dependent diseases that regulate or inhibit unwanted cell proliferation. In the present invention, direct therapy or prophylaxis using the pharmaceutical composition of the compound and an effective amount of the compound are administered to prevent unwanted effects such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis and psoriasis. A number of other diseases associated with angiogenesis and / or cell proliferation are proposed as well as methods for treating cancer.
公开号:KR20020073505A
申请号:KR1020027009194
申请日:2001-01-18
公开日:2002-09-26
发明作者:셰그프라이드헤인즈 레이치；테드미첼 블랙맨；수잔엘리자베쓰 케파트；윌리엄헨리3세 로미네스；미첼비. 웰레이스
申请人:아구론 파마슈티컬스, 인크.；
IPC主号:

专利说明:

Indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation}
[5] Uncontrolled cell proliferation leads to cancer. Cell proliferation in response to various stimuli results in disruption of the cell division cycle, which proceeds by cell proliferation and cell division. Tumor cells are damaged directly or indirectly by genes that regulate the cell division cycle.
[6] Diseases caused by overproliferation of cells, including cancers, are characterized by the disordered growth of cells due to cell cycles in which cell growth is not regulated due to damage in genes that directly or indirectly regulate progression through circulation. Agents that regulate cell cycle and hyperplasia can thus be used to treat a variety of diseases associated with unregulated or unwanted cell proliferation. Also in cancer chemotherapeutic agents, cell cycle inhibitors have been suggested as antiparasitic agents (see Gray et al., Curr. Med. Chem. 6 , 859-875 (1999)), and in recent Proven as a viral agent (see Schang et al., J. Virol. 74 , 2107-2120 (2000)). Moreover, the scope of application of antiproliferative agnets is defined as cardiovascular maladies such as artherosclerosis or restenosis (Braun-Dullaeus et al., Circulation , 98 , 82). -89 (1998)) and arthritis (see Taniguchi et al., Nature Med., 5, 760-767 (1999)) or inflammatory diseases such as psoriasis, have.
[7] The mechanism of cell proliferation consists of irradiation of activity at the cellular and molecular level. At the cellular level, disruption of cell cycle regulation, free angiogenesis, or stimulation of inflammatory pathways is observed, which abolishes control of signal pathways, while at the molecular level these responses are regulated by various proteins that are thought to be protein kinases. . Reduction of overall proliferation also results in cell death or apoptosis, which is regulated through multipath containing some proteolytic enzymes.
[8] Among the regulatory proteins, protein kinases are a group of enzymes that catalyze the phosphorylation of the hydroxy group of specific tyrosine, serine or threonine residues in the protein. In general, phosphorylation dramatically disrupts protein function, so protein kinases play a pivotal role in the regulation of a wide range of cellular actions, including metabolism, cell proliferation, cell differentiation and cell survival. Some actions of many other cell functions known to require protein kinases are targets for therapeutic intervention for certain diseases. For example, cell cycle regulation and angiogenesis, protein kinases play a pivotal role in processes that are important for the development of solid tumors as well as other diseases.
[9] CDKs are either in the resting phase of the cell cycle, from G ₁ (between the onset and somatic division of DNA replication for entry into a new cell division stage) to S (active DNA replication stage) or active somatic cell division at G ₂ . And enzymes that play a decisive role in regulating mutations to other stages, such as the process leading to M stages of cell division (the articles compiled in Science , Vol. 274 (1996) pp . 1643-1677; Ann. Rev. Cell Dev. Biol. , Vol. 13 (1997), pp. 261-291). CDK complexes are formed through the binding of regulatory cyclin subunits (cyclin A, B1, B2, D1, D2, D3 and E) and catalytic kinase subunits (cdc2 (CDK1), CDK2, CDK4, CDK5 and CDK6). The name CDKs implies an absolute dependence on cyclin subunits for phosphorylating their target substrates and other kinases / cyclines that regulate progression through specific parts of the cell cycle.
[10] Cyclin D is sensitive to extracellular growth signals and is activated in response to mitogen during the G ₁ phase of the cell cycle. CDK4 / cyclin D plays an important role in regulating cell cycle progression by inactivating retinoblastoma protein (hereinafter referred to as “Rb”) by phosphorylation. Hypophosphorylated Rb binds to a population of transcriptional regulators, whereas hyperphosphorylated Rb due to CDK4 / cyclin D produces a substance for the transcription factors to undergo S phase progression. Free activating genes. Rb phosphorylation and inactivation by CDK4 / cyclin D allow passage of cells beyond the restriction point of the G ₁ stage. The result is cell division that misses sensitive extracellular growth or inhibition signals. Rb is also phosphorylated and inactivated by CDK2 / cyclin E at the end of G ₁ , and recently CDK2 / cyclin E can regulate progression to S phase via a parallel pathway that does not depend on Rb phosphorylation reaction. This is known (see Lukas et al., "Cyclin E-induced S Phase Without Activation of the pRb / E2F Pathway", Genes and Dev., Vol. 11 (1997), pp. 1479-1492).
[11] The progression from G ₁ to S phase, consisting of CDK4 / cyclin D and CDK2 / cyclin E activity, is premised on several growth regulatory metabolism, including both negative and positive. Growth stimuli due to mitotics and the like increase the synthesis of cyclin D1 and thus increase functional CDK4. In contrast, cell growth may be "reined in" in response to DNA damage or negative growth stimuli resulting from the induction of endogenous inhibitory proteins. Protein inhibitor caused by these inherent are p21 ^{WAF1 / CIP1,} p27 ^KIP1, and p16 ^INK4 set to suppress only the CDK4 (Harper, "Cyclin Dependent Kinase Inhibitors", Cancet Surv., Vol. 29 (1997), pp. 91-107, see ) Is included. Deviations from some of these regulatory systems that affect the function of CDK4 and CDK2 are caused by high proliferation of malignancies, such as hereditary melanomas, esophageal carcinomas, and pancreatic cancers. (Hall and Peters, "Genetic Alterations of Cyclins, Cyclin-Dependent Kinases, and CDK Inhibitors in Human Cancer", Adv. Cancer Res. , Vol. 68 (1996), pp. 67-108; and Kamb et al., "A Cell Cycle Regulator Potentially Involved in Genesis of Many Tumor Types", Science , vol. 264 (1994), pp. 436-440). Over-expression of cyclin D1 is associated with esophageal, breast, and squamous cell carcinomas (DelSal et al., "Cell Cycle and Cancer: Critical Events at the G ₁ Restriction Point ", Critical Rev. Oncogenesis , Vol. 71 (1996), pp. 127-142). Genes encoding CDK4-specific inhibitors of the p16 family are genetic melanomas, gliomas, leukemias, sarcomas and pancreatic and pancreatic, non-small cell lung ) And head and neck carcinoma have deficiencies and mutations (Nobori et al., "Deletions of the Cyclin-Dependent Kinase-4 Inhibitor Gene in Multiple Human Cancers", Nature, Vol. 368 ( 1994), pp. 753-756). Amplification and / or overexpression of cyclin E is also observed in a wide variety of solid tumors, and increased levels of cyclin E are correlated with poor prognosis. In addition, the cellular level of CDK inhibitor p27, which acts as a substrate and inhibitor of CDK2 / cyclin E, is abnormally low in breast cancer, colon cancer and prostate cancers, and the expression level of p27 is inversely proportional to the stage of the disease. (Loda et al., "Increased Proteasome-dependent Degradation of the Cyclin-Dependent Kinase Inhibitor p27 in Aggressive Colorectal Carcinomas", Nature Medicine , Vol. 3 (1997), pp. 231-234). Recently it has been known that CDK4 / cyclin D binds to p27 (Sherr, et al., Genes Dev. , Vol. 13 (1999), pp. 1501-1512). P21 proteins also appear as p53 delivers tumor-suppressive signals to CDKs; Thus, the mutation of p53, which accounts for about 50% of all human cancers, is a direct result of abolishing CDK activity.
[12] The new data supply strong potency on the use of compounds that inhibit CDKs, particularly CDK4 and CDK2, as antiproliferative therapies. Certain biomolecules are being used for this efficacy. For example, US Pat. No. 5,621,082 (Xiong et al.) Discloses hexanes encoding inhibitors of CDK6, and International Patent Application WO 99/06540 discloses hexanes encoding inhibitors of CDK. EP 0 666 270 A2, Bandara, et al., Nature Biotechnology , Vol. 15 (1997), pp. 896-901 and Chen, et al., Proceedings of the National Academy of Science, USA, Vol. 96 (1999), pp. 4325-4329 describe inhibitors of peptides and peptidomimetics. Several small molecules have been identified as CDK inhibitors (Webster, "The Therapeutic Potential of Targeting the Cell Cycle", Exp. Opin. Invest.Drugs , Vol. 7 (1998), pp. 865-887 and Stover, et al., "Recent advances in protein kinase inhibition: current molecular scaffolds used for inhibitor synthesis", Current Opinion in Drug Discovery and Development , Vol. 2 (1999), pp. 274-285). The flavone flavopyridol shows a low selectivity for inhibition of CDK in addition to other kinases, but CDK4, CDK2 and CDK1 inhibit equally in the IC ₅₀ s 0.1-0.3 μM range. Flavopyridol is currently in the second phase of clinical research with oncology chemotherapy (Sedlacek et al., "Flavopiridol (L86-8275; NSC 649890), A New Kinase Inhibitor for Tumor Therapy", Int. J. Oncol ., Vol. 9 (1996), pp. 1143-1168). Analogs of flavopyridols are disclosed in US Pat. No. 5,733,920 (Mansuri et al., WO 97/16447) and WO 97/42949 and WO 98/17662. Derivative products based on purine are described in Schow et al., Bioorg. Med. Chem. Lett ., Vol. 7 (1997), pp. 2697-2702; Grant et al., Proc. Amer. Assoc. Cancer Res ., Vol. 39 (1998), Abst. 1207; Legravend et al., Bioorg. Med. Chem. Lett ., Vol. 8 (1998), pp. 793-798; Gray et al., Science , Vol. 281 (1998), pp. 533-538; Chang et al., Chemistry & Biology , Vol. 6 (1999), pp. 361-375, WO 99/02162, WO 99/43675 and WO 99/43676. Furthermore, the publications described below disclose specific pyrimidines that inhibit cyclin-dependent kinases and growth factor related kinases: International Publication No. WO 98/33798; Ruetz et al., Proc. Amer. Assoc. Cancer Res ., Vol. 39 (1998), Abst. 3796; And Meyer et al., Proc. Amer. Assoc. Cancer Res ., Vol. 39 (1998), Abst. 3794.
[13] Benzensulfonamides that block cells at G ₁ have been developed by Eisai (see Owa, et al., J. Med. Chem ., Vol. 42 (1999), pp. 3789-3799). Oxindole CDK inhibitors are being developed by Glaxo-Wellcome (see Luzzio, et al., Proc. Amer. Assoc. Cancer Res., Vol. (1999), Abst. 4102 and WO 99/15500). . Paulones have been found in collaboration with NCI (Schultz, et al., J. Med. Chem ., Vol. (1999), pp. 2909-2919). Indenopyrazoles are disclosed in WO 99/17769 and Seitz, et al., 218 ^th ACS Natl. Mtg . (Aug. 22-26, 1999, New Orleans), Abst MEDI 316). Aminothiazoles are described in WO 99/24416 and WO 99/21845.
[14] CHK1 is another protein kinase. CHK1 plays an important role as a checkpoint in cell cycle progression. Checkpoints are regulatory systems that regulate cell cycle progression due to effects on the generation, activation and subsequent inactivation of cyclin-dependent kinases. Checkpoints prevent cell cycle progression at improper times to maintain the metabolic balance of cells while the cells are at rest, and can cause apoptosis (planned apoptosis) if the checkpoints are not reached. have. O'Connor, Cancer Surveys , 29 , 151-182 (1997); Nurse, Cell , 91 , 865-867 (1997); Hartwell et al., Science , 266 , 1821-1828 (1994); See Hartwell et al., Science , 246 , 629-634 (1989).
[15] A series of checkpoints are monitored in the complete genome, and these "DNA damage checkpoints", where DNA damage is recognized, prevent cell cycle progression at the G ₁ and G ₂ stages and progress slowly to the S stage. O'Connor, Cancer Surveys , 29 , 151-182 (1997); Hartwell et al., Science , 266 , 1821-1828 (1994). The activity involves DNA repair to complete their work before genome replication and subsequent isolation of the genetic material from new daughter cells. In particular, the p53 tumor suppressor gene, the most common mutant gene in human cancer, produces a DNA damage checkpoint protein that disrupts cell cycle progression in G ₁ and / or causes cell death (planned apoptosis) following DNA damage. Hartwell et al., Science , 266 , 1821-1828 (1994). P53 tumor suppressors also increase the activity of DNA damage checkpoints at the G ₂ stage of the cell cycle. Bunz et al., Science , 28 , 1497-1501 (1998); Winters et al., Oncogene , 17 , 673-684 (1998); Thompson, Oncogene , 15 , 3025-3035 (1997).
[16] Therapeutic interventions are actively being developed to develop vulnerabilities in p53-deficient cancer cells due to important properties of the p53 tumor suppressor pathway in human cancers. A new vulnerability can be found in the action of G ₂ checkpoints in p53 deficient cancer cells. Cancer cells, due to lack of G ₁ checkpoint regulation, are particularly susceptible to breakdown of the last remaining barrier that protects them from the cancer killing effects of DNA-damaging agents at G ₂ checkpoints. G ₂ checkpoints are regulated by regulatory systems that are conserved from yeast to humans. Important in this conserved system is CHK1, a kinase that progresses mitosis entry by signaling to the inhibitory activity of cyclin B / Cdc2 kinase in the DNA-sensory complex (Peng et al., Science , 277 , 1501-1505 (1997); Sanchez et al., Science , 277 , 1497-1501 (1997). Inactivation of CHK1 not only results in preferential killing of generated checkpoint deficient cells, but also inhibits the inhibition of G ₂ caused by DNA damage due to anticancer agents or endogenous DNA damage (Nurse, Cell , 91 , 865-867 (1997). Weinert, Science , 277 , 1450-1451 (1997); Walworth et al., Nature , 363 , 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell , 5 , 147-160 (1994).
[17] Selective manipulation of checkpoint regulation in cancer cells is widely available in chemotherapy and radiation therapy of cancer and also provides a "genetic instability" common hallmark of human cancer that is used as a selective criterion for destroying cancer cells. . Numerous factors recognize CHK1 as an important target in DNA-damage checkpoint regulation. See Zeng et al., Nature , 395 , 507-510 (1998); Matsuoka, Science , 282 , 1893-1897 (1998), which have been shown to interact with CHK1 to regulate the progression of the S phase and to explain the inhibitors. Functionally associated with kinases such as CDS1 / CHK2 provide important novel therapeutics for the treatment of cancer.
[18] Another group of kinases is tyrosine kinases. Tyrosine kinases may be in receptor form (having extracellular, transmembrane and intracellular domains) or non-receptor form. At least one of the non-receptor protein tyrosine kinases, called LCK, is known to regulate transformation in T-cells as a signal due to the interaction of cell surface proteins (Cd4) with cross-linked anti-Cd4 antibodies. A more detailed description of non-receptor tyrosine kinases is described in Bolen, Oncogenes , 8 , 2025-2031 (1993), which is incorporated herein by reference.
[19] In addition, protein kinases play a crucial role in angiogenesis, a metabolism in which new capillaries are formed from existing blood vessels. When needed, the vascular system has the potential to create new capillary networks to maintain the inherent function of tissues and organs. However, when they mature, angiogenesis is completely limited and only occurs during the process of wound healing and menstrual neovascularization (Merenmies, J., Parada, LF, Henkemeyer, M., Cell Growth & Differentiation). , 8 , 3-10 (1997)). Unwanted angiogenesis, on the other hand, is a hallmark of several diseases such as retinopathy, psoriasis, rheumatoid arthritis, age-related macular degeneration and cancer (solid tumors) (Folkman, Nature Med ., 1 , 27-31 (1995). Protein kinases known to be involved in the angiogenic process include three of the growth factor receptor tyrosine kinase families: VEGF-R2 (kinase insert domain receptor (KDR) and endothelial growth factor receptor 2, also known as FLK-1); FGF-R (fibroblast growth factor receptor); And TEK (also known as Tie-2).
[20] VEGF-R2, expressed only in endothelial cells, binds to the potent angiogenic growth factor VEGF and thus modulates signal transduction through activation of intracellular kinase activity. Therefore, direct inhibition of kinase activity of VEGF-R2 results in exogenous VEGF (see Strawn et al., Cancer Research , 56 , 3540-3545 (1996)), a mutant of VEGF-R2 that fails to modulate signaling. Presence is expected to result in a decrease in angiogenesis (Millauer et al., Cancer Research , 56 , 1615-1620 (1996)). Moreover, VEGF-R2 has no function other than modulating angiogenic activity of VEGF in adults. Therefore, selective inhibitors of kinase activity of VEGF-R2 are expected to show little toxicity.
[21] Similarly, FGF-R binds to angiogenic growth factors aFGF and bFGF and modulates subsequent intracellular signal transduction. Recently, growth factors such as bFGF have been known to play a pivotal role in inducing angiogenesis in solid tumors of constant size (Yoshiji et al., Cancer Research , 57 , 3924-3928 (1997)). Unlike VEGF-R2, FGF-R is expressed throughout a number of different cell types throughout the body and may or may not play an important role in other normal physiology in adults. Nevertheless, systemic administration of low molecular weight inhibitors of kinase activity of FGF-R is not toxic and has been reported to prevent bFGF-induced angiogenesis in mice (Mohammad et al., EMBO Journal , 17 , 5996-5904 ( 1998)).
[22] TEK (also referred to as Tie-2) is expressed only in endothelial cells where it appears that angiogenesis occurs with another receptor tyrosine kinase. Combined with angiopoietin-1 factor, TEK's kinase domain undergoes autophosphorylation and modulates the interaction of endothelial and peri-endothelial supplying cells to promote signal transduction that promotes maturation of new angiogenesis. do. On the other hand, angiopoietin-2 factor stops angiogenesis by halving the activity of TEK and angiopoietin-1 (Maisonpierre et al., Science , 277 , 55-60 (1997)).
[23] As discussed above, angiogenesis was treated with compounds that inhibit the kinase activity of VEGF-R2, FGF-R and / or TEK. For example, WIPO International Publication No. WO 97/34876 relates to abnormal angiogenesis and / or cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and Vascular permeability such as chronic nephropathies, atheroma, arterial restinosis, autoimmune diseases, acute inflammation and ocular diseases due to retinal vascular proliferation Cinoline derivatives are disclosed as inhibitors of VEGF-R2 used for the treatment of increasing disease states. Many other protein kinases are considered as therapeutic targets along with the protein kinases, and a great deal of publications disclose kinase activity inhibitors. McMahon et al., Current Opinion in Drug Discovery & Development , 1 , 131-146 (1998); Strawn et al., Exp. Opin. Invest. See Drugs , 7 , 553-573 (1998).
[24] However, there is still a need for other small molecule compounds that are easy to synthesize and act as potent inhibitors of cell proliferation, as inhibitors of one or more protein kinases such as CHK1, VEGF, CDKs or CDK / cycline complexes. Because CDK4 acts as a common activator of cell division in most cells, specific inhibitors of CDK4 and / or CDK2 are needed to treat one or more types of tumors.
[25] It is an object of the present invention to provide a potent antiproliferative agent. It is therefore an object of the present invention to provide compounds and pharmaceutical compositions which inhibit the activity of one or more kinases, such as CDKs, VEGF and CHK-1, or their cyclin complexes. Another object of the present invention is to provide a pharmaceutical composition containing a compound having an effect of preventing the metastasis of cancer cells in the proliferation stage. The advantages of the present invention in view of the above objects and the details detailed below are obtained through the use of the cell cycle modulators of the invention described below.
[26] In order to achieve the above object, the present invention provides a compound represented by Formula (I):
[27] (Ⅰ)
[28] From here,
[29] R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
[30] ,
[31] Wherein R ₄ is H or lower alkyl and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
[32] R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
[33] ,
[34] Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
[35] Pharmaceutically acceptable salts of compounds of formula I; Or a prodrug or pharmaceutically active metabolite of Formula I, or a pharmaceutically acceptable salt of the prodrug or metabolite.
[36] In addition, to achieve the object of the present invention, the present invention provides a compound represented by the following general formula (II):
[37]
[38] Wherein R ₁ ′ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle, Group,
[39] Wherein R ₄ is individually H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
[40] R ₂ ′ is substituted or unsubstituted amino, nitro, alkenyl, alkyl, aryl, heteroaryl, carbocycle, or heterocycle, Group,
[41] Wherein R ₄ is independently H or lower alkyl, and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
[42] Pharmaceutically acceptable salts of compounds of formula II; Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt of the prodrug or metabolite.
[43] The present invention also relates to a pharmaceutical composition comprising the following items.
[44] (a) Cell cycle regulators selected below:
[45] (Iii) a compound of formula (I) or (II),
[46] (Ii) pharmaceutically acceptable salts of compounds of Formula I or II; or
[47] (Iii) a prodrug or pharmaceutically active metabolite of a compound of Formula I or II or a pharmaceutically acceptable salt of said prodrug or metabolite; And
[48] (b) pharmaceutically acceptable carriers
[49] The present invention also relates to a process for the preparation of compounds of formulas (I) and (II).
[50] Furthermore, the present invention provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt of a compound of formula (I) or (II) to treat a disease or condition modulated by inhibition of kinases in a patient in need thereof; Or prodrugs or pharmaceutically active metabolites of the compounds of Formula I or II or pharmaceutically acceptable salts of the prodrugs or metabolites as cell cycle regulators.
[51] Also provided herein are pharmaceutically acceptable salts of a compound of Formula I or II or a compound of Formula I or II to a patient in need thereof; Or mycotic infection, malignancies, including the administration of an effective amount of a prodrug or pharmaceutically active metabolite of the compound of Formula I or II or a pharmaceutically acceptable salt of said prodrug or metabolite Or a method of treating cancer as well as other diseases associated with unwanted angiogenesis and / or cell proliferation.
[52] Also provided herein are pharmaceutically acceptable salts of a compound of Formula I or II or a compound of Formula I or II to a patient in need thereof; Or to a method for modulating and / or inhibiting kinase activity by administering a prodrug or a pharmaceutically active metabolite of the compound of Formula I or II or a pharmaceutically acceptable salt of said prodrug or metabolite.
[53] The present invention also provides a pharmaceutically acceptable salt of a compound of Formula I or II or a compound of Formula I or II; Or diabetic retinopathy, as well as pharmaceutical compositions and cancers containing a prodrug or pharmaceutically active metabolite of the compound of Formula I or II, or a pharmaceutically acceptable salt of said prodrug or metabolite, A method of treating a composition for treating a disease modulated by other disease kinase activity associated with undesired angiogenesis and / or cell proliferation, such as neovascular glaucoma, rheumatoid arthritis and psoriasis.
[54] In the pharmaceutical composition according to the present invention and a method for preparing the same, R ₁ in Formulas I and II may be hydrogen.
[55] The formulations of the present invention and compositions containing such formulations may be combined with uncontrollable or unwanted cell proliferation such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative diseases and cardiovascular diseases, and the like. It is used to treat various related diseases or disorders.
[56] Further aspects, advantages and features of the invention will be described in more detail below.
[1] Cross Reference to Related Applications
[2] This application claims the priority of US Provisional Application No. 60 / 176,484, filed January 18, 2000.
[3] FIELD OF THE INVENTION
[4] The present invention relates to an indazole compound that modulates or inhibits cell proliferation by inhibiting the activity of protein kinases such as VEGF, CHK-1, and cyclin-dependent kinases (CDKs) such as CDK1, CDK2, CDK4, CDK6. The invention further relates to pharmaceutical compositions containing said indazole compounds and to methods of administering an effective amount of said compounds to treat unwanted angiogenesis and / or cancer as well as various other diseases associated with cell proliferation. .
[57] The compounds and compositions according to the invention are used as antiproliferative and inhibitors of mammalian kinase complexes, insect kinases or fungal kinase complexes. For example, it can inhibit VEGF, CHK-1 and / or CDK complexes. The compounds and compositions of the present invention are also used for the purpose of controlling proliferation, differentiation and / or killing.
[58] Preferred examples of R ₁ , R ₂ , R ₁ ′ and R ₂ ′ in the compounds of formula I or II are as described below:
[59]
[60] Preferably, R ₁ and R ₁ ′ are
[61]
[62] ,
[63] Wherein Y is CH, N or CR ₃ , X is as defined above and R ₃ is H or substituted or unsubstituted alkyl, alkenyl, aryl, heteroaryl, carbocycle, heterocycle, hydroxy, One or more substituents located on a ring such as halogen, alkoxy, aryloxy, heteroaryloxy, thioalkyl, thioaryl, thioacyl, thioheteroaryl or amino; or
[64] ,
[65] Where two Y's may be the same or different.
[66] In the example above, R ₁ and R ₁ ′ If present, one or more R ₃ substituents may be present in the phenyl ring.
[67] More preferably, R ₁ and R ₁ ′ are substituted or unsubstituted
[68] ,
[69] Wherein the R ₃ group is as defined above. And two R ₃ ′ adjacent to nitrogen form a heteroaryl or heterocycle ring.
[70] Preferably phenyl in which R ₂ and R ₂ ′ are substituted or unsubstituted or
[71] ,
[72] Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted group selected from alkyl, aryl, heteroaryl, carbocycle or heterocycle.
[73] Other preferred R ₂ and R ₂ ′ groups are substituted or unsubstituted heteroaryls as follows:
[74]
[75] Other preferred R ₂ and R ₂ 'groups are
[76]
[77] Where R ₃ is as defined above.
[78] Particularly preferred substituents for R ₂ phenyl include alkoxy groups such as fluorine, chlorine, hydroxyl groups or methoxy. Preferred examples of the R group, X and Y group can be found in the following example compounds.
[79] Preferred Y is nitrogen.
[80] Preferred Xs are aryl, heteroaryl, carbocycle or heterocycle, with phenyl being most preferred.
[81] R ₂ and R ₂ ′ may also be amino (—NR′R ″), where R ′ and R ″ are independently of R ₃ as defined above and may form a ring with adjacent nitrogen.
[82] Preferred R ₄ is hydrogen, or may be substituted or unsubstituted lower alkyl having 1-6 carbon atoms. Two R ₄ ′ may be the same or different.
[83] Other preferred R ₁ , R ₂ , R ₁ 'and R ₂ ' groups can be found in the following example compounds.
[84] Optionally desired alkyl groups may be used as R ₁ , R ₂ , R ₁ ′, R ₂ ′, R ₃ or X. Alkyl groups are straight or branched chain alkyl groups having 1-12 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl and the like. Alkyl groups may or may not be substituted. Preferred substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like. Can be.
[85] Optionally required aryl, heteroaryl, carbocycle or heterocycle groups may be used as R ₁ , R ₂ , R ₁ ′, R ₂ ′, R ₃ or X. The groups can be fused or unfused, monocyclic or polycyclic.
[86] Preferred aryl and heteroaryl groups include monocyclic and polycyclic substituted or aromatic ring structures, which are referred to as "aryl" if carbocycle and "heteroaryl" for heterocycle. Examples of ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl (pyridinyl), pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-oxadia Oxadiazolyl, 1,3,4-oxadiazolyl, 1H-tetrazol-5-yl, indolyl, quinolinyl, benzothiophenyl (thianaphthenyl) (benzothiophenyl (thianaphthenyl), furanyl, thiophenyl, oxazolyl isoxazolyl, thiazolyl, triazolyl, tetrazolyl, tetrazolyl, isoquinolin Isoquinolinyl, acridinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, and the like.
[87] Preferred carbocycle groups have 3-12 carbon atoms and have bicyclic and tricyclic cycloalkyl structures. Preferred carbocycle groups include cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and the like.
[88] Preferred heterocycle groups include saturated rings containing carbon atoms, for example containing 4 or 5 ring carbon atoms and at least one heteroatom selected from nitrogen, carbon, sulfur and have no unsaturateds. Preferred heterocycle groups include pyrrolidinyl, piperidinyl, thiazinyl and morpholinyl.
[89] R ₁ , R ₂ , R ₃ , Y, X and other R groups may or may not be substituted with the required substituents or substituents that do not adversely affect the required activity in the compound. Examples of preferred substituents can be found in the compounds of the examples which follow, including halogen (chloro, iodo, bromo or fluoro); C _1-6 -alkyl; C _1-6 -alkenyl; C _1-6 -alkynyl; Hydroxyl; C _1-6 -alkoxy; Amino; Nitro; Thiols; Thioethers; immigrant; Cyano; Amido; Phosphonato; Phosphine; Carboxyl; Thiocarbonyl; Sulfonyl; Sulfonamides; Ketones; Aldehydes; ester; Oxygen (= O); Haloalkyl (eg trifluoromethyl); Carbocyclic cycloalkyl which is monocyclic or fused or unfused polycyclic (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or monocyclic or fused or unfused polycyclic (pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl or thiazinyl, etc.) heterocycloalkyl; Kirbocyclic or heterocyclic, monocyclic or fused or unfused polycyclic aryl (phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, tria Zolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) ; Amino (primary, secondary or tertiary amine); Nitro; Thiols; Thioether, O-lower alkyl; O-aryl, aryl; Aryl-lower alkyl; CO ₂ CH ₃ ; CONH ₂ ; OCH ₂ CONH ₂ ; NH ₂ ; SO ₂ NH ₂ ; OCHF ₂ ; CF ₃ ; OCF ₃ etc. are mentioned.
[90] Some of these may also be optionally substituted with fused ring structures or bridge bonds, such as OCH ₂ -O.
[91] These substituents are also to be substituted with substituents selected from the following groups.
[92] Preferred compounds include the following:
[93]
[94] The invention also relates to intermediates used to prepare the compounds of formula (I) or (II). Particularly preferred intermediates have the structure
[95]
[96] Another preferred intermediate structure is
[97]
[98] Another preferred intermediate structure is
[99] X is halogen, NO ₂
[100] Can be mentioned.
[101] Benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (BOC), tetra hydropyranyl (THP) and fluorene-9-methyloxycarbonyl (FMOC), which are well known instead of SEM in the three intermediates Other protecting groups can be used.
[102] Other preferred intermediates include the following materials:
[103]
[104] "SEM" and "PMB" are abbreviations for (trimethyl silyl) ethoxy methyl and p-methoxybenzyl, respectively.
[105] As the structure of the preferred intermediate
[106]
[107] Wherein PG is a protecting group, T is a substituted or unsubstituted reaction group such as boron, halogen, NO ₂ or NH ₂ , and T ′ is CHO, CO ₂ H, CO ₂ R ₃ , CONR ₃ R _3, or the like. Is a reaction group, and R ₃ is as defined above.
[108] The pharmaceutical composition according to the present invention may optionally contain a compound of Formula I or II, or a pharmaceutically acceptable salt of a compound of Formula I or II, or a prodrug or pharmaceutically active metabolite of a compound of Formula I or II. Or a pharmaceutically acceptable salt of said prodrug or metabolite as an active ingredient. Such compounds, salts, prodrugs and metabolites are described herein collectively as "cell cycle regulators."
[109] The term "prodrug" means a metabolic precursor of a pharmaceutically acceptable compound of Formula I or II (or salts thereof). Prodrugs are inactivated when administered to a patient, but are converted to the active compounds of Formula I or II in vivo. The term "active metabolite" means a metabolite product of a compound of Formula I or II that is pharmaceutically acceptable and potent.
[110] Prodrugs and active metabolites of compounds can be prepared using conventional techniques known in the art. Bertolini et al., J. Med. Chem ., 40 , 2011-2016 (1997); Shan, et al., J. Pharm. Sci. , 86 (7) , 765-767; Bagshawe, Drug Dev. Res ., 34 , 220-230 (1995); Bodor, Advances in Drug Res ., 13 , 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); And Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., Eds., Harwood Academic Publicshers, 1991).
[111] In the present invention, the compounds of formula (I) or (II) exhibit tautomerism and the formulas within the present specification represent only one of the possible tautomeric forms. It will be appreciated that the present invention includes tautomeric forms that modulate and / or inhibit kinase activity and are not limited to the tautomeric forms used in the formulas herein.
[112] Some of the compounds of the present invention exist as single stereoisomers (essentially free from other stereoisomers), racemates and / or mixtures of enantiomers and / or diastereomers. Such single stereoisomers, racemates and mixtures thereof are all considered to be within the scope of the present invention. Preferably the optically active compounds of the invention are used in optically pure form.
[113] In general, according to techniques known in the art, an optically pure compound having one chiral center (one asymmetric carbon atom) consists essentially of one of the two possible enantiomers (enantiomerically accommodating), Optically pure compounds having one or more chiral centers exist in both diastereomerically pure and enantiomerically pure forms. Preferably, at least 90% or more of the compounds according to the invention are used in optically pure form, in which case at least 90% or more of the single isomers (more than 80% enantiomeric (hereinafter referred to as "ee") or more than diastereomeric) (Hereinafter referred to as "de"), more preferably at least 95% or more (90% ee or de), even more preferably at least 97.5% or more (95% ee or de), And most preferably at least 99% (98% ee or de).
[114] Formulas I and II also include solvated forms as well as unsolvated forms of the found structures. For example, formulas (I) and (II) include compounds having structures represented in both hydrogenated and nonhydrogenated forms. Other examples of solvates include combined structures with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine.
[115] "Pharmaceutically acceptable salt" means a salt that is free of biological or otherwise side effects while maintaining the biological effects of the free acids and bases of a particular compound. The compounds of the present invention are sufficiently acidic, sufficiently basic or have two functional groups and thus react with many inorganic or organic bases and inorganic or organic acids in the form of pharmaceutically acceptable salts. Examples of the pharmaceutically acceptable salts include minerals or organic acids or inorganic salts and their salts prepared by the interaction of the compounds of the present invention, such salts include sulfates, pyrosulfates, bisulfates, Sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogen-phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodine Iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, and caproates ), Heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumaric acid (fumarates), maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates , Chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfone Xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrate, lactates, γ-hydroxybutyrates, glycolates Tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates And mandelates.
[116] If the compound according to the invention is a base, preferred pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; Or acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, Organic acids such as glycolic acid, salicylic acid; Pyranosidyl acid, such as glucuronic acid or galacturonic acid; Alphahydroxy acids such as citric acid or tartaric acid; Amino acids such as aspartic acid or glutamic acid; Known conventional treatments of free bases with aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc. It can be prepared by the phosphorus method.
[117] If the compound according to the invention is an acid, preferred pharmaceutically acceptable salts are free acids such as inorganic or organic bases, such as amines (primary, secondary or tertiary), alkali metal hydroxides or alkaline earth metal hydroxides. It may be prepared by a known conventional method of treating. Examples of suitable salts include amino acids such as glycine and arginine; Ammonia, primary, secondary, tertiary amines; And cyclic amines such as piperidine, morpholine and piperazine; And inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
[118] When the agent is a solid, it is understood that the compounds and salts of the present invention may exist in various other forms of crystal structure or in various forms, all of which may be intentionally included within the scope of the present invention and the specific formulas above. It can be understood by.
[119] The cell cycle modulator according to the present invention is used as a medicament for treating proliferative diseases resulting from unwanted proliferation of endogenous tissues of mammals, especially humans. The compounds of formula (I) or (II) are used for the treatment of patients with diseases associated with excess cell proliferation such as cancer, psoriasis, immune diseases including aberrant proliferation of leukocytes, restenosis and other smooth-muscle diseases. The compounds according to the invention are also used to prevent complete differentiation of tissues and / or cells after mitosis.
[120] Diseases or disorders associated with uncontrolled or abnormal cell proliferation are not particularly limited and include the following:
[121] Carcinoma, hematopoietic tumor of lymphoid lineage, hematopoietic tumor of bone marrow, mesenchymal origin, tumor of central and peripheral nervous system and black Various cancers including other tumors such as melanoma, seminoma and Kaposi's sarcoma
[122] -Benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, angioplasty progression of abnormal cell proliferation, including restenosis, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxin shock and fungal infection following angioplasty and vascular surgery
[123] Cancer (not limited to the form described above), viral infection (but not particularly limited to, herpesvirus, poxvirus, Epstein-Barr virus, Sindvis) Viruses (such as Sindbis virus and adenovirus), prevention of AIDS outbreaks infected with HIV, autoimmune diseases (including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, Autoimmune, inflammatory bowel disease and autoimmune diabetes associated with glomerulonephritis, degenerative neurological diseases (including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, and retinitis pigmentosa) ), Parkin's disease, AIDS-related dementia, spinal muscular atrophy, and cerebellar degeneration. ), Myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and refusion injury, arrhythmia , Arteriosclerosis, liver disease associated with toxic content or alcohol, hematological diseases (including but not limited to aplastic anemia), degenerative diseases (but not particularly limited to, osteoporosis and arthritis) Death-related diseases such as aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.
[124] The active agents of the present invention are also used to inhibit the growth of invasive cancers, tumors, angiogenesis, metastasis.
[125] In addition, the active agent of the present invention is used as an inhibitor of CDKs to regulate the level of RNA and DNA synthesis in the cell, and therefore, HIV, human papilloma virus, herpes virus, Epstein-Bar virus (Epstein). -Barr virus), adenovirus, Sindbis virus, Fox virus, etc. can be used to treat the infection.
[126] Compounds and compositions according to the present invention inhibit kinase activity, such as CDK / cycline complexes activated at the G ₀ or G ₁ stage of the cell cycle, such as CDK2, CDK4, CDK6 complexes.
[127] Certain doses of cell cycle modulators administered to achieve a therapeutic or inhibitory effect are nominated in a conventional manner, depending upon the particular circumstances surrounding the particular agent being administered, the route of administration, the condition of treatment, the patient or host being treated. An example of the total daily dose of the cell cycle regulator that may be administered in single or multiple doses may be administered at a dosage level of about 0.01 mg / kg to about 50 mg / kg of body weight.
[128] Cell cycle regulators according to the invention can be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, intranasally through various routes. The cell cycle modulator is preferably administered in the form of a composition suitable for the route required before administration.
[129] A pharmaceutical composition or formulation according to the present invention comprises an effective amount of a cell cycle regulator, optionally one or more other active agents, and a pharmaceutically acceptable carrier such as a diluent or excipient for the formulation. If the carrier is given as a diluent, it may be a solid, semisolid, or liquid substance which acts as a carrier, excipient or medium for the active ingredient. The composition according to the present invention can be prepared by mixing the active ingredient with the carrier, diluting with the carrier, or encapsulating or sealing the carrier together in the form of a capsule, sachet, paper container or the like. Examples of ingredients added as one or more cell cycle regulators and other active ingredients include Avicell (microcrystalline cellulose), starch, lactose, calcium phosphate dihydrate, terra alba, sucrose, mica, gelatin , Agar, pectin, acacia, magnesium stearate, stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween 80 (polysorbate 80), 1,3-butanediol, cocoa Butter, beeswax, polyethylene glycol, propylene glycol, sorbitan monostearate, polysorbate 60, 2-octyldodecanol, benzyl alcohol, glycine, sorbic acid, potassium sorbate, disodium hydride Gen phosphate, sodium chloride, water, etc. are mentioned.
[130] The pharmaceutical composition may be used in various pharmaceutical forms depending on the dosage form required. For example, pharmaceutical compositions may be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or Liquid preservatives), ointments (containing at least 10% of the cell cycle regulator vaginal), soft and hard capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
[131] Similarly, carriers or diluents are time-delays known in the art, such as glyceryl monostearate or glyceryl stearate, alone or in combination with wax, ethylcellulose, hydroxypropylmethylcellulose methylmethacrylate. Or a time-release material.
[132] Various pharmaceutical forms may also be used. Thus, if a solid carrier is used, the formulation can be tableted and included in the cured gelatin capsules in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g. If liquid carriers are used, the formulations will be in the form of syrups, emulsions, soft gelatin capsules, sterile injectable solutions or ampoules or suspensions in vials or non-aqueous liquid suspensions.
[133] In order to obtain a stable water soluble dosage form, the pharmaceutically acceptable salt of the agent according to the invention is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 ml solution of succinic acid or citric acid. If a form of water soluble salt is not available, the agent may be dissolved in a suitable cosolvent or combination of cosolvents. Examples of suitable cosolvents include, but are not particularly limited to, alcohols, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like, with a concentration range of 0-60% relative to the total volume. Have According to the examples, the compounds of formula I or II are dissolved in DMSO and diluted with water. The composition may also be in the form of a solution containing the active ingredient in the form of a salt in a suitable aqueous carrier such as water or isotonic saline or dextrose solution.
[134] The compositions of the present invention are commonly known methods of preparing pharmaceutical compositions, for example mixing, dissolving, granulating, dragging-making, levigating, emulsifying, encapsulating, entrapping ( It can be prepared using conventional techniques such as entrapping or lyophilizing. The pharmaceutical composition may be formulated in a conventional manner using one or more physiologically acceptable carriers selected from excipients and auxiliaries to aid in the process of making the active compound a pharmaceutically usable agent. .
[135] Proper formulation is dependent upon the route of administration chosen. In the case of injection, the agents of the invention are in liquid form, preferably in dissolved form in a physiologically compatible buffer such as Hanks's solution, Ringer's solution or physiological saline buffer. Can be formulated. For transmucosal administration, suitable penetrants may be used in the formulation to allow passage through the barrier membrane. Such wetting agents are commonly known in the art.
[136] In the case of oral administration, the mixtures can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers may be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by the patient to be treated. do. Pharmaceutical preparations for oral use can be obtained using a mixture of active ingredients (agents) and solid excipients, if necessary, further grinding the obtained mixture, adding appropriate auxiliaries and then granulating the mixture. Can be obtained as tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; And cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose or polyvinylpi Ralidone (PVP) and the like. If desired, disintegrating agents such as crosslinked polyvinyl pyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate and the like may be added.
[137] Dragee cores perform the appropriate coating. For this purpose, concentrated sugar solutions can be used, which are optionally gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions ( lacquer solutions) and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active agents, a dye or pigment may be added to the tablet or dragee codings.
[138] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of plasticizers such as gelatin and glycerol or sorbitol. The fit capsule may comprise a mixture of the active ingredient and a filler such as lactose, a binder such as starch and / or lubricants such as talc or magnesium stearate, and may optionally further comprise a stabilizer. In the case of soft capsules, the active agents may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration must be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated by conventional methods.
[139] Compositions for use according to the invention, for administration intranasally or by inhalation, together with suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, It can be conveniently transported in a form in which an aerosol spray is released from a compressed pack or sprayer. In the case of a compressed aerosol, the dosage unit can be determined by providing a valve for transporting a quantified amount. Gelatin capsules and cartridges for use in an inhaler or insufflator or the like may be formulated containing a powder mixture of the present compound and a suitable powder base such as lactose or starch.
[140] The compositions may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be present in unit-dosage form, with preservatives, for example in ampoules or in multi-dose containers. The compositions may take the form of suspensions, solutions or emulsions with emulsifying or liquid carriers, and may contain agents such as suspending, stabilizing and / or dispersing agents.
[141] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active agents can be prepared as appropriate emulsion injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or synthetic fatty acid esters or liposomes such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that can increase the solubility of the compound to allow a high concentration of solution to be prepared.
[142] For administration to the eye, the compound is transported with a pharmaceutically acceptable ophthalmic vehicle so that the compound remains in contact with the eye surface for a sufficient time, so that the compound is present in the cornea and internal region of the eye. Can penetrate into, for example, the anterior chamber, the posterior chamber, the vitreous body, the aqueous humor, the vitreous fluid, the cornea, the iris, the lens, the choroid / retina and the selera. . Pharmaceutically acceptable ocular carriers include ointments, vegetable oils or encapsulating materials, and the like. In addition, the compounds of the present invention can be injected directly into the vitreous and aqueous solutions.
[143] The active ingredient may also be in powder form for composition with a suitable carrier, eg, sterile pyrogen-free water, prior to use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas containing conventionally known suppository bases such as cocoa butter or other glycerides.
[144] In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such formulations that last a long time may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the present compounds may be prepared in combination with a suitable polymeric or hydrophobic material (such as an emulsion in an acceptable oil) or an ion exchange resin, or almost insoluble, such as a sparingly soluble salt. May be formulated as derivatives.
[145] Pharmaceutical carriers for hydrophobic compounds are cosolvents including benzyl alcohol, nonpolar surfactants, organic polymers that can be mixed with water and an aqueous phase. The cosolvent system may be a VPD cosolvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v nonpolar interfacial polysorbate 80 and 65% w / v polyethylene glycol 300, with the remaining volume 100% ethanol. The VPD cosolvent system (VPD: 5W) contains VPD diluted with 5% aqueous dextran solution in a ratio of 1: 1. This cosolvent system dissolves hydrophobic compounds well, and itself shows low toxicity even when administered systemically. Naturally, the proportion of cosolvent system can vary considerably as long as it does not destroy its solubility and toxic properties. In addition, the homogeneity of the cosolvent elements may vary. For example, if it is of low toxicity, other nonpolar surfactants may be used instead of polysorbate 80. The fraction size of polyethylene glycol can also vary. If biocompatible, other polymers such as polyvinyl pyrrolidone and the like can also replace polyethylene glycol. Other sugars or polysaccharides may also replace dextrose.
[146] In addition, other transport systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are known examples of transport vehicles or carriers for hydrophobic agents. In general, although there are significant toxicity values, certain organic solvents such as dimethylsulfoxide may also be used. In addition, the compounds can be transported using sustained-release systems, such as semipermeable mattresses of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are established and known in the art. Sustained-release capsules, depending on their chemical nature, release the compounds from several weeks to over 100 days. In view of the chemical properties and biological stability of the therapeutic reactants, additional strategies for protein stabilization can be used.
[147] In addition, the pharmaceutical compositions may comprise a carrier or excipient in a suitable solid- or gel-like state. Examples of such carriers or excipients include polymers such as calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polyethylene glycol.
[148] Some compounds of the present invention may be provided as salts formed with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed by various acids including hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid and the like. Salts tend to dissolve better in water-soluble or other protonic solvents than the corresponding free-base form.
[149] The pharmaceutical composition according to the present invention optionally contains one or more other active ingredients of suitable known antiproliferative agents which are compatible with cell cycle modulators and cell cycle modulators and exhibit treatment.
[150] These compounds are used as agents for modulating or inhibiting the activity of anti-angiogenic agents and protein kinases and thus are used to treat cancer or other diseases associated with cell proliferation by protein kinases.
[151] A therapeutically effective amount of the agent according to the invention can be used to treat diseases associated with the modulation or regulation of protein kinases. "Effective amount" means the amount of an agent that, when administered to a mammal in need thereof, has a sufficient therapeutic effect against diseases caused by the activity of one or more protein kinases. Thus, a therapeutically effective amount of a compound of Formula (I) or (II), their salts, active metabolites or prodrugs modulates, modulates, or modulates the activity of one or more kinases involved in a disease that is modulated due to decreased or alleviated kinase activity. Say enough amount to restrain. It means the minimum amount by which the effects of protein kinases are controlled. These compositions are prepared in a single dose in an appropriate amount for the mode of administration, for example parenteral or oral administration.
[152] “Treating” is the least alleviation of a disease that occurs in a mammal, such as a human, and is somewhat affected by the activity of at least one or more kinases; In particular, although the mammal has not yet been diagnosed as having developed a disease, it prevents diseases occurring in the mammal, such as finding out in advance of causing the disease; modulating and / or inhibiting the disease; And / or diagnosing a disease.
[153] The formulation of the present invention was prepared through the reaction and synthesis procedures described below by techniques commonly used using readily available starting materials.
[154] Compounds of the present invention were prepared in the same manner as shown in the general schemes 1-6 described below.
[155]
[156] The halogenated intermediate A can be prepared by usually diazotizing 5-amino-andazole and treating the resulting diazonium salt with a suitable halogen salt such as CuCl or KI. Then, halogenated by treating a halogen element such as iodine with a suitable base such as sodium hydroxide or potassium hydroxide to prepare 3-haloindazole B. Intermediate B is protected with any number of suitable protecting groups and treated (preferably stoichiometrically) with a Pd catalyst such as alkyl or boronic acid or ester and a suitable Pd (PPh ₃ ) ₄ to position C-3 Selectively affected. Then reacted with a second alkyl or aryl boronic acid or ester and a suitable Pd catalyst were prepared for any intermediate E is a 3,5- (di) substituted vaporizing the intermediate E is deprotected to the final compound F Manufacture. Examples of deprotection conditions associated with particular protecting groups include those carried out in acidic conditions for the removal of THP protecting groups. R ₁ and R ₂ are as defined above, and R ₁ 'and R ₂ ' are also possible.
[157] [Modification of Scheme 1]
[158]
[159] The selective synthetic transformation in Scheme 1 comprising the step of the intermediate X in the intermediates G C produced by processing the hexamethyl ditin (ditin) alkyl and di tinjong Cl, such as a suitable Pd catalyst. Intermediate G is reacted with an alkyl or aryl halide and a suitable Pd catalyst to produce intermediate D in a more complex manner than above.
[160]
[161] As in Scheme 2, 5-nitroindazole may be halogenated with the intermediate A described above, and optionally, an intermediate H such as an appropriate base such as sodium hydroxide or potassium hydroxide and an elemental halogen such as iodide may be treated. May be prepared, or intermediate I may be prepared by a standard protecting group reaction with a suitable protecting group. Intermediate I is treated with alkyl ditin species such as hexamethyl ditin and the appropriate Pd catalyst to prepare intermediate J. The 3-substituted indazole K is prepared by reacting the nitro compound J with an alkyl or aryl boronic acid or ester and a suitable Pd catalyst. The indazole K is reduced with a suitable reducing agent such as hydrogen and a palladium catalyst or SnCl ₂ to prepare an amine. The resulting 5-amino indazole is diazotized, and the resulting diazonium salt is treated with a suitable halogenated salt such as CuCl or KI to prepare an intermediate halo compound L. The intermediate L by reacting with an alkyl or aryl boronic acid or ester and a suitable Pd catalyst can be prepared the intermediates M, vaporizes the intermediate M is deprotected to prepare the final compounds F. R ₁ and R ₂ are as defined above, and R ₁ 'and R ₂ ' are also possible.
[162]
[163] In Scheme 3, 3-carboxyindazole is activated to produce an active acylating species such as carbonyldiimidazole, and then treated with a suitable alkoxy-alkyl amine such as N, N-dimethylhydroxyamine. To prepare amine A ' . Intermediate A ' is selectively halogenated with an elemental halogen such as bromine or iodine and a suitable catalyst such as bis (trifluoroacetoxy) iodosobenzene or bis (acetoxy) iodosobenzene to give 5-haloindazole B. 'Is prepared. The intermediate B ' is subjected to protecting group reaction with a suitable protecting group such as PMB or THP under standard conditions to prepare protecting group amine C' . The intermediate C ' is reduced with a suitable reducing agent such as lithium aluminum hydride or an equivalent hydride reducing agent to prepare aldehyde D' as the main intermediate. R ₃ is as defined above and preferably uses substituted or unsubstituted alkyl, preferably lower alkyl.
[164]
[165] Scheme 4 shows that intermediate D ' reacts with a suitable oxidant such as substituted diamine B " and sulfur to produce benzimidazole C" . The production of the C "a diphenoquinone or coke Todi boron (dipinacolatodiboron) such as diboron (diboron) species or other electrophilic source of boron, and an appropriate palladium catalyst and the acid was esterified D reaction." To produce an intermediate D "by the reaction with an aryl or alkyl halide under palladium catalyst 5-substituted indazole intermediate E" produced, and the intermediate E "Deprotection vaporized, finally the compound H" a.
[166] Optionally, the starting compound D 'bis (pinacolato) diborane to such a diborane reacts with the ronjong or other suitable electrophilic source and a suitable palladium boron catalyst Ron "to prepare a Compound F" boron ester F the above described carried out as in intermediate D 'to switch to the intermediate D ".
[167] In another selective conversion, aldehyde F ″ is reacted with a substituted aryl or alkyl halide and palladium catalyst to provide R ₂ to prepare compound G ″ . This compound G " is reacted with a suitable oxidizing agent such as substituted diamine B" and sulfur to form benzimidazole E " . Finally, deprotection of compound E" produces compound H " . R ₂ is defined above. And R ₂ ′ and R ₃ are also as defined above.
[168] Intermediate E ″ may also be prepared directly by treatment of the appropriate alkyl boronic acid or ester in the presence of a suitable palladium catalyst for compound C ″ .
[169] Additional electrophilic boron species may be used having the following structure:
[170]
[171] Here, R ₃ is as defined above, and two R ₃ groups may form a ring. Specific examples of the electrophilic boron species include those represented by the following chemical formulas:
[172]
[173]
[174] In Scheme 5, an alcohol intermediate X ₁ is reacted with a sulfonyl halide such as methanesulfonyl chloride, a suitable base such as triethylamine, and an electrophilic species to react with a nucleophile such as a substituted amine to react with intermediate X _2. To prepare a compound X ₃ by deprotecting the intermediate X ₂ under appropriate conditions. R ₂ is as defined above, and R ₂ ′ and R ₃ are also as defined above.
[175]
[176] Scheme 6 shows that the core indazole structure is formed by the cyclization reaction of 2-halo-5-nitrophenyl aryl ketone Y1 with hydrazine to prepare the essential 3-aryl-5-nitroindazole Y2 . Subsequently, amine Y4 is manufactured through a protecting group reaction and a reduction reaction. The amine Y4 is subjected to a diazotization reaction as shown in Scheme 2, and KI is treated with the diazonium salt, and the iodine intermediate and the aryl boronic acid are combined with a Pd catalyst to form a protected group 3,5-bisarylindazole intermediate Y6 . Manufacture. Intermediate Y6 is deprotected in conventional manner to produce the final product. R ₁ and R ₂ are as defined above, and R ₁ 'and R ₂ ' are also possible.
[177] While the preparation of the preferred compounds of the present invention is described in detail in the following examples, it is recognized by those skilled in the art that the described chemical reactions can be readily employed to prepare numerous other protein kinase inhibitors of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention may be accomplished by modifying other suitable reagents known in the art, for example, by appropriately protecting the hindered groups, through modifications and the like apparent to those skilled in the art. Or through the usual modification of the reaction conditions. It will also be appreciated that other reactions disclosed herein or known in the art can be applied to prepare other compounds of the present invention.
[178] In the following examples, unless otherwise noted, all temperatures are 4 ° C. and all parts and percentages are expressed in weight. Reagents were purchased from a manufacturer such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used as such without further purification unless otherwise noted. Tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) were purchased from Aldrich in Sure seal bottles and used as is. All solvents were purified using conventional standard methods known in the art unless otherwise noted.
[179] In general, rubber diaphragms for introducing substrates and reagents through syringes are installed in the following reactors and reaction flasks where anhydrous solvents are reacted under positive pressure of argon or nitrogen or in a drying tube at ambient temperature (unless otherwise noted). The glassware was dried in an oven and / or heat. Analytical thin layer chromatography (hereinafter referred to as "TLC") was performed on a backing glass silica gel 60 F 254 plate Analtech 0.25 mm and eluted with an appropriate solvent ratio (v / v) to suitably display. The reaction was analyzed by thin layer chromatography and terminated when the starting material was consumed.
[180] Visualization of TLC cultures is accomplished by visualizing the tip plates with p-anisaldehyde colorant or phosphomolybdic acid reagent (with 20 wt% of Aldrich Chemical in ethanol) and by thermal activation. Indicated. After finishing by doubling the reaction volume of the reaction solvent or the extraction solvent, wash with an aqueous solution corresponding to 25% of the volume of the extract unless otherwise indicated. The resulting solution was filtered and dried with anhydrous Na ₂ SO ₄ or MgSO ₄ prior to evaporating the solvent under reduced pressure in a rotary evaporator and the solvent was removed in vacuo. Fast column chromatography (Still et al., J. Org. Chem ., 43 , 2923 (1978)) uses baker grade fast silica gel (47-61 μm) and does not indicate otherwise, and the silica gel and crude material The ratio was about 20: 1 to 50: 1. The hydrocracking reaction was carried out at the pressure or ambient pressure specified in the examples.
[181] ^{The 1} H-NMR spectra were labeled using a Bruker instrument operating at 300 MHz and the ¹³ C-NMR spectra were labeled operating at 75 MHz. NMR spectra are either standards (7.25 ppm and 77.00 ppm) or CD ₃ OD (3.4, 4.8 ppm and 49.3 ppm) as a solution of CDCl ₃ (reported in ppm) using chloroform or intrinsically tetramethylsilane as required. ) (0.00ppm) was purchased and used. Other NMR solvents were used as needed. When describing the peak overlap, s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublets, and dt is doublet of triplets. Given coupling constants are expressed in hertz (Hz).
[182] Infrared spectra were expressed as wave number (cm ⁻¹ ) using Perkin-Elmer FT-IR spectrometer as neat oil or KBr pellets. Mass spectra were obtained using LSIMS or electrospray. All the melting points (mp) did not coincide.
[183] Starting materials used in the examples were used that are commercially available and / or can be prepared by conventional techniques in the art.
[184] Example 1 5-phenyl-3-styryl-1H-indazole
[185]
[186] (a) Intermediate 1a-5-chloro-3-iodo-1H-indazole:
[187] 5-amino-1H-indazole (15.41 g, 116 mmol) was added to a mixture of water (250 mL), ice (250 mL) and concentrated HCl (100 mL). The mixture was cooled in an ice-salt bath having an internal temperature of -5 ° C. Then to the mixture was added a solution of sodium nitrite (8.78 g, 127 mmol) in water (75 mL) and cooled to 0 ° C. The resulting diazonium solution was stirred at −5 ° C. for 15 minutes. A solution of copper chloride (I) (8.78 g, 127 mmol) dissolved in concentrated HCl (150 mL) was cooled to 0 ° C. and dropped into the diazonium solution to give an orange precipitate. The cooling bath was removed and reacted by warming to room temperature. Gas discharge was started at an internal temperature of 10 ° C. After stirring at room temperature for 1.5 hours, gas evolution was stopped. The flask was then heated at 60 ° C. for 30 minutes and then cooled to 15 ° C. or lower to produce a brown precipitate. The precipitate was collected by suction filtration and dried for 16 hours in a vacuum dessicator in the presence of NaOH to give crude 5-chloro-1H-indazole (25.6 g) as a brown powder.
[188] The crude product was dissolved in 1,4-dioxane (400 mL). 3M water soluble NaOH (400 mL) and iodine flakes (35.3 g, 139 mmol) were added to the solution. After stirring for 2 hours at room temperature, the reaction mixture was neutralized with 20% aqueous citric acid to pH = 6 and the dark color changed to light green. Saturated aqueous sodium thiosulfate (˜400 mL) was added to the solution, followed by extraction with ethyl acetate (3 × 1000 mL). The combined organic extracts were dried over sodium sulfate, suction filtered through coarse frit and concentrated to green sludge. The green sludge was then dissolved again in ethyl acetate (500 mL), filtered through a Celite pad and concentrated to a green solid. Purified by silica gel chromatography (25% ethyl acetate / hexane) to give 44% yield from 5-chloro-3-iodo-1H-indazole 1a (14.18g, 5-amino-1H-idazole in the form of an off-white solid. ) Was obtained: mp = 198-199 ° C; R _f = 0.53 (50% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ 7.44 (m, 2H), 7.60 (d, 1H, J = 8.7 Hz), 13.68 (s, 1H). Anal. (C ₇ H ₄ ClIN ₂ ) C, H, N.
[189] (b) Intermediate 1b- 5-chloro-3-iodine-1- [2- (trimethylsilany) -ethoxymethyl] -1 H-indazole:
[190] 5-Chloro-3-iodine-1H-indazole 1a (8.86 g, 31.8 mmol) was dissolved in THF (100 mL) and cooled in a 0 ° C. ice-salt bath. Solid t-butoxide sodium (3.67 g, 38.2 mmol) was added to the mixture, followed by stirring at 0 ° C. for 1 hour. Then 2- (trimethylsilyl) ethoxymethyl chloride (7.96 g, 38.2 mmol) was added and stirred at 0 ° C. for 1 h more. The solution was diluted with ethyl acetate (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. Silicagel chromatography (5 to 20% ethyl acetate / hexanes) gave intermediate 1b (9.75 g, 75%) in the form of a yellow oil: R _f = 0.39 (5% ethyl acetate / hexanes); ¹ H NMR (CDCl ₃ ) δ-0.06 (s, 9H), 0.87 (t, 2H, J = 8.1 Hz), 3.55 (t, 2H, J = 8.1 Hz), 5.70 (s, 2H), 7.43 (dd , 1H, J = 8.9, 1.7 Hz), 7.49 (m, 2H). Anal. (C ₁₃ H ₁₈ ClIN ₂ OSi) C, H, N.
[191] (c) Intermediate 1c-5-chloro-3-styryl-1- [2- (trimethylsilanyl) -ethoxymethyl] -1 H-indazole:
[192] 5-chloro-3-iodine-2-SEM-indazole 1b (553 mg, 1.35 mmol), styryl boronic acid (300 mg, 2.03 mmol) and tetrakis (triphenylphosphine) palladium (tetrakis) triphenylphosphine) palladium) (78.2 mg, 0.068 mmol) was dissolved in toluene (10 mL) and methanol (1.4 mL). To the mixture was added saturated aqueous bicarbonate sodium solution (1.7 mL) and then heated in a 90 ° C. oil bath for 3 hours. A slight backflow was observed at this time. The mixture was cooled to room temperature and then diluted with water (15 mL) and diluted with ethyl acetate (4x50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (toluene) gave pure intermediate 1c (350.7 mg, 67%) in the form of a yellow oil: R _f = 0.20 (toluene); ¹ H NMR (CDCl ₃ ) δ-0.09 (s, 9H), 0.86 (t, 2H, J = 8.1 Hz), 3.55 (t, 2H, J = 8.3 Hz), 5.65 (s, 2H), 7.2-7.4 (m, 7H), 7.54 (d, 2H, J = 7.6 Hz), 7.93 (d, 1H, J = 1.6 Hz). ¹³ C NMR (CDCl ₃ ) δ-1.5, 17.7, 66.5, 77.9, 111.0, 119.2, 120.3, 123.6, 126.5, 127.3, 127.4, 128.0, 128.7, 131.6, 136.9, 139.4, 142.5. Anal. (C ₂₁ H ₂₅ ClN ₂ OSi.0.02 CHCl ₃ ) C, H, N.
[193] (d) Intermediate 1d-5-phenyl-3-styryl-1- [2- (trimethylsilanyl) -ethoxymethyl] -1 H-indazole:
[194] Phenyl boronic acid (69.6 mg, 0.571 mmol), cesium in a solution of 5-chloro-3-styryl-2-SEM-indazole 1c (209.4 mg, 0.544 mmol) in dry 1,4-dioxane (0.5 mL) (cesium) carbonate (213 mg, 0.653 mmol) and tris (dibenzyl-idineacetone) dipalladium (10.0 mg, 0.0108 mmol) were added. To the mixture was added a solution of tri-tert-butyl phosphine dissolved in 1,4-dioxane (0.1M, 0.217 mL) and then heated to 80 ° C. for 6 hours. Then, after cooling to room temperature, the mixture was diluted with ethyl ether (20 mL) and filtered through a pad of celite to remove black palladium precipitate. The filtrate was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (toluene) to give intermediate 1d (77.2 mg, 33%) in the form of a clear oil: R _f = 0.09 (toluene); ¹ H NMR (CDCl ₃ ) δ-0.04 (s, 9H), 0.93 (t, 2H, J = 8.1 Hz), 3.62 (t, 2H, J = 8.1 Hz), 5.76 (s, 2H, J), 7.3 -7.7 (m, 14 H), 8.17 (s, 1 H). Anal. (C ₂₇ H ₃₀ N ₂ OSi0.2 H ₂ O) C, H, N.
[195] (e) Compound 1-5-phenyl-3-styryl-1H-indazole:
[196] Intermediate 1d (68.1 mg, 0.16 mmol) was dissolved in pure ethanol (2.0 mL) and 3M HCl (2.0 mL). The solution was heated to reflux for 20 hours, then cooled to room temperature and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (25-50% ethyl acetate / hexanes) to give 5-phenyl-3-styryl-1H-indazole (19.2 mg) as a white solid. , 40%) was obtained: R _f = 0.14 (25% ethyl acetate / hexanes); ¹ H NMR (CDCl ₃ ) δ6.92 (d, 1H, J = 6.3 Hz), 7.3-7.7 (m, 13H), 8.20 (s, 1H), 10.3 (br s, 1H). HRMS calcd for C ₂₁ H ₁₇ N ₂ 297.1392 (MH ⁺ ), found 297.1398. Anal. (C ₂₁ H ₁₆ N ₂ 0.7 H ₂ O) C, H, N.
[197] Example 2 3,5-Distyryl-1H-indazole
[198]
[199] (a) Intermediate 2a-5-iodo-1H-indazole:
[200] 5-amino-1H-indazole (10.21 g, 76.7 mmol) was added to a mixed solution of water (100 mL), ice (100 mL), and concentrated HCl (35 mL). The mixture was cooled in an ice-salt bath having an internal temperature of -5 ° C. To the mixture was added a solution of sodium nitrite (5.82 g, 84.4 mmol) in water (30 mL) and cooled to 0 ° C. The resulting diazonium solution was stirred at −5 ° C. for 10 minutes, and then a solution of potassium iodide (15.3 g, 92 mmol) dissolved in water (50 mL) was slowly added dropwise. The first few drops of the KI solution produced significant bubbles and later formed a black tarry gum. After all of the KI solution was added, the reaction mixture was heated to 90 ° C. for 1 hour. The reaction is then cooled to room temperature to form a light brown precipitate. The precipitate was collected by suction filtration and dried in vacuo to afford 5-iodineindazole 2a (14.12 g, 75%) in the form of a brown powder: R _f = 0.28 (50% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ 7.40 (d, 1H, J = 9.0 Hz), 7.56 (dd, 1H, J = 8.5, 1.5 Hz), 8.01 (s, 1H), 8.16 (s, 1H) , 13.23 (s, 1 H). Anal. (C ₇ H ₅ IN ₂ ) C, H, I, N.
[201] (b) Intermediate 2b-3,5-diiodo-1H-indazole:
[202] Intermediate 2b was prepared by the same synthesis method as the synthesis of intermediate 1a . Treatment of iodine and intermediate 2a with sodium hydroxide yielded 3,5-diiodo-1H-indazole 2b (84%) in the form of a yellow solid: R _f = 0.39 (30% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ 7.41 (d, 1H, J = 8.7 Hz), 7.66 (dd, 1H, J = 8.7, 1.5 Hz), 7.77 (d, 1H, J = 0.9 Hz), 13.65 ( s, 1 H).
[203] (c) Intermediate 2c- 3,5-Diiodo-1- [2- (trimethylsilanyl) -ethoxymethyl] -1 H-indazole:
[204] In the same manner as in the synthesis of intermediate 1a , 3,5-diiodo-1H-indazole 2b and t-butoxide sodium were treated with 2- (trimethylsilyl) ethoxymethyl chloride in the form of a yellow oil. Diiodine-1- [2- (trimethylsilanyl) -ethoxymethyl] -1H-indazole 2c (64%) was obtained: R _f = 0.53 (30% ethyl acetate / hexane); ¹ H NMR (CDCl ₃ ) δ-0.05 (s, 9H), 0.86 (t, 2H, J = 8.1 Hz), 3.54 (t, 2H, J = 8.1 Hz), 5.69 (s, 2H), 7.34 (d , 1H, J = 8.7 Hz, 7.69 (dd, 1H, J = 8.7, 1.5 Hz), 7.87 (d, 1H, J = 1.5 Hz).
[205] (d) Intermediate 2d-3,5-distyryl-1- [2- (trimethylsilanyl) -ethoxymethyl] -1 H-indazole:
[206] Styryl boronic acid (186 mg, 1.26 mmol) was added to intermediate 2c (210.0 mg, 0.42 mmol) and toluene (3.5 mL) and methanol (0.5 mL) in tetrakis (triphenylphosphine) palladium (48.5 mg, 0.042 mmol). Was added to the dissolved solution. To the mixture was added saturated aqueous bicarbonate sodium solution (1.05 mL) and heated in a 90 ° C. oil bath (lightly refluxed) for 4 hours. The mixture was cooled to room temperature and then poured into water (15 mL) and extracted with ethyl acetate (4 × 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (toluene) to give intermediate 2d (170.9 mg, 90%) in the form of a yellow oil: R _f = 0.10 (toluene); ¹ H NMR (CDCl ₃ ) δ0.01 (s, 9H), 0.98 (t, 2H, J = 8.5 Hz), 3.67 (t, 2H, J = 8.5 Hz), 5.73 (s, 2H), 7.17 (d , 1H, J = 16 Hz), 7.3-7.7 (m, 15H), 8.05 (s, 1H). ¹³ C NMR (CDCl ₃ ) δ-1.5, 17.6, 66.4, 77.7, 110.1, 119.4, 119.8, 123.3, 125.1, 126.3, 126.5, 127.8, 128.6, 128.7, 128.9, 131.3, 137.1, 137.3, 140.6, 143.3. Anal. (C ₂₉ H ₃₂ N ₂ OSi.0.1 CHCl ₃ ) C, H, N.
[207] (e) Compounds 2-3,5-Distyryl-1H-indazole:
[208] Compound 2 was treated with intermediate 2d and 3M HCl in the same manner as compound 1 to give 3,5-distyryl-1H-indazole (33%) as a light yellow solid: R _f = 0.11 (25% ethyl Acetate / hexane); ¹ H NMR (CDCl ₃ ) δ7.2-7.7 (m, 16H), 8.076 (s, 1H), 10.05 (br s, 1H). HRMS calcd for C ₂₃ H ₁₉ N ₂ , 323.1548 (MH ⁺ ), found 323.1552. _{Anal. (C 23 H 18 N} 2 · 0.5 H 2 O) C, H, N.
[209] Example 3: 3- (1H-benzoimidazol-2-yl) -5-phenyl-1H-indazole
[210]
[211] (a) Intermediate 3a- 1- [2- (trimethylsilanyl) -ethoxymethyl] -1 H-benzoimidazole:
[212] (Whitten et. Al., J. Org. Chem. 51 , 1891 (1986), incorporated herein by reference in the same manner.): Sodium hydride (mineral oil) in DMF (350 mL). Solid 1H-benzoimidazole (30 g, 254 mmol) was added little by little at room temperature to a solution in which 10.2 g, 254 mmol) of sodium hydride dispersed in 60% in water was dissolved. The mixture was stirred for 3 hours and then cooled in an 0 ° C. ice bath. 2- (trimethylsilyl) ethoxymethyl chloride (46.57 g, 279 mmol) was added dropwise over 10 minutes. The reaction was stirred for 16 hours, dissolved in an ice bath, warmed to room temperature, poured into water (1 L), dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (50 to 85% ethyl acetate / hexane). Intermediate 3a (56.63 g, 90%) in the form of a yellow oil was obtained: R _f = 0.40 (50% ethyl acetate / hexanes); ¹ H NMR (CDCl ₃ ) δ-0.04 (s, 9H), 0.90 (t, 2H, J = 8.1 Hz), 3.50 (t, 2H, J = 8.1 Hz), 5.53 (s, 2H), 7.31 (m , 2H), 7.54 (m, 1H), 7.81 (m, 1H), 7.96 (s, 1H). Anal. (C ₁₃ H ₂₀ N ₂ OSi0.5 H ₂ O) C, H, N.
[213] (b) Intermediate 3b- 2-iodo-1- [2- (trimethylsilanyl) -ethoxymethyl] -1 H-benzoimidazole:
[214] A solution of N-SEM-benzoimidazole (intermediate 3a ) (19.19 g, 77.25 mmol) in dry ethyl ether (150 mL) was cooled in a -78 ° C. dry ice / acetone bath and the mixture was dried ethyl ether ( 150 ml) was added dropwise via cannula to a solution of n-butyllithium (46 ml, 116 mmol in 2.5 M hexane) and cooled in a -78 ° C dry ice / acetone bath. It was. Benzimidazole solution was added for 10 minutes and stirring continued for at least 15 minutes while changing to dark red color. The aryllithium solution produced above was added dropwise via cannula to iodine flakes (49 g, 193 mmol) dissolved in dry ether (500 ml), and then dried in a -78 ° C ice / acetone bath. Cooled at. When the addition reaction was complete (about 10 minutes) the cooling bath was removed and the reaction mixture was warmed to internal temperature -10 ° C for 30 minutes. Water (250 mL) was added to the mixture and washed with saturated aqueous sodium bisulfite solution (2 × 200 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography to obtain 3-iodo-N-SEM-benzimidazole 3b (22.84g, 80%) as a yellow solid: mp = 60-63 ° C. ; R _f = 0.70 (ethyl acetate); ¹ H NMR (CDCl ₃ ) δ-0.04 (s, 9H), 0.92 (t, 2H, J = 8.1 Hz), 3.58 (t, 2H, J = 8.1 Hz), 5.53 (s, 2H), 7.27 (m , 2H), 7.51 (m, 1H), 7.73 (m, 1H). HRMS calcd for C ₁₃ H ₁₉ IN ₂ OSiNa 397.0209 (MNa ⁺ ), found 397.0204. Anal. (C ₁₃ H ₁₉ IN ₂ OSi) C, H, I, N.
[215] (c) Intermediate 3c-5-Chloro-1- [2- (trimethylsilanyl) -ethoxymethyl] -3- (trimethylstannyl-1H-indazole:
[216] Intermediate 1b (6.25 g, 15.3 mmol), hexamethylditin (10.2 g, 30.5 mmol) and bis (triphenylphosphine) palladium (II) dibromide (242 mg, 0.306 mmol) in toluene (20 mL) ) Was heated to reflux for 30 minutes, then cooled, filtered and concentrated. Purification by silica gel chromatography (5 to 50% ethyl acetate / hexanes) gave intermediate 3c (6.34 g, 93%) in the form of a pale yellow oil: R _f = 0.21 (5% ethyl acetate / hexanes), R _f = 0.23 (toluene); ¹ H NMR (CDCl ₃ ) δ-0.06 (s, 9H), 0.56 (small edge band s, 9H), 0.87 (t, 2H, J = 8.4 Hz), 3.54 (t, 2H, J = 8.4 Hz), 5.75 (s, 2H), 7.34 (dd, 1H, J = 8.7, 1.8 Hz), 7.51 (d, 1H, J = 8.7 Hz), 7.66 (d, 1H, J = 1.8 Hz). Anal. (C ₁₆ H ₂₇ ClN ₂ OSiSn) C, H, Cl, N.
[217] (d) Intermediate 3d-5-chloro-1- [2- (trimethylsilanyl) -ethoxymethyl] -3- {1- [2- (trimethylsilanyl) -ethoxymethyl] -1H-benzo Imidazol-2-yl} -1 H-indazole:
[218] THF (100 mL) intermediate 3c (4.47 g, 10.03 mmol), intermediate 3b (4.12 g, 11.03 mmol), tetrakis (triphenylphosphine) palladium (0) (579 mg, 0.50 mmol) and copper iodide A mixture of (I) (190 mg, 1.00 mmol) was heated to reflux for 1 hour. Additional catalyst (580 mg, 0.50 mmol) and CuI (200 mg, 1.05 mmol) was added to the mixture and the reflux was continued for 20 hours. After cooling the mixture to room temperature, the black precipitate was filtered to concentrate the filtrate, and then the residue was purified by silica gel chromatography (toluene) to obtain a pure oil in the form of a transparent intermediate 3d (2.29 g, 43%). Obtained: mp = 80-82 ° C .; R _f = 0.12 (10% ethyl acetate / hexane), R _f = 0.13 (toluene); ¹ H NMR (CDCl ₃ ) δ-0.15 (s, 9H), -0.06 (s, 9H), 0.85 (t, 2H, J = 8.1 Hz), 0.91 (t, 2H, J = 8.4 Hz), 3.60 ( t, 2H, J = 8.4 Hz), 3.61 (t, 2H, J = 8.1 Hz), 5.80 (s, 2H), 6.24 (s, 2H), 7.36 (m, 2H), 7.47 (dd, 1H, J) = 9.0, 2.1 Hz), 7.57 (d, 1H, J = 9.0 Hz), 7.62 (m, 1H), 7.91 (m, 1H), 8.73 (d, 1H, J = 2.1 Hz). Anal. (C ₂₆ H ₃₇ ClN ₄ O ₂ Si ₂ ) C, H, Cl, N.
[219] (e) Intermediate 3e-5-phenyl-1- [2- (trimethylsilanyl) -ethoxymethyl] -3- {1- [2- (trimethylsilanyl) -ethoxymethyl] -1 H-benzo Imidazol-2-yl} -1 H-indazole:
[220] 1,4-dioxane (3.6 ml), intermediate 3d (192.0 mg, 0.363 mmol), phenylboronic acid (66.4 mg, 0.544 mmol), palladium (II) acetate (3.3 mg, 0.0145 mmol), CyMAP-1 (Old) et al., J. Am. Chem. Soc ., 120 , 9722 (1998)) (5.7 mg, 0.0145 mmol) and cesium fluoride (165 mg, 1.09 mmol) in a mixture of 100 ° C oil. Heated in bath for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and filtered to remove the black precipitate. The filtrate was washed with 1M aqueous sodium hydroxide (20 mL), dried over magnesium sulfate, concentrated and purified by silica gel chromatography (0-4% methanol / dichloromethane) to give the intermediate 3e (107.0 mg) as pale yellow oil. , 52%) was obtained: R _f = 0.26 (dichloromethane); ¹ H NMR (CDCl ₃ ) δ-0.15 (s, 9H), -0.04 (s, 9H), 0.86 (t, 2H, J = 8.1 hz), 0.95 (t, 2H, J = 8.1 Hz), 3.61 ( t, 2H, J = 8.1 Hz, 3.66 (t, 2H, J = 8.1 Hz), 5.85 (s, 2H), 6.28 (s, 2H), 7.37 (m, 3H), 7.49 (t, 2H, J = 7.5 Hz), 7.63-7.80 (m, 5H), 7.91 (m, 1H), 8.88 (s, 1H). Anal. (C ₃₂ H ₄₂ N ₄ O ₂ Si ₂ .0.4 H ₂ O) C, H, N.
[221] (f) Compound 3-3- (1H-benzoimidazol-2-yl) -5-phenyl-1H-indazole:
[222] Tetrabutylammonium fluoride (dissolved at 1.0 M in THF, 3.16 mL) and 1,2-diaminoethane (95 mg, 1.58 mmol) were added to intermediate 3e (90.2 mg, 0.158 mmol). The solution was heated in a 70 ° C. oil bath for 20 hours and then refluxed for at least 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with saturated bicarbonate sodium solution (20 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (25-50% ethyl acetate / hexane) to give 3- (1H-benzoimidazol-2-yl) -5-phenyl-1H as a white solid. -Indazole 3 (33.9 mg, 69%) was obtained: R _f = 0.30 (50% ethyl acetate / hexanes); ¹ H NMR (CDCl ₃ ) δ7.21 (quintet of d, 2H, J = 5.7, 1.5 Hz), 7.39 (t, 1H, J = 7.4 Hz), 7.53 (t, 3H, J = 7.5 Hz), 7.76 (m, 5H), 8.71 (s, 1H), 13.01 (s, 1H), 13.70 (s, 1H). HRMS calcd for C ₂₀ H ₁₅ N ₄ 311.1297 (MH ⁺ ), found 311.1283.
[223] Example 4: 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -phenol
[224]
[225] (a) Intermediate 4a-5- (3-methoxyphenyl) -1- [2- (trimethylsilanyl) -ethoxymethyl] -3- {1- [2- (trimethylsilanyl) -ethoxy Methyl] -1 H-benzoimidazol-2-yl} -1 H-indazole:
[226] 1,4-dioxane (7.1 mL) intermediate 3d (371.5 mg, 0.702 mmol), 3-methoxyphenylboronic acid (160 mg, 1.05 mmol), palladium (II) acetate (7.9 mg, 0.0355 mmol), CyMAP -1 (see Old et al., J. Am. Chem. Soc. , 120 , 9722 (1998)) (14 mg, 0.0355 mmol) and cesium fluoride (320 mg, 2.11 mmol) in a mixture of 90 ° C. oil Heated in bath for 22 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered to remove the black precipitate. The filtrate was dried over magnesium sulfate, filtered and purified by silica gel chromatography (10% ethyl acetate / hexane) to give intermediate 4a (178.3 mg, 42%) in the form of a pale yellow oil: R _f = 0.20 (10% Ethyl acetate / hexane); ¹ H NMR (CDCl ₃ ) δ-0.14 (s, 9H), -0.03 (s, 9H), 0.86 (t, 2H, J = 8.1 Hz), 0.95 (t, 2H, J = 8.1 Hz), 3.61 ( t, 2H, J = 8.1 Hz), 3.66 (t, 2H, J = 8.1 Hz), 3.91 (s, 3H), 5.85 (s, 2H), 6.27 (s, 2H), 6.93 (ddd, 1H, J) = 1.1, 2.5, 8.1 Hz), 7.27-7.40 (m, 5H), 7.63-7.70 (m, 2H), 7.77 (dd, 1H, J = 1.5, 8.7 Hz), 7.93 (m, 1H), 8.87 ( s, 1 H). Anal. (C ₃₃ H ₄₂ N ₄ O ₃ Si ₂ ) C, H, N.
[227] (b) Compound 4-3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -phenol:
[228] Boron tribromide-methyl sulfide complex (1.0M in dichloromethane) in a solution of intermediate 4a (88.3 mg, 0.147 mmol) dissolved in 1,2-dichloroethane (3.0 mL) 0.588 mL) was heated and refluxed for 1 h. The mixture was then stirred for 16 hours at room temperature. Then water (5.0 mL) was added to the mixture, which was then stirred for 30 minutes at room temperature. The mixture was diluted with diethyl ether (30 mL) and washed with saturated aqueous bicarbonate sodium solution (20 mL). The organic layer was washed with 1M NaOH (3 × 30 mL). The combined aqueous precipitate was acidified to pH = 1 by addition of 6M HCl and then extracted with ether (30 mL), ethyl acetate (30 mL) and dichloromethanol (2x20 mL). The organic extract was obtained, dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (50-75% ethyl acetate / hexane) to give phenol 4 (11.6 mg, 24%) in the form of a white powder: ¹ H NMR ( DMSO-d ₆ ) δ6.78 (dd, 1H, J = 1.9, 7.7 Hz), 7.12-7.27 (m, 4H), 7.31 (t, 1H, J = 7.7 Hz), 7.52 (dd, 1H, J = 2.1, 6.6 Hz, 7.71 (d, 2H, J = 1.1 Hz), 7.76 (dd, 1H, J = 1.5, 6.8 Hz), 8.67 (s, 1H), 9.57 (s, 1H), 13.00 (s, 1H), 13.68 (s, 1H). HRMS calcd for C ₂₀ H ₁₅ N ₄ O 327.1246 (MH ⁺ ), found 327.1231.
[229] Example 5: 3- (1H-benzoimidazol-2-yl) -5- (3-methoxyphenyl) -1H-indazole
[230]
[231] (a) Compound 5-3- (1H-benzoimidazol-2-yl) -5- (3-methoxyphenyl) -1H-indazole:
[232] From the compound obtained in Example 4, the same crude reaction mixture was obtained with methoxyphenyl analog 5 in the following manner:
[233] A solution of intermediate 4a (88.3 mg, 0.147 mmol) dissolved in 1,2-dichloroethane (3.0 mL) was treated with boron tribromide-methyl sulfide complex (dissolved in 1.0M in dichloromethane, 0.588 mL) for 1 hour. Heated to reflux. Then continued stirring at room temperature for 16 hours. Water (5.0 ml) was added to the mixture, followed by stirring at room temperature for 30 minutes. The mixture was diluted with diethyl ether (30 mL) and washed with saturated aqueous bicarbonate sodium solution (20 mL). The organic layer was washed with 1M NaOH (3 × 30 mL). The organic layer was then dried, filtered, concentrated and purified by silica gel chromatography (50-75% ethyl acetate / hexanes) to give compound 5 (9.3 mg, 19%) in the form of a white powder: ¹ H NMR (DMSO-d ₆ δ 3.86 (s, 3H), 6.98 (dd, 1H, J = 2.1, 7.8 Hz), 7.19-7.23 (m, 3H), 7.30 (d, 1H, J = 7.8 Hz), 7.45 (t, 1H) , J = 7.8 Hz), 7.52 (dd, 1H, J = 1.8, 5.7 Hz), 7.75 (m, 3H), 8.70 (s, 1H), 13.00 (s, 1H), 13.70 (s, 1H). HRMS calcd for C ₂₁ H ₁₆ N ₄ ONa 363.1222 (MNa ⁺ ), found 363.1225.
[234] Example 6: 3- (1H-benzoimidazol-2-yl) -5- (2-fluorophenyl) -1H-indazole
[235]
[236] (a) Intermediate 6a-5- (2-fluorophenyl) -1- [2- (trimethylsilanyl) -ethoxymethyl] -3- {1- [2- (trimethylsilanyl) -ethoxy Methyl] -1 H-benzoimidazol-2-yl} -1 H-indazole:
[237] 1,4-dioxane (8.0 ml) intermediate 3d (419.0 mg, 0.792 mmol), 2-fluorophenylboronic acid (166 mg, 1.19 mmol), palladium (II) acetate (9.0 mg, 0.04 mmol), CyMAP -1 (see Old et. Al., J. Am. Chem. Soc ., 120 , 9722 (1998), incorporated herein by reference) and cesium fluoride (361 mg, 2.38 mmol) dissolved Heated in a 70 ° C. oil bath for 1 hour. When partial conversion was observed, palladium (II) acetate (12 mg, 0.05 mmol) and CyMAP-1 (14 mg, 0.035 mmol) were added and then stirred at 70 ° C. for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered to remove the black precipitate. The filtrate was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (10% ethyl acetate / hexane) to give an intermediate 6a (155.6 mg, 43%) in the form of a clear oil: ¹ H NMR (CDCl ₃ ) δ -0.14 (s, 9H), -0.03 (s, 9H), 0.86 (t, 2H, J = 8.1 Hz), 0.95 (t, 2H, J = 8.1 Hz), 3.61 (t, 2H, J = 8.1 Hz ), 3.66 (t, 2H, J = 8.1 Hz), 5.86 (s, 2H), 6.27 (s, 2H), 7.15-7.39 (m, 5H), 7.57-7.75 (m, 4H), 7.88 (m, 1H), 8.82 (s, 1 H). Anal. (C ₃₂ H ₄₁ FN ₄ O ₂ Si ₂ .0.4 H ₂ O) C, H, N.
[238] (b) Compound 6-3- (1H-benzoimidazol-2-yl) -5- (2-fluorophenyl) -1H-indazole:
[239] Compound 6 was prepared in the same manner as Compound 3. Treatment of tetrabutylammonium fluoride with intermediate 6a gave compound 6 (21.2 mg, 18%) in the form of a white powder: R _f = 0.35 (50% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ 7.20 (m, 2H), 7.33-7.52 (m, 4H), 7.62 (m, 2H), 7.74 (m, 2H), 8.65 (s, 1H), 13.02 ( s, 1 H), 13.75 (s, 1 H). HRMS calcd for C ₂₀ H ₁₄ FN ₄ 329.1202 (MH ⁺ ), found 329.1212. Anal. (C ₂₀ H ₁₃ FN ₄ .1.1 H ₂ O) C, H, N.
[240] Example 7: 3- (1H-benzoimidazol-2-yl) -5- (4-methoxyphenyl) -1H-indazole
[241]
[242] (a) Intermediate 7a'- 5-iodo-3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazole:
[243] Intermediate 7a ' is 6-nitroindazole (Kania, Braganza, et al., Patent application "Compounds and Pharmaceutical Compositions for Inhibiting Protein Kinases, and Methods for Their Use", page 52, lines 10 to 53, line 26; and 59 Line 16 to Line 4 on page 60; the entire United States Provisional Application No. 60 / 142,130, filed July 2, 1999, is incorporated herein by reference) from 6-iodo-3-((E)- 5-nitroindazole (Acros organics, a division of Fisher Scientific) in 5 steps to prepare styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole , Pittsburg, PA): ¹ H NMR (CDCl ₃ ) δ-0.06 (s, 9H), 0.89 (t, 2H, J = 8.4 Hz), 3.57 (t, 2H, J = 8.4 Hz), 5.70 (s, 2H), 7.29-7.44 (m, 6H), 7.59 (d, 2H, J = 7.0 Hz), 7.67 (dd, 1H, J = 8.7, 1.5 Hz), 8.36 (s, 1H).
[244] (b) Intermediate 7b'- 5-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H- Sol-3-carbaldehyde:
[245] A solution of 5-iodo-3-styryl-2-SEM-indazole 7a ' (4.93 g, 10.35 mmol) in dichloromethane (500 mL) was bubbled with ozone at -78 ° C. After 20 minutes the solution changed from orange to dark blue. The mixture was purged with argon for 30 minutes to remove the remaining ozone and then dimethylsulfide (1.29 g, 20.7 mmol) was added. The cooling bath was removed and stirred for about 2 hours until reaching an internal temperature of 15 ° C. The solution was washed with water (2x200 mL), dried over magnesium sulfate, filtered and concentrated. The solution was purified by silica gel chromatography (10% ethyl acetate / hexanes) to give aldehyde 7b ' (2.74 g, 66%) in the form of a yellow oil: ¹ H NMR (CDCl ₃ ) δ-0.05 (s, 9H), 0.89 (t, 2H, J = 8.4 Hz), 3.56 (t, 2H, J = 8.4 Hz), 5.79 (s, 2H), 7.43 (d, 1H, J = 8.7 Hz), 7.76 (dd, 1H, J = 8.8, 1.5 Hz), 8.71 (s, 1 H), 10.22 (s, 1 H).
[246] (c) Intermediate 7c'- 3- (1H-benzoimidazol-2-yl) -5-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole:
[247] 1,2-phenylenediamine (0.74 g, 6.81 mmol) and elemental sulfur (0.26 g, 8.2 mmol) in a solution of aldehyde 7b ' (2.74 g, 6.81 mmol) in DMF (130 mL) ) Was added. The mixture was heated in a 95 ° C. oil bath for 14.5 hours and then cooled to room temperature and diluted with ethyl acetate (500 mL). The solution was washed with a solution of saturated aqueous sodium chloride (100 mL) and water (100 mL). The organic layer was then washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and water (100 mL), dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (20% ethyl acetate / hexane) to give pale. 7c ' containing impurities in the form of a yellow solid was precipitated with chloroform / hexanes to give pure 7c' (2.15 g, 64%) in the form of a white powder: R _f = 0.23 (20% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ-0.12 (s, 9H), 0.82 (t, 2H, J = 7.9 Hz), 3.59 (t, 2H, J = 7.9 Hz), 5.87 (s, 2H), 7.23 (m, 2H), 7.52 (d, 1H, J = 7.2 Hz), 7.73-7.84 (m, 3H), 8.94 (s, 1H), 13.13 (s, 1H). HRMS calcd for C ₂₀ H ₂₃ IN ₄ OSi 491.0759 (MH ⁺ ), found 491.0738.
[248] (d) Intermediate 7d'- 3- (1H-benzoimidazol-2-yl) -5- (4-methoxy-phenyl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H- Indazole:
[249] 2M water soluble sodium carbonate solution (6.4 ml) was prepared with intermediate 7c ' (2.50 g, 5.10 mmol), 4-methoxyphenyl boronic acid (1.01 g, 6.63 mmol) and tetrakis (triphenylphosphine) palladium (0.59 g, 0.51 mmol) was added to a solution of 1,4-dioxane (35 mL) and a mixture of methanol (15 mL). The mixture was heated to reflux for 5 hours, then cooled and partitioned into a mixture of ethyl acetate, saturated aqueous sodium chloride (100 mL) and water (100 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (20% ethyl acetate / hexane) to obtain a dark brown solid. The solid was precipitated with dichloromethane / hexanes to give pure 7d ' (948.6 mg, 40%) in the form of a white powder: R _f = 0.13 (20% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ-0.10 (s, 9H), 0.85 (t, 2H, J = 7.9 Hz), 3.63 (t, 2H, J = 7.9 Hz), 3.82 (s, 3H), 5.91 (s, 2H), 7.10 (d, 2H, J = 8.7 Hz), 7.23 (m, 2H), 7.43 (m, 1H), 7.54 (d, 1H, J = 6.8 Hz), 7.69 (d, 2H, J = 8.7 Hz), 7.80 (m, 1H), 7.92 (d, 1H, J = 8.9 hz), 8.70 (s, 1H), 13.08 (s, 1H).
[250] (e) Compound 7'- 3- (1H-benzoimidazol-2-yl) -5- (4-methoxy-phenyl) -1 H-indazole:
[251] Boron tribromide (dissolved at 1.0 M in dichloromethane, 4.73 ml) was treated with a solution of intermediate 7d ' (148.4 mg, 0.315 mmol) in ethyl acetate (15 ml) at -78 ° C. The solution was stirred for 17 hours and then slowly warmed to room temperature. Water (10 mL) was added to the solution and stirred for 6 days at room temperature. The solution was treated with 3M sodium hydroxide solution, adjusted to pH 10, and extracted with ethyl acetate (3x20 mL). The obtained organic extract was dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (50% ethyl acetate / hexane) to obtain an intermediate 7 ' (60.5 mg, 56%) in the form of a white powder: R _f = 0.21 (50% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ3.82 (s, 3H), 7.08 (d, 2H, J = 8.9 Hz), 7.21 (m, 2H), 7.53-7.78 (m, 6H), 8.66 (s, 1H), 12.96 (s, 1H), 13.63 (s, 1H). Anal. (C ₂₁ H ₁₆ N ₄ O.0.25 CH ₂ Cl ₂ ) C, H, N.
[252] Example 8 ': 4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -phenol
[253]
[254] A solution of anisole 7 ' (44.6 mg, 0.131 mmol) and pyridine hydrochloride (912 mg, 7.9 mmol) was heated in a 180 ° C. oil bath for 3 hours. The pyridine salt is liquefied at this temperature. The mixture was cooled to room temperature and then partitioned between ethyl acetate (20 mL) and saturated aqueous bicarbonate sodium (15 mL). The aqueous layer was extracted with ethyl acetate (3x20 mL). The organic extract obtained was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (50% ethyl acetate / hexane) to give pure phenols 8 ' (29.4 mg, 69%) in the form of a pale yellow oil: R _f = 0.23 (60% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ6.91 (d, 2H, J = 8.4 Hz), 7.21 (m, 2H), 7.53 (m, 3H), 7.68 (s, 2H), 7.75 (d, 1H, J = 6.9 Hz), 8.61 (s, 1H), 9.53 (s, 1H), 12.98 (s, 1H), 13.63 (s, 1H). HRMS calcd for C ₂₀ H ₁₄ N ₄ O 327.1246 (MH ⁺ ), found 327.1253. Anal. (C ₂₀ H ₁₃ N ₄ O 0.8 DMSO) C, H, N.
[255] Example 9 ': 3- (1H-benzoimidazol-2-yl) -5- (3-methoxy-2-methyl-phenyl) -1 H-indazole
[256]
[257] (a) Intermediate 9a'- 3-methoxy-2-methyl-phenylamine:
[258] Suspension was prepared by mixing a solution of 2-methyl-3-nitroanisole (Aldrich Chemicals) (8.87 g, 53 mmol) and 10% Pd-C (10% palladium on carbon) (800 mg) in ethanol (400 mL). Shake for 1 hour in the presence of 40 psi hydrogen. The solution was filtered through a Celite pad, concentrated and purified by silica gel chromatography (30% ethyl acetate / hexane) to give aniline 9a ' (6.94 g, 95%) as a pale orange oil. Obtained: R _f = 0.20 (25% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ1.88 (s, 3H), 3.68 (s, 3H), 4.74 (br s, 2H), 6.17 (d, 1H, J = 8.1 Hz), 6.26 (d, 1H , J = 8.1 Hz), 6.81 (t, 1H, J = 8.1 Hz). Anal. (C ₈ H ₁₁ NO) C, H, N.
[259] (b) Intermediate 9b'- 1-iodo-3-methoxy-2-methyl-benzene:
[260] 3-methoxy-2-methyl-phenylamine (5.28 g, 38.5 mmol) was tested by DeGraw, et al. [DeGraw, JI; Brown, VH; Colwell, WT; Morrison, NE, J. Med. Chem ., 17 , 762 (1974), incorporated herein by reference, to diazotized to give aryl iodide 9b ' (4.17 g, 44%) in the form of a yellow oil: R _f = 0.53 ( 10% ethyl acetate / hexanes); ¹ H NMR (CDCl ₃ ) δ 2.36 (s, 3H), 3.80 (s, 3H), 6.81 (m, 2H), 7.42 (dd, 1H, J = 7.5, 1.5 Hz).
[261] (c) Intermediate 9c'- 2- (3-methoxy-2-methyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane:
[262] 1-iodo-3-methoxy-2-methyl-benzene (3.80 g, 15.3 mmol), bis (pinacolato) diboron (4.28 g, 16.8 mmol), potassium acetate (4.51 g, 46.0 mmol) and 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (1,1'-bis (diphenylphosphino) ferrocenedichloropalladium) (II) (625 mg, 0.766 mmol) in DMSO (70 mL) It melt | dissolved and heated to internal temperature of 80 degreeC for 1 hour. The mixture was cooled, diluted with toluene (400 mL), washed with water (2x100 mL), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5-20% ethyl acetate / hexanes) afforded the boronic ester 9c ' (19.6 g, 52%) as a white crystalline solid: R _f = 0.27 (5% ethyl) Acetate / hexane); ¹ H NMR (CDCl ₃ ) δ1.34 (s, 12H), 2.42 (s, 3H), 3.81 (s, 3H), 6.91 (d, 1H, J = 8.1 Hz), 7.14 (t, 1H, J = 7.8 Hz), 7.34 (d, 1 H, J = 7.5 Hz). Anal. (C ₁₄ H ₂₁ BO ₃ ) C, H.
[263] (d) Intermediate 9d'- 3- (1H-benzoimidazol-2-yl) -5- (3-methoxy-2-methyl-phenyl) -1- (2-trimethylsilanyl-ethoxymethyl ) -1H-indazole:
[264] Aqueous sodium carbonate solution (2M, 2.65 mL) was added to DMF (12 mL) to intermediate 7c ' (519.4 mg, 1.06 mmol), boronic ester 9c' (262.8 mg, 1.06 mmol) and 1,1'-bis (di Phenylphosphino) ferrocenedichloropalladium (II) (43.2 mg, 0.053 mmol) was added to the dissolved solution. The mixture was heated in a 75 ° C. oil bath for 4.5 hours, then cooled and partitioned into a mixture of ethyl acetate (100 mL), saturated aqueous sodium chloride (50 mL) and water (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated, but only 60% of the ¹ H NMR of this crude product was changed. The crude mixture was again dissolved in DMF (12 mL) and additionally boronic ester (253 mg, 1.01 mmol), catalyst (140 mg, 0.17 mmol) and sodium carbonate solution (2.65 mL) were added. The mixture was subsequently stirred at 80 ° C. for 15.5 h. After the above operation, the ¹ H NMR of the crude product had less than 5% residual 7c ' . Purification by silica gel chromatography (10-30% ethyl acetate / hexanes) gave intermediate 9d ' (410.7 mg, 80%) in the form of a white bubble: R _f = 0.37 (30% ethyl acetate / hexanes, intermediate 7c'). Is equal to); ¹ H NMR (DMSO-d ₆ ) δ-0.10 (s, 9H), 0.85 (t, 2H, J = 7.9 Hz), 2.06 (s, 3H), 3.64 (t, 2H, J = 7.9 Hz), 3.85 (s, 3H), 5.92 (s, 2H), 6.92 (d, 1H, J = 7.2 Hz), 7.02 (d, 1H, J = 8.3 Hz), 7.17-7.30 (m, 3H), 7.47-7.53 ( m, 2H), 7.70 (d, 1H, J = 7.7 Hz), 7.90 (d, 1H, J = 8.7 Hz), 8.45 (s, 1H), 13.09 (s, 1H). Anal. (C ₂₈ H ₃₂ N ₄ O ₂ Si0.3 H ₂ O) C, H, N.
[265] (e) Compound 9'- 3- (1H-benzoimidazol-2-yl) -5- (3-methoxy-2-methyl-phenyl) -1 H-indazole:
[266] Intermediate 9d ' and tetrabutylammonium fluoride were treated in the same manner as compound 3 to give compound 9' (47.2 mg, 30%) in the form of a white powder: R _f = 0.23 (5% methanol / dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ2.07 (s, 3H), 3.85 (s, 3H), 6.91 (d, 1H, J = 7.4 Hz), 7.01 (d, 1H, J = 8.1 Hz), 7.24 (m, 3H), 7.39 (dd, 1H, J = 8.7, 1.5 Hz), 7.50 (m, 1H), 7.68 (d, 2H, J = 8.5 Hz), 8.40 (s, 1H), 12.96 (s, 1H), 13.66 (s, 1H). Anal. (C ₂₂ H ₁₈ N ₄ O.0.3 H ₂ O) C, H, N.
[267] Example 10 ': 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -2-methyl-phenol
[268]
[269] Intermediate 9 ' and pyridine hydrochloride were treated to give the same method as phenol 8' to give phenol 10 ' (20.8 mg, 70%) in off-white solid form: R _f = 0.21 (60% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ2.04 (s, 3H), 6.75 (d, 1H, J = 7.0 Hz), 6.85 (d, 1H, J = 7.7 Hz), 7.08 (t, 1H, J = 7.7 Hz), 7.19 (quint, 2H, J = 7.7 Hz), 7.39 (dd, 1H, J = 8.7, 1.5 Hz), 7.50 (d, 1H, J = 7.5 Hz), 7.68 (m, 2H), 8.39 (s, 1H), 9.39 (s, 1H), 12.95 (s, 1H), 13.64 (s, 1H). HRMS calcd for C ₂₁ H ₁₆ N ₄ O 341.1402 (MH ⁺ ), found 341.1410. Anal. (C ₂₁ H ₁₆ N ₄ O. 1.0 MeOH) C, H, N.
[270] Example 11: 5- (2-methylphenyl) -3-phenyl-1H-indazole
[271]
[272] (a) Intermediate 11a-5-nitro-3-phenyl-1H-indazole
[273] Hydrazine monohydrate (50 mL, 1 mol) was added to a solution of 2-chloro-5-nitrobenzophenone (15 g, 57 mmol) in ethanol (300 mL). The product was stirred overnight at ambient temperature (16 hours) then poured into water (2 L) and stirred for another 2 hours. The mixture was filtered, and the resulting precipitate was washed with water (2 × 100 mL) and air dried to give 5-nitro-3-phenyl-1H-indazole 11a (13.1 g, 80%) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ 7.48 (tt, 1H, J = 1.3, 7.4 Hz), 7.58 (dd, 2H, J = 7.1, 7.4 Hz), 7.78 (d, 1H, J = 9.2 Hz), 8.01 ( dd, 2H, J = 1.3, 7.1 Hz, 8.25 (dd, 1H, J = 2.1, 9.2 Hz), 8.91 (d, 1h, J = 2.1 Hz), 13.88 (s, 1H). Anal. (C ₁₃ H ₉ N ₃ O ₂ ) C, H, N.
[274] (b) Intermediate 11b-5-nitro-3-phenyl-1- [2- (trimethylsilanyl) ethoxymeth Tyl] -1 H-indazole:
[275] To a solution of 5-nitro-3-phenyl-1H-indazole 11a (13 g, 54.3 mmol) and 2- (trimethylsilyl) ethoxymethyl chloride (15 g, 90 mmol) in acetonitrile (400 mL) Diisopropylethylamine (15 ml, 86.1 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then poured into water (1 L) and extracted with ethyl acetate (3x300 mL). The organic extract obtained was dried over sodium sulfate and concentrated. The residue obtained was dissolved in toluene (40 mL). To the solution was added 2- (trimethylsilyl) ethoxymethyl chloride (3 mL, 17 mmol), tetrabutylammonium bromide (500 mg) and silica (40 g). The mixture was stirred at ambient temperature overnight and then filtered and the filtrate was concentrated. Purification by silica gel chromatography (5% ethyl acetate / hexanes) gave intermediate 11b (15 g, 75%) in the form of a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ-0.11 (s, 9H), 0.83 ( t, 2H, J = 7.9 Hz), 3.62 (t, 2H, J = 7.9 Hz), 5.91 (s, 2H), 7.52 (tt, 1H, J = 0.7, 7.4 Hz), 7.60 (dd, 2H, J = 7.1, 7.4 Hz), 8.00 (d, 1H, J = 9.2 Hz), 8.02 (dd, 2H, J = 0.7, 7.1 Hz), 8.35 (dd, 1H, J = 2.1, 9.2 Hz), 8.91 (d , 1H, J = 2.1 Hz).
[276] (c) Intermediate 11c-5-amino-3-phenyl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole:
[277] 5-nitro-3-phenyl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole 11b (14 g, 37.9 mmol) and 10% Pd-C (10%) in ethyl acetate (500 mL) A mixture of palladium on carbon) (1 g) was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to afford intermediate 11c (12.2 g, 95%) as a white solid: ¹ H NMR (DMSO-d ₆ ) δ-0.12 (s, 9H), 0.80 (t , 2H, J = 8.0 Hz), 3.54 (t, 2H, J = 8.0 Hz), 5.01 (br s, 2H), 5.67 (s, 2H), 6.89 (dd, 1H, J = 1.8, 8.8 Hz), 7.12 (d, 1H, J = 1.8 Hz), 7.37 (tt, 1H, J = 0.5, 7.4 Hz), 7.47 (d, 1H, J = 8.8 Hz), 7.50 (dd, 2H, J = 7.2, 7.4 Hz ), 7.87 (dd, 2H, J = 0.5, 7.2 Hz).
[278] (d) Intermediate 11d- 5-iodo-3-phenyl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole:
[279] Intermediate 11c (12 g, 35.3 mmol) was dissolved in a solution of acetic acid (300 mL) and water (50 mL). The mixture was cooled to -5 ° C in an ice-salt bath. To the mixture was slowly added a solution in which sodium nitrite (4.5 g, 65.2 mmol) was dissolved in water (10 mL), and the reaction temperature was maintained at 3 ° C or lower. The resulting diazonium solution was stirred at 0 ° C. for 20 minutes. Then, a mixture of potassium iodide (6.5 g, 39.2 mmol) dissolved in water (10 mL) was slowly added to the solution, and the reaction temperature was maintained at 3 ° C or lower. The reaction was stirred to the left overnight to slowly reach a temperature equal to room temperature. Water (300 mL) was poured into the crude reaction mixture and extracted with ethyl acetate (2 × 500 mL). The combined organic extracts were dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (5% ethyl acetate / hexanes) gave intermediate 11d (4 g, 25%) in the form of a yellow oil: ¹ H NMR (DMSO-d ₆ ) δ-0.12 (s, 9H), 0.83 ( t, 2H, J = 7.9 Hz), 3.57 (t, 2H, J = 7.9 Hz), 5.80 (s, 2H), 7.45 (tt, 1H, J = 1.3, 7.5 Hz), 7.54 (dd, 2H, J = 7.1, 7.5 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.75 (dd, 1H, J = 1.5, 8.8 Hz), 7.94 (dd, 2H, J = 1.3, 7.1 Hz), 8.40 (d , 1H, J = 1.5 Hz).
[280] (e) Intermediate 11e- 5- (2-methylphenyl) -3-phenyl-1- [2- (trimethylsilanyl) ethoxymethyl] -1 H-indazole:
[281] Intermediate 11d (130 mg, 0.3 mmol), 2-methylphenyl boronic acid (120 mg, 0.9 mmol) and tetrakis (triphenylphosphine) palladium (0) (25 mg, 0.02 mmol) was added water-soluble saturated bicarbonate sodium (2 mL). The reaction mixture was heated in a 90 ° C. oil bath for 18 hours. Then, the crude reaction mixture was cooled to room temperature, followed by pouring water (50 mL) and extracting with ethyl acetate (2x25 mL). The organic extract obtained was dried over sodium sulfate and concentrated. Purification by silica gel chromatography (10% ethyl acetate / hexanes) gave intermediate 11e (100 mg, 84%) as an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ-0.10 (s, 9H), 0.85 (t, 2H, J = 8.0 Hz), 2.24 (s, 3H), 3.62 (t, 2H, J = 8.0 Hz), 5.85 (s, 2H), 7.29 (m, 4H), 7.42 (tt, 1H, J = 1.4, 7.4 Hz), 7.47 (dd, 1H, J = 1.5, 8.3 Hz), 7.52 (dd, 2H, J = 7.1, 7.4 Hz), 7.84 (d, 1H, J = 8.3 Hz), 7.93 ( d, 1H, J = 1.5 Hz), 7.99 (dd, 2H, J = 1.4, 7.1 Hz).
[282] (f) Compound 11-5- (2-methylphenyl) -3-phenyl-1H-indazole:
[283] Tetrabutylammonium fluoride (dissolved at 1.0 M in THF, 2 ml) was added to a solution of intermediate 11e (100 mg, 0.24 mmol) dissolved in tetrahydrofuran (5 ml). The solution was heated for 16 h in a 60 ° C. oil bath, then water (25 mL) was poured and extracted with ethyl acetate (2 × 25 mL). The organic extract obtained was dried over sodium sulfate and concentrated. Purification by silica gel chromatography (20% ethyl acetate / hexanes) gave 5- (2-methylphenyl) -3-phenyl-1H-indazole, compound 11 (55 mg, 80%) in the form of an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ 2.24 (s, 3H), 7.28 (m, 4H), 7.37 (dd, 1H, J = 1.5, 8.6 Hz), 7.38 (tt, 1H, J = 1.4, 7.5 Hz), 7.50 (dd, 2H, J = 7.1, 7.5 Hz), 7.64 (d, 1H, J = 8.6 Hz), 7.91 (d, 1H, J = 1.5 hz), 7.99 (dd, 2H, J = 1.4, 7.1 Hz ), 13.30 (s, 1 H). _{Anal. (C 20 H 16 N} 2 · 0.25 H 2 O) C, H, N.
[284] Example 12: 3-phenyl-5- [2- (trifluoromethyl) phenyl] -1 H-indazole
[285]
[286] (a) Intermediate 12a- 3-phenyl 5- [2- (trifluoromethyl) phenyl] -1- [2- (trimethylsilanyl) ethoxymethyl] -1 H-indazole:
[287] Intermediate 12a was prepared in the same manner as intermediate 11e . Palladium catalyzed the intermediate 11d and 2- (trifluoromethyl) phenylboronic acid as a couple to give intermediate 12a (48%) in the form of a white solid: ¹ H NMR (DMSO-d ₆ ) δ-0.12 (s , 9H), 0.87 (t, 2H, J = 8.1 Hz), 3.72 (t, 2H, J = 8.1 Hz), 5.62 (s, 2H), 7.32 (m, 1H), 7.38 (tt, 1H, J = 0.8, 7.4 Hz), 7.48 (dd, 2H, J = 7.1, 7.4 Hz), 7.51 (m, 1H), 7.63 (dd, 1H, J = 7.2, 7.7 Hz), 7.66 (dd, 1H, J = 1.6 , 8.6 Hz), 7.75 (m, 1H), 7.82 (d, 1H, J = 8.6 Hz), 7.91 (d, 1H, J = 1.6 Hz), 7.96 (dd, 2H, J = 0.8, 7.1 Hz).
[288] (b) Compound 12- 3-phenyl 5- [2- (trifluoromethyl) phenyl] -1 H-indazole:
[289] Compound 12 was prepared by the same method as the method of preparing compound 11. Treatment of intermediate 12a with tetrabutylammonium fluoride gave 3-phenyl 5- [2- (trifluoromethyl) phenyl] -1H-indazole, compound 12 (74%) in the form of a white solid: ¹ H NMR (DMSO-d ₆ ) δ 7.34 (m, 1H), 7.38 (tt, 1H, J = 1.3, 7.3 Hz), 7.49 (dd, 2H, J = 7.1, 7.3 Hz), 7.52 (m, 1H), 7.62 (dd, 1H, J = 7.4, 7.7 Hz), 7.65 (dd, 1H, J = 1.9, 8.6 Hz), 7.73 (dd, J = 7.2, 7.5 Hz), 7.85 (d, 1H, J = 8.6 Hz) , 7.94 (d, 1H, J = 1.9 Hz), 7.96 (dd, 2H, J = 1.3, 7.1 Hz). Anal. (C ₂₀ H ₁₃ N ₂ F ₃ .0.1 H ₂ O) C, H, N.
[290] Example 13: 5- (4-hydroxy-2-methylphenyl) -3-phenyl-1H-indazole
[291]
[292] (a) Intermediate 13a- 5- (2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenyl) -3-phenyl-1- [2- (trimethylsilanyl) ethoxymethyl ] -1H-indazole:
[293] Intermediate 13a was prepared in the same manner as Intermediate 11e . Palladium catalyzed the intermediate 11d and (2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenyl) boronic acid as a couple to give intermediate 13a (59%) in the form of a pale yellow bubble: ¹ H NMR (DMSO-d ₆ ) δ-0.09 (s, 9H), 0.00 (s, 9H), 0.85 (t, 2H, J = 8.0 Hz), 0.92 (t, 2H, J = 8.1 Hz), 2.22 (s, 3H), 3.62 (t, 2H, J = 8.0 Hz), 3.73 (t, 2H, J = 8.1 Hz), 5.25 (s, 2H), 5.85 (s, 2H), 6.93 (dd, 1H, J = 2.6, 8.3 Hz), 6.98 (d, 1H, J = 2.6 Hz), 7.22 (d, 1H, J = 8.3 Hz), 7.43 (tt, 1H, J = 0.9, 7.7 Hz), 7.45 (dd, 1H, J = 1.3, 8.6 Hz), 7.52 (dd, 2H, J = 7.2, 7.7 Hz), 7.82 (d, 1H, J = 8.6 Hz), 7.89 (d, 1H, J = 1.3 Hz), 7.99 ( dd, 2H, J = 0.9, 7.2 Hz).
[294] (b) Compound 13- 5- (4-hydroxy-2-methylphenyl) -3-phenyl-1H-indazole:
[295] Compound 13 was prepared by the same method as the preparation method of compound 11. Treatment of intermediate 13a with tetrabutylammonium fluoride gave 5- (4-hydroxy-2-methylphenyl) -3-phenyl-1H-indazole, compound 13 (75%) in the form of a pale yellow solid: ¹ H NMR (DMSO-d ₆ ) δ2.17 (s, 3H), 6.66 (dd, 1H, J = 2.3, 8.2 Hz), 6.70 (d, 1H, J = 2.3 Hz), 7.08 (d, 1H, J = 8.2 Hz), 7.32 (dd, 1H, J = 1.5, 8.6 Hz), 7.39 (tt, 1H, J = 1.4, 7.7 Hz), 7.50 (dd, 2H, J = 7.2, 7.7 Hz), 7.59 (d, 1H, J = 8.6 Hz), 7.83 (d, 1H, J = 1.5 Hz), 7.97 (dd, 2H, J = 1.4, 7.2 Hz), 9.28 (s, 1H), 13.22 (s, 1H). Anal. (C ₂₀ H ₁₆ N ₂ O.0.8 H ₂ O) C, H, N.
[296] Example 14 3-phenyl-5- (Pyrid-4-yl) -1H-indazole
[297]
[298] (a) Intermediate 14a- 3-phenyl-5- (pyrid-4-yl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole:
[299] Intermediate 14a was prepared in the same manner as in the preparation of intermediate 11e . Palladium catalyzed the intermediate 11d and pyridine-4-boronic acid as a couple to give intermediate 14a (76%) as a pale white solid: ¹ H NMR (DMSO-d ₆ ) δ-0.11 (s, 9H), 0.84 (t, 2H, J = 7.9 Hz), 3.62 (t, 2H, J = 7.9 Hz), 5.86 (s, 2H), 7.46 (tt, 1H, J = 1.1, 7.4 Hz), 7.51 (d, 1H , J = 8.3 Hz), 7.56 (dd, 2H, J = 7.1, 7.4 Hz), 7.80 (dd, 1H, J = 1.4, 8.3 Hz), 7.85 (dd, 2H, J = 1.6, 4.5 Hz), 8.07 (dd, 2H, J = 1.1, 7.1 Hz), 8.41 (d, 1H, J = 1.4 Hz), 8.64 (dd, 2H, J = 1.6, 4.5 Hz).
[300] (b) Compound 14-3-phenyl-5- (pyrid-4-yl) -1H-indazole:
[301] Compound 14 was prepared by the same method as the method of preparing compound 11. Treatment of intermediate 14a with tetrabutylammonium fluoride gave 3-phenyl-5- (pyrid-4-yl) -1H-indazole, compound 14 (85%) in the form of a pale white solid: ¹ H NMR ( DMSO-d ₆ ) δ 7.43 (tt, 1H, J = 1.2, 7.6 Hz), 7.54 (dd, 2H, J = 7.1, 7.6 Hz), 7.72 (d, 1H, J = 8.8 Hz), 7.83 (d , 2H, J = 1.6, 4.5 Hz), 7.84 (dd, 1H, J = 1.5, 8.8 Hz), 8.07 (dd, 2H, J = 1.2, 7.1 Hz), 8.40 (d, 1H, J = 1.5 Hz) , 8.63 (dd, 2H, J = 1.6, 4.5 Hz), 13.39 (s, 1H). Anal. (C ₁₈ H ₁₃ N ₃ .0.2 H ₂ O) C, H, N.
[302] Example 14b: 3-phenyl-5- (pyrid-3-yl) -1H-indazole
[303]
[304] (a) Intermediate 14b'- 3-phenyl-5- (pyrid-3-yl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole:
[305] Intermediate 14b ' was prepared in the same manner as in Example 11e . Palladium catalyzed the intermediate 11d and pyridine-3-boronic acid as a couple to give intermediate 14b ' (66%) as a pale white solid: ¹ H NMR (DMSO-d ₆ ) δ-0.10 (s, 9H) , 0.83 (t, 2H, J = 7.9 Hz), 3.63 (t, 2H, J = 7.9 Hz), 5.86 (s, 2H), 7.43 (tt, 1H, J = 1.2, 7.5 Hz), 7.51 (dd, 1H, J = 4.7, 8.0 Hz), 7.54 (dd, 2H, J = 7.1, 7.5 Hz), 7.65 (d, 1H, J = 8.6 Hz), 7.73 (dd, 1H, J = 1.5, 8.6 Hz), 8.07 (dd, 2H, J = 1.2, 7.1 Hz), 8.18 (ddd, 1H, J = 1.6, 2.3, 8.0 Hz), 8.32 (d, 1H, J = 1.5 Hz), 8.56 (dd, 1H, J = 1.6, 4.7 Hz), 8.90 (d, 1H, J = 2.3 Hz).
[306] (b) Intermediate 14b-3-phenyl-5- (pyrid-3-yl) -1H-indazole:
[307] Intermediate 14b was prepared in the same manner as in Example 11. Treatment of intermediate 14b ' with tetrabutylammonium fluoride gave 3-phenyl-5- (pyrid-3-yl) -1H-indazole, intermediate 14b (79%) in the form of a pale white solid: ¹ H NMR (DMSO-d ₆ ) δ 7.41 (tt, 1H, J = 1.3, 7.4 Hz), 7.49 (dd, 1H, J = 4.7, 7.9 Hz), 7.53 (dd, 2H, J = 7.1, 7.4 Hz) , 7.70 (d, 1H, J = 8.7 Hz), 7.76 (dd, 1H, J = 1.5, 8.7 Hz), 8.08 (dd, 2H, J = 1.3, 7.1 Hz), 8.17 (ddd, 1H, J = 1.7 , 2.0, 7.9 Hz), 8.31 (d, 1H, J = 1.5 Hz), 8.56 (dd, 1H, J = 1.7, 4.7 Hz), 8.99 (d, 1H, J = 2.0 Hz), 13.35 (s, 1H ). Anal. (C ₁₈ H ₁₃ N ₃ ) C, H, N.
[308] Example 15: 2-Methyl-3- [3-((E) -styryl) -1 H-indazol-5-yl] -phenol
[309]
[310] (a) Intermediate 15a'- 5- (3-methoxy-2-methyl-phenyl) -3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H Indazole:
[311] Intermediate 15a ' obtained styryl analog 15a' (442.5mmol, 66%) in the form of a yellow oil from intermediate 7a ' (571.8 mg, 1.42 mmol) in the same manner as in the preparation of intermediate 9d' : ¹ H NMR (DMSO-d ₆ ) δ-0.10 (s, 9H), 0.83 (t, 2H, J = 8.1 Hz), 2.07 (s, 3H), 3.58 (t, 2H, J = 7.9 Hz), 3.84 (s, 3H), 5.79 (s, 2H), 6.91 (d, 1H, J = 7.6 Hz), 6.99 (d, 1H, J = 8.3 Hz), 7.22-7.41 (m, 5H), 7.56 (d, 2H, J = 5.1 Hz), 7.70-7.78 (m, 3H), 8.09 (s, 1H).
[312] (b) Intermediate 15b'- 5- (3-methoxy-2-methyl-phenyl) -3-((E) -styryl) -1 H-indazole:
[313] Intermediate 15b ' was prepared in the same manner as in the preparation of compound 3. Intermediate 15a ' (211.4 mg, 0.449 mmol) was treated to give 15b' (132.7 mg, 87%) in the form of a white bubble: R _f = 0.38 (50% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ 1.98 (s, 3H), 3.84 (s, 3H), 6.91 (d, 1H, J = 7.5 Hz), 6.98 (d, 1H, J = 8.1 Hz), 7.21 -7.61 (m, 8H), 7.70 (d, 2H, J = 7.4 Hz), 8.05 (s, 1H), 13.18 (s, 1H). HRMS calcd for C ₂₃ H ₂₀ N ₂ O 341.1648 (MH ⁺ ), found 341.1638. Anal. (C ₂₃ H ₂₀ N ₂ O.0.2 H ₂ O) C, H, N.
[314] (c) Compound 15-2-Methyl-3- [3-((E) -styryl) -1 H-indazol-5-yl] -phenol:
[315] Phenol 15 ' was prepared in the same manner as phenol 8' . Treatment of intermediate 15b ' (63.1 mg, 0.185 mmol) with pyridine hydrochloride gave phenol 15' (39.7 mg, 66%) in off-white solid form: R _f = 0.24 (50% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ2.05 (s, 3H), 6.74 (d, 1H, J = 7.5 Hz), 6.83 (d, 1H, J = 7.9 Hz), 7.05 (t, 1H, J = 7.7 Hz), 7.25-7.62 (m, 7H), 7.70 (d, 2H, J = 7.2 Hz), 8.03 (s, 1H), 9.34 (s, 1H), 13.16 (s, 1H). HRMS calcd for C ₂₂ H ₁₈ N ₂ O 327.1497 (MH ⁺ ), found 327.1487. Anal. (C ₂₂ H ₁₈ N ₂ O0.5 H ₂ O) C, H, N.
[316] Example 16: 4- [3-((E) -styryl) -1 H-indazol-5yl] -isoquinoline
[317]
[318] (a) Intermediate 16a-3-((E) -styryl) -5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1 -(2-trimethylsilanyl-ethoxymethyl) -1 H-indazole:
[319] Intermediate 7a ' (2.0 g, 4.2 mmol), bis (pinacolato) diboron (1.17 g, 4.6 mmol), potassium acetate (1.24 g, 12.6 mmol) and DMSO (25 mL) The gas was removed in vacuo with argon over. To the mixture was added 1,1-bis (diphenylphosphino) ferrocenedichloropalladium (II) -CH ₂ Cl ₂ (0.172 g, 0.21 mmol) and the gas was removed again. The reaction was heated at 80 ° C. for 1 h and then poured into water, extracted with ethyl acetate-hexane (2: 1), washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography with silica (6: 1 hexanes-Et ₂ O) gave intermediate 16a (1.09 g, 55%): ¹ H NMR (CDCl ₃ ) δ8.51 (s, 1H), 7.88 (d , 1H, J = 8.4 Hz), 7.64 (d, 1H, J = 7.2 Hz), 7.58 (m, 2H), 7.48 (s, 1H), 7.41 (m, 3H), 7.31 (m, 1H), 3.59 (t, 2H, J = 7.3 Hz), 1.41 (s, 12H), 0.91 (t, 2H, J = 8.3 Hz), -0.06 (s, 9H). Anal. (C ₂₇ H ₃₇ N ₂ O ₃ SiB) C, H, N.
[320] (b) Intermediate 16b-4- [3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazol-5-yl] -isoquinoline:
[321] Intermediate 16a (0.218g, 0.47mmol), 4-bromoisoquinoline (0.082g, 0.39mmol) and Na ₂ CO ₃ (0.1g, 0.95mol) were combined with 3ml DME and 0.5ml water and the mixture Was purified by degassing with argon. Tetrakis (triphenylphosphino) palladium (0) (0.023 g, 0.02 mmol) was added to the mixture, degassed again, and heated to reflux in the presence of argon for 15 hours. Aqueous with intermediate 16a and purified by chromatography with silica (4: 1 hexane-ethyl acetate) to give intermediate 16b (0.181 g, 96%): ¹ H NMR (CDCl ₃ ) δ8.59 (s, 1H), 8.13 (m, 2H), 7.97 (d, 1H, J = 7.6 Hz), 7.73 (m, 3H), 7.58 (m, 3H), 7.50 (d, 2H, J = 9.5 Hz), 7.26 ( m, 4H), 5.82 (s, 2H), 3.68 (t, 2H, J = 8.1 Hz), 0.97 (t, 2H, J = 8.3 Hz), -0.03 (s, 9H). Anal. (C ₃₀ H ₃₁ N ₃ OSi 0.75 H ₂ O) C, H, N.
[322] (c) Compound 16- 4- [3-((E) -styryl) -1 H-indazol-5-yl] -isoquinoline:
[323] Intermediate 16b (0.17 g, 0.35 mmol) dissolved in tetrabutylammonium fluoride (1 M in THF, 3.6 mL) and ethylenediamine (0.475 uL, 0.427 g, 7.1 mmol) heated under reflux for 1 hour It was. The mixture was diluted with ethyl acetate, adjusted to pH 7 with 0.4M HCl, washed with brine and then concentrated to dryness with MgSO ₄ . Purification by chromatography with silica (1: 1 hexane-ethyl acetate) gave Compound 16 (0.07 g, 64%) in the form of a white solid: ¹ H NMR (CDCl ₃ ) δ10.20 (brs, 1H), 9.31 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 8.09 (d, 1H, J = 7.2 Hz), 7.93 (d, 1H, J = 7.2 Hz), 7.20-7.75 (m, 11H). Anal. (C ₂₄ H ₁₇ N ₃ .0.4 H ₂ O) C, H, N.
[324] Example 17: 4- [3-((E) -styryl) -1 H-indazol-5-yl] -quinoline
[325]
[326] (a) Intermediate 17a- 4- [3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazol-5-yl] -quinoline:
[327] Intermediate 17a was prepared by the same process as the method for preparing intermediate 16b . Intermediate 17a was prepared using 4-chloroquinoline in a yield of 79%: ¹ H NMR (CDCl ₃ ) δ8.99 (d, 1H, J = 4.4 Hz), 8.21 (d, 1H, J = 7.9 Hz ), 8.15 (s, 1H), 7.95 (d, 1H, J = 8.4 Hz), 7.72 (m, 2H), 7.42-7.62 (m, 10H), 5.82 (s, 2H), 3.67 (t, 2H, J = 9.3 Hz), 0.97 (t, 2H, J = 8.3 Hz), -0.02 (s, 9H). Anal. (C ₃₀ H ₃₁ N ₃ OSi0.5 H ₂ O) C, H, N.
[328] (b) Compound 17- 4- [3-((E) -styryl) -1 H-indazol-5-yl] -quinoline:
[329] Compound 17 was prepared in the same manner as Intermediate 16 . Compound 17 in white solid form was prepared from intermediate 17a in 50% yield: ¹ H NMR (CDCl ₃ ) δ 13.10 (brs, 1H), 8.98 (d, 1H, J = 4.4 Hz), 8.37 (s, 1H), 8.15 (d, 1H, J = 8.4 Hz), 8.00 (d, 1H, J = 8.4 Hz), 7.54-7.79 (m, 9H), 7.37 (m, 2H), 7.26 (m, 1H). Anal. (C ₂₄ H ₁₇ N ₃ .1.0 H ₂ O) C, H, N.
[330] Example 18 5- (4-Pyridyl) -3- (2-Pyrrolyl) -1H-indazole
[331]
[332] (a) Intermediate 18a- 2-Fluoro-5-nitrobenzoyl chloride:
[333] A solution of 2-chloro-5-nitrobenzoic acid (10.3 g, 56 mmol) dissolved in thionyl chloride (90 mL, 1.2 mol) was heated under reflux for 2 hours. The remaining thionyl chloride was removed by concentration in vacuo. The obtained residue was dissolved in ether (150 mL) and concentrated to give intermediate 18a (11.21 g, 99%) in the form of 2-fluoro-5-nitrobenzoyl chloride, off-white solid: ¹ H NMR (DMSO-d ₆ ) δ7.62 (dd, 1H, J = 9.1, 9.6 Hz), 8.48 (ddd, 1H, J = 3.0, 6.9, 9.1 Hz), 8.60 (dd, 1H, J = 3.0, 6.3 Hz). Anal. (C ₇ H ₃ NO ₃ ClF) C, H, N, Cl.
[334] (b) Intermediate 18b-1- (2-fluoro-5-nitrophenyl) -1- (1H-pyrrol-2-yl) methanone:
[335] A mixture of intermediate 18a (10.04 g, 49 mmol) and pyrrole (3.4 mL, 3.29 g, 49 mmol) dissolved in 1,2-dichloroethane (110 mL) was cooled to 0 ° C., followed by solid AlCl ₃ (6.61). g, 49.6 mmol) was added. The resulting reaction mixture was stirred overnight and slowly warmed to room temperature. The crude product was added to a mixed solution of concentrated HCl (20 mL) and ice water (200 mL). The mixture was then further stirred for 90 minutes, then phase separated to extract the aqueous phase with CH ₂ Cl ₂ ( ₂ × ₂₀₀ mL). The obtained organic extract was washed with water (200 mL) and saturated NaHCO ₃ (200 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (25% ethyl acetate / hexanes) gave intermediate 18b (7.23 g, 63%) in the form of a pale yellow solid: ¹ H NMR (DMSO-d ₆ ) δ6.28 (ddd, 1H, J = 2.1, 2.3, 3.6 Hz), 6.74 (ddd, 1H, J = 1.3, 2.3, 2.5 Hz), 7.32 (ddd, 1H, J = 1.3, 2.4, 3.6 Hz), 7.65 (dd, 1H, J = 9.0, 9.1 Hz), 8.39 (dd, 1H, J = 3.0, 5.8 Hz), 8.45 (ddd, 1H, J = 3.0, 4.4, 9.1 Hz), 12.33 (broad, 1H). Anal. (C ₁₁ H ₇ N ₂ O ₃ F0.1 HCl) C, H, N.
[336] (c) Intermediate 18c-1- (2-fluoro-5-nitrophenyl) -1- (1- [2- (trimethylsilanyl) ethoxymethyl] -1H-pyrrol-2-yl) methanone :
[337] A solution of intermediate 18b (1.72 g, 7.3 mmol) dissolved in THF (30 mL) was dissolved in NaH (350 mg, 8.75 mmol) in THF (15 mL) and dropped into a solution stirred at 0 ° C. under argon. Added. The mixture was stirred at 0 ° C. for 45 minutes and then pure liquid 2- (trimethylsilyl) ethoxymethyl chloride (1.70 g, 10.2 mmol) was added in one portion. The resulting reaction mixture is stirred at ambient temperature overnight and then saturated NaHCO ₃ (80 mL) is poured. Phase separated and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The obtained organic extract was washed with brine (60 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (10% ethyl acetate / hexanes) gave intermediate 18c (2.24 g, 84%) in the form of a yellow syrup: ¹ H NMR (DMSO-d ₆ ) δ-0.07 (s, 9H), 0.83 (t, 2H, J = 7.8 Hz), 3.53 (t, 2H, J = 7.8 Hz), 5.74 (s, 2H), 6.27 (dd, 1H, J = 2.5, 4.0 Hz), 6.75 (dd, 1H, J = 1.4, 4.0 Hz), 7.57 (dd, 1H, J = 1.4, 2.5 Hz), 7.64 (dd, 1H, J = 9.0, 9.1 Hz), 8.29 (dd, 1H, J = 3.0, 5.8 Hz), 8.45 (ddd, 1H, J = 3.0, 4.6, 9.1 Hz). Anal. (C ₁₇ H ₂₁ N ₂ O ₄ FSi) C, H, N.
[338] (d) Intermediate 18d-1- (5-amino-2-fluorophenyl) -1- (1- [2- (trimethylsilanyl) ethoxymethyl] -1H-pyrrol-2-yl) methanone :
[339] A mixture of intermediate 18c (3.63 g, 10 mmol) and a solution of 10% Pd-C (365 mg) in ethyl acetate (90 mL) was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to give intermediate 18d (3.30 g, 99%) in the form of a yellow syrup: ¹ H NMR (DMSO-d ₆ ) δ-0.07 (s, 9H), 0.82 ( t, 2H, J = 8.0 Hz), 3.50 (t, 2H, J = 8.0 Hz), 5.12 (br s, 2H), 5.71 (s, 2H), 6.20 (dd, 1H, J = 2.5, 3.9 Hz) , 6.59 (dd, 1H, J = 2.9, 5.6 Hz), 6.60 (dd, 1H, J = 1.8, 3.9 Hz), 6.66 (ddd, 1H, J = 2.9, 4.3, 8.8 Hz), 6.93 (dd, 1H , J = 8.8, 9.7 Hz), 7.42 (dd, 1H, J = 1.8, 2.5 Hz). Anal. (C ₁₇ H ₂₃ N ₂ O ₂ FSi) C, H, N.
[340] (e) Intermediate 18e- 1- (2-fluoro-5-iodophenyl) -1- (1- [2- (trimethylsilanyl) ethoxymethyl] -1 H-pyrrol-2-yl) meta Paddy fields:
[341] Intermediate 18d (332 mg, 1.0 mmol) was dissolved in a mixture of acetic acid (10 mL) and acetonitrile (10 mL). The mixture was vigorously stirred and cooled in a -5 ° C ice-salt bath and then a solution of sodium nitrite (83 mg, 1.2 mmol) dissolved in water (10 mL) was added. The resulting diazonium solution was stirred for 45 minutes and slowly warmed to 5 ° C. The mixture was then cooled to -5 ° C and a solution of potassium iodide (232 mg, 1.4 mmol) dissolved in water (3 mL) was added. The resulting mixture was further stirred for 2 hours, warmed to 15 ° C. and then added to a solution of K ₂ CO ₃ (30 g) and ice water (100 mL). The aqueous mixture was extracted with ethyl acetate (2x50 mL). The combined organic extracts were washed with 10% aqueous Na ₂ S ₂ O ₃ (50 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (5% ethyl acetate / hexanes) gave intermediate 18e (160 mg, 36%) in the form of a clear oil: ¹ H NMR (DMSO-d ₆ ) δ-0.08 (s, 9H), 0.81 (t, 2H, J = 7.9 Hz), 3.50 (t, 2H, J = 7.9 Hz), 5.71 (s, 2H), 6.24 (dd, 1H, J = 2.6, 4.0 Hz), 6.63 (dd, 1H , J = 1.7, 4.0 Hz), 7.18 (dd, 1H, J = 8.7, 9.7 Hz), 7.51 (dd, 1H, J = 1.7, 2.6 Hz), 7.74 (dd, 1H, J = 2.3, 6.4 Hz) , 7.90 (ddd, 1H, J = 2.3, 4.9, 8.7 Hz). Anal. (C ₁₇ H ₂₁ NO ₂ FSiI) C, H, N, I.
[342] (f) Intermediate 18f-1- [2-fluoro-5- (4-pyridyl) phenyl] -1- (1- [2- (trimethylsilanyl) ethoxymethyl] -1H-pyrrole-2 -Methanone:
[343] DMF (20 mL) intermediate 18e (798 mg, 1.8 mmol), tetrakis (triphenylphosphine) palladium (0) (65 mg, 0.06 mmol) and pyridine-4-boronic acid (323 mg, 2.6 mmol) Diisopropylethylamine (1.3 mL, 7.5 mmol) was added to the solution in which the solution was dissolved. The resulting reaction mixture was heated for 18 h in an argon atmosphere in a 90 ° C. oil bath. After the crude product was cooled to room temperature, water (100 mL) was poured and extracted with ethyl acetate (2 × 75 mL). The combined organic extracts were washed with water (6 × 75 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (20% ethyl acetate / CH ₂ Cl ₂ ) gave intermediate 18f (407 mg, 57%) in the form of a pale yellow oil: ¹ H NMR (DMSO-d ₆ ) δ-0.06 (s , 9H), 0.84 (t, 2H, J = 7.9 Hz), 3.54 (t, 2H, J = 7.9 Hz), 5.76 (s, 2H), 6.24 (dd, 1H, J = 2.6, 4.0 Hz), 6.68 (dd, 1H, J = 1.8, 4.0 Hz), 7.49 (dd, 1H, J = 8.7, 9.3 Hz), 7.51 (dd, 1H, J = 1.8, 2.6 Hz), 7.72 (d, 2H, J = 6.2 Hz), 7.87 (dd, 1H, J = 2.4, 6.5 Hz), 8.02 (ddd, 1H, J = 2.4, 4.9, 8.7 Hz), 8.63 (d, 2H, J = 6.2 Hz). Anal. (C ₂₂ H ₂₅ N ₂ O ₂ FSi) C, H, N.
[344] (g) Intermediate 18 g-5- (4-pyridyl) -3- (1- [2- (trimethylsilanyl) ethoxymethyl] -1 H-pyrrol-2-yl) -1 H-indazole:
[345] A solution of intermediate 18f (504 mg, 1.3 mmol) and hydrazine monohydrate (1.7 mL, 35 mmol) in ethanol (35 mL) was heated to reflux for 42 hours. The mixture was then concentrated in vacuo to remove ethanol. The obtained residue was partitioned between water (25 mL) and ethyl acetate (25 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (25 mL). The obtained organic extract was washed with saturated NaHCO ₃ (30 mL), dried over sodium sulfate and concentrated. Purification by silica gel chromatography (3% CH ₃ OH / CH ₂ Cl ₂ ) gave 18 g (430 mg, 87%) of an intermediate in the form of an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ-0.28 (s, 9H), 0.63 (t, 2H, J = 8.0 Hz), 3.28 (t, 2H, J = 8.0 Hz), 5.72 (s, 2H), 6.26 (dd, 1H, J = 2.8, 3.5 Hz), 6.79 ( dd, 1H, J = 1.7, 3.5 Hz, 7.10 (dd, 1H, J = 1.7, 2.8 Hz), 7.67 (d, 1H, J = 8.9 Hz), 7.77 (d, 2H, J = 6.2 Hz), 7.81 (dd, 1H, J = 1.6, 8.9 Hz), 8.19 (d, 1H, J = 1.6 Hz), 8.61 (d, 2H, J = 6.2 Hz), 13.25 (s, 1H). Anal. (C ₂₂ H ₂₆ N ₄ OSi) C, H, N.
[346] (h) Compound 18- 5- (4-pyridyl) -3- (2-pyrrolyl) -1H-indazole:
[347] Tetrabutylammonium fluoride (dissolved at 1.0 M in THF, 5 ml) in tetrahydrofuran (20 ml) 18 g (366 mg, 0.9 mmol) intermediate and 1,2-diaminoethane (150 mg, 2.5 mmol) Was added to the dissolved solution. The solution was heated to reflux for 42 h and then poured into saturated NaHCO ₃ (30 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic extracts were dried over sodium sulfate and concentrated. Purified by silica gel chromatography (3% CH ₃ OH / CH ₂ Cl ₂ ) to give 5- (4-pyridyl) -3- (2-pyrrolyl) -1H-indazole, compound 18 (71 mg) as an off-white solid. , 29%): ¹ H NMR (DMSO-d ₆ ) δ6.20 (dd, 1H, J = 2.6, 5.6 Hz), 6.82-6.92 (m, 2H), 7.64 (d, 1H, J = 8.7 Hz), 7.81 (dd, 1H, J = 1.4, 8.7 Hz), 7.83 (d, 2H, J = 6.1 Hz), 8.37 (d, 1H, J = 1.4 Hz), 8.62 (d, 2H, J = 6.1 Hz), 11.37 (s, 1 H), 13.09 (s, 1 H). Anal. (C ₁₆ H ₁₂ N ₄ .0.05 CH ₂ Cl ₂ ) C, H, N.
[348] Example 18b '5-5-nitro-3- (2-pyrrolyl) -1H-indazole
[349]
[350] Compound 18b ' was prepared in the same manner as the intermediate 11a . Intermediate 18b and hydrazine hydrate were treated to give 5-nitro-3- (2-pyrrolyl) -1H-indazole, compound 18b ' (75%) in the form of an orange-red solid: ¹ H NMR (DMSO-d ₆ ) δ6.23 (ddd, 1H, J = 2.4, 2.6, 3.6 Hz), 6.81 (ddd, 1H, J = 1.5, 2.5, 3.6 Hz), 6.93 (ddd, 1H, J = 1.5, 2.1, 2.6 Hz), 7.70 (d, 1H, J = 9.2 Hz), 8.21 (dd, 1H, J = 2.0, 9.2 Hz), 8.90 (d, 1H, J = 2.0 Hz), 11.57 (broad, 1H) , 13.62 (s, 1 H). Anal. (C ₁₁ H ₈ N ₄ O ₃ ) C, H, N.
[351] Example 19: 4- [3- (4-Chloro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline
[352]
[353] (a) Intermediate 19a-1H-indazol-3-carboxylic acid methoxy-methyl-amide:
[354] Carbonyldiimidazole (110 g, 678 mmol) was treated in a solution of 3-carboxyindazole (100 g, 617 mmol) in 1 L DMF while releasing gas at 25 ° C. for 15 minutes. To the mixture was added N, O-dimethylhydroxylamine-HCl (66.2 g, 678 mmol) as a solid and then heated at 65 ° C. for 3 hours. The reaction was concentrated to a paste, dissolved in ₂ LCH ₂ Cl ₂ and washed with water and then with 2N HCl. The product appeared distinct in solution. The solid was filtered, separated and rinsed with ethyl acetate. The ethanol acetate and CH ₂ Cl ₂ layers were separated, washed with NaHCO ₃ and brine, dried over MgSO ₄ and concentrated. The resulting solid was obtained, triturated with a 1: 1 CH ₂ Cl ₂ -ether mixture, filtered and dried to give intermediate 19a (1.6 g, 84%) in the form of a white solid: R _f = 0.38 (75% ethyl). Acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ13.60 (s, 1H), 7.80 (d, 1H, J = 8.2 Hz), 7.60 (d, 1H, J = 8.2 Hz), 7.41 (t, 1H, J = 8.0 Hz), 7.22 (t, 1H, J = 8.0 Hz), 3.77 (s, 3H), 3.44 (s, 3H). Anal. (C ₁₀ H ₁₁ N ₃ O ₂ ) C, H, N.
[355] (b) Intermediate 19b- 5-iodo-1H-indazole-3-carboxylic acid methoxy-methyl-amide:
[356] Bis (trifluoroacetoxy) iodobenzene (46g, 107mmol) was added to a solution of amide 19a (20g, 97.4mmol) in 1LCH ₂ Cl ₂ , and iodine (14.84g, 58.5mmol) was added little by little at 25 ° C. Added. After 1 hour, saturated Na ₂ HSO ₃ (600 mL) was added to form a precipitate, and the remaining CH ₂ Cl ₂ was filtered off. The filtrate was washed with brine, dried over MgSO ₄ , concentrated and the remaining solid was triturated with a minimum amount of CH ₂ Cl ₂ . The obtained solid was dried in vacuo with KOH to give white solid iodide 19b (29.26 g, 91%): R _f = 0.31 (50% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ13.79 (s, 1H), 8.39 (s, 1H), 7.65 (d, 1H, J = 8.7 Hz), 7.48 (d, 1H, J = 8.7 Hz), 3.76 (s, 3 H), 3.44 (s, 3 H). Anal. (C ₁₀ H ₁₀ N ₃ IO ₂ ) C, H.
[357] (c) Intermediate 19c- 5-iodo-1- (4-methoxy-benzyl) -1H-indazole-3-carboxylic acid methoxy-methyl-amide:
[358] NaH (1 .9 g, 1.14 g, 47.6 mmol) dispersed in 60% mineral oil was added to a solution of iodide 19b (15 g, 45.3 mmol) dissolved in 200 mL THF while releasing gas. After 15 minutes the mixture was cooled to 0 ° C. and p-methoxybenzyl chloride (8.51 g, 54.4 mmol) was added followed by NaI (679 mg, 4.5 mmol). The mixture was heated to 45 ° C. for 9 hours and cooled to 25 ° C. The solution was diluted with ethyl acetate, washed with saturated aqueous NH ₄ Cl, brine, dried over MgSO ₄ and concentrated to viscous oil. Ether was added to the oil, and the resulting solid was filtered and rinsed with ether to give intermediate 19c (14.18 _g , 70%) in the form of a pale yellow solid: R _f = 0.42 (50% ethyl acetate / hexane); ¹ H NMR (CDCl ₃ ) δ8.60 (s, 1H), 7.56 (dd, 1H, J = 8.8, 1.6 Hz), 7.11 (m, 3H), 6.80 (dd, 2H, J = 6.7, 2.1 Hz) , 5.52 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.51 (s, 3H). Anal. (C ₁₈ H ₁₈ N ₃ O ₃ I) C, H, N, I.
[359] (d) Intermediate 19d- 5-iodo-1- (4-methoxy-benzyl) -1H-indazole-3-carbaldehyde:
[360] A solution of amide 19c (12.8 g, 28.3 mmol) in 300 mL THF was cooled to -5 ° C and LiAlH ₄ (1.29 g, 34 mmol) was added in portions over 10 minutes. After 30 minutes the reaction was stopped by slow addition of ethyl acetate at -5 ° C and poured 0.4N NaHSO ₄ . The organic layer was washed with brine, dried over MgSO ₄ and concentrated to give a weak off-white solid, which was triturated with a minimum amount of ether, filtered, washed with ether and dried to form aldehyde 19d (9.79 g, 88%) in the form of a white solid. Obtained: R _f = 0.57 (50% ethyl acetate / hexanes); ¹ H NMR (CDCl ₃ ) δ10.20 (s, 1H), 8.96 (s, 1H), 7.63 (dd, 1H, J = 8.8, 1.6 Hz), 7.18 (m, 3H), 6.83 (d, 1H, J = 8.7 Hz), 5.57 (s, 3 H), 3.75 (s, 3 H). Anal. (C ₁₆ H ₁₃ N ₂ O ₂ I. 0.1 ethyl acetate) C, H, N, I.
[361] (e) Intermediate 19e- 1- (4-methoxy-benzyl) -5- (4,4,5,5-tetramethyl- [1,3,2] -dioxanborolan-2- Yl) -1H-indazole-3-carbaldehyde:
[362] Bis (pinacolato) diborone (Aldrich Chemicals) (7.05g, 27.8mmol), iodide 19d (9.90g, 25.24mmol), potassium acetate (12.4g, 126mmol) and 1,1'-bis (diphenylforce) Fino) ferrocenedichloropalladium (II) (515 mg, 0.631 mmol) was dissolved in dimethyl sulfoxide (150 mL), degassed and heated in an 80 ° C. oil bath for 1 hour. The mixture was cooled to room temperature and partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (25% ethyl acetate / hexane) to give boronic ester 19e (9.75 g, 98%) in the form of an off-white solid: R _f = 0.37 (25) % Ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ1.31 (s, 12H), 3.69 (s, 3H), 5.75 (s, 2H), 6.87 (d, 2H, J = 8.7 Hz), 7.27 (d, 2H, J = 8.7 Hz), 7.74 (d, 1H, J = 8.4 Hz), 7.91 (d, 1H, J = 8.4 Hz), 8.52 (s, 1H), 10.17 (s, 1H). Anal. (C ₂₂ H ₂₅ BN ₂ O ₄ ) C, H, N.
[363] (f) Intermediate 19f-5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazole-3-carbaldehyde:
[364] Soluble boronic ester 19e (6.00 g, 15.30 mmol) and 4-bromoisoquinoline (5.17 g, 24.8 mmol) in ethylene glycol dimethyl ether (DME, 76 ml) , 38.2 mL, 76.4 mmol) was added followed by tetrakis (triphenylphosphine) palladium (0) (883 mg, 0.76 mmol). The mixture was heated for 5 hours in an 80 ° C. oil bath to reach a maximum internal temperature of 78 ° C. The mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with water (100 mL) and saturated aqueous sodium chloride solution (50 mL). The organic extract was dried over magnesium sulfate, filtered and concentrated to give intermediate 19f (3.56 g, 59%) as an off-white solid form via column (silica gel, 30-70% ethyl acetate / hexanes): R _f = 0.016 ( 50% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ3.71 (s, 3H), 5.83 (s, 2H), 6.92 (d, 2H, J = 8.7 Hz), 7.38 (d, 2H, J = 8.7 Hz), 7.74 (m, 4H), 8.10 (d, 1H, J = 8.7 Hz), 8.22 (m, 2H), 8.48 (s, 1H), 9.37 (s, 1H), 10.21 (s, 1H).
[365] (g) 19 g of intermediates-3-chloro-benzene-1,2-diamine:
[366] A solution of sodium borohydride (1.90 g, 50.2 mmol) dissolved in water (40 mL) was added to a suspension in which 10% Pd-C (250 mg) was dissolved in water (40 mL) through a pipette while foaming with argon. A solution of 3-chloro-2-nitroaniline (Astatech Chemicals) (4.33 g, 25.1 mmol) dissolved in 2N aqueous sodium hydroxide (125 mL) was added to the solution by dropping into a funnel and added under a condition of slowly releasing gas. The mixture was stirred at room temperature for 10 minutes, filtered through a pad of celite, acidified with 3N aqueous hydrochloric acid, and extracted with dichloromethane (3x200 mL). The organic layer obtained was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (1 to 20% ethyl acetate / dichloromethane) to give 19 g (2.13 g , 60%) of diamine in the form of a yellow oil: R _f = 0.30 (dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ4.60 (br s, 2H), 4.80 (br s, 2H), 6.37 (t, 1H, J = 7.8 Hz), 6.48 (m, 2H). Anal. (C ₆ H ₇ ClN) C, H, Cl, N.
[367] (h) Intermediate 19h-4- [3- (4-Chloro-1H-benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1H-indazol-5-yl]- Isoquinoline:
[368] Aldehyde 19f (405.6㎎, 1.03mmol) and diamine 19g (147㎎, 1.03mmol) of solid sulfur (50㎎, 1.55mmol) Intermediate 7c Intermediate yellow oily condensation in the manner similar to that of the 'in the presence 19h (275.5 mg, 52%) was prepared: R _f = 0.12 (50% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ3.74 (s, 3H), 5.83 (s, 2H), 6.93 (d, 2H, J = 8.8 Hz), 7.22 (m, 2H), 7.38 (d, 2H, J = 8.5 Hz), 7.48 (d, 1H, J = 7.2 Hz), 7.67 (dd, 1H, J = 8.7, 1.5 Hz), 7.76 (m, 3H), 8.04 (d, 1H, J = 8.7 Hz) , 8.26 (dd, 1H, J = 7.4, 1.5 Hz), 8.54 (s, 1H), 8.64 (s, 1H), 9.40 (s, 1H), 13.41 (s, 1H).
[369] (i) Compound 19- 4- [3- (4-Chloro-1H-benzoimidazol-2-yl) -1 H-indazol-5-yl] -isoquinoline:
[370] Intermediate 19h was concentrated sulfuric acid (0.3㎖) was dissolved in a solution of acetic acid (3.0㎖) was added to (121.6㎎, 0.236mmol) in trifluoroacetic and the mixture was stirred at room temperature for 19 hours. The mixture was diluted with water (50 mL) and then concentrated aqueous ammonium hydroxide was added to pH 8 and extracted with ethyl acetate (3x50 mL). The resulting organic extract was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography to give compound 19 (41.5 mg, 44%) in the form of a white solid: R _f = 0.40 (75% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 7.22 (m, 2H), 7.48 (d, 1H, J = 7.2 Hz), 7.64 (d, 1H, J = 8.7), 7.79 (m, 4H), 8.27 (d, 1H, J = 7.5), 8.55 (s, 1H), 8.63 (s, 1H), 9.40 (s, 1H), 13.39 and 13.56 (2s, 1 H together), 13.94 (s, 1 H). Anal. (C ₂₃ H ₁₄ ClN ₅ .1.2 CH ₃ OH) C, H, Cl, N.
[371] Example 20: 4- {3- [5- (4-Methyl-piperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-dazol-5-yl} -isoquinoline
[372]
[373] (a) Intermediate 20a- 4- {1- (4-methoxy-benzyl) -3- [5- (4-methyl-piperazin-1-yl) -1 H-benzoimidazol-2-yl] -1H-indazol-5-yl} -isoquinoline:
[374] 5- (4-Methyl-piperazin-1-yl) -2-nitro-phenylamine (513.0 mg, 2.17 mmol) in ethyl acetate (50 mL) [Kim, Jung Sun, et al. J. Med. Chem ., 39 ; 992 (1996)] and a suspension of 10% Pd-C (200.8 mg) was shaken at 40 psi H ₂ for 17 hours. The catalyst was removed by filtration with a pad of celite and the mixture was concentrated to give crude 4- (4-methyl-piperazin-1-yl) -benzene-1,2-diamine (522 mg) in the form of a yellow bubble. The crude diamine was added to a solution of aldehyde 19f (853.7 mg, 2.17 mmol) and solid sulfur (83 mg, 32.60 mmol) in anhydrous dimethylformamide (40 mL) and heated in an 80 ° C. oil bath for 6 hours. The solution was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (concentrated with aqueous NH ₄ OH: EtOH: CH ₂ Cl ₂ = 1: 20: 400) to obtain an intermediate of orange-brown foam form 20a (623 mg). , 50%) was prepared: R _f = 0.20 (10% ethanol / dichloromethane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 2.23 (s, 1H), 2.49 (m, 4H), 3.10 (m, 4H ), 3.71 (s, 3H), 5.80 (s, 2H), 6.91 (m, 4H), 7.36 and 7.47 (2d, 3H together, J = 8.3, 8.7 Hz), 7.64 (d, 1H, J = 8.9 Hz ), 7.77 (m, 3H), 7.99 (m, 1H), 8.25 (d, 1H, J = 7.2 Hz), 8.53 (s, 1H), 8.62 and 8.64 (2s, 1H together), 9.39 (s, 1H) ), 12.78 and 12.83 (2s, 1H together). Anal. (C ₃₆ H ₃₃ N ₇ O.0.9 H ₂ O) C, H, N.
[375] (b) compound 20- 4- {3- [5- (4-methyl = piperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-indazol-5-yl} -iso Quinoline:
[376] Anisole (229.4 mg, 2.12 mmol) was added to a solution of intermediate 20a (123.0 mg, 0.212 mmol) dissolved in glacial acetic acid (2.12 mL). To the mixture was added concentrated aqueous hydrobromic acid (2.12 mL) and heated to reflux for 21 h. After cooling the mixture, dichloromethane (50 mL), tetrahydrofuran (20 mL) and saturated water-soluble bicarbonate sodium (30 mL) were added dropwise to the mixed solution. The phases were separated and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate (20 mL) and water (20 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (concentrated with aqueous NH ₄ OH: EtOH: CH ₂ Cl ₂ = 1: 20: 50) to obtain a pink bubble, which contained some impurities 20 ( 47.1 mg, 48%) was prepared: R _f = 0.20 (concentrated to aqueous NH ₄ OH: EtOH: CH ₂ Cl ₂ = 1: 20: 50); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 2.23 (s, 3H), 2.49 (m, 4H), 3.11 (m, 4H ), 6.91 (m, 2H), 7.35 and 7.47 (2d, 1H together, J = 9.0, 8.9 Hz), 7.61 (d, 1H, J = 8.9 Hz), 7.80 (m, 4H), 8.26 (d, 1H) , J = 7.7 Hz), 8.54 (s, 1H), 8.59 and 8.62 (2s, 1H together), 9.39 (s, 1H), 12.74 and 12.79 (2s, 1H together), 13.73 and 13.76 (2s, 1H together) . Anal. (C ₂₈ H ₂₅ N ₇ O.0.7 H ₂ O) C, H, N.
[377] Example 21: 2- [5- (3-hydroxy-2-methyl-phenyl) -1 H-indazol-3-yl] -1 H-benzoimidazol-4-ol
[378]
[379] (a) Intermediate 21a- 2- [5-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazol-3yl] -1 H-benzoimidazole-4-ol:
[380] In the presence of solid sulfur in the same manner as the preparation of intermediate 7c ' using aldehyde 7b' (2.66 g, 6.62 mmol) and 2,3-diaminophenol (commercialized by Aldrich Chemicals) (822 mg, 6.62 mmol). Intermediate 21a (2.04 g, 61%) in the form of a yellow solid was prepared: R _f = 0.15 (25% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ-0.13 (s, 9H), 0.82 (t, 2H, J = 8.1 Hz), 3.59 (t, 2H, J = 7.8 Hz), 5.85 (s, 2H), 6.59 (d, 1H, J = 7.5 Hz), 7.01 (m, 2H), 7.71 (d, 1H, J = 8.7 Hz), 7.81 (dd, 1H, J = 8.8, 1.5 Hz), 8.90 and 9.04 (2s, 1H together), 9.49 and 9.74 (2S, 1H together), 12.69 and 12.96 (2s, 1H together). Anal. (C ₂₀ H ₂₃ IN ₄ O ₂ Si) C, H, N.
[381] (b) Intermediate 21b-2- [5- (3-methoxy-2-methyl-phenyl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazol-3-yl]- 1H-benzoimidazol-4-ol:
[382] Intermediate 21b (256.7 mg, in yellow foam) was prepared in the same manner as the intermediate 9d ' using boronic ester 9c' (250 mg, 1.01 mmol) and iodide 21a (510.6 mg, 1.01 mmol). 51%) was prepared: R _f = 0.22 (30% ethyl acetate / hexanes, observed with intermediate 21a ); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ-0.11 (s, 9H), 0.85 (t, 2H, J = 8.1 Hz), 2.06 (s, 3H), 3.64 (t, 2H, J = 7.7 Hz), 3.85 (s, 3H), 5.90 (s, 2H), 6.55 (dd, 1H, J = 7.2, 1.1 Hz), 6.96 (m , 4H), 7.26 (t, 1H, J = 7.9 Hz), 7.46 (dd, 1H, J = 8.7, 1.5 Hz), 7.87 (d, 1H, J = 8.7 Hz), 8.40 and 8.55 (2s, 1H together ), 9.45 and 9.61 (2s, 1H together), 12.62 and 12.91 (2s, 1H together). Anal. (C ₂₈ H ₃₂ N ₄ O ₃ Si.0.4 H ₂ O) C, H, N.
[383] (c) Intermediate 21c-2- [5- (3-methoxy-2-methyl-phenyl) -1 H-indazol-3-yl] -1 H-benzoimidazol-4-ol:
[384] In the same manner as the preparation of the compound 3 , the intermediate 21c (59.8 mg, 46%) in the form of an off-white solid was prepared using the intermediate 21b (174.5 mg, 0.349 mmol) and tetrabutylmonium fluoride: R _f = 0.26 (5% methanol / dichloromethane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 2.07 (s, 3H), 3.85 (s, 3H), 6.53 and 6.62 (2d , 1H together, J = 7.4, 7.7 Hz), 6.96 (m, 4H), 7.26 (t, 1H, J = 7.9 Hz), 7.37 (d, 1H, J = 8.5 Hz), 7.66 (d, 1H, J = 8.5 Hz), 8.35 and 8.49 (2s, 1H together), 9.45 and 9.55 (2s, 1H together), 12.53 and 12.78 (2s, 1H together), 13.57 and 13.62 (2s, 1H together). HRMS calcd for C ₂₂ H ₁₉ N ₄ O ₂ 371.1508 (MH ⁺ ), found 371.1523.
[385] (d) Compound 21- 2- [5- (3-hydroxy-2-methyl-phenyl) -1 H-indazol-3-yl] -1 H-benzoimidazol-4-ol:
[386] Compound 21 (29.0 mg, 66%) in the form of a brown powder was prepared by treating intermediate 21c (45.9 mg, 0.124 mmol) and pyridine hydrochloride in the same manner as for phenol 8 ′ : R _f = 0.28 (10% methanol / Dichloromethane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 2.04 (s, 3H), 6.54 and 6.62 (dd and d, 1H together, J = 7.2, 1.3 and 7.7 Hz), 6.75 (d, 1H, J = 7.4 Hz), 6.85 (d, 1H, J = 7.9 Hz), 7.01 (m, 3H), 7.37 and 7.38 (dd and dd, 1H together) , J = 8.5, 1.5 Hz), 7.65 and 7.66 (2d, 1H together, J = 8.7 Hz respectively, 8.35 and 8.48 (2s, 1H together), 9.38 and 9.39 (2s, 1H together), 9.46 and 9.56 ( 2s, 1H together), 12.52 and 12.77 (2s, 1H together), 13.55 and 13.60 (2s, 1H together). HRMS calcd for C ₂₁ H ₁₇ N ₄ O ₂ , 357.1351 (MH ⁺ ), found 357.1360. Anal. (C ₂₁ H ₁₆ N ₄ O ₂ 0.8 CH ₃ OH) C, H, N.
[387] Example 22 6- (3-hydroxy-propyl) -2-methyl-3- [3-((E) -styryl) -1 H-indazol-5-yl] -phenol
[388]
[389] (a) Intermediate 22a- 3-Amino-2-methyl-phenol:
[390] A suspension of 2-methyl-3-nitro-phenol (Aldrich Chemicals) (29.8 g, 194.6 mmol) and 10% Pd-C (3.01 g) in ethanol (350 mL) was shaken for 3.5 h in the presence of 40 psi hydrogen. . The solution was filtered through a pad of celite, concentrated and purified by silica gel chromatography (50% ethyl acetate / hexanes) to prepare aniline 22a (20.32 g, 85%) as a clear solid: R _f = 0.50 (50%). Ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ 1.87 (s, 3H), 4.63 (s, 2H), 6.08 (dd, 2H, J = 7.9, 10.5 Hz), 6.64 (t, 1H, J = 7.9 Hz) , 8.76 (s, 1 H). Anal. (C ₇ H ₇ NO) C, H, N.
[391] (b) Intermediate 22b- 3-iodo-2-methyl-phenol:
[392] Intermediate 22a (18.35 g, 149 mmol) was prepared using DeGraw, et al. [DeGraw, JI; Brown, VH; Colwell, WT; Morrison, NE, J. Med. Chem. , 17 , 762 (1974). Column chromatography (10-50% ethyl acetate / hexanes) separated aryl iodide 22b (9.06 g, 26%) in the form of an orange solid. This was then purified by recrystallization from hexane to give 5.63 g of a pale orange needles: R _f = 0.35 (20% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ2.22 (s, 3H), 6.80 (m, 2H), 7.24 (dd, 1H, J = 7.5, 1.5 Hz), 9.75 (s, 1H).
[393] (c) Intermediate 22c-1-Allyloxy-3-iodo-2-methyl-benzene:
[394] Allyl bromide (1.57 g, 13.0 mmol) was added to a solution in which 3-iodo-2-methylphenol (2.026 g, 8.66 mmol) was dissolved in acetone (18 mL). The solution was heated to reflux for 2 hours, then cooled to room temperature, diluted with ethyl acetate (50 mL), and acidified with 1N aqueous hydrochloric acid until pH = 2. After phase separation the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The obtained organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (5% ethyl acetate / hexane) to give allyl ether 22c (2.1353 g, 90%) in the form of a yellow oil: R _f = 0.60 (20) % Ethyl acetate / hexane); ¹ H NMR (CDCl ₃ ) δ 2.40 (s, 3H), 4.53 (d of t, 2H, J = 5.1, 1.5 Hz), 5.28 (d of q, 1H, J = 10.6, 1.5 Hz), 5.42 ( d of q, 1H, J = 17.3, 1.5 Hz, 6.05 (m, 1H), 6.82 (m, 2H), 7.43 (dd, 1H, J = 7.2, 1.9 Hz).
[395] (d) Intermediate 22d-6-allyl-3-iodo-2-methyl-phenol:
[396] Intermediate 22c (1.0954 g, 3.996 mmol) was placed in a sealed tube, heated in a 200 ° C. oil bath for 2 hours, cooled and subjected to column chromatography to give phenol 22d (767.2 mg, 70%) as a yellow oil: R _f = 0.31 (10% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ2.30 (s, 3H), 3.28 (d, 2H, J = 6.6 Hz), 5.02 (m, 2H), 5.90 (m, 1H), 6.66 (d, 1H, J = 7.9 Hz), 7.26 (d, 1H, J = 8.1 Hz), 8.63 (s, 1H).
[397] (e) Intermediate 22e-6- (3-hydroxy-propyl) -3-iodo-2-methyl-phenol:
[398] Borane-dimethylsulfide complex (0.159 mL, 1.68 mmol borane) was added dropwise to a solution cooled to 0 ° C. with intermediate 22d (459.8 mg, 1.677 mmol) in dry ether (5.0 mL). . The cold bath was removed and stirring continued for 1 hour. To the mixture was added pure ethanol (2.5 mL) followed by water soluble sodium hydroxide (2.5 N, 3.35 mL). The mixture was cooled back to 0 ° C. and hydrogen peroxide (dissolved in water at 30 wt%, 0.27 mL) was added. The mixture was stirred at 0 ° C. for 15 minutes, then the cooling bath was removed and allowed to warm to room temperature for at least 1 hour. The solution was partitioned between ether (50 mL) and 1N aqueous hydrochloric acid (final aqueous solution pH 2-3). The organic layer was dried over magnesium sulfate, filtered and concentrated to an orange oil. Purification by silica gel chromatography yielded alcohol 22e (353.1 mg, 72%) in the form of a yellow oil: R _f = 0.11 (20% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ 1.64 (quint, 2H, J = 7.0 Hz), 2.29 (s, 3H), 2.54 (t, 2H, J = 7.5 Hz), 3.39 (t, 2H, J = 6.5 hz), 4.54 (br s, 1H), 6.68 (d, 1H, J = 8.1 Hz), 7.23 (d, 1H, J = 8.1 Hz), 8.58 (s, 1H).
[399] (f) Intermediate 22f-6- (3-hydroxy-propyl) -2-methyl-3- [3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -phenol:
[400] Aqueous sodium carbonate solution (2M, 1.79 mL) was added to DMF (3.2 mL) to boronic ester 16a (534.1 mg, 1.12 mmol), aryl iodide 22e (209.1 mg, 0.716 mmol) and 1,1'-bis (diphenylphosph). Pino) ferrocenedichloropalladium (II) (29 mg, 0.036 mmol) was dissolved and added to the degassed solution. The mixture was heated in an 80 ° C. oil bath for 1.5 hours, then cooled and partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (20-50% ethyl acetate / hexanes) gave intermediate 22f (301.9 mg, 82%) in the form of a yellow bubble: R _f = 0.07 (20% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ-0.09 (s, 9H), 0.83 (t, 2H, J = 7.9 Hz), 1.73 (quint, 2H, J = 7.5 Hz), 2.09 (s, 3H), 2.65 (t, 2H, J = 7.5 Hz), 3.46 (t, 2H, J = 6.5 Hz), 3.58 (t, 2H, J = 8.0 Hz), 5.78 (s, 2H), 6.74 (d, 1H, J = 7.7 Hz), 6.98 (d, 1H, J = 7.9 Hz), 7.27 (m, 1H), 7.37 (m, 3H), 7.56 (m, 2H), 7.73 (m, 3H), 8.06 (s, 1H) , 8.25 (br s, 1 H). Anal. (C ₃₁ H ₃₈ N ₂ O ₃ Si0.5 CH ₂ Cl ₂ ) C, H, N.
[401] (g) Compound 22-6- (3-hydroxy-propyl) -2-methyl-3- [3-((E) -styryl) -1 H-indazol-5-yl] -phenol:
[402] Compound 22 was prepared in the same manner as Compound 3 of Example 3 by treating Intermediate 22f (202.9 mg, 0.394 mmol) with tetrabutylammonium fluoride to give Compound 22 (34.3 mg, 23%) in the form of a white powder: R _f = 0.19 (50% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ1.72 (quint, 2H, J = 7.4 Hz), 2.10 (s, 3H), 2.64 (t, 2H, J = 7.4 Hz), 3.45 (t, 2H, J = 6.2 Hz), 4.59 (br s, 1H), 6.74 (d, 1H, J = 7.7 Hz), 6.97 (d, 1H, J = 7.7 Hz), 7.33 (m, 4H), 7.45 (m, 5H), 8.02 (s, 1 H), 8.26 (s, 1 H), 13.18 (s, 1 H). _{Anal. (C 25 H 24 N} 2 O 2 · 0.6 H 2 O) C, H, N.
[403] Example 23: 3- [3- (4-hydroxymethyl-1H-benzoimidazol-2-yl) -1H-indazol-5- Japanese] -2-methyl-phenol
[404]
[405] (a) Intermediate 23a-(2-Amino-3-nitro-phenyl) -methanol:
[406] 3-nitroanthranilic acid (Chapman, E. and Stephen, H., J. Chem. Soc ., 127 , 1791 (1925)] (5.00 g, 27.45 mmol) using a borane-dimethylsulfide complex using Mikelson, et al. [Mickelson, John W. et al., J. Med. Chem. , 39 , 4654 (1996) to give benzyl alcohol 23a (4.27 g, 93%) in the form of an orange crystalline solid: R _f = 0.22 (75% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ4.50 (d, 2H, J = 5.4 Hz), 5.43 (t, 1H, J = 5.4 Hz), 6.65 (dd, 1H, J = 8.7, 7.2 Hz), 7.10 (br s, 2H), 7.47 (d, 1H, J = 7.0 Hz), 7.94 (dd, 1H, J = 8.8, 1.5 Hz). Anal. (C ₇ H ₈ N ₂ O ₃ ) C, H, N.
[407] (b) Intermediate 23b- (2,3-Diamino-phenyl) -methanol:
[408] In the same manner as the synthesis of intermediate 9a ' , intermediate 23a was hydrogenated in ethanol (300 mL) to prepare intermediate 23b (2.23 g, 86%) as a brown solid. Then purified by recrystallization in ethanol to give intermediate 23b (1.04 g, 40%) in the form of a yellow needle: R _f = 0.17 (75% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) δ 4.36 (br s, 6H), 4.90 (br s, 1H), 6.42 (m, 3H). Anal. (C ₇ H ₁₀ N ₂ O) C, H, N.
[409] (c) Intermediate 23c-{2- [5-iodo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-3-yl] -1H-benzoimidazol-4-yl } -Methanol:
[410] Intermediate 23c was prepared in the same manner as intermediate 7c ' . Diamine 23b (587.3 mg, 4.25 mmol) was condensed with aldehyde 7b ' (1.71 g, 4.25 mmol) in the presence of a sulfur atom to prepare intermediate 23c (1.57 g, 71%) as a yellow solid: ¹ H NMR (DMSO- d ₆ ) [some peaks are doubled by tautomeric isomerization] δ-0.13 (s, 9H), 0.82 (t, 2H, J = 7.7 Hz), 3.58 (t, 2H, J = 7.9 Hz), 4.87 (br s, 1H), 5.04 (br s, 1H), 5.22 (br s, 1H), 5.87 (s, 2H), 7.26 (m, 2H), 7.39 and 7.67 (m and br s, 1H together), 7.75 (d, 1H, J = 8.7 Hz), 7.83 (dd, 1H, J = 8.8, 1.5 Hz), 8.95 (d, 1H, J = 1.1 Hz), 12.97 and 13.13 (2s , 1H together). Anal. (C ₂₁ H ₂₅ IN ₄ O ₂ Si) C, H, I, N.
[411] (d) Intermediate 23d-2-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol:
[412] Iodine 22b (1.21 g, 5.17 mmol) was converted to boronic ester 23d (1.15 g, 95%) in the form of a white crystalline solid in the same manner as the intermediate 9c ' synthesis: R _f = 0.18 (10% ethyl acetate / Hexane); ¹ H NMR (CDCl ₃ ) δ 1.35 (s, 12H), 2.46 (s, 3H), 6.87 (dd, 1H, J = 7.9, 1.0 Hz), 7.08 (t, 1H, J = 7.5 Hz), 7.35 (dd, 1H, J = 7.4, 1.1 Hz). _{Anal. (C 13 H 19 BO} 3 · 0.2 H 2 O) C, H.
[413] (e) Intermediate 23e-3- [3- (4-hydroxymethyl-1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole- 5-yl] -2-methyl-phenol:
[414] Intermediate 23e was prepared by the same method as the synthesis of intermediate 9d ' . Iodide 23c (276.3 mg, 0.514 mmol) and boronic ester 23d (300 mg, 1.28 mmol) were combined to yield intermediate 23e (128.2 mg, 50%) as a yellow solid: R _f = 0.16 (40% ethyl). Acetate / hexane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ-0.11 (s, 9H), 0.85 (t, 2H, J = 7.9 Hz), 2.03 and 2.07 (2s, 3H together), 3.63 (t, 2H, J = 7.7 Hz), 4.87 and 4.97 (2d, 2H together, J = 5.8 and 5.5 Hz), 5.11 and 5.25 (2t, 1H together, J = 5.6 and 6.1 Hz), 5.92 and 5.93 (2s, 2H together), 6.76 (dd, 1H, J = 7.5, 3.4 Hz), 6.86 (d, 1H, J = 7.9 Hz), 7.17 (m, 3H), 7.39 and 7.60 (dd and d, 1H together, J = 6.8, 2.1 and 7.9 Hz), 7.49 (d, 1H, J = 8.7 Hz), 7.89 (d, 1H, J = 8.9 Hz), 8.44 and 8.47 (2s, 1 Htogether), 9.46 and 9.48 (2s, 1H together), 12.91 and 13.09 (2s, 1H together). Anal. (C ₂₈ H ₃₂ N ₄ O ₃ Si0.3 H ₂ O) C, H, N.
[415] (f) Compound 23- 3- [3- (4-hydroxymethyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -2-methyl-phenol:
[416] Compound 23 was prepared in the same manner as in the preparation of compound 3 . Intermediate 23e (130.7 mg, 0.261 mmol) and tetrabutylammonium fluoride were treated to give compound 23 (61.6 mg, 64%) in the form of a white solid: R _f = 0.22 (70% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 2.04 and 2.07 (2s, 3H together), 4.86 and 4.97 (2d, 2H together, J = 6.0 and 5.7 Hz), 5.10 and 5.23 (2t, 1H together, J = 5.6 and 6.0 Hz), 6.76 (d, 1H, J = 7.2 Hz), 6.85 (d, 1H, J = 8.1 Hz), 7.14 (m, 3H), 7.37 and 7.58 (dd and d, 1H together, J = 7.2, 1.9 and 7.7 Hz), 7.40 (dd, 1H, J = 8.5, 1.5 Hz), 7.67 (d, 1H, J = 8.1 Hz), 8.39 and 8.42 (2s, 1H together), 9.43 and 9.45 (2s, 1H together), 12.81 and 12.96 (2s, 1H together), 13.65 and 13.70 (2s, 1H together). Anal. (C ₂₄ H ₁₈ N ₄ O ₂ Si.1.0 CH ₃ OH) C, H, N.
[417] Example 24: 7- [3-((E) -styryl) -1H-indazol-5-yl] -isoquinoline
[418]
[419] (a) Intermediate 24a-1,1,1-trifluoro-methanesulfonic acid isoquinolin-7-yl ester:
[420] Trifluoromethanesulphonic anhydride (4.54 g, 16.10 mmol) was added by dropping 7-hydroxyisoquinoline (1.9477 g, 13.24 mmol, Lancaster Chemicals) in pyridine (14 mL) to a mixture cooled to 0 ° C. It was. The mixture was stirred at 0 ° C. for 1 h and then stirred at room temperature for 24 h. The solution was partitioned between dichloromethane and saturated aqueous bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (50% ethyl acetate / hexane) to give triflate 24a (3.27 g, 88%) as a pale yellow oil: R _f = 0.23 (50% ethyl acetate / hexane): ^l H NMR (DMSO-d ₆ ) δ7.72 (dd, lH, J = 9.0, 2.5 Hz), 7.80 (d, lH, J = 5.8 Hz), 8.06 (d, 1H, J = 9.0 Hz), 8.23 (d, lH, J = 2.5 Hz), 8.55 (d, lH, J = 5.7 Hz), 9.39 (s, lH). ^{l 3} C NMR (DMSO-d ₆ ) δ118.33 (q, J = 320 Hz), 119.35, 1l9.99, 124.17, 128.03, l29.9, 134.31, l44.09, 147.02, 152.46. Anal. (C ₁₀ H ₆ F ₃ NO ₃ S0.1 H ₂ O) C, H, N, S.
[421] (b) Intermediate 24b- 7- [3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazol-5-yl] -isoquinoline:
[422] 1,4-dioxane (10 ml) to boronic ester 16a (282.9 mg, 0.594 mmol), potassium phosphate powder (344 mg, 1.62 mmol), 1, l'-bis (diphenylphosphino) ferrocenedichloropalladium ( II) Isoquinoline triflate 24a (150 mg, 0.540) in a degassed solution by dissolving (13 mg, 0.016 mmol) and 1, l'-bis (diphenylphosphino) ferrocenene (9 mg, 0.016 mmol). mmol) was added. The mixture was heated in an 80 ° C. oil bath for 6 hours, then cooled and partitioned between ethyl acetate (50 mL) and saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over magnesium sulfate and filtered. Purification by silica gel chromatography (10-75% ethyl acetate / hexanes) gave intermediate 24b (92.7 mg, 36%) as a fluorescent pink gel: R _f = 0.06 (20% ethyl acetate / hexanes); _{^{l H NMR (CDCl 3) δ}} -0.04 (s, 9H), 0.94 (t, 2H, J = 8.4 Hz), 3.64 (t, 2H, J = 8.1 Hz), 5.79 (s, 2H), 7.30-8.09 (m, l 4 H), 8.26 (d, 2H, J = 12.9 Hz).
[423] (c) compound 24-7- [3-((E) -styryl) -1 H-indazol-5-yl] -isoquinoline:
[424] Intermediate 24b (86 mg, 0.18 mmol) and tetrabutylammonium fluoride were treated in the same manner as the preparation of compound 3 to obtain compound 24 (27.2 mg, 43%) in the form of a white powder: R _f = 0.11 (70) % Ethyl acetate / hexane): ^l H NMR (DMSO-d ₆ ) δ 7.29 (t, lH, J = 7.2 Hz), 7.41 (t, 2H, J = 7.2 Hz), 7.66 (m, 5H), 7.88 (t, 2H, J = 5.7 Hz), 8.09 (d, lH, J = 8.7 Hz), 8.29 (dd, lH, J = 8.4, 1.8 Hz), 8.51 (m, 3H), 9.41 (s, lH) , 13.28 (s, lH). Anal. (C ₂₄ H ₁₇ N ₃ .6 CH ₂ OH) C, H, N.
[425] Example 25: 4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline
[426]
[427] (a) Intermediate 25a- 3- (1H-benzoimidazol-2-yl) -5- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2 -Yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole:
[428] Iodide 7c ' (2.36 g, 4.81 mmol) was converted to boronic ester 25a (1.43 g, 61%) in the form of a white crystalline solid in the same manner as for the preparation of boronic ester 19f : ^l H NMR (DMSO- d ₆ ) δ0.l3 (s, 9H), 0.82 (t 2H, J = 7.7 Hz), 1.35 (s, l2H), 3.59 (t, 2H, J = 7.9 Hz), 5.89 (s, 2H), 7.24 (m, 2H), 7.53 (m, lH), 7.83 (m, 3H), 8.95 (s, lH), 13.15 (s, lH). Anal. (C ₂₆ H ₃₅ BN ₄ O ₃ Si) C, H, N.
[429] (b) Intermediate 25b-4- [3- (lH-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -iso Quinoline:
[430] In the same manner as the preparation of intermediate 19f , 4-bromoisoquinoline (238 mg, l.14 mmol) was combined with boronic ester 25a (280.4 mg, 0.572 mmol) to give an intermediate 25b (237.5 mg, 84%) was obtained: R _f = 0.20 (50% ethyl acetate / hexanes); _{^{l H NMR (DMSO-d 6}} ) δ-0.07 (s, 9H), 0.86 (m, 2H), 3.67 (t, 2H, J = 7.9 Hz), 5.98 (s, 2H), 7.20 (br m, 2H ), 7.55 (br m, lH), 7.65 (br m, lH), 7.71 (m, 4H), 8.07 (d, lH, J = 8.7 Hz), 8.27 (dd, lH, J = 7.2, 1.7 Hz) , 8.56 (s, lH), 8.66 (d, lH, J = 0.8 Hz), 9.41 (s, lH), 13.17 (s, lH).
[431] (c) Compound 25- 4- [3- (lH-benzoimidazol-2-yl) -1 H-indazol-5-yl] -isoquinoline:
[432] Compound 25 was prepared in the same manner as in Example 3. Intermediate 25b (152.4 mg, 0.310 mmol) was treated with tetrabutylammonium fluoride to give compound 25 (61.9 mg, 55%) in the form of a white bubble: R _f = 0.16 (70% ethyl acetate / hexane); _{^{l H NMR (DMSO-d 6}} ) δ7.18 (br m, 2H), 7.56 (br m, 2H), 7.63 (dd, lH, J = 8.5, 1.7 Hz), 7.81 (m, 4H), 8.27 ( dd, lH, J = 7.4, 1.2 Hz), 8.55 (s, lH), 8.62 (s, lH), 9.40 (s, lH), 13.05 (br s, lH), 13.84 (s, lH).
[433] Example 26 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -6- (3-hydroxy-propyl) -2-methyl-phenol
[434]
[435] (a) Intermediate 26a-3- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -6 -(3-hydroxy-propyl) -2-methyl-phenol:
[436] In the same manner as the preparation of the intermediate 25b , boronic ester 25a (303 mg, 0.618 mmol) was combined with iodide 22e (180.5 mg, 0.618 mmol) to give an intermediate 26a (124.4 mg, 38%) in the form of a white solid. Obtained: R _f = 0.30 (50% ethyl acetate / hexanes); _{^{l H NMR (DMSO-d 6}} ) δ-0.11 (s, 9H), 0.85 (t, 2H, J = 7.9 Hz), 1.74 (quint, 2H, J = 7.0 Hz), 2.08 (s, 3H), 2.66 (t, 2H, J = 7.7 Hz), 3.47 (q, 2H, J = 5.3 Hz), 3.63 (t, 2H, J = 7.9 Hz), 4.60 (t, lH, J = 5.0 Hz), 5.91 (s , 2H), 6.75 (d, lH, J = 7.7 Hz), 7.01 (d, lH, J = 7.7 Hz), 7.20 (quint, 2H, J = 8.1 Hz), 7.49 (m, 2H), 7.71 (d , lH J = 7.7 Hz), 7.88 (d, lH, J = 8.7 Hz), 8.33 (s, 1H), 8.42 (s, lH), 13.11 (s, lH). Anal. (C ₃₀ H ₃₆ N ₄ O ₃ Si.0.6 Ethyl Acetate) C, H, N.
[437] (b) Compound 26- 3- [3- (lH-benzoimidazol-2-yl) -1H-indazol-5-yl] -6- (3-hydroxy-propyl) -2-methyl-phenol :
[438] In the same manner as in Example 3, intermediate 26a (99.4 mg, 0.188 mmol) was deprotected with tetrabutylammonium fluoride to give compound 26 (26.9 mg, 36%) as a white solid: R _f = 0.19 ( 70% ethyl acetate / hexanes); _{^{l H NMR (DMSO-d 6}} ) δ0.74 (quint, 2H, J = 7.4 Hz), 2.08 (s, 3H), 2.66 (t, 2H, J = 7.4 Hz), 3.47 (q, 2H, J = 5.1 Hz), 4.59 (t, lH, J = 5.1 Hz), 6.74 (d, lH, J = 7.7 Hz), 7.00 (d, lH, J = 7.7 Hz), 7.19 (quint, 2H, J = 7.9 Hz ), 7.38 (dd, 1H, J = 8.5, 1.5 Hz), 7.50 (d, lH, J = 7.4 Hz), 7.67 (m, 2H), 8.30 (s, lH), 8.37 (s, lH), 12.96 (s, lH), 13.66 (s, lH). Anal. (C ₂₄ H ₂₂ N ₄ O _{2 .4} ethyl acetate) C, H, N.
[439] Example 27 1- [3-((E) -styryl) -1 H-indazol-5-yl] -piperidin-4-ol
[440]
[441] (a) Intermediate 27a- 4- (tert-butyl-dimethyl-silanyloxy) -piperidine:
[442] Imidazole (4.18 g, 61.4 mmol), 4-hydroxypiperidine (2.07 g, 20.46 mmol), and tert-butyldimethylsilyl chloride (4.63 g, 30.7 mmol) were dissolved in dichloromethane (50 mL) and 23 Stir at 4 ° C. for 4 h. The mixture was then washed with saturated aqueous bicarbonate sodium solution (3x50 mL) and water (50 mL), dried over magnesium sulfate, filtered and concentrated in high vacuum to give an intermediate 27a as a yellow oil. 2.60 g, 59%) (crystallized in that state): ^l H NMR (CDCl ₃ ) δ0.05 (s, 6H), 0.90 (s, 9H), 1.46 (m, 2H), 1.81 (m, 2H), 2.71 (m, 2H), 3.09 (m, 3H), 3.77 (septet, lH, J = 3.9 Hz). Anal. (C ₁₁ H ₂₅ NOSi · O ₂ CH ₂ Cl ₂ ) C, H, N.
[443] (b) Intermediate 27b- 5- {4-[(dimethyl-ethyl) -dimethyl-silanyloxy] -piperidin-1-yl} -3-((E) -styryl) -1- ( 2-trimethylsilanyl-ethoxymethyl) -1 H-indazole:
[444] Sodium tert-butoxide (163 mg, 1.70 mmol), tris (dibenzylideneacetone) -dipalladium (0) (26 mg, 0.03 mmol), and CyMAP-1 (Old et al. For the structure of the ligands) al., J. Am. chem. Soc ., 120, 9722 (l998)) (33 mg, 0.085 mmol) in ethylene glycol dimethyl ether (DME, 2.0 mL) as intermediate 27a (241.1 mg, 1.12 mmol). And iodide 7a ' (269.3 mg, 0.565 mmol) was added to the degassed solution. The mixture was heated in an 80 ° C. oil bath for 17 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered to remove black precipitate. The filtrate was washed with water (10 mL) and saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (10-50% ethyl acetate / hexane) to form an orange oil. Intermediate 27b (177.7 mg, 56%) was obtained: R _f = 0.28 (20% ethyl acetate / hexanes); _{^{l H NMR (CDCl 3) δ}} -0.06 (s, 9H), 0.09 (s, 6H), 0.90 (m, 2H), 0.92 (s, 9H), 1.80 (m, 2H), 1.97 (m, 2H) , 3.07 (m, 2H), 3.44 (m, 2H), 3.58 (t, 2H, J = 8.4 Hz), 3.92 (m, lH), 5.69 (s, 2H), 7.29 (m, 2H), 7.41 ( m, 6H), 7.61 (d, 2H, J = 8.7 Hz).
[445] (c) Compound 27-1- [3-((E) -styryl) -1 H-indazol-5-yl] -piperidin-4-ol:
[446] In the same manner as in Example 3, treatment with Intermediate 27b (121.4 mg, 0.22 mmol) and tetrabutylammonium fluoride yielded Compound 27 (33.1 mg, 47%) in the form of a yellow bubble: R _f = 0.15 (70%) Ethyl acetate / hexane); _{^{l H NMR (DMSO-d 6}} ) δ1.55 (m, 2H), 1.86 (m, 2H), 2.83 (m, 2H), 3.47 (m, 2H), 3.61 (m, lH), 4.68 (d, lH, J = 4.2 Hz), 7.22 (m, 2H), 7.37 (m, 5H), 7.55 (d, 1H, J = 16.5 Hz), 7.69 (d, 2H, J = 7.2 Hz), 12.89 (s, lH). Anal. (C ₂₀ H ₂₁ N ₃ O.0.4 H ₂ O ethyl acetate) C, H, N.
[447] Compound 28: 1- [3-((E) -styryl) -1H-indazol-5-yl] -piperidin-3-ol
[448]
[449] (a) Intermediate 28a- 3- (tert-butyl-dimethyl-silanyloxy) -piperidine:
[450] In the same manner as the preparation of intermediate 27a , hydroxypiperidine hydrochloride (2.76 g, 20.06 mmol) was converted to intermediate 28a (2.92 g, 68%) (as crystallized) in the form of a yellow oil: ^l H NMR (CDCl ₃ ) δ0.05 (s, 6H), 0.89 (s, 9H), 1.46 (m, 2H), 1.77 (m, 2H), 2.39 (br s, lH), 2.61 (m, 2H) 2.82 (m, lH), 2.97 (dd, lH, J = l2.3, 2.7 Hz), 3.66 (septet, lH, J = 3.6 Hz). _{Anal. (C ll H 25 NOSi} · O.2 CH 2 Cl 2) C, H, N.
[451] (b) Intermediate 28b- 5- {3-[(dimethyl-ethyl) -dimethyl-silanyloxy] -piperidin-1-yl} -3-((E) -styryl) -1- ( 2-trimethylsilanyl-ethoxymethyl) -1 H-indazole:
[452] Intermediate 28b was prepared by the same preparation method as Intermediate 27b . Intermediate 28b (212.0 mg, 66%) in the form of a brown oil was prepared using intermediate 7a ' (269.3 mg, 0.565 mmol) and intermediate 28a (244 mg, 1.13 mmol): R _f = 0.17 (10%). Ethyl acetate / hexane); _{^{l H NMR (CDCl 3) δ}} -0.05 (s, 9H), 0.09 (s, 6H), 0.92 (m, 2H), 0.96 (s, 9H), 1.44 (m, lH), 1.65-2.05 (m, 3H), 2.69 (m, 2H), 3.56 (m, 4H), 3.92 (m, 1H), 5.70 (s, 2H), 7.25 (m, 2H), 7.40 (m, 6H), 7.60 (d, 2H) , J = 8.4 Hz). _{Anal. (C 32 H 49 N} 3 O 2 Si 2 · 0.6 H 2 O) C, H, N.
[453] (c) Compound 28-l- [3-((E) -styryl) -1 H-indazol-5-yl] -piperidin-3-ol:
[454] In the same manner as in Example 3, Intermediate 28b (l 81.5 mg, 0.322 mmol) and tetrabutylammonium fluoride were treated to give Compound 28 (47.6 mg, 46%) in the form of a yellow bubble: R _f = 0.19 (70% ethyl acetate / hexanes); _{^{l H NMR (DMSO-d 6}} ) δ1.34 (m, lH), 1.70 (m, lH), 1.95 (m, 2H), 2.55 (m, lH), 2.72 (m, lH), 3.46 (m, lH), 3.63 (m, lH), 3.74 (m, lH), 4.88 (d, lH, J = 4.5 Hz), 7.24 (dd, lH, J = 9.0, 1.8 Hz), 7.33 (t, lH, J = 7.2 Hz), 7.42 (m, 5H), 7.63 (d, lH, J = 16.5 Hz), 7.76 (d, 2H, J = 7.2 Hz), l2.97 (s, lH). Anal. (C ₂₀ H ₂₁ N ₃ O.0.3 H 2 O) C, H, N.
[455] Example 29: [2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzoimidazol-4-yl] -methanol
[456]
[457] (a) Intermediate 29a-{2- [5- (4,4,5,5-tetramethyl- [l, 3,2] dioxaborolan-2-yl) -1- (2-trimethylsilanyl -Ethoxymethyl) -1H-indazol-3-yl] -1H-benzoimidazol-4-yl} -methanol:
[458] In the same manner as for the preparation of boronic ester l9e , iodide 23c (512.6 mg, 0.985 mmol) was converted to boric ester 29a (312.0 mg, 61%) in the form of a white bubble: R _f = 0.28 (5% ethyl) Acetate / hexane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ-0.13 (s, 9H), 0.83 (t, 2H, J = 7.7 Hz), 1.35 (s, l2H), 3.60 (t, 2H, J = 8.1 Hz), 4.87 (br s, lH), 5.06 (br s, lH), 5.24 (m, lH), 5.90 (s, 2H), 7.26 (m, 2H), 7.40 and 7.71 (2 d, lHtogether, J = 7.2 and 7.9 Hz), 7.82 (m, 2H), 8.95 (s, lH), l2.93 and 13.10 (2 s, lH together). Anal. (C ₂₇ H ₃₇ BN ₄ O ₄ Si0.5 H ₂ O) C, H, N.
[459] (b) Intermediate 29b-{2- [5-isoquinolin-4-yl-1- (2-trimethylsilanyl-ethoxy-methyl) -1 H-indazol-3-yl] -1 H-benzoimimi Dazol-4-yl} -methanol:
[460] In the same manner as the intermediate 19f , 4-bromoisoquinoline (193 mg, 0.927 mmol) was combined with boronic ester 29a (241.2, 0.463 mmol) to give a white foamed intermediate 29b (171.1 mg, 71%). Was prepared: R _f = 0.22 (75% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ-0.08 (s, 9H), 0.88 (t, 2H, J = 7.7 Hz), 3.68 (t, 2H, J = 7.9 Hz), 4.88 (d, 2H, J = 5.3 Hz), 5.05 and 5.25 (2 br s, lH together), 5.98 (s, 2H), 7.22 (m, 2H), 7.40 and 7.57 (2 m, lH together), 7.7 (m, 4H), 8.07 (d, lH, J = 8.5 Hz), 8.27 (dd, lH, J = 7.2, 1.5 Hz), 8.57 (s, 1H), 8.70 (br s, lH), 9.41 (s, 1H), 12.97 and 13.14 (2 s, 1H together). Anal. (C ₃₀ H ₃₁ N ₅ O ₂ Si.0.4 H ₂ O) C, H, N.
[461] (c) Compound 29-[2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzoimida Zol-4-yl] -methanol:
[462] Compound 29 was prepared in the same manner as in Example 3. Treatment of intermediate 29b (129.0 mg, 0.247 mmol) with tetrabutylammonium fluoride gave compound 29 (58.3 mg, 60%) in the form of a white powder: R _f = 0.17 (75% ethyl acetate / hexane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 4.88 (t, 2H, J = 6.2 Hz), 5.03 and 5.23 (2t, 1H together, J = 5.6 and 6.2 Hz), 7.20 (m, 2H), 7.38 and 7.53 (m and d, lH together, J = 7.4 Hz for the doublet), 7.63 (dd, lH, J = 8.7, 1.3 Hz) , 7.82 (m, 4H), 8.27 (d, lH, J = 7.4 Hz), 8.55 (s, 1H), 6.63 and 8.66 (2 s, lH together), 9.40 (s, lH), 12.87 and 13.02 (2s , lH together), 13.81 and 13.86 (2s, 1H togeter). Anal. (C ₂₄ H ₁₇ N ₅ O.0.4 H ₂ O.0.3 CH ₂ Cl ₂ ) C, H, N.
[463] Example 30: 2- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-yl] -ethanol
[464]
[465] (a) Intermediate 30a-2- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimidazole- 4-yl} -ethanol:
[466] 10% Pd-C (66 mg) and 2- (2-amino-3-nitrophenyl) ethanol in pure ethanol (50 mL) [Seno, kaoru; Hagishita, Sanji: Sato, Tomohiro; Kuriyama, kaoru; J. Chem. Soc. Perkin Trans. One; 2012 (1984)] (531.5 mg, 2.92 mmol) was dissolved in a 40 psi hydrogen atmosphere for 3 hours. The mixture was filtered and concentrated to afford crude 2- (2,3-diaminophenyl) ethanol (474.4 mg) in the form of a red oil which crystallized as such: R _f = 0.08 (75% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) δ2.58 (t, 2H, J = 6.9 Hz), 3.53 (t, 2H, J = 7.2 Hz), 4.32 (br s, 5H), 6.29 (m, 2H), 6.40 (dd, 1H, J = 6.9, 2.1 Hz).
[467] In the same manner as the intermediate 7c ' , the crude crude diamine was concentrated to aldehyde 19f (1.10 g, 2.81 mmol) in the presence of sulfur to prepare intermediate 30a (930.8 mg, 63%) in the form of a yellow bubble: R _f = 0.19 (ethyl acetate); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 3.10 (m, 2H), 3.71 (s, 3H), 3.74 (m, 2H ), 4.66 and 4.80 (2 br s, lH together), 5.82 (s, 2H), 6.93 (d, 2H, J = 8.7 Hz), 7.05 (m, 2H), 7.39 (m, 3H), 7.65 (d , lH, J = 9.2 Hz), 7.81 (m, 3H), 8.00 (m, lH), 8.26 (dd, lH, J = 7.2, 2.1 Hz), 8.54 (s, 1H), 8.65 (s, 1H) , 9.39 (s, lH), 12.96 and 13.02 (2s, lH together).
[468] (b) Compound 30- 2- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -lH-benzoimidazol-4-yl] -ethanol:
[469] Intermediate 30a (169.1 mg, 0.32 mmol) was deprotected in the same manner as in Example 19 to give compound 30 (28.2 mg, 2%) in the form of a white powder: R _f = 0.33 (ethyl acetate); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 3.11 (m, 2H), 3.73 (m, 2H), 4.68 and 4.85 (2t , lH together, J = 5.2 and 5.5 Hz), 7.04 (m, 2H), 7.35 and 7.47 (2d, lH together, J = 7.9 and 7.2 Hz), 7.63 (d, lH, J = 8.7 Hz), 7.83 ( m, 4H), 8.26 (d, lH, J = 7.5), 8.55 (s, 1H), 8.63 (s, lH), 9.39 (s, lH), 12.97 and 13.01 (2s, lH together), 13.86 and 13.87 (2s, 1H together). _{Anal. (C 25 H l9 N} 5 O · O.3 H 2 O · 0.4 ethyl acetate · 0.06 S) C, H, N.
[470] Example 31: [2- (5-Isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzoimidazol-4-ylmethyl] -dimethyl-amine
[471]
[472] (a) Intermediate 31a-{2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimidazole-4- Nitrol-Methanol:
[473] In the same manner as the intermediate 19h , aldehyde 19f (3.67g, 9.33mmol) and diamine 23b (1.29g, 9.33mmol) were combined in the presence of sulfur to prepare intermediate 3la ( 2.60g , 54%) in the form of a yellow solid. R _f = 0.19 (75% ethyl acetate / hexanes); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 3.71 (s, 3H), 4.88 (d, 2H, J = 5.5 Hz), 5.04 and 5.25 (2t, 1H together, J = 5.6 and 6.1 Hz), 5.81 and 5.83 (2s, 2H together), 6.93 (d, 2H, J = 8.5 Hz), 7.21 (m, 2H), 7.38 and 7.5 ( 2d, 3H together, J = 7.4 and 7.5 Hz), 7.66 (d, 1H, J = 8.7 Hz), 7.7 (m, 3H), 8.01 (dd, 1H, J = 8.7, 4.0 Hz), 8.26 (d, 1H, J = 7.7 Hz), 8.54 and 8.55 (2s, 1H together), 8,65 and 8.68 (2s, 1H together), 9.39 (s, 1H), 12.88 and 13.05 (2s, 1H together). _{Anal. (C 32 H 25 N} 5 O 2 · 0.3 H 2 O) C, H, N.
[474] (b) Intermediate 31b-{2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimidazole-4- Monomethyl} -dimethyl-amine:
[475] Methane sulfonyl chloride (119.3 mg, 1.04 mmol) was dissolved in tetrahydrofuran (12.0 mL) in an 0 ° C ice bath, and intermediate 31a (527.5 mg, 1.03 mmol) and diisopropylethylene amine (153.3 mg, 1.19 mmol) were dissolved. Dropped into solution and added. After stirring for 2.5 hours at 0 ° C., the reaction flask was placed in a cold finger condenser cooled with dry ice to liquefy the dimethyl amine gas until the volume of the reaction solution increased to 5 ml. Then, the mixture was stirred at 0 ° C. for 4 hours and then stirred at room temperature for 15 hours. The mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic extract was dried over magnesium sulfate, filtered, concentrated and columned with silica gel (5-10% methanol / dichloromethane) to give intermediate 31b (250.2 mg, 45%) as a pale yellow solid: R _f = 0.26 (10% methanol / dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ2.20 (s, 6H), 3.71 (s, 3H), 3.84 (s, 2H), 5.83 (s, 2H), 6.93 (d, 2H, J = 8.7 Hz) , 7.14 (m, 2H), 7.36 (d, 2H, J = 8.5 Hz), 7.48 (m, 1H). 7.67 (d, 1H, J = 8.9 Hz), 7.7 (quintet, 2H, J = 6.4 Hz), 7.89 (m, 1H), 8.00 (d, 1H, J = 8.9 Hz), 8.26 (d, 1H, J = 7.5 Hz), 8.55 (s, 1H), 8.71 (s, 1H), 9.39 (s, 1H), 13.03 (br s, 1H). Anal. C ₃₄ H ₃₀ N ₆ O. 1.1 H ₂ O) C, H, N.
[476] (c) Compound 31- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-ylmethyl] -dimethyl-amine:
[477] The mixture of intermediate 31b (125.7 mg, 0.233 mmol), anisole (252 mg, 2.33 mmol), trifluoroacetic acid (2.3 mL), and concentrated sulfuric acid (0.2 mL) was stirred at room temperature for 66 hours. A solution of saturated aqueous sodium bicarbonate (75 mL) and ethyl acetate (25 mL) was added dropwise rapidly. After phase separation the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The obtained organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (25-40% methanol / dichloromethane) to give compound 31 (35.8 mg, 37%) in the form of a white powder: R _f = 0.09 (10% methanol / dichloromethane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomericisomerization) δ 2.15 and 2.2 l (2 br s, 6H together), 3.80 (s, 2H), 7.12 (br s, 2H), 7.40 and 7.54 (2m, 1H together), 7.64 (d, 1H, J = 9.0 Hz), 7.83 (m, 4H), 8.26 (d, 1H, J = 7.5 Hz), 8.55 (s, 1H), 8.63 and 8.73 (2 br s, 1H together), 9.39 (s, 1H), 13.02 (br s, 1H), 13.83 (br s, 1H). Anal. (C ₂₆ H ₂₂ N ₆ .0.7 H ₂ O.lO CH ₃ OH) C, H, N.
[478] Example 32 [2- (5-Isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-ylmethyl] -methyl-amine
[479]
[480] (a) Intermediate 32a-{2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimidazole-4- Monomethyl} -methyl-amine:
[481] In the same manner as the intermediate 31b , alcohol 31a (516.6 mg, 1.01 mmol) was treated with methanolsulfonyl chloride and diisopropylethyl amine for 1 hour at 0 ° C. A solution of methyleneamine dissolved in tetrahydrofuran (2.0 M, 5.0 mL) was added instead of the concentrated gas, followed by continuous stirring at room temperature for 15 hours. After extraction and purification by silica gel chromatography in the same manner as intermediate 31b , an intermediate 32a (170.5 mg, 32%) in the form of an off-white solid was prepared: R _f = 0.16 (1: 20: 300 concentrated aqueous NH ₄ OH: Ethanol: dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ2.26 (s, 3H), 3.71 (s, 3H), 4.03 (s, 2H), 5.82 (s, 2H), 6.93 (d, 2H, J = 8.7 Hz) , 7.14 (d, 2H, J = 4.7 Hz), 7.37 (d, 2H, J = 8.7 Hz), 7.46 (m, 1H), 7.67 (dd, lH, J = 8.7, 1.3 Hz), 7.77 (m, 2H), 7.89 (d, 1H, J = 7.7 Hz), 8.01 (d, 1H, J = 8.5 Hz), 8.25 (dd, 1H, J = 7.0, 1.8 Hz), 8.55 (s, 1H), 8.68 ( s, 1 H), 9.39 (s, 1 H). Anal. (C ₃₃ H ₂₈ N ₆ O.0.6 H ₂ O) C, H, N.
[482] (b) Compound 32- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-ylmethyl] -methyl-amine:
[483] Deprotection was carried out in the same manner as compound 31 to prepare compound 32 (47.5 mg, 63%) in the form of an off-white foam: R _f = 0.29 (concentrated water-soluble NH ₄ OH: ethanol: dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ2.30 (s, 3H), 4.07 (s, 2H), 7.15 (d, 2H, J = 4.5 Hz), 7.47 (m, 1H), 7.64 (dd, 1H, J = 8.5, 1.5 Hz), 7.83 (m, 4H), 8.26 (d, 1H, J = 7.2 Hz), 8.56 (s, 1H), 8.66 (s, 1H), 9.39 (s, 1H). Anal. (C ₂₅ H ₂₀ N ₆ O. 1.0 hexane) C, H, N.
[484] Example 33: 4- [3- (4-Pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline
[485]
[486] (a) Intermediate 33a- 4- [l- (4-methoxy-benzyl) -3- (4-pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl) -1H- Sol-5-yl] -isoquinoline:
[487] In the same manner as the intermediate 3lb , alcohol 3la (435.0 mg, 0.850 mmol) was treated with methanesulfonyl chloride and diisopropylethylamine for 2 hours at 0 ° C. Pyrrolidine (605 mg, 8.5 mmol) was added and the reaction mixture was warmed at room temperature for at least 20 hours. The mixture was extracted in the same manner as the intermediate 31b and purified by silica gel chromatography to obtain 33a (303.0 mg, 63%) in the form of an intermediate yellow bubble: R _f = 0.13 (1: 20: 400 concentrated aqueous NH ₄ OH) : Ethanol: dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ 1.61 (br s, 4H), 2.51 (br s, 4H), 3.71 (s, 3H), 3.97 (s, 2H), 5.83 (s, 2H), 6.93 (d , 2H, J = 8.8 Hz, 7.14 (d, 2H, J = 3.6 Hz), 7.36 (d, 2H, J = 8.7 Hz), 7.45 (m, 1H), 7.67 (d, 1H, J = 8.5 Hz ), 7.76 (m, 2H), 7.89 (m, 1H), 8.00 (d, 1H, J = 8.7 Hz), 8.25 (d, 1H, J = 6.6 Hz), 8.54 (s, 1H), 8.70 (br s, 1 H), 9.39 (s, 1 H), 13.03 (br s, 1 H). Anal. (C ₃₆ H ₃₂ N ₆ O.0.2 CH ₂ Cl ₂ ) C, H, N.
[488] (b) Compound 33- 4- [3- (4-Pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl) -1 H-indazol-5-yl] -isoquinoline:
[489] A solution of intermediate 33a (109.2 mg, 0.193 mmol) in 25% concentrated sulfuric acid / trifluol acetic acid (2.0 mL) was stirred at room temperature for 21 hours, followed by tetrahydrofuran (25 mL) and saturated aqueous sodium carbonate (25 mL). The mixed solution mixed with was quickly added. Ethyl acetate (25 mL) and water (15 mL) were added and phase separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL), and the obtained organics were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1: 20: 100 concentrated aqueous NH ₄ OH: ethanol: dichloromethane) gave compound 33 (25.4 mg, 30%) in the form of a white powder: ¹ H NMR (CD ₃ OD) δ1 .77 (br s, 4H), 2.69 (br s, 4H), 4.12 (s, 2H), 7.24 (d, 2H, J = 4.0 Hz), 7.80 (m, 5H), 8.06 (d, 1H, J = 7.9 Hz), 8.23 (d, 1H, J = 7.5 Hz), 8.53 (s, 1H), 8.69 (s, 1H), 9.29 (s, 1H). Anal. (C ₂₈ H ₂₄ N ₆ .0.9 MeOH) C, H, N.
[490] Example 34: 4- {3- [4- (2-Pyrrolidin-1-yl-ethyl) -1H-benzoimidazol-2-yl] -1H-indazol-5-yl} -isoquinoline
[491]
[492] (a) Intermediate 34a-4- {l- (4-methoxy-benzyl) -3- [4- (2-pyrrolidin-l-yl- Yl) -1H-benzoimidazol-2-yl] -1H-indazol-5-yl} -isoquinoline:
[493] In the same manner as the preparation of intermediate 33a , alcohol 30a (441.5 mg, 0.84 mmol) was converted to intermediate 34a (204.6 mg, 42%) in the form of an off-white foam: R _f = 0.08 (1: 20: 400 concentrated) Water soluble NH ₄ OH: ethanol: dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ 1.38 (br s, 4H), 2.31 (br s, 4H), 2.79 (m, 2H), 3.07 (m, 2H), 3.71 (s, 3H), 5.81 (s , 2H), 6.93 (d, 2H, J = 8.8 Hz), 6.98 (d, 1H, J = 7.2 Hz), 7.08 (t, 1H, J = 7.7 Hz), 7.36 (d, 2H, J = 8.7 Hz ), 7.39 (m, 1H), 7.66 (dd, 1H, J = 8.5, 1.5 Hz), 7.76 (m, 2H), 7.89 (d, 1H, J = 7.7 Hz), 8.01 (d, 1H, J = 8.7 Hz), 8.25 (d, 1H, J = 7.4 Hz), 8.53 (s, 1H), 8.75 (br s, 1H), 9.38 (s, 1H), 13.00 (br s, lH). Anal. (C ₃₇ H ₃₄ N ₆ O.0.6 H ₂ O) C, H, N.
[494] (b) compound 34- 4- {3- [4- (2-pyrrolidin-1-yl-ethyl) -1 H-benzoimidazol-2-yl] -1 H-indazol-5-yl}- Isoquinoline:
[495] Compound 34 was prepared by the same method as Compound 33 . Treatment with intermediate 34a (66.2 mg, 0.114 mmol) and 3: 1 trifluoroacetic acid / sulfuric acid gave compound 34 (24.7 mg, 47%) in the form of a white powder: R _f = 0.38 (1: 20: 100 concentrated) Water soluble NH ₄ OH: ethanol: dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ 1.37 (br m, 6H), 2.27 (br m, 2H), 2.80 (m, 2H), 3.07 (m, 2H), 6.98 (d, 1H, J = 7.2 Hz), 7.09 (t, 1H, J = 7.5 Hz), 7.36 (br s, 1H), 7.63 (dd, 1H, J = 8.5, 1.5 Hz), 7.82 (m, 4H), 8.26 (d, 1H, J = 7.4 Hz), 8.54 (s, 1H), 8.75 (br s, 1H), 9.39 (s, 1H), 12.98 (br s, 1H), 13.79 (s, 1H). Anal. (C ₂₉ H ₂₆ N ₆ .7 EtOH) C, H, N.
[496] Example 35: 3-{[2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-ylmethyl] -amino} -2-methyl-propane -1-ol
[497]
[498] (a) Intermediate 35a-cyclopropylmethyl- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimimi Dazol-4-ylmethyl} -amine:
[499] In the same manner as the preparation of intermediate 31b , alcohol 31a (512.0 mg, 1.00 mmol) was treated with methanesulfonyl chloride and diisopropylethyl amine for 1 hour at 0 ° C. Aminomethylcyclopropane (712 mg, 10.0 mmol) was added to the mixture, followed by stirring at room temperature for 15 hours. Extracted in the same manner as the intermediate 31b and purified by column chromatography to give 35a (209.3 mg, 37%) as an off-white powder: R _f = 0.16 (1: 20: 300 concentrated aqueous NH ₄ OH: ethanol) : Dichloromethane); ¹ H NMR (DMSO-d ₆ ) δ-0.24 (br s, 2H), -0.04 (br s, 2H), 0.66 (br s, 1H), 2.30 (br s, 2H), 3.71 (s, 3H) , 4.04 (br s, 2H), 5.83 (s, 2H), 6.93 (d, 2H, J = 8.7 Hz), 7.11 (m, 2H), 7.37 (d, 2H, J = 8.7 Hz), 7.42 (m , 1H), 7.67 (dd, 1H, J = 8.7, 1.5 Hz), 7.76 (m, 2H), 7.87 (d, 1H, J = 8.1 Hz), 8.02 (d, 1H, J = 8.7 Hz), 8.25 (dd, 1H, J = 6.8, 1.9 Hz), 8.53 (s, 1H), 8.68 (br s, 1H), 9.38 (s, 1H). Anal. (C ₃₆ H ₃₂ N ₆ O0.5 H ₂ O) C, H, N.
[500] (b) compound 35- 3-{[2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzoimidazol-4-ylmethyl] -amino} -2- Methyl-propan-1-ol:
[501] Compound 35 was prepared in the same manner as Compound 33 . Intermediate 35a (107.1 mg, 0.19 mmol) and 3: 1 trifluoroacetic acid / sulfuric acid were treated to give Compound 35 (25.3 mg, 29%) in the form of a white powder: R _f = 0.35 (1: 20: 100). Concentrated aqueous NH ₄ OH: ethanol: dichloromethane); ¹ H NMR (CD ₃ OD) δ 0.67 (d, 3H, J = 6.8 Hz), 1.33 (m, 1H), 1.8O (m, 1H), 2.60 (m, 1H), 2.75 (m, 1H) , 3.20 (m, 1H), 4.26 (s, 2H), 7.22 (m, 2H), 7.57 (d, 1H, J = 7.7 Hz), 7.63 (dd, 1H, J = 8.7, 1.7 Hz), 7.79 ( m, 3H), 7.99 (d, 1H, J = 7.5 Hz), 8.22 (d, 1H, J = 7.5 Hz), 8.5 l (s, 1H), 8.72 (br s, 1H), 9.29 (s, 1H ). ¹³ C NMR (CD ₃ OD, DEPT) δ15.0 (CH ₃ ), 35.6 (CH), 50.9 (CH ₂ ), 54.0 (CH ₂ ), 67.4 (CH ₂ ), 111.7 (CH), 123.4 (CH) , 124.0 (CH), 124.3 (CH), 125.8 (CH), 128.9 (CH), 129.3 (CH), 130.4 (CH), 132.6 (CH), 142.9 (CH)), 152.6 (CH). Anal. (C ₂₈ H ₂₆ N ₆ O.6CH ₂ Cl ₂ .0.4 Hexane) C, H, N.
[502] Example 36 diethyl- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-ylmethyl] -amine
[503]
[504] (a) Intermediate 36a-Diethyl- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimidazole -4-ylmethyl} -amine:
[505] In the same manner as the intermediate 3lb , alcohol 31a (511.4 mg, 1.00 mmol) was treated with methanesulfonyl chloride and diisopropylethyl amine for 2.5 hours at 0 ° C. Diethylamine (731.4 mg, 10.0 mmol) was added to the mixture, followed by stirring at room temperature for 25 hours. Extracted in the same manner as the intermediate 31b and purified by column chromatography to obtain intermediate 36a (434.6 mg, 77%) in the form of a yellow bubble: R _f = 0.22 (1: 20: 400 concentrated aqueous NH ₄ OH: ethanol : Dichloromethane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 0.87 and 1.01 (2 br s, 6H together), 2.41 and 2.56 (2 br s , 4H together), 3.71 (s, 3H), 3.89 and 3.94 (2 br s, 2H together), 5.82 (s, 2H), 6.92 (d, 2H, J = 8.7 Hz), 7.13 (m, 2H), 7.37 (d, 2H, J = 8.5 Hz), 7.50 (m, 1H), 7.67 (d, 1H, J = 8.7 Hz), 7.76 (m, 2H), 7.91 (m, 1H), 8.01 (d, 1H , J = 8.7 Hz), 8.25 (dd, 1H, J = 6.6, 1.9 Hz), 8.53 (s, 1H), 8.63 and 8.77 (2 br s, lH together), 9.38 (s, 1H), 13.02 (s , 1H). Anal. (C ₃₆ H ₃₄ N ₆ O.0.4 H ₂ O) C, H, N.
[506] (b) Compound 36-diethyl- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-ylmethyl] -amine:
[507] In the same manner as the preparation of Compound 33 , Intermediate 36a (266.5 mg, 0.47 mmol) and 3: 1 trifluoroacetic acid / sulfuric acid were treated to give Compound 36 (67.5 mg, 32%) in the form of a white powder: R _f = 0.30 (concentrated aqueous NH ₄ OH: ethanol: dichloromethane); ¹ H NMR (DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 0.94 (br m, 6H), 2.44 and 2.55 (2 br s, 4H together) , 3.94 (br s, 2H), 7.14 (br s, 2H), 7.39 and 7.50 (2 br s, 1H together), 7.64 (dd, lH, J = 8.7, 1.5 Hz), 7.77 (m, 4H), 8.25 (d, 1H, J = 7.4 Hz), 8.54 (s, 1H), 8.63 and 8.74 (2 br s, 1H together), 9.39 (s, 1H), 12.99 (s, 1H), 13.81 (s, 1H ). _{Anal. (C 28 H 26 N} 6 · 0.5 EtOH) C, H, N.
[508] Example 37: ethyl- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-ylmethyl] -amine
[509]
[510] (a) Intermediate 37a-Ethyl- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1 H-benzoimidazole- 4-ylmethyl} -amine:
[511] In the same manner as intermediate 31b , alcohol 3la (371.5 mg, 0.726 mmol) was treated with methanesulfonyl chloride and diisopropylethyl amine for 2.5 hours at 0 ° C. The reaction flask was fitted with a cold finger condenser cooled with dry ice and ethylene amine gas was condensed until the volume of the reaction solution increased to about 5 ml. Then stirred at room temperature for 15 hours. Extracted in the same manner as the intermediate 31b and purified by column chromatography to obtain intermediate 37a (260.1 mg, 67%) in the form of a pale yellow bubble: ¹ H NMR (DMSO-d ₆ ) δ 0.84 (br s, 3H ), 3.39 (br s, 2H), 3.71 (s, 3H), 4.04 (s, 2H), 5.82 (s, 2H), 6.93 (d, 2H, J = 8.7 Hz), 7.12 (m, 2H), 7.37 (d, 2H, J = 8.7 Hz), 7.44 (m, lH), 7.67 (dd, 1H, J = 8.7, 1.5 Hz), 7.76 (m, 2H), 7.89 (m, 1H), 8.01 (d , 1H, J = 8.7 Hz, 8.25 (dd, 1H, J = 6.6, l.9 Hz), 8.54 (s, 1H), 8.67 (s, 1H), 9.39 (3, 1H). Anal. (C ₃₄ H ₃₀ N ₆ O.0.7 H ₂ O) C, H, N.
[512] (b) Compound 37-Ethyl- [2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzoimidazol-4-ylmethyl] -amine:
[513] In the same manner as compound 33 , intermediate 37a (123.3 mg, 0.29 mmol) and 3: 1 trifluoroacetic acid / sulfuric acid were treated to give compound 37 (21.8 mg, 23%) as an off-white powder: ¹ H NMR ( DMSO-d ₆ ) δ 0.84 (br s, 3H), 2.57 (br s, 2H), 4.10 (s, 2H), 7.13 (m, 2H), 7.46 (m, 1H), 7.64 (dd, 1H, J = 8.7, 1.7 Hz), 7.80 (m, 4H), 8.26 (dd, 1H, J = 7.2, 1.7 Hz), 8.55 (s, 1H), 8.66 (s, 1H), 9.39 (s, 1H), 13.85 (br s, 1 H). Anal. (C ₂₆ H ₂₂ N ₆ .O.6 EtOH.1.0 CH ₂ Cl ₂ ) C, H, N.
[514] Example 38: Isopropyl- [2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzoimidazol-4-ylmethyl] -amine
[515]
[516] (a) Intermediate 38a-Isopropyl- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1 H-indazol-3-yl] -1 H-benzoimidazole -4-ylmethyl} -amine:
[517] In the same manner as the intermediate 3lb , alcohol 3la (518.0 mg, 1.01 mmol), methanesulfonyl chloride and diisopropyl amine were treated for 2.5 hours at 0 ° C. Isopropyl amine (597 mg, 10.1 mmol) was added to the mixture, followed by stirring at room temperature for 24 hours. Extracted in the same manner as the intermediate 31b and purified by column chromatography to give the intermediate 38a (417.8 mg, 75%) in the form of a yellow bubble: ¹ H NMR (DMSO-d ₆ ) δ0.77 (br s, 6H) , 2.63 (br s, 1H), 3.71 (s, 3H), 4.02 (br s, 2H), 5.82 (s, 2H), 6.93 (d, 2H, J = 8.7 Hz), 7.11 (m, 2H), 7.37 (d, 2H, J = 8.7 Hz), 7.42 (m, lH), 7.67 (dd, 1H, J = 8.7, 1.5 Hz), 7.76 (m, 2H), 7.88 (d, 1H, J = 7.7 Hz ), 8.02 (d, 1H, J = 8.7 Hz), 8.25 (dd, 1H, J = 6.6, 2.1 Hz), 8.53 (s, 1H), 8.69 (br s, 1H), 9.38 (s, 1H). Anal. (C ₃₅ H ₃₂ N ₆ O.0.7 H ₂ O) C, H, N.
[518] (b) Compound 38-Isopropyl- [2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzo-imidazol-4-ylmethyl] -amine:
[519] Compound 38 was prepared by the same method as compound 33 . Intermediate 38a (243.3 mg, 0.44 mmol) was treated with 3: 1 trifluoroacetone / sulfuric acid to give compound 38 (89.9 mg, 47%) in the form of an off-white powder. ¹ H NMR (DMSO-d ₆ ) δ1.03 (d , 6H, J = 6.4 Hz, 2.99 (septet, 1H, J = 6.4 Hz), 4.27 (s, 2H), 7.23 (m, 2H), 7.57 (dd, 1H, J = 7.7, 1.1 Hz), 7.67 (dd, 1H, J = 8.7, 1.7 Hz), 7.81 (m, 3H), 8.01 (d, 1H, J = 8.3 Hz), 8.23 (d, 1H, J = 7.5 Hz), 8.51 (s, lH) , 8.7 l (br s, 1 H), 9.30 (s, l H).
[520] Example 39 tert-butyl- [2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzoimidazol-4-ylmethyl] -amine
[521]
[522] (a) Intermediate 39a-tert-butyl- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimim Dazol-4-ylmethyl} -amine:
[523] In the same manner as in Example 31b , alcohol 31a (623.2 mg, 1.2 mmol), methanesulfonyl chloride, and diisopropylethyl amine were treated at 0 ° C. for 1 hour. tert-Butylamine (890 mg, 12.2 mmol) was added, followed by stirring at room temperature for 20 hours. Extracted in the same manner as 3lb intermediate, and purified by column chromatography to obtain intermediate 39a (299.7 mg, 43%) in the form of a yellow bubble: ¹ H NMR (CD ₃ OD) δ 1.01 (s, 9H) , 3.76 (s, 3H), 4.11 (s, 2H), 5.78 (s, 2H), 6.91 (d, 2H, J = 8.7 Hz), 7.19 (m, 2H), 7.36 (d, 2H, J = 8.7 Hz), 7.50 (dd, 1H, J = 7.9, 1.1 Hz), 7.62 (dd, 1H, J = 8.7, 1.7 Hz), 7.77 (m, 3H), 7.95 (d, 1H, J = 7.9 Hz), 8.22 (dd, 1H, J = 7.0, 1.7 Hz), 8.48 (s, 1H), 8.74 (s, 1H), 9.29 (s, 1H). Anal. (C ₃₆ H ₃₄ N ₆ O.0.3 H ₂ O) C, H, N.
[524] (b) Compound 39-tert-butyl- [2- (5-isoquinolin-4-yl-1 H-indazol-3-yl) -1 H-benzo-imidazol-4-ylmethyl] -amine:
[525] A solution of the intermediate 39a (103.7 mg, 0.183 mmol), trifluoromethanesulfonic acid (0.46 mL), and trifluoroacetic acid (1.6 mL) was stirred at room temperature for 17 hours and then stirred at 100 ° C. for 1.5 hours. It was. Concentrated aqueous NH ₄ OH (10 mL), water (10 mL) and ethyl acetate (10 mL) were added to the solution with rapid stirring. The mixture was extracted and purified in the same manner as in compound 33 to obtain compound 39 (40.2 mg, 49%) in the form of a white powder: ¹ H NMR (CD ₃ OD) δ 1.30 (s, 9H), 4.56 (s , 2H), 7.33 (m, 2H), 7.68 (m, 2H), 7.81 (m, 3H), 8.01 (d, 1H, J = 8.5 Hz), 8.25 (d, 1H, J = 8.5 Hz), 8.51 (s, 1 H), 8.73 (s, 1 H), 9.32 (s, 1 H). Anal. (C ₂₈ H ₂₆ N ₆ l.6 HOAc) C, H, N.
[526] Example 40: 4- [3- (4-imidazol-1-ylmethyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline
[527]
[528] (a) Intermediate 40a-4- [3- (4-imidazol-1-ylmethyl-1H-benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1H-indazole -5-yl] -isoquinoline:
[529] In the same manner as in Example 31b , alcohol 31a (572.0 mg, 1.12 mmol), methanesulfonyl chloride, and diisopropylethyl amine were treated for 1 hour at 0 ° C. Imidazole (761 mg, 11.2 mmol) was added and then stirred at room temperature for 24 hours. Extracted in the same manner as 3lb intermediate and purified by column chromatography to give intermediate 40a (269.1 mg, 43%) in the form of a white powder: ¹ H NMR (CD ₃ OD) δ 3.77 (s, 3H) , 5.58 (s, 2H), 5.79 (s, 2H), 6.73 (br s, lH), 6.91 (d, 2H, J = 8.8 Hz), 7.07 (d, 1H, J = 7.4 Hz), 7.23 (m , 2H), 7.36 (d, 2H, J = 8.8 Hz), 7.53-7.83 (m, 6H), 8.03 (d, 1H, J = 7.9 Hz), 8.22 (d, 1H, J = 7.9 Hz), 8.51 (s, 1 H), 8.73 (br s, 1 H), 9.28 (s, 1 H). Anal. (C ₃₅ H ₂₇ N ₇ O) C, H, N.
[530] (b) Compound 40- 4- [3- (4-imidazol-1-ylmethyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline:
[531] A solution of intermediate 40a (152.0 mg, 0.271 mmol), trifluoromethanesulfonic acid (0.271 mL), and trifluoroacetic acid (2.71 mL) was stirred at 60 ° C. for 1 hour. Concentrated aqueous NH ₄ OH (10 mL), water (10 mL) and THF (10 mL) were added to the solution with rapid stirring. The mixture was extracted and purified in the same manner as in compound 33 to obtain compound 40 (24.9 mg) in the form of a pink solid which appeared to contain a impurities in the ¹ H NMR spectrum. Trituration with acetonitrile gave pure compound 40 (11.0 mg, 9%) in the form of a pink powder: ¹ H NMR (CD ₃ OD) δ 5.59 (s, 2H), 6.74 (br s, 1H), 7.08 (d , 1H, J = 7.4 Hz), 7.25 (m, 2H), 7.55-7-85 (m, 6H), 8.07 (d, 1H, J = 7.9 Hz), 8.24 (d, 1H, J = 7.5 Hz) , 8.54 (s, lH), 8.72 (br s, 1 H), 9.30 (s, 1 H). HRMS calcd for C ₂₇ H ₂₀ N ₇ 442.1780 (MH ⁺ ), found 442.1794.
[532] Example 41 5- (3-methyl-pyridin-4-yl) -3- (E) -styryl-1H-indazole
[533]
[534] (a) Intermediate 41a- 5- (3-methyl-pyridin-4-yl) -3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H- Sol:
[535] In an argon-purified flask with DME (6 mL) / H ₂ O (1 mL), intermediate 16a (300 mg, 0.63 mmol), 4-bromo-3-methyl-pyridine (BaliKi et al., Gazz. Chim. Ital., 124 , 9, l994, 385-386) (112 mg, 0.65 mmol), and sodium carbonate (140 mg, 1.3 mmol) were added and stirred. Tetrakis (triphenylphosphine) palladium (0) (60 mg, 0.05 mmol) was added and stirred under reflux for 24 hours in the presence of argon. The solution was diluted with ethyl acetate, washed with H ₂ O and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by silica gel chromatography (20% ethyl acetate / hexanes) gave 234 mg (84%) of intermediate 41a in the form of a clear oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ8.56 (s, 1H), 8.52 (d, 1H, J = 7.8 Hz), 7.95 (s, 1H), 7.24-7.67 (m, 1OH), 5.78 (s, 2H), 3.64 (t, 2H, J = 8.1 Hz), 2.33 (s, 3H), 0.94 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H). Anal. (C ₂₇ H ₃₁ N ₃ OSi0.2H ₂ O) C, H, N.
[536] (b) Compound 41-5- (3-methyl-pyridin-4-yl) -3- (E) -styryl-1H-indazole:
[537] Intermediate 41a (218 mg, 0.49 mmol) was added to ethyleneamine (0.34 mL, 4.9 mmol) and TBAF (dissolved in 1 M in THF, 2.5 mL, 2.5 mmol) and stirred at 72 ° C. for 20 hours. The solution was diluted with ethyl acetate, washed with saturated NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (1: 1: 1 ethyl acetate / THF / hexane) yielded 12 mg (79%) of compound 41 in the form of a white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δl 3.29 ( s, 1H), 8.52 (s, 1H), 8.46 (d, 1H, J = 4.8 Hz), 8.22 (s, 1H), 7.55-7.73 (m, 5H), 7.26-7.44 (m, 5H), 2.31 (s, 3 H). Anal. (C ₂₁ H ₁₇ N ₃ ) C, H, N. MS (ES) [m + H] / z calc. 312, found 312; [mH] / z calculated 310, measured 310.
[538] Example 42 5- (4-Chloro-pyridin-3-yl) -3- (E) -styryl-1H-indazole
[539]
[540] (a) Intermediate 42a- 5- (4-Chloro-pyridin-3-yl) -3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H- Sol:
[541] Intermediate 42a was prepared in the same manner as in the preparation of intermediate 41a using intermediate 16a and 4-chloro-3-iodo-pyridine (see Cho et al., Heterocycles , 43, 8 , 1996, 1641-1652). Prepared in 73% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ8.67 (s, 1H), 8.52 (d, 1H, J = 7.8 Hz), 8.08 (s, 1H), 7.26-7.70 (m , 1OH), 5.79 (s, 2H), 3.64 (t, 2H, J = 8.1 Hz), 0.94 (t, 2H, J = 8.1 Hz), -0.03 (s, 9H). Anal. (C ₂₆ H ₁₄ ClN ₃ OSi.O.03 H ₂ O) C, H, N.
[542] (b) Compound 42- 5- (4-Chloro-pyridin-3-yl) -3 (E) -styryl-1H-indazole:
[543] Compound 42 was prepared in 66% yield by SEM-deprotecting the intermediate 42a in the same manner as in the preparation of compound 41 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.30 (s, 1H), 8.70 (s, 1H), 8.56 (d, 1H, J = 5.4 Hz), 8.31 (s, 1H), 7.63-7.73 (m, 4H), 7.57 (d, 2H, J = 4.2 Hz), 7.50 (dd , 1H, J = 8.4, l.2 Hz), 7.26-7.40 (m, 3H). Anal. (C ₂₀ H ₁₄ ClN ₃ .0.05 H ₂ O) C, H, N. MS (ES) [m +] / z calc. 332/334, found 332/334; [mH] / z calc. 330/332, measured 330/332.
[544] Example 43 5- (4-Methyl-pyridin-3-yl) -3- (E) -styryl-1H-indazole
[545]
[546] (a) Intermediate 43a- 5- (4-Methyl-pyridin-3-yl) -3-((E) -styryl) -l- (2-trimethylsilanyl-ethoxymethyl) -lH- Sol:
[547] Intermediate 43a was prepared in the same manner as the preparation of intermediate 41a using intermediate 16a and 3-bromo-4-methyl-pyridine in 90% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ8. 54 (s, 1H), 8.50 (d, 1H, J = 7.8 Hz), 7.95 (s, 1H), 7.23-7.67 (m, 10H), 5.78 (s, 2H), 3.64 (t, 2H, J = 8.1 Hz), 2.33 (s, 3H), 0.94 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H). Anal. (C ₂₇ H ₃₁ N ₃ OSi) C, H, N.
[548] (b) Compound 43- 5- (4-Methyl-pyridin-3-yl) -3- (E) -styryl-1H-indazole:
[549] Compound 43 was prepared in 48% yield by SEM-deprotecting the intermediate 43a in the same manner as in the preparation of Compound 41 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.26 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H, J = 4.8 Hz), 8.20 (s, 1H), 7.71 (d, 2H, J = 7.2 Hz), 7.55-7.64 (m, 3H), 7.26-7.42 (m, 5 H), 2.31 (s, 3 H). _{. Anal (C 2l H l7 N} 3 · 0.13 H 2 O) C, H, N.MS (ES) [m + H] / z calculated 312, the measurements 312; [mH] / z calculated 310, measured 310.
[550] Example 44 5-Fluoro-4- [3-((E) -styryl) -1 H-indazol-5-yl] -isoquinoline
[551]
[552] (a) Intermediate 44a- 4-Bromo-5-fluoro-isoquinoline:
[553] 5-amino-4-bromo-isoquinoline (Gordon et a1., J. Heterocycl. Chem., 4 , 1967, 410-411) (1.86 g, 8.34 mmol) with 48% fluoroboric acid (15 ML) / EtOH (15 mL) and stirred until completely dissolved. The solution was cooled to 0 ° C. and a solution of sodium nitrite (660 mg, 9.59 mmol) dissolved in H ₂ O (1 mL) was added dropwise. The solution was diluted with Et ₂ O (30 mL), filtered to give a brown diazonium fluorate salt and dried in vacuo. The solid was placed in a flask and carefully heated to remove nitrogen. The dark brown residue was diluted with 10% NaOH and extracted with chloroform. The organics were washed with brine, dried over MgSO ₄ and concentrated in vacuo. Purification by silica gel chromatography (40% -50% ethyl acetate / hexanes) gave 798 mg (42%) of 4-bromo-5-fluoro-isoquinoline in the form of a white solid: ¹ H NMR (300 MHz, CDCl). ₃ ) δ9.36 (d, 1H, J = 2.4 Hz), 8.74 (s, 1H), 8.O7-8.11 (m, 1H), 7.70-7.80 (m, 2H). Anal. (C ₉ H ₅ BrFN) C, H, N.
[554] (b) Intermediate 44b-5-fluoro-4- [3-((E) -styryl) -1- (2-trimethylsilyl-ethoxymethyl) -1 H-indazol-5-yl] Isoquinoline:
[555] Intermediate 44b was prepared in the same manner as the preparation of intermediate 41a using intermediate 16a and 4-bromo-5-fluoro-isoquinoline in 83% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ9.32 (d, 1H, J = 1.8 Hz), 8.52 (s, 1H), 8.07 (9, 1H), 7.91 (dd, 1H, J = 8.1, 0.99 Hz), 7.26-7.66 (m, 11H), 5.80 (s, 2H), 3.67 (t, 2H, J = 8.1 Hz), 0.95 (t, 2H, J = 8.1 Hz), -0.03 (s, 9H). Anal. (C ₃₀ H ₃₀ FN ₃ OSi0.2 H ₂ O) C, H, N.
[556] (c) Compound 44- 5-Fluoro-4- [3-((E) -styryl) -1 H-indazol-5-yl] -isoquinoline:
[557] Compound 44 was prepared in 83% yield by SEM-deprotecting the intermediate 44b in the same manner as in the preparation of Compound 41 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.26 (s, 1H), 9.44 (d, 1H, J = l.8 Hz), 8.47 (s, 1H), 8.29 (s, 1H), 8.l2 (d, 1H, J = 7.2 Hz), 7.44-7.78 (m, 8H) , 7.35 (t, 2H, J = 7.2 Hz), 7.24 (t, 1H, J = 7.2 Hz). Anal. (C ₂₄ H ₁₆ FN ₃ .0.6 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 366, found 366; [mH] / z calculated 364, measured 364.
[558] Example 45: 4- [3-((E) -styryl) -1H-indazol-5-yl] -isoquinolin-8-ylamine
[559]
[560] (a) Intermediate 45a-4- [3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazol-5-yl] -isoquinoline-8 Ilamine:
[561] Intermediate 45a is intermediate 16a and 8-amino-4-bromo-isoquinoline (.... Elpern et al , J. Amer Chem Soc, reference 68, 1946, 1436) a method for producing intermediates 41a using Prepared in 82% yield in the same manner as: ¹ H NMR (300 MHz, CDCl ₃ ) δ9.36 (d, 1H, J = O.6 Hz), 8.53 (s, 1H), 8.13 (s, 1H) 7.26-7.72 (m, 11H), 6.86 (dd, 1H, J = 7.5, 0.6 Hz), 5.81 (s, 2H), 4.51 (s, 2H), 3.66 (t, 2H, J = 8.1 Hz) , 0.96 (t, 2H, J = 6.1 Hz), -0.O3 (s, 9H). Anal. (C ₃₀ H ₃₂ N ₄ OSi) C, H, N.
[562] (b) Compound 45- 4- [3-((E) -styryl) -1 H-indazol-5-yl] -isoquinolin-8-ylamine:
[563] Compound 45 was prepared in 83% yield by SEM-deprotecting the intermediate 45a in the same manner as in the preparation of Compound 41 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.30 (s, 1H), 9.50 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 7.24-7.71 (m, lOH), 6.91 (d, 1H, J = 7.8 Hz), 6.77 (t, 1H, J = 7.8 Hz), 6.33 (s, 2 H). Anal. (C ₂₄ H ₁₈ N ₄ .0.45 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 363, found 363.
[564] Example 46: 5- (4-Chloro-5-ethyl-pyridin-3-yl) -3- (E) -styryl-1H-indazole
[565]
[566] (a) Intermediate 46a- 4-Chloro-3-ethyl-5-iodo-pyridine:
[567] LDA was added n-butyllithium (2.5 M in hexane, 0.95 ml, 2.38 mmol) in a solution of diisopropylamine (0.345 ml, 2.42 mmol) in THF (5 ml) at -20 ° C. After 10 minutes the solution was cooled to -78 ° C. To the mixture was added dropwise a solution of 4-chloro-3-iodo-pyridine (500 mg, 2.09 mmol) in THF (3 mL), and stirred for 30 minutes, followed by iodine ethane (0.2 mL, 2.5 mmol). Add, stir at −78 ° C. for 1 h and then warm to 0 ° C. for 1 h. The reaction was stopped with saturated NH ₄ Cl, basified with saturated NaHCO ₃ and extracted with ethyl acetate. The organics were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by silica gel chromatography (20% ethyl acetate / hexanes) gave 429 mg (77%) of 4-chloro-3-ethyl-5-iodo-pyridine in the form of a soft white solid: ¹ H NMR (300 MHz, CDCl). ₃ ) δ 8.78 (s, 1H), 8.33 (s, 1H), 2.83 (q, 2H, J = 7.5 Hz), 1.26 (t, 3H, J = 7.5 Hz). Anal. (C ₇ H ₇ ClIN) C, H, N.
[568] (b) Intermediate 46b-5- (4-Chloro-5-ethyl-pyridin-3-yl) -3-((E) -styryl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole:
[569] Intermediate 46b was prepared in the same manner as the preparation of intermediate 41a using intermediate 16a and 4-chloro-3-ethyl-5-iodo-pyridine in 69% yield: ¹ H NMR (300 MHz, CDCl). ₃ ) δ 8.49 (d, 2H, J = 3.3 Hz), 8.06 (s, 1H) 7.26-7.69 (m, 9H), 5.79 (s, 2H), 3.65 (t, 2H, J = 8.1 Hz), 2.88 (q, 2H, J = 7.5 Hz), 1.35 (t, 3H, J = 7.5 Hz), 0.95 (t, 2H, J = 8.1 Hz), -0.03 (s, 9H). Anal. (C ₂₈ H ₃₂ ClN ₃ OSi) C, H, N.
[570] (c) Compound 46- 5- (4-Chloro-5-ethyl-pyridin-3-yl) -3- (E) -styryl-1H-indazole:
[571] Compound 46 was prepared in 80% yield by SEM-deprotecting the intermediate 46b in the same manner as in the preparation of Compound 41 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.25 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.55-7.72 (m, 5H), 7.26-7.48 (m, 4H), 2.83 (q, 2H, J = 7.5 Hz) , 1.26 (t, 2H, J = 7.5 Hz). Anal. (C ₂₂ H ₁₈ N ₃ Cl0.3 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 360, measured 360.
[572] Example 47: 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -2-methoxy-phenol
[573]
[574] (a) Intermediate 47a- 3- (1H-benzoimidazol-2-yl) -5- {2-methoxy-3- {2- (2-trimethylsilanyl-ethoxymethyl] -phenyl}- 1- (2-Trimethylsilanyl-ethoxymethyl) -1 H-indazole:
[575] The target compound was prepared using intermediates 7c 'and 2-methoxy-3- [2- (2-trimethylsilanyl-ethoxy) -ethoxy] boron acid (Found in: Kania, Braganza, et al., Patent application "Compounds and Pharmaceutical Compositions for Inhibiting Protein Kinases, and Methods for Their Use ", p. 52, line 10 to p. 53, line 26; and p.59, line 16 to p. 60, line 4, US Provisional Serial N0. 60 / 142,130, filed July 2, l999, incorporated by reference herein in its entirety). ¹ H NMR (300 MHz, CDCl ₃ ) δ9.92 (s, lH), 8.79 (s, lH), 7.86-7.89 (m, lH), 7.79 (dd, lH, J = 8.7, 1.5Hz), 7.63 (d, 1H, J = 8.7 Hz), 7.49-7.52 (m, lH), 7.28-7.31 (m, 3H), 7.19 (dd, lH, J = 8.4, 1.8 Hz), 7.15 (d, lH, J = 7.8 Hz), 5.82 (s, 2H), 5.34 (s, 2H), 3.86 (t, 2H, J = 8.4 Hz), 3.65 (t, 2H, J = 8.l Hz), 3.59 (s, 3H) , 0.92-1.02 (m, 4H), 0.02 (s, 9H), -0.03 (s, 9H).
[576] (b) Compound 47- 3- [3- (lH-benzoimidazol-2-yl) -1H-indazol-5-yl] -2-methok Cy-phenol:
[577] The desired compound was prepared in 61% yield by SEM-deprotection of intermediate 47a in a similar manner as in Example 41. ^l H NMR (300 MHz, DMSO- d ₆ ) δ 13.64 (s, lH), l 2.98 (s, lH), 9.36 (s, lH), 8.59 (s, lH), 7.68 (dd, lH, J = 8.4, O.6 Hz), 7.60 (br s, 2H), 7.59 (dd, lH, J = 8.4, l.5 Hz), 7.18-7.22 (m, 2H), 7,03 (t, lH, J = 7.8 Hz), 6.83-6.92 (m, 2H), 3.46 (s, 3H). _{. Anal (C 2l H l6 N} 4 O 2 and _{1.0 H 2 O) C, H} , N. MS (ES) [m + H] / z calculated 357, the measurements 357: [mH] / z calculated 355, the measurements 355 .
[578] Example 48: 3- (1H-benzoimidazol-2-yl) -5- (1H-yldol-4-yl) -1H-indazole
[579]
[580] (a) Intermediate 48a-4-Bromo- ( tert -Butyl-dimethyl-silanyl) -1H-indole:
[581] Sodium hydride (60% dispersed in mineral oil, 1.84 g, 46 mmol) was washed with hexane and stirred at 0 ° C. in THF (30 mL) solution under argon. 4-Bromoindole (3.0 g, 15.3 mmol) was added slowly to THF (10 mL) solution, and it stirred for 1 hour, keeping warm at room temperature. tert -Butyl-dimethylsilyl chloride (3.5 g, 23 mmol) was added and the reaction proceeded with stirring for 16 h and slowly cooled with H ₂ O before dilution with ether (100 mL). The organics were separated, washed with brine, dried over Na ₂ SO ₄ and condensed in vacuo. Purification by silica gel chromatography (5% ether / hexane) gave 4.28 g (90%) of the intermediate 48a as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (d, 1H, J = 8.4 Hz), 7.27 (d, lH, J = 8.4 Hz), 7.22 (d, 1H, J = 3.3 Hz), 7.00 ( t, lH, J = 8.l Hz), 6.67 (dd, lH, J = 3.3, 0.99 Hz), 0.92 (s, 9H), 0.60 (s, 6H). Anal. (C _{l 4} H ₂₀ BrNSi) C, H, N.
[582] (b) Intermediate 48b-l- ( tert -Butyl-dimethyl-silanyl) -1H-indole-4-boron acid:
[583] Intermediate 48a (2.22 g, 7.16 mmol) was stirred in dry THF (15 mL) at -78 ° C. Then n-butyllithium (2.5M in hexane, 3.45 mL, 8.6 mmol) was added slowly. In a flask of trimethyl borate (8.0 mL, 72 mmol), the reaction was stirred for 20 minutes in dry THF (10 mL) at -78 ° C before being transferred through the cannula. Then, the reaction was stirred for 30 minutes at -78 ℃, and then stirred for 3 hours while maintaining a warm to room temperature. Then cooled with H ₂ O and extracted with ether. The organics were then washed with brine, dried over Na ₂ SO ₄ and condensed in vacuo. Purification by silica gel chromatography (33% ethyl acetate / hexane) afforded 1.28 g (65%) of intermediate 48b as a white foam. ^{l H NMR (300 MHz, DMSO-} d 6 w / D 2 O) δ 7.55 (d, lH, J = 8.4Hz), 7.45 (d, lH, J = 8.4Hz), 7.28 (s, lH), 7.03 -7.09 (m, lH), 6.96 (s, lH), 0.84 (s, 9H), 0.57 (s, 6H). Anal. (C ₁₄ H ₂₂ BNO ₂ Si-0.9 H ₂ O) C, H, N.
[584] (c) Intermediate 48c-3- (1H-benzoimidazol-2-yl) -5- [1- (tert-butyl-dimethyl-silanyl) -1H-indol-4-yl] -1- ( 2-trimethylsilanyl-ethoxymethyl) -1H-indazole:
[585] The desired compound was prepared from intermediates 7c 'and 48b in a yield similar to intermediate 7d' in 95% yield. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.90 (s, lH), 8.96 (d, lH, J = O.9Hz), 7.84-7.90 (m, 2H), 7.69 (d, lH, J = 8.7 Hz), 7.48-7.53 (m, 2H), 7.23-7.33 (m, 5H), 6.82 (d, lH, J = 3-3 Hz), 5.84 (s, 2H), 3.67 (t, 2H, J = 8.1 Hz), 0.96 (s, 9H), 0.94 (t, 2H, J = 8.1 Hz), 0.65 (s, 6H), -0.03 (s, 9H). Anal. (C ₃₄ H ₄₃ N ₅ OSi ₂ ) C, H, N.
[586] (d) Compound 48- 3- (1H-benzoimidazol-2-yl) -5- (1H-indol-4-yl) -1H-indazole:
[587] The desired compound was prepared in 79% yield by SEM, TBDMS-deprotection of Intermediate 48c by a similar preparation method as in Example 41. ^{l H NMR (300 MHz, DMSO-} d 6) δ13.66 (s, lH), 12.97 (s, lH), 11.25 (s, lH), 8.78 (s, lH), 7.68-7.81 (m, 3H) , 7.51 (d, lH, J = 7.2 Hz), 7.42-7.46 (m, 2H), 7.14-7.26 (m, 4H), 6.59 (t, lH, J = 2.l Hz). Anal. (C ₂₂ H ₁₅ N ₅ 0.3H ₂ 0) C, H, N. MS (ES) [m + H] / z calc. 350, measured 350; [mH] / z calc. 348. found 348.
[588] Example 49: 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -2,4-difluoro-phenol
[589]
[590] (a) Intermediate 49a- [2- (2,4-Difluoro-phenoxymethoxy) -ethyl] -trimethyl-silane:
[591] 2,4-difluoro-phenol (6.0 g, 46.1 mmol) and DIEA (9.64 mL, 55.3 mmol) were stirred in dry CH ₂ Cl ₂ at room temperature. 2- (trimethylsilyl) ethoxymethyl chloride (9.0 mL, 50.8 mmol) was added and the reaction proceeded with stirring for 1 hour. The solution was then washed with H ₂ O and brine, dried over Na ₂ SO ₄ and condensed in vacuo. Then, the residue was purified by silica gel chromatography to obtain 10.88 g (91%) of the title compound as a transparent oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.11-7.20 (m, lH), 6.74-6.89 (m, 2H), 5.20 (s, 2H), 3.77-3.83 (m, 2H), 0.93-0.99 ( m, 2H), 0.01 (s, 9H).
[592] (b) Intermediate 49b-3- (1H-benzoimidazol-2-yl) -5 {2,6-difluoro-3- [2- (2-trimethylsilanyl-ethoxy-ethoxy] -Phenyl} -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole:
[593] Intermediate 49a (1.4 g, 5.38 mmol) was stirred in dry THF (16 mL) under -78 ° C under argon. n-butyllithium (2.5M in hexane, 2.32 mL, 5.8 mmol) was added dropwise and stirred for 20 hours. The solution was then transferred through a cannula into a flask of dry zinc chloride at room temperature, under argon. After 30 minutes, intermediate 7c '(320 mg, 0.65 mmol) and tetrakis (triphenylphosphine) palladium (0) (60 mg, 0.05 mmol) were added and the reaction was carried out. The mixture was stirred at room temperature for 2 hours. The solution was diluted with ether and washed with H ₂ O, saturated NaHCO ₃ , and brine. The organics were then dried over Na ₂ SO ₄ and condensed in vacuo. Then, the residue was purified by silica gel chromatography (20% to 30% Et ₂ O / hexane) to obtain 372 mg (92%) of the title compound as a white solid. ^{l H NMR (300 MHz, CDCl} 3) δ9.89 (s, lH), 8.80 (s, lH), 7.86-7.89 (m, lH), 7.70 (dd, lH, J = 8.7, O.9Hz), 7.58 (dd, lH, J = 8.7, 1.2 Hz), 7.49-7.53 (m, lH), 7.17-7.31 (m, 3H), 6.90-6.97 (m, 1H), 5.82 (s, 2H), 5.28 ( s, 2H), 3.66 (t, 2H, J = 8.4 Hz), 3.67 (t, 2H, J = 8.l Hz), 0.92-1.04 (m, 4H), 0.02 (s, 9H), -0.02 (s , 9H). Anal. (C ₃₂ H ₄₀ F ₂ N ₄ O ₃ Si ₂ ㆍ 0.25 H ₂ O) C, H, N.
[594] (c) Compound 49- 3- [3- (lH-benzoimidazol-2-yl) -1H-indazol-5-yl] -2,4-difluoro-phenol:
[595] The desired compound was prepared in 70% yield by SEM-deprotection of intermediate 49b in a preparation method similar to Example 41. ^{l H NMR (300 MHz, DMSO-} d 6) δ13.75 (s, 1H), 13.00 (s, 1 H), 9.88 (s, lH), 8.56 (s, lH), 7.70-7.78 (m, 2H ), 7.48-7.53 (m, 2H), 7.17-7.25 (m, 2H), 6.99-7.05 (m, 2H). Anal. (C ₂₀ H ₁₂ FN ₄ O.0.33 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 363, measured 363; [mH] / z calculated 361, measured 361.
[596] Example 50: 4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -3,5-difluoro-phenol and
[597] Example 51: 2-[-3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -3,5-difluoro-phenol
[598]
[599] (a) Intermediate 50a- [2- (3,5-Difluoro-phenoxymethoxy) -ethyl] -trimethyl-silane:
[600] The desired compound was prepared in a yield of 94% from 3,5-difluorophenol in a similar process to intermediate 49a. ^{l H NMR (300 MHz, CDCl} 3) δ6.55-6.60 (m, 2H), 6.40-6.48 (m, lH), 5.18 (s, 2H), 3.70-3.76 (m, 2H), 0.92-0.98 ( m, 2H), 0.01 (s, 9H).
[601] (b) Intermediate mixture 50b and 50c-3- (1H-benzoimidazol-2-yl) -5 {2,6-difluoro-4- [2- (2-trimethylsilanyl-ethoxy- Ethoxy] -phenyl} -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole and 3- (1H-benzoimidazol-2-yl) -5 {2,4-difluoro- 6- [2- (2-Trimethylsilanyl-ethoxy-ethoxy] -phenyl} -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazole:
[602] The desired compound was prepared in a 52% yield in the form of a mixture which could not be separated from intermediate 50a by a process similar to intermediate 49b. ^l H NMR (300 MHz, CDCl ₃ ) δ 9.89 (s, lH), 8.44-8.75 (m, lH), 7.83-7.93 (m, lH), 7.45-7.69 (m, 3H), 7.26-7.39 (m , 2.5H), 6.58-6.88 (m, 1.5H), 5.81 (s, lH), 5.80 (s, 1H), 5.26 (s, lH), 5.13 (s, 1H), 3.57-3.82 (m , 4H), 0.86-1.04 (m, 4H), -0.06-0.02 (m, l8H).
[603] (c) Compound 50- 4-[-3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -3,5-difluoro-phenol:
[604] The desired compound was prepared in 36% yield by SEM-deprotection of intermediate mixtures 50b and 50c in a similar manner to Example 41. ^{l H NMR (300 MHz, DMSO-} d 6) δ13.73 (s, lH), 13.01 (s, lH), 10.50 (s, lH), 8.50 (s, lH), 7.70-7.74 (m, 2H) 7.43-7.52 (m, 2H), 7.15-7.25 (m, 2H), 6.62 (dd, 2H, J = 13.8, 1.5 Hz). Anal. (C ₂₀ H ₁₂ FN _{4 O.0.7} H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 363, measured 363; [mH] / z calc. 361. found 361.
[605] (d) Compound 51-2 [-3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -3,5-difluoro-phenol:
[606] The desired compound was prepared in a yield similar to that of Example 41 by SEM-deprotection of intermediates 50b and 50c in 40% yield. ^l H NMR (300 MHz, DMSO- d ₆ ) δ 13.65 (s, lH), 12.98 (s, lH), 10.39 (s, 1H), 8.47 (s, lH), 7.66-7.72 (m, 2H) , 7.50 (d, 1H, J = 7.2 Hz), 7.40 (d, lH, J = 8.4 Hz), 7.14-7.24 (m, 2H), 6.73-6.80 (m, 1H), 6.64 (d, 1 H, J = l0.5 Hz). Anal. (C ₂₀ H ₁₂ FN _{4 O.0.9} H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 363, measured 363; [mH] / z calc. 361. found 361.
[607] Example 52: 3- (1H-Benzoimidazol-2-yl) -5- (4-chloro-pyridin-3-yl) -1 H-indazole
[608]
[609] (a) Intermediate 52a- 3- (1H-Benzoimidazol-2-yl) -5- (4-chloro-pyridin-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl)- 1H-indazole:
[610] The desired compound was prepared from intermediate 25a and 4-chloro-3-idido-pyridine in 88% yield in a similar manner to intermediate 41a. _{^{l H NMR (300MHz, CDCl 3}} ) δ9.96 (s, 1H), 8077 (s, 1H), 8.72 (s, lH), 8.53 (d, lH, J = 5.4Hz), 7.85-7.89 (m, lH), 7.72 (dd, 1H, J = 8.7, 0.9 Hz), 7.61 (dd, lH, J = 8.7, 1.5 Hz), 7.50-7.53 (m, lH), 7.47 (d, lH, J = 5.4 Hz ), 7.28-7.35 (m, 2H), 5.84 (s, 2H), 3.65 (t, 2H, J = 8.1 Hz), 0.95 (t, 2H, J = 8.lHz), -0.03 (s, 9H) .
[611] (b) Compound 52- 3- (1H-benzoimidazol-2-yl) -5- (4-chloro-pyridin-3-yl) -1 H-indazole:
[612] The desired compound was prepared in a yield similar to that of Example 41 by SEM-dehobo of intermediate 52a in 54% yield. ^l H NMR (300 MHz, DMSO- d ₆ ) δ 13.81 (s, lH), 13.02 (s, lH), 8.70 (s, lH), 8.56-8.60 (m, 2H), 8.22 (s, lH) , 7.55-7.80 (m, 5H), 7.20 (d, 5H, J = 3.6 Hz). Anal. (C ₂₂ H ₁₈ ClN ₃ 0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 346, measured 346.
[613] Example 53: 5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl- [3,4 '] bipyridinyl
[614]
[615] (a) Intermediate 53a- 5- (Bromo-4-methyl- [3,4 '] bipyridinyl:
[616] Argon-purified flasks with 3,5-dibromo-4-methyl-pyridine (2.21 g, 8.8 mmol), 4-pyridylborone acid (1.08 g, 8.8 mmol) and calcium phosphate (2.8 g, 13.2 mmol) was stirred in DMA (50 mL) / (6 mL). Tetrakis (triphenylphosphine) palladium (O) (812 mg, 0.7 mmol) was added and the reaction was stirred for 16 hours under argon. The solution was condensed in vacuo and the residue was dissolved in ethyl acetate. The organics were then washed with H ₂ O and brine, dried (Na ₂ SO ₄ ) and condensed in vacuo. Thereafter, the residue was purified by silica gel chromatography (40% to 50% ethyl acetate / hexane) to obtain an intermediate 53a as a white solid. _{^{l H NMR (300MHz, CDCl 3}} ) δ8.73 (dd, 2H, J = 4.5, l.5Hz), 8.72 (s, lH), 8.32 (s, lH), 7.25 (dd, 2H, J = 4.5, 1.5 Hz), 2.35 (s, 3H). Anal. _{(C ll H 9 BrN 2)} C, H, N.
[617] (b) Intermediate 53b-5- [3- (1H-Benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -4 -Methyl- [3,4 '] bipyridinyl:
[618] The desired compound was prepared in a yield of 64% from intermediates 25a and 53a by a preparation method similar to intermediate 41a. ^l H NMR (300 MHz, CDCl ₃ ) δ10.2l (s, lH), 8.70-8.76 (m, 3H), 8.61 (s, lH), 8.46 (s, lH), 7.85-7.88 (m, lH) , 7.72 (dd, lH, J = 8.7, O.9 Hz), 7.47-7.53 (m, 2H), 7.24-7.37 (m, 4H), 5.84 (s, 2H), 3.64 (t, 2H, J = 8.1 Hz), 2.19 (s, 3H), 0.94 (t, 2H, J = 8. 1 Hz), -0.04 (s, 9H).
[619] (c) Compound 53- 5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl- [3,4 '] bipyridinyl:
[620] The desired compound was prepared in a yield similar to that of Example 41 by SEM-deprotection of intermediate 53b in 71% yield. ^{l H NMR (300 MHz, DMSO-} d 6) δl3.79 (s, 1H), 13.02 (s, 1H), 8.71 (d, 2H, J = 4.8Hz), 8.55 (s, 1H), 8.51 (s , 1H), 8.47 (s, 1H), 7.78 (d, 1H, J = 8.7 Hz), 7.52-7.58 (m, 5H), 7.l8-7.2l (m, 2H), 2.17 (s, 3H) . Anal. (C ₂₅ H ₁₈ N ₆ 0.75 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 403, measured 403: [mH] / z calculated 401, measured 401.
[621] Example 54: 5- [3- (1H-Benzolimidazol-2-yl) -1H-indazol-5-yl] -1,2,3,4,4a, 8a-hexahydro- [1, 7] naphthyridine
[622]
[623] (a) Intermediate 54a- 3- (3,5-Dibromo-pyridin-4-yl) -propylamine:
[624] LDA was prepared by adding n-butyllithium (2.5 M in hexane, 6.8 mL) to a solution of diisopropylamine (2.5 mL, 17.8 mmol) in THF (40 mL) at 20 ° C. After 10 minutes, the solution was cooled to -78 ° C. Next, 3,5-dibromopyridine (3.84 g, 16.2 mmol) was added dropwise and reacted with stirring for 30 minutes. 1- (3-bromopropyl) -2,2,5,5, -tetramethyl-1-aza-2,5-disilacyclopentate (5 g, 17.8 mmol) was added and at -78 ° C. After the reaction was stirred for 1 hour, the mixture was stirred for 1 hour while maintaining the temperature at 0 ° C. Next, sat. Prepared with saturated NaHCO ₃ . Cooled with NH ₄ Cl and extracted with ethyl acetate. The organics were washed with brine, dried over Na ₂ SO ₄ and condensed in vacuo. Purification by silica gel chromatography (15% MeOH / CHCl ₃ ) afforded 2.72 g (54%) of intermediate 54a as a light brown oil. _{^{l HNMR (300 MHz, CDCl 3}} ) δ8.55 (d, 2H), 2.72-3.05 (m, 6H), l.70-1.77 (m, 2H).
[625] (b) Intermediate 54b- 2-Trimethylsilanyl-ethanesulfone EXID [3- (3,5-Dibromo-pyridin-4-yl) -propyl] -amine:
[626] At 0 ° C. the intermediate 54a (2.7 g, 9.2 mmol) was stirred in dry DMF (20 mL) with triethylamine (1.92 mL, 13.8 mmol). 2-trimethylsilanyl-ethalsulfonyl chloride, SES-Cl, (see Weinreb et al., Tet. Lett. 27, 19, 1986, 2099-2102) (1.9 g, 9.5 mmol) were added slowly and 0 ° C. The reaction was stirred for 1.5 hours at. Then diluted with H ₂ O and extracted with ether. The organics were washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. Then, the residue was purified by silica gel chromatography (33% ethyl acetate / hexane) to give 2.37 g (56%) of an intermediate 54b as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ8.58 (s, 2H), 4.36 (t, 1H, J = 6.3 Hz), 3.26 (q, 2H, J = 6.3 Hz), 2.93-3.06 (m, 4H ), 1.81-1.89 (m, 2H), 1.00-1.07 (m, 2H), 0.07 (s, 9H). Anal. (C _{l 3} H ₂₂ Br ₂ N ₂ O ₂ SSi) C, H, N, S.
[627] (c) Intermediate 54c- 5-Bromo-l- (2-trimethylsilanyl-ethalsulfonyl) -1,2,3,4-tetrahydro- [1,7] naphthyridine:
[628] Intermediate 54b (860 mg, 1.88 mmol) and calcium carbonate (390 mg, 2.82 mmol) were stirred in dry toluene (15 mL) in a flask purified with argon. Tetrakis (triphenylphosphine) palladium (O) (218 mg, 0.19 mmol) was added and reacted by stirring under argon at 102 ° C. for 48 hours. Then diluted with ethyl acetate, washed with brine, dried (Na ₂ SO ₄ ) and condensed in vacuo. Thereafter, the residue was purified by silica gel chromatography (25% ethyl acetate / hexane) to obtain a smooth white solid as an intermediate 54c, 372 mg (52%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.42 (s, 1H), 3.72-3.76 (m, 2H), 3.07-3.14 (m, 2H), 2.83 (t, 2H, J = 6.9 Hz), 2.07-2.12 (m, 2H), l.04-l.11 (m, 2H), 0.05 (s, 9H). Anal. (C ₁₃ H ₂₁ BrN ₂ O ₂ SSi) C, H, N, S.
[629] (d) Intermediate 54d-5- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-5-yl] -1- (2-Trimethylsilanyl-ethanesulfonyl) -1,2,3,4,4a, 8a-hexahydro- [1,7] naphthyridine:
[630] The desired compound was prepared in 51% yield from Intermediate 25a and Intermediate 54c by a preparation method similar to Intermediate 41a. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.36 (s, 1H), 8.88 (s, 1H), 8.64 (t, 1H, J = O.9 Hz), 8.29 (s, 1H), 3.82-3.86 ( m, 1H), 7.69 (dd, 1H, J = 8.7, 0.1 Hz), 7.50-7.52 (m, 1H), 7.41 (dd, 1H, J = 8.7, 1.5 Hz), 7.26-7.33 (m, 2H ), 5.83 (s, 2H), 3.80 (t, 2H, J = 5.7 Hz), 3.63 (t, 2H, J = 8.1 Hz), 3.13-3.20 (m, 2H), 2.72 (t, 2H, J = 6.6 Hz), 1.93-1.99 (m, 2H), 1.10-1.16 (m, 2H), 0.94 (t, 2H, J = 8.1 Hz), 0.09 (s, 9H), -0.05 (s, 9H).
[631] (e) compound 54- 5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -1,2,3,4,4a, 8a-hexahydro- [ 1,7] naphthyridine:
[632] The desired compound was prepared in a similar manner to Example 41 in a yield of 64% by SEM, SES-deprotection of intermediate 54d. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.71 (s, 1H), 13.00 (s, lH), 8.41 (s, 1H), 7.82 (s, 1H), 7.69 (d, 2H, J = 8.7 Hz), 7.63 (s, 1 H), 7.50 (d, 1 H, J = 7.2 Hz), 7.44 (dd, 1H, J = 8.7, 1.5 Hz), 7.16-7.22 (m, 2H), 6.11 (s, 1H), 3.23 (br s, 2H), 2.55 (t, 2H, J = 6.OHz), 1.68-1.73 (m, 2H). Anal. (C ₂₂ H ₁₈ N ₆ .0.45 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 366, measured 366.
[633] Example 55 N- {4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinolin-8-yl} -nicotinamide
[634]
[635] (a) Intermediate 55a-N- (4-Bromo-isoquinolin-8-yl) -nicotinamide:
[636] 8-amino-4-bromo-isoquinoline (328 mg, 1.47 mmol), triethylamine (820 μl, 5.9 mmol), and DMAP (10 mg) were stirred in CH ₂ Cl ₂ (50 mL). Nicotinoyl chloride, hydrochloride (395 mg, 2.2 mmol) was added and refluxed for 18 hours and stirred. It was then condensed in vacuo and purified by silica gel chromatography (3% MeOH / ethyl acetate) to give 272 mg (56%) of intermediate 55a as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.95 (s, 1H), 9.46 (s, 1H), 9.25 (d, 1H, J = 1.5 Hz), 8.81 (dd, 2H, J = 4.8, 1.5 Hz ), 8.40-8.45 (m, 1 H), 7.92-8.06 (m, 3 H), 7.59-7.64 (m, 1 H). Anal. (C ₁₅ H ₁₀ BrN ₃ O) C, H, N.
[637] (b) Intermediate 55b-N- {4- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl ] -Isoquinolin-8-yl} -nicotinamide:
[638] The desired compound was prepared in 76% yield from Intermediate 25a and Intermediate 55a in a process similar to Intermediate 41a. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.27 (s, 1H), 9.48 (s, 1H), 9.29 (d, 1H, J = 1.8 Hz), 8.83-8.88 (m, 2H), 8.79 (s , 1H), 8.58 (s, 1H), 8,36 (d, 1H, J = 7.8 Hz), 8.02 (d, 1H, J = 6.9 Hz), 7.73-7.81 (m, 3H), 7.58-7.65 ( m, 2H), 7.47-7.53 (m, 2H), 7.24-7.29 (m, 2H), 5.86 (s, 2H), 3.67 (t, 2H, J = 8.1 Hz), 0.96 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H).
[639] (c) Compound 55-N- {4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinolin-8-yl} -nicotinamide:
[640] The desired compound was prepared in 78% yield by SEM-deprotection of intermediate 55b in a similar manner as in Example 41. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.85 (s, 1 H), 13.04 (s, 1 H), 10.98 (s, 1 H), 9.54 (s, 1 H), 9.30 (d, 2H, J = 1.8 Hz), 8.83 (dd, 1H, J = 4.8, 1.8 Hz), 8.65 (s, 1H), 8.59 (s, 1H), 8.45-8.50 (m, 4H), 7.52-7.66 (m, 4H), 7.18 (br s, 2 H). Anal. (C ₂₉ H ₁₉ N ₇ O.0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 482, c. 482.
[641] Example 56 N- {4- [3- (1H-benzoimidazol-2-yl) 1H-indazol-5-yl] -isoquinolin-8-yl} -acetamide
[642]
[643] (a) Intermediate 56a-N- (4-bromo-isoquinolin-8-yl) -acetamide:
[644] 8-amino-4-bromo-isoquinoline (300 mg, 1.35 mmol), DIEA (0.94 mL, 5.38 mmol), and acetic anhydride (255 μL, 2.7 mmol) were added to chloroform (20 mL). At reflux and stirred for 16 h. The solution was washed with H ₂ O and brine, dried (Na ₂ SO ₄ ) and condensed in vacuo. The residue was stirred for 20 h in ethanol (6 mL) with HOAc (2 mL) at 72 ° C. The organics were washed with 1N NaOH and brine, dried (MgSO ₄ ) and condensed in vacuo. Then, the residue was purified by silica gel chromatography (ethyl acetate) to obtain the intermediate 56a, 232 mg (65%) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.31 (s, 1H), 9.47 (s, 1H), 8.77 (s, lH), 7.90-7.97 (m, 3H), 2.21 (s, 3H). Anal. (C _ll H ₉ BrN ₂ O) C, H, N.
[645] (b) Intermediate 56b-N- {4- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl ] -Isoquinolin-8-yl} -acetamide:
[646] The desired compound was prepared in 80% yield from Intermediate 25a and Intermediate 56a by a preparation method similar to Intermediate 41a. ^{l H NMR (300 MHz, CDCl} 3) δ10.39 (s, 1H), 9.46 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 7.91 (d , 1H, J = 7.2 Hz), 7.89 (d, 1H, J = 7.2 Hz), 7.62-7.72 (m, 3H), 7.48-7.57 (m, 3H), 7.24-7.28 (m, 1H), 5.83 ( s, 2H), 3.65 (t, 2H, J = 8.1 Hz), 2.35 (s, 3H), 0.95 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H).
[647] (c) Compound 56-N- {4- [3- (1H-benzoimidazol-2-yl) 1H-indazol-5-yl] -isoquinolin-8-yl} acetaldehyde
[648] The desired compound was prepared in a similar manner to Example 41 in a yield of 68% by SEM-deprotection of intermediate 56b. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.84 (s, 1 H), 13.03 (s, 1 H), 10.34 (s, 1 H), 9.56 (s, 1 H), 8.61 (s, 1 H), 8.55 (s, 1H), 7.82-7.89 (m, 2H), 7.74 (t, 1H, J = 7.2 Hz), 7.59-7.66 (m, 3H), 7.51 (d, 1H, J = 7.2 Hz), 7.13- 7.21 (m, 2 H), 2.25 (s, 3 H). Anal. (C ₂₅ H ₁₈ N ₆ O.0.4 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 419, measured 411.
[649] Example 57: N- {4- [3- (1H-Benzoimidazol-2-yl) 1H-indazol-5-yl] -isoquinolin-8-yl} -benzyl-amine
[650]
[651] (a) Intermediate 57a-Benzyl- (4-bromo-isoquinolin-8-yl) -amine:
[652] 8-amino-4-bromo-isoquinoline (220 mg, 0.99 mmol) and benzaldehyde (110 μl, 1.1 mmol) were refluxed and stirred in ethanol (15 mL) / HOAc (0.2 mL) for 24 hours. Next, it cooled to 0 degreeC, and sodium cyanoborohydride (622 mg, 9.9 mmol) was added. After stirring for 1 hour, the mixture was diluted with H ₂ O and extracted with ethyl acetate. The organics were then washed with brine, dried (Na ₂ SO ₄ ) and condensed in vacuo. Purification by silica gel chromatography (33% ethyl acetate / hexanes) gave an intermediate 57a, 136 mg (44%) as a light yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.6l (s, 1H), 8.64 (s, 1H), 7.79 (t, 1H, J = 5.7 Hz), 7.55 (t, 1H, J = 8.1 Hz), 7.28-7.42 (m, 4H), 7.15-7.24 (m, 2H), 6.58 (d, 1H, J = 8.4 Hz), 4.53 (d, 2H, J = 5.7 Hz). Anal. (C ₁₆ H ₁₃ BrN ₃ ) C, H, N.
[653] (b) Intermediate 57b-N- {4- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl ] -Isoquinolin-8-yl} -benzyl-amine:
[654] The desired compound was prepared in 72% yield from Intermediate 25a and Intermediate 57a by a process similar to Intermediate 41a. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 9.38 (s, 1H), 8.82 (s, 1H), 8.56 (s, 1H), 7.82 (d, 1H, J = 8.7 Hz ), 7.73 (d, 1H, J = 8.7 Hz), 7.63 (dd, 1H, J = 8.4, l.5 Hz), 7.24, -7.52 (m, 9H), 7.17 (d, 1H, J = 8.4 Hz) , 6.69 (d, 1H, J = 7.5Hz), 5.86 (s, 2H), 5.23 (s, 1H), 4.58 (d, 2H, J = 4.5Hz), 3.67 (t, 2H, J = 8.1Hz) , 0.97 (t, 2H, J = 8.1 Hz), -0.03 (s, 9H).
[655] (c) Compound 57-N- {4- [3- (1H-benzoimidazol-2-yl) 1H-indazol-5-yl] -isoquinolin-8-yl} -benzyl-amine:
[656] The desired compound was prepared in 72% yield by SEM-deprotection of intermediate 57b in a preparation analogous to Example 41. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.80 (s, 1H), 13.01 (s, 1H), 9.71 (s, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 7.71 -7.81 (m, 2H), 7.30-7.63 (m, 8H), 7.17-7.25 (m, 3H), 6.90 (d, 1H, J = 7.2 Hz), 6.52 (d, 1H, J = 7.2 Hz), 4.57 (d, 2H, J = 5.4 Hz). Anal. (C ₃₀ H ₂₂ N ₆ 0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 467, measured 467.
[657] Example 58: 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl- [3,3 '] bipyridinyl
[658]
[659] (a) Intermediate 58a-5-bromo-4-methyl- [3,3 '] bipyridinyl:
[660] The desired compound was prepared in a yield of 54% from 3,5-dibromo-4-methyl-pyridine and 3-pyridyl boronexide in a preparation analogous to intermediate 53a. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.67-8.71 (m, 2H), 8.59 (dd, 1H, J = 2.4, 0.6 Hz), 8.33 (s, 1H), 7.62-7.66 (m, 1H) , 7.39-7.44 (m, 1 H), 2.35 (m, 3 H). Anal. (C ₁₁ H ₉ BrN ₂ 0.1 H ₂ O) C, H, N.
[661] (b) Intermediate 58b-3- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -4 -Methyl- [3,3 '] bipyridinyl:
[662] The desired compound was prepared in 37% yield from Intermediate 25a and Intermediate 58a by a preparation method similar to Intermediate 41a. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.24 (s, 1H), 8.68-8.71 (m, 3H), 8.61 (s, 1H), 8.47 (s, 1H], 7.85-7.88 (m, 1H), 7.70-7.78 (m, 2H), 7.42-7.53 (m, 3H), 7.26-7.33 (m, 2H), 5.83 (s, 2H), 3.64 (t, 2H, J = 8.1 Hz), 2.19 (s, 3H), 0.95 (t, 2H, J = 8.1 Hz), -0.05 (s, 9H).
[663] (c) Compound 58- 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl- [3,3 '] bipyridinyl:
[664] The desired compound was prepared in 74% yield by SEM-deprotection of intermediate 58b in a similar manner as in Example 41. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.79 (s, 1 H), 13.02 (s, 1 H), 8.72 (d, 1 H, J = 1.5 Hz), 8.65 (dd, 1H, J = 4.8, l.5 Hz), 8.54 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 7.96-8.00 (m, 1H), 7.78 (d, 1H, J = 8.7 Hz), 7.69 (d , 1H, J = 7.5 Hz), 7.49-7.57 (m, 3H), 7.17-7.23 (m, 2H), 2.16 (s, 3H). Anal. (C ₂₅ H ₁₈ N ₆ 0.6 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 403, measured 403.
[665] Example 59: (E) -3- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl} -pro Ph-2-en-1-ol and
[666] Example 60: (E) -3- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl} -propane -1-ol
[667]
[668] (a) Intermediate 59a- 5-Bromo-4-methyl-pyridine-3-carbaaldehyde:
[669] 3,5-Dibromo-4-methyl-pyridine (3.8 g, 15.1 mmol) was stirred in dry THF (150 mL) at -100 ° C (N ₂ / ether) under argon. n-butyllithium (2.5M in hexane, 6.2 mL, 15.4 mmol) was added dropwise and stirred for 5 minutes to proceed with reaction. Then DMF (1.8 mL, 23.2 mmol) was added and stirred at −100 ° C. for 20 minutes, followed by further stirring at −78 ° C. for 1 hour. Then sat. Quenched with NH ₄ Cl and extracted with ether. The organics were washed with brine, dried over Na 2 SO 4 and condensed in vacuo. Then purified by silica gel chromatography (20% ethyl acetate / hexane) to give 2.18 g (72%) of intermediate 59a in the form of a clear oil which slowly solidified. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.25 (s, 1H), 8.84 (s, 1H), 8.83 (s, 1H), 2.76 (s, 3H). Anal. (C ₇ H ₆ BrNO) C, H, N.
[670] (b) Intermediate 59b-(E) -3- (5-bromo-4-methyl-pyridin-3-yl) -acrylic acid ethyl ester:
[671] Intermediate 59a (690 mg, 3.45 mmol), ethyl hydrogen malonate (600 mg, 4.5 mmol) and piperidine (170 μl, 1.73 mmol) were converted into pyridine (5 mL). The reaction was then condensed in vacuo and purified by silica gel chromatography to yield 59b, 560 mg (60%) as a smooth white solid, ¹ H NMR (300 MHz, CDCl ₃ ) δ8.65 (s, 1H), 8.57 (s, 1H), 7.87 (d, 1H, J = l5.9 Hz), 6.39 (d, 1H, J = l5.9 Hz), 4.29 (q, 2H, J = 7.2 Hz) , 2.50 (s, 3H), 1.35 (t, 3H, J = 7.2 Hz) Anal. (C ₁₁ H ₁₂ BrNO ₂ ) C, H, N.
[672] (c) Intermediate 59c-(E) -3- {5- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole -5-yl] -4-methyl-pyridin-3-yl} -acrylic acid ethyl ester:
[673] The desired compound was prepared in 83% yield from Intermediate 25a and Intermediate 59b by a process similar to Intermediate 41a. ¹ H NMR (30MHz, CDCl ₃ ) δ10.00 (s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 7.99 (d, 1H, J = l5.9 Hz ), 7.83-7.87 (m, 1H), 7.71 (d, 1H, J = 8.7 Hz), 7.50-7.53 (m, 1H), 7.43 (dd, 1H, J = 8.7, l.5 Hz), 7.27-7.32 (m, 2H), 6.50 (d, 1H, J = l5.9 Hz), 5.84 (s, 2H), 4.31 (q, 2H, J = 7.2 Hz), 3.65 (t, 2H, J = 8.1 Hz), 2.36 (s, 3H), 1.37 (t, 3H, J = 7.2 Hz), 0.95 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H).
[674] (d) Intermediate 59d-(E) -3- {5- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole -5-yl] -4-methyl-pyridin-3-yl} -prop-2-en-1-ol:
[675] To a 59c solution of intermediate in ether (10 mL) was added dropwise a suspension of LAH (180 mg, 4.74 mmol) in ether (10 mL) at 0 ° C. The reaction was carried out by stirring for 3 hours while keeping warm to room temperature. It was quenched with water and extracted with ethyl acetate. The organics were washed with brine, dried over Na ₂ SO ₄ and condensed in vacuo. Then, the mixture was purified by silica gel chromatography (50-100% ethyl acetate / hexane) to obtain 59d, 72 mg (19%) of the intermediate in the form of a white foam (medium 59e, 186 mg (50%) was obtained). . ¹ H NMR (300MHz, CDCl ₃ ) δ9.99 (s, 1H), 8.64 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 7.83-7.87 (m, 1H), 7.69 ( d, 1H, J = 8.7 Hz), 7.50-7.53 (m, 1H), 7.43 (dd, 1H, J = 8.7, 1.5 Hz), 7.26-7.32 (m, 2H), 6.86 (d, 1H, J = l5.9 Hz), 6.33-6.41 (m, 1H), 5.84 (s, 2H), 4.42 (br s, 2H), 3.65 (t, 2H, J = 8.1 Hz), 2.28 (s, 3H), 1.73 ( br s, 1 H), 0.95 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H).
[676] (e) Intermediate 59e-(E) -3- {5- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl /)-1H- Sol-5-yl] -4-methyl-pyridin-3-yl} -propan-1-ol:
[677] See the preparation of the intermediate 59d. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.17 (s, 1H), 8.63 (s, 1H), 8.40 (s, 2H), 7.83-7.87 (m, 1H), 7.68 (d, 1H, J = 8.7 Hz), 7.49-7.52 (m, 1H), 7.43 (dd, 1H, J = 8.7, l.5 Hz), 7.26-7.31 (m, 2H), 5.83 (s, 2H), 3.77 (t, 2H, J = 6.3 Hz), 3.65 (t, 2H, J = 8.1 Hz), 2.82 (t, 2H, J = 7.5 Hz), 2.24 (s, 3H), 1.88-1.95 (m, 2H), 1.74 (br s , 1H), 0.94 (t, 2H, J = 8.1 Hz), -0.05 (s, 9H).
[678] (f) Compound 59- (E) -3- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl } -Prop-2-en-1-ol:
[679] The desired compound was prepared in a yield similar to that of Example 41 by SEM-deprotection of the intermediate 59d in 50% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ13.78 (s, 1H), 13.02 (s, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 7.75 (d, 1H, J = 8.7 Hz), 7.63 (br s, 1H), 7.55 (br s, 1H), 7.46 (dd, 1H, J = 8.7, 1.5 Hz), 7.20 (br s, 2H), 6.83 (d, 1H, J = l5.9 Hz), 6.37-6.46 (m, 1H), 4.99 (t, 1H, J = 5.4 Hz), 4.l9 (s, 2H), 2.23 (s, 3H). Anal. (C ₂₃ H ₁₉ N ₅ O.0.6 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 382, measured 382.
[680] (g) Compound 60- (E) -3- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl } -Propan-1-ol:
[681] The desired compound was prepared in 62% yield by SEM-deprotection of intermediate 59e in a preparation method similar to Example 41. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.77 (s, 1 H), 13.02 (s, 1 H), 8.41 (s, 1 H), 8.37 (s, 1 H), 8.30 (s, 1 H), 7.73 (d, 1H, J = 8.7 Hz), 7.67 (br. s, 1H), 7.52 (br s, 1H), 7.44 (dd, 1H, J = 8.7, 1.5 Hz), 7.19 (br s, 2H), 4.57 (t, 1H, J = 5.1 Hz), 3.49 (q, 2H, J = 6.OHz), 2.74 (t, 2H, J = 7.8 Hz), 2.21 (s, 3H), l.69-l. 79 (m, 2 H). Anal. (C ₂₃ H ₂₁ N ₅ O.0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 384, measured 384.
[682] Example 61 5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-ethyl- [3,4 '] bipyridinyl
[683]
[684] (a) Intermediate 61a- 3,5-Dibromo-4-ethyl-pyridine:
[685] The target compound was prepared in a yield of 74% by replacing iodoethane with iodomethane in the method for preparing 3,5-dibromo-4-methyl-pyridine. (see Gu, et al., Tet. Lett., 37, 15, 1996, 2565-2568). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (s, 2H), 2.92 (q, 2H, J = 7.5 Hz), 1.12 (t, 3H, J = 7.5 Hz).
[686] (b) Intermediate 61b- 5- (Bromo-4-ethyl- [3,4 '] bipyridinyl:
[687] The desired compound was prepared in 51% yield from intermediates 61a and 4-pyridyl boron exit in a similar process to intermediate 53a. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.71-8.74 (m, 3H), 8.28 (s, 1H), 7.24 (dd, 2H, J = 4.5, 1.5 Hz), 2.70 (q, 2H, J = 7.5 Hz), 1 .10 (t, 3H, J = 7.5 Hz). Anal. (C ₁₂ H ₁₁ BrN ₂ ) C, H, N. MS (ES) [m + H] / z calc. 263/265, found 263/265.
[688] (c) Intermediate 61c-5- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -4 -Ethyl- [3,4 '] bipyridinyl:
[689] Intermediate 61b (188 mg, 0.71 mmol), Intermediate 25a (385 mg, 0.79 mmol) and Potassium Phosphate (226 mg, 1.06 mmol) in a flask purified with argon DMA (6 mL) / H ₂ O ( 0.8 mL). Tetrakis (triphenylphosphine) palladium (O) (82 mg, 0.07 mmol) was then added and stirred at 92 ° C. under argon for 16 hours. The solution was diluted with ethyl acetate and washed with H ₂ O and brine, dried over Na ₂ SO ₄ and condensed in vacuo. Purification by silica gel chromatography (75% -100% ethyl acetate / hexane) afforded 232 mg (60%) of intermediate 61c as a transparent oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.18 (s, 1H), 8.7l-8.75 (m, 3H), 8.57 (s, 1H), 8.41 (s, 1H), 7.84-7-87 (m , 1H), 7.71 (d, 1H, J = 8.Hz), 7.48-7.53 (m, 2H), 7.36 (dd, 2H, J = 4.5, 1.5 Hz), 7.26-7.32 (m, 2H), 5.84 (s, 2H), 3.65 (t, 2H, J = 8.1 Hz), 2.64 (q, 2H, J = 7.5 Hz), 0.94 (t, 2H, J = 8.1 Hz), 0.77 (t, 3H, J = 7.5 Hz), -0.04 (s, 9H).
[690] (d) Compound 61- 5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-ethyl- [3,4 '] bipyridinyl:
[691] The desired compound was prepared in 61% yield by SEM-deprotection of the intermediate 61c by a preparation method similar to Example 41. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ3.79 (s, 1H), 13.02 (s, 1H), 8.71 (dd, 2H, J = 4.5, l.5 Hz), 8.51 (s, 2H), 8.40 (s, 1H), 7.78 (d, 1H, J = 8.7 Hz), 7.68 (d, 1H, J = 7.5 Hz), 7.49-7.56 (m, 4H), 7.14-7.25 (m, 2H), 2.59 (q, 2H, J = 7.5 Hz), 0.69 (t, 3H, J = 7.5 Hz). Anal. (C ₂₆ H ₂₀ N ₆ .0.3 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 417, measured 417.
[692] Example 62: 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl- [2,3 '] bipyridinyl
[693]
[694] (a) Intermediate 62a- 3- (1H-benzoimidazol-2-yl) -5-iodo-1- (4-methoxy-benzyl) -1H-indazole:
[695] The desired compound was prepared in 59% yield from intermediate 19d and phenylenediamine in a similar manner to intermediate 7c '. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ13.06 (s, 1H), 8.91 (s, 1H), 7.70-7.78 (m, 3H), 7.51 (dd, 1H, J = 6.3, 2.1 Hz) , 7.19-7.28 (m, 4H), 6.88 (dd, 2H, J = 6.6, 2.1 Hz), 5.72 (s, 2H), 3.69 (s, 3H). Anal. (C ₂₂ H ₁₇ IN ₄ O) C, H, N.
[696] (b) Intermediate 62b-3- (1H-benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -5- (4,4, 5,5-tetramethyl [1,3 , 2] dioxaborolan-2-yl) -1H-indazole:
[697] The desired compound was prepared in 73% yield from intermediate 62a by a preparation method similar to intermediate 19e. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.03 (s, 1 H), 8.93 (d, 1 H, J = 4.2 Hz), 7.78-7.84 (m, 2H), 7.73 (dd, 1H, J = 8.7, O.9Hz), 7.51 (d, 1H, J = 7.2Hz), 7.20-7.27 (m, 4H), 6.87 (d, 2H, J = 8.7Hz), 5.74 (s, 2H), 3.68 (s , 3H), 1.34 (s, l 2 H). Anal. (C ₂₈ H ₂₉ BN ₄ O ₃ ) C, H, N.
[698] (c) intermediate 62c- 5'-bromo-4'-methyl- [2,3 '] bipyridinyl:
[699] Dioxane in a flask of 3,5-dibromo-4-methyl-pyridine (2.0 g, 7.8 mmol) and 2-tributylstannanyl-pyridine (2.4 g, 6.5 mmol) purified with argon Stir at (20 mL). Tetrakis (triphenylphosphine) -palladium (O) (600 mg, 0.5 mmol) was added and stirred at 100 ° C. for 80 hours. Then, the solution was condensed in vacuo and purified by silica gel chromatography (30 ~ 50% ethyl acetate / hexane) to give a white solid intermediate 62c, 788 mg (49%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72-8.75 (m, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 7.78-7.84 (m, 1H), 7.31-7.42 (m, 2H), 2.42 (s, 3H). Anal. (C ₁₁ H ₉ BrN ₂ ) C, H, N.
[700] (d) Intermediate 62d-3- [3- (1H-Benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1 H-indazol-5-yl] -4-methyl- [2,3 '] bipyridinyl:
[701] The desired compound was prepared in 76% yield from Intermediate 62b and Intermediate 62c by a method similar to Intermediate 61c. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.08 (s, 1 H), 8.73 (d, 1 H, J = 4.2 Hz), 8.52-8.57 (m, 3H), 7.92-7.98 (m, 2H) , 7.68-7.72 (m, 2H), 7.58 (dd, 1H, J = 8.7, l.5 Hz), 7.51 (d, 1H, J = 7.2 Hz), 7.43-7.47 (m, 1H), 7.36 (d, 2H, J = 8.7 Hz), 7.17-7.23 (m, 2H), 6.91 (d, 2H, J = 8.7 Hz), 5.79 (s, 2H), 3.70 (s, 3H), 2.21 (s, 3H). Anal. (C ₃₃ H ₂₆ N ₆ O) C, H, N.
[702] (e) Compound 62- 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl- [2,3 '] bipyridinyl:
[703] Intermediate 62d (400 mg, 9.77 mmol) was stirred for 48 h in concentrated H ₂ SO ₄ (1 mL) and anisole (1 mL) in TFA (8 mL). The solution was then condensed to 3 mL in vacuo and sat. Quench with NaHCO ₃ and extract with 4: 1 ethyl acetate / THF. The organics were washed with brine, dried (MgSO ₄ ) and condensed in vacuo. Then, the residue was purified by silica gel chromatography (0.2% NH ₄ OH / 6% to 10% MeOH / ethyl acetate) to give Example 62, 102 mg (33%) as a white solid. ^{1 H NMR (300 MHz, DMSO-} d 6) δ13.78 (s, 1H), 13.02 (s, 1H), 8.74 (d, 1H, J = 4.2Hz), 8.57 (s, 1H), 8.53 (s , 1H), 7.51 (s, 1H), 7.93-7.99 (m, 1H), 7.77 (d, 1H, J = 8.7 Hz), 7.70 (d, 2H, J = 7.8 Hz), 7.43-7.56 (m, 3H), 7.20 (br s, 2 H), 2.23 (s, 3 H). Anal. (C ₂₅ H ₁₈ N ₆ 0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 403, measured 403.
[704] Example 63: 1- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -3,4-dihydro-2H- [1,7] naphthyl Din-1-yl} -ethanone
[705]
[706] (a) Intermediate 63a-5-Bromo-1,2,3,4-tetrahydro- [1,7] naphthyridine
[707] Intermediate 54c (1.16 g, 3.08 mmol) was stirred at 72 ° C. in tetrabutylammonium fluoride hydrate (2.0 g, 7.65 mmol) in acetonitrile (16 mL) for 18 h. The solution was cooled and diluted with ethyl acetate. Sat organics. Washed with NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and condensed in vacuo. Purified by silica gel chromatography to give the intermediate 63a, 524 mg (80%) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.74 (s, 1H), 4.00 (br s, 1H), 3.28-3.33 (m, 2H), 2.74 (q, 2H, J = 6.6 Hz), 1.92-2.0 l (m, 2H). Anal. (C ₈ H ₉ BrN ₂ ) C, H, N.
[708] (b) Intermediate 63b-1- (5-Bromo-3,4-dihydro-2H- [1,7] naphthyridin-1-yl) -ethanone:
[709] Intermediate 63a (212 mg, 1.0 mmol), DIEA (1.4 mL, 8.0 mmol), and acetic anhydride (4.0 mmol) were stirred in dry chloroform (10 mL) at 68 ° C. for 40 h. The solution was washed with saturated NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (70% ethyl acetate / hexane) afforded 242 mg (95%) of an intermediate 63b as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ8.61 (br s, 1H), 8.46 (s, 1H), 3.79 (q, 2H, J = 6.0 Hz), 2.83 (t, 2H, J = 6.9 Hz) , 2.93 (s, 3 H), 2.01-2.08 (m, 2 H). Anal. (C ₁₀ H ₁₁ BrN ₂ O) C, H, N.
[710] (c) Intermediate 63c-1- {5- [3- (1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl ] -3,4-dihydro-2H- [1,7] naphthyridin-1-yl} -ethanone:
[711] The desired compound was prepared in 83% yield from Intermediate 25a and Intermediate 63c by a preparation method similar to Intermediate 61c. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.06 (s, 1H), 8.68 (s, 1H), 8.55 (br s, 1H), 8.42 (s, 1H), 7.84-7.67 (m, 1H), 7.71 (d, 1H, J = 8.7 Hz), 7.50-7.53 (m, 1H), 7.46 (dd, 1H, J = 8.7, 1.5 Hz), 7.27-7.32 (m, 2H), 5.84 (s, 2H) , 3.84 (t, 2H, J = 6.6 Hz), 3.64 (t, 2H, J = 8.1 Hz), 2.70 (t, 2H, J = 6.6 Hz), 2.36 (s, 3H), 1.87-1.93 (m, 2H), 0.94 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H). Anal. (C ₃₀ H ₃₄ N ₆ O ₂ Si0.5 H ₂ O) C, H, N.
[712] (d) Example 63- 1- {5- [3-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -3,4-dihydro-2H- [1,7 ] Naphthyridin-1-yl} -ethanone:
[713] The desired compound was prepared in a yield similar to that of Example 41 by SEM-deprotection of intermediate 63c in 65% yield. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.77 (s, 1 H), 13.02 (s, 1 H), 8.78 (s, 1 H), 8.46 (br s, 1 H), 8.27 (s, 1 H), 7.75 (d, 1H, J = 8.7 Hz), 7.67 (br. S, 1H), 7.49 (dd, 2H, J = 5.7, 1.5 Hz), 7.20 (br s, 2H), 3.74 (t, 2H, J = 6.3 Hz), 2.63 (t, 2H, J = 6.3 Hz), 2.27 (s, 3H), l.79-l.85 (m, 2H). Anal. (C ₂₄ H ₂₀ N ₆ O) C, H, N. MS (ES) [m + H] / z calc. 409, found 409.
[714] Example 64: 5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-nicotinamide
[715]
[716] (a) Intermediate 64a- 3-bromo-4-methyl-5-carboxamoyl-pyridine:
[717] The solution of 3,5-dibromopyridine (3 g, 1 l.9 mmol) in 150 mL dry THF was cooled to -100 ° C (ether-N ₂ batch) and BuLi (2.5 M solution in hexane, 5 mL, 12.5 mmol) One drop was added for at least 3 minutes. After 2 minutes, trimethylsilic isocyanate (3.8 mL of 85% solution, 3.24 g, 24 mmol) was added as a yellow anion and the whole was stirred at -100 ° C for 30 minutes, at -60 ° C for 30 minutes, and then at 25 ° C. After reaching, stirred for 12 hours. NH ₄ Cl was poured into saturated aqueous solution, extracted with ethyl acetate, the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and condensed. The residue was purified by silica chromatography (5: 1 to 10: 1 hexane-ethyl acetate, and then 100% ethyl acetate) to obtain amide 64a, 236 mg (9%). R _f = 0.09 (ethylacetate in 50% hexanes); ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (bs, 1H), 8.54 (bs, 1H), 5.98 (bs, 1H), 5.93 (bs, 1H). (LCMS: M ⁺ 2l5).
[718] (b) Intermediate 64b-5- [3- (1H-Benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -4 Methyl-nicotinamide:
[719] The desired compound was prepared in 75% yield from Intermediate 25a and Intermediate 64a by a process similar to Intermediate 61c. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.18 (s, 1H), 8.66 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.82-7.86 (m, 1H), 7.70 (d, 1H, J = 8.4Hz), 7.48-7.52 (m, 1H), 7.42 (dd, 1H, J = 8.4, l.5Hz), 7.26-7.31 (m, 2H), 6.13 (br s, 1H ), 5.91 (br s, 1H), 5.83 (s, 2H), 3.64 (t, 2H, J = 8.1 Hz), 2.40 (s, 3H), 0.94 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H).
[720] (c) Compound 64- 5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-nicotinamide:
[721] The desired compound was prepared in 77% yield by SEM-deprotection of intermediate 64b in a similar manner as in Example 41. ¹ H NMR (300MHz, DMSO- d ₆ ) δ 13.80 (s, 1H), 13.03 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8.05 ( s, 1H), 7.76 (d, 1H, J = 8.7 Hz), 7.68 (br. s, 2H), 7.44-7.52 (m, 2H), 7.16-7.22 (m, 2H), 2.29 (s, 3H) . Anal. (C _{2 l} H ₁₆ N _{6 O.0.55} H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 369, measured 369.
[722] Example 65: 3- (1H-Benzoimidazol-2-yl) -5- [5- (1H-imidazol-4-yl) -4-methyl-pyridin-3-yl] -1H-indazole
[723]
[724] (a) Intermediate 65a- 3-Bromo-4-methyl-5-1H-imidazol-4-yl-pyridine:
[725] Fine powder NaCN (5 g) in suspension of tosylmethyl isocyanide (1.02 g, 5.25 mmol) and 3-bromo-4-methyl-5-formyl pyridine (1.0 g, 5 mmol) in 5 mL of dry ethanol. 25 mg, 0.5 mmol) was added at 25 ° C. After 30 minutes, it was condensed with oil. Ammonia solution in dry methanol was added to the remaining oil in a sealed tube and heated to 100 ° C. for 24 hours. Then, the mixture was cooled and purified by silica gel chromatography (10: 1 ethyl acetate-hexane) to give 65a, 167 mg (14%) of a white solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.45 (bs, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 7.83 (s, 1H), 7.52 (s, 1H), 2.56 (s, 3 H).
[726] (b) Intermediate 65b- 3-Bromo-4-methyl-5- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-4-yl] -pyridine:
[727] Intermediate 65a was prepared in 45% yield by SEM-deprotection in a similar process to intermediate 49a. ¹ H NMR (300 MHz, CDCl ₃ ) δ8.67 (s, 1H), 8.60 (s, 1H), 7.70 (s, 1H), 7.21 (d, 1H, J = l.2 Hz), 5.33 (s, 2H), 3.56 (t, 2H, J = 8.1 Hz), 2.58 (s, 3H), 0.94 (t, 2H, J = 8.1 Hz), 0.00 (s, 9H). Anal. (C ₁₅ H ₂₂ BrN ₃ OSi) C, H, N.
[728] (c) Intermediate 65c-3- (1H-benzoimidazol-2-yl) -5- {5- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-4-yl ] -4-methyl-pyridin-3-yl} -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole:
[729] The desired compound was prepared in 83% yield from Intermediate 25a and Intermediate 65b by a process similar to Intermediate 61c. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.09 (s, 1H), 8.85 (s, 1H), 7.70 (s, 1H), 8.50 (s, 1H), 7.84-7.88 (m, 1H), 7.68 -7.74 (m, 2H), 7.47-7.52 (m, 2H), 7.26-7.31 (m, 3H), 5.84 (s,
[730] 2H), 5.36 (s, 2H), 3.55-3.68 (m, 4H), 2.41 (s, 3H), 0.92-0.98 (m, 4H), -0.01 (s, 9H), -0.05 (s, 9H) .
[731] (d) Compound 65- 3- (1H-benzoimidazol-2-yl) -5- [5- (1H-imidazol-4-yl) -4-methyl-pyridin-3-yl] -1 H- Indazole:
[732] The desired compound was prepared in a yield of 43% by SEM-deprotection of intermediate 65c in a similar manner to Example 41. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ13.78 (s, 1H), 13.02 (s, 1H), 12.38 (s, 1H), 8.83 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.83 (d, 1H, J = O.9 Hz), 7.76 (d, 1H, J = 8.4 Hz), 8.69 (d, 1H, J = 7.5 Hz), 7.47-7.51 (m, 3H ), 7.16-7.2 (m, 2H), 2.37 (s, 3H). Anal. (C ₂₃ H ₁₇ N ₇ .2.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 392, measured 392.
[733] Example 66: 4- [3- (4,5,6,7-Tetrahydro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline
[734]
[735] (a) Intermediate 66a- 5-iodo-3- (4,5,6,7-tetrahydra-1H-benzoimidazol-2-yl) -1H-indazole:
[736] Intermediate 7b '(500 mg, 1.24 mmol), l, 2-cyclohexanedione (146 mg, 1.3 mmol), and ammonium acetate (575 mg, 7.44 mmol) in ethanol (12 mL) were refluxed for 4 hours. And stirred. Then, the mixture was diluted with ethyl acetate, washed with brine, dried (Na ₂ SO ₄ ) and condensed in vacuo. Purification by silica gel chromatography (20% ethyl acetate / hexane) afforded 366 mg (60%) of the title compound as a light yellow foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.47 (br s, 1H), 8.88 (d, 1H, J = O.9 Hz), 7.69 (dd, 1H, J = 8.7, 1.5 Hz), 7.31 (d , l1, J = 8.7 Hz), 5.67 (s, 2H), 3.52 (t, 2H, J = 8.1 Hz), 2.70 (br s, 4H), 1.89 (br s, 4H), 0.88 (t, 2H, J = 8.1 Hz), -0.06 (s, 9H). Anal. (C ₂₀ H ₂₇ IN ₄ OSi) C, H, N.
[737] (b) Intermediate 66b-4- [3- (4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl)- 1H-indazol-5-yl] -isoquinoline:
[738] The desired compound was prepared in 75% yield from intermediate 66a and isoquinoline-4-borone acid (EP 976747) in a process similar to intermediate 7d '. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.57 (br s, 1H), 9.28 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8,04-8.08 (m, 1H ), 7.85-7.89 (s, 1H), 7.57-7.70 (m, 4H), 5.80 (s, 2H), 3.63 (t, 2H, J = 8.1 Hz), 2.7 (br s, 4H), 1.86 (br s, 4H), 0.96 (t, 2H, J = 8.1 Hz), -0.03 (s, 9H).
[739] (c) compound 66- 4- [3- (4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline:
[740] The desired compound was prepared in a yield of 64% by SEM-deprotection of intermediate 66b in a preparation method similar to Example 41. ¹ H NMR (300MHz, DMSO- d ₆ ) δ3.31 (s, 1H), 12.25 (s, 1H), 9.36 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.24 ( d, 1H, J = 7.8 Hz), 7.69-7.85 (m, 4H), 7.53 (dd, 1H, J = 8.7, l.8 Hz), 2.50 (br s, 4H), 1.73 (br s, 4H). Anal. (C ₂₃ H ₁₉ N ₅ .0.2 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 366, measured 366.
[741] Example 67: 4- [3- (4-Methyl-5-phenyl-1 H-imidazol-2-yl) -1 H-indazol-5-yl] -isoquinoline
[742]
[743] (a) Intermediate 67a- 5-iodo-1- (4-methoxy-benzyl) -3- (4-methyl-5-phenyl-1H-imidazol-2-yl) -1H-indazole:
[744] The desired compound was prepared from intermediate 19d and 1-phenyl-1,2-propanedione in a similar process to intermediate 66a. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.87 (br s, 0.5 H), 9.71 (br s, 0.5 H), 8.98 (br s, 0.5 H), 8.92 (br s, 0.5 H) ), 7.84 (d, 1H, J = 7.2 Hz), 7.61 (dd, 1H, J = 8.7, 1.5 Hz), 7.44-7.53 (m, 3H), 7.31 (d, 1H, J = 7.5 Hz), 7.11 (app d, 3H, J = 8.7 Hz), 6.81 (dd, 2H, J = 6.6, l.8 Hz), 5.49 (s, 2H), 3.77 (s, 3H), 2.55 (s, 3H). Anal. (C ₂₅ H ₂₁ IN ₄ O) C, H, N.
[745] (b) Intermediate 67b-4- [1- (4-methoxy-benzyl) -3- (4-methyl-5-phenyl-1 H-imidazol-2-yl) -1 H-indazol-5 -Work] -isoquinoline:
[746] The desired compound was prepared in 75% yield from intermediate 67a and isoquinoline-4-boronexide (EP 976747) in a process similar to intermediate 7d '. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.97 (br s, 0.5H), 9.85 (br s, 0.5H), 9.28 (s, 1H), 8.76 (br s, 0.5H), 8.70 (br s, O.5H), 8.59 (s, 1H), 8.03-8.10 (m, 1H), 7.90 (br s, 1H), 7.75 (br s, 1H), 7.37-7.68 (m, 8H), 7.20-7.26 (m, 2H), 6.86 (dd, 2H, J = 6.6, l.5 Hz), 5.60 (s, 2H), 3.78 (s, 3H), 2.54 (br s, 1.5H), 2.49 (br s, l. 5 H).
[747] (c) Compound 67-4 [3- (4-Methyl-5-phenyl-1 H-imidazol-2-yl) -1 H-indazol-5-yl] -isoquinoline:
[748] The desired compound was prepared in a yield of 15% by PMB-deprotection of intermediate 67b in a preparation analogous to Example 62. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.67 (s, 1H), 13.02 (s, 1H), 9.38 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.25 (d, 1H, J = 7.5 Hz), 7.66-7.91 (m, 6H), 7.57 (dd, 1H, J = 8.7, l.5 Hz), 7.30-7.33 (m, 2H), 7.15-7.18 (m, 1H), 2.50 (s, 3H). Anal. (C ₂₆ H ₁₉ N ₅ 0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 402, measured 402.
[749] Example 68: Dimethyl-{-[5- (4-methyl- [3,4 '] bipyridinyl-5-yl} -1 H-indazol-3-yl] -1 H-benzoimidazol-4-yl Methyl} -amine
[750]
[751] (a) Intermediate 68a-{2- [5-iodo-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimidazol-4-ylmethyl]- Methanol:
[752] The desired compound was prepared in a yield similar to that of Intermediate 7c 'in 40% yield from Intermediate 19d and Intermediate 23b. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.02 (s, 0.5H), 12.87 (s, 0.5H), 8.91 (s, 1H), 7.64-7.77 (m, 2.5H), 7.37 ( dd, O.5H, J = 7.5, 1.5 Hz), 7.18-7.27 (m, 4H), 6.88 (d, 2H, J = 8.4 Hz), 5.73 (s, 1H), 5.71 (s, 1H), 5.14-5.24 (m, 1H), 5.03 (d, 1H, J = 5.7 Hz), 4.86 (d, 1H, J = 5.7 Hz), 3.69 (s, 3H).
[753] (b) Intermediate 68b-{2- [5-iodo-1- (4-methoxy-benzyl) -1 H-indazol-3- General] -1H-benzoimidazol-4-ylmethyl} -dimethyl-amine:
[754] Intermediate 68a (2.5 g, 4.9 mmol) and DIEA (1.38 mL, 10 mmol) were stirred in THF (90 mL) at 0 ° C. Methanesulfonyl chloride (0.76 mL, 9.8 mmol) was added and stirred at 0 ° C. for 2.5 h. Dimethylamine was bubbled into the solution for 1 minute and stirred for 2 hours while keeping warm to room temperature. The solution was quenched with H ₂ O and extracted with ethyl acetate. Sat organics. Washed with NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and condensed in vacuo. Purification by silica gel chromatography (0.2% NH ₄ OH / 3% MeOH / ethyl acetate) yielded 2.56 g (97%) of the intermediate 68b as a white foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.07 (d, 1H, J = O.9 Hz), 7.80 (d, 1H, J = 7.8 Hz), 7.63 (dd, 1H, J = 8.7, l.5 Hz ), 7.07-7.25 (m, 5H), 6.85 (dd, 2H, J = 6.6, l.8 Hz), 5.61 (s, 2H), 3.77 (app s, 5H), 2.33 (s, 6H).
[755] (c) Intermediate 68c-{2- [1- (4-methoxy-benzyl) -5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) -1H-indazol-3-yl] -1H-benzoimidazol-4-ylmethyl} -dimethyl-amine:
[756] The desired compound was prepared in a yield of 62% from intermediate 68b by a preparation method similar to intermediate 19e. ¹ H NMR (300 MHz, CDCl ₃ ) δ9.11 (s, 1H), 7.82 (dd, 2H, J = 8.4, O.9 Hz), 7.35 (dd, 1H, J = 8.4, O.9 Hz), 7.16 -7.21 (m, 4H), 6.85 (dd, 2H, J = 6.9, 1.9 Hz), 5.64 (s, 2H), 3.80 (br s, 2H), 3.76 (s, 3H), 2.35 (s, 6H ), 1.37 (s, l 2 H).
[757] (d) Intermediate 68d-Dimethyl- {2- [5- (4-methyl- [3,4 '] bipyridinyl-5-yl) -1- (4-methoxy-benzyl) -1H- Zol-3-yl] -1 H-benzoimidazol-4-ylmethyl) -amine:
[758] The desired compound was prepared in 85% yield from Intermediate 68c and Intermediate 53a by a process similar to Intermediate 61c. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.69-8.75 (m, 4H), 8.57 (s, 1H), 8.43 (s, 1H), 7.75 (d, 1H, J = 8.1 Hz), 7.46 (d , 1H, J = 8.7 Hz), 7.34-7.40 (m, 3H), 7.25-7.28 (m, 1H), 7.19 (t, 1H, J = 7.6 Hz), 7.08 (d, 1H, J = 7.2 Hz) , 6.89 (d, 2H, J = 8.7 Hz), 5.70 (s, 2H), 3.79 (app s, 5H), 2.34 (s, 6H), 2.l9 (s, 3H).
[759] (e) Compound 68-Dimethyl- {2- [5- (4-methyl- [3,4 '] bipyridinyl-5-yl) -1H-indazol-3-yl] -1H-benzoimidazole -4-ylmethyl} -amine:
[760] The desired compound was prepared in a yield of 20% by PMB-deprotection of the intermediate 68d in a similar process as in Example 62. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.80 (s, 1 H), 13.01 (s, 1 H), 8.71 (dd, 2H, J = 4.5, 1.5 Hz), 8.56 (br s, 2H), 8.47 (s, 1H), 7.78 (d, 1H, J = 8.7 Hz), 7.39-7.58 (m, 4H), 7.17 (br s, 2H), 3.76-3.99 (m, 2H), 2.14-7.29 (m, 9H). Anal. (C ₂₈ H ₂₅ N ₇ .1.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 460, measured 460.
[761] Example 69: (3- {5- [3-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl} -phenyl) -methanol
[762]
[763] (a) Intermediate 69a- [3- (5-Bromo-4-methyl-pyridin-3-yl) -phenyl] -methanol:
[764] The desired compound was prepared in a yield similar to that of Intermediate 53a from 3,5-dibromo-4-methyl-pyridine and 3- (hydroxymethyl) -phenyl-boroneex with 79% yield. ¹ H NMR (300 MHz, CDCl ₃ ) δ8.62 (s, 1H), 8.22 (s, 1H), 7.42-7.46 (m, 2H), 7.29 (s, 1H), 7.16-7.20 (m, 1H) , 4.76 (d, 2H, J = 5.7 Hz), 2.48 (t, 1H, J = 5.7 Hz), 2.32 (s, 3H)-Anal. (C ₁₃ H ₁₂ BrNO.0.2 H ₂ O) C, H, N.
[765] (b) Intermediate 69b-(3- {5- [3- (1H-benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1H-indazol-5-yl]- 4-Methyl-pyridin-3-yl} -phenyl) -methanol:
[766] The desired compound was prepared in 83% yield from Intermediate 62b and Intermediate 69a in a process similar to Intermediate 61c. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.39 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 8.36 (s, lH), 7.83-7.87 (m, 1H), 7.36 -7.49 (m, 7H), 7.22-7.31 (m, 4H), 6.84 (d, 2H, J = 8.7 Hz), 5.60 (s, 2H), 4.79 (s, 2H), 3.76 (s, 3H), 2.51 (br s, 1 H), 2.11 (s, 3 H).
[767] (c) compound 69- (3- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl} -phenyl Methanol:
[768] The desired compound was prepared in 41% yield by PMB-deprotection of intermediate 69b in a similar manner as in Example 62. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ13.79 (s, 1H), 13.02 (s, 1H), 849 (d, 2H, J = 6.3 Hz), 8.41 (s, 1H), 7.76 (d , 1H, J = 8.7 Hz), 7.34-7.69 (m, 7H), 7.19-7.22 (m, 2H), 5.25 (br s, lH), 4.58 (s, 2H), 2.15 (s, 3H). Anal. (C ₂₇ H ₂₁ N ₅ O ₂ 1.2 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 432, measured 432.
[769] Example 70 N- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl} -3H-benzoimidazol-5-yl} -methanesulfonamide:
[770]
[771] (a) Intermediate 70a-N- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -3H-benzoimidazole- 5-yl} -methanesulfonamide:
[772] The desired compound was prepared in a similar manner to intermediate 7c 'using intermediate 19f and N- (3,4-diaminophenyl) methanesulfonamide (see Rajappa et al., Indian J. Chem. Sect. B , 19, 7, l980, 533-535) with a yield of 89%. ^{1 H NMR (300 MHz, MeOD-} d 6) δ9.26 (s, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 8.20 (d, 1H, J = 7.8Hz), 7.96 (d , 1H, J = 7.8Hz), 7.72-7.81 (m, 3H), 7.58-7.63 (m, 3H), 7.35 (d, 2H, J = 8.7Hz), 7.16 (br s, 1H), 6.89 (d , 2H, J = 8.7 Hz), 5.76 (s, 2H), 3.75 (s, 3H), 2.93 (s, 3H).
[773] (b) Compound 70-N- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -3H-benzoimidazol-5-yl] -methanesulfonamide:
[774] The desired compound was prepared in 48% yield by PMB-deprotection of intermediate 70a in a similar manner as in Example 62. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.83 (s, 1 H), 13.04 (s, 1 H), 9.54 (br s, 1 H), 9.40 (s, 1 H), 8.60 (s, 1 H), 8.55 (s, 1H), 8.27 (d, 1H, J = 8.7 Hz), 7.72-7.88 (m, 4H), 7.63 (dd, 1H, J = 8.7, l.5 Hz), 7.54 (br s, 1H) , 7.46 (s, 1 H), 7.07 (d, 1 H, J = 7.8 Hz), 2.91 (s, 3H). Anal. (C ₂₄ H ₁₈ N ₆ O ₂ S.1.05 H ₂ O) C, H, N, S. MS (ES) [m + H] / z calc. 455, measured 455.
[775] Example 71 N- {2- [5- (4-methyl- [3,4 '] bipyridinyl-5-yl) -1H-indazol-3-yl) -3H-benzoimidazole-5- General] -methanesulfonamide
[776]
[777] (a) Intermediate 71a- 1- (4-methoxy-benzyl) -5- (4-methyl- [3,4 '] bipyridinyl-5-yl) -1H-indazol-3-carb Aldehyde:
[778] Intermediate 71a was prepared in the same manner as the preparation of intermediate 61c using intermediate 19e and intermediate 53a in 76% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ10.28 (s, 1H), 8.73 (dd, 2H, J = 4.5, 1.5 Hz), 8.49 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 7.53 (d, 1H, J = 8.7 Hz), 7.40 (dd , 1H, J = 8.7, 1.5 Hz, 7.26-7.34 (m, 4H), 6.89 (d, 2H, J = 8.7 Hz), 5.67 (s, 2H), 3.79 (s, 3H), 2.15 (s, 3H). _{Anal. (C 27 H 22 N} 4 O 2 · 0.25 H 2 O) C, H, N.
[779] (b) Intermediate 71b-N- {2- [5- (4-methyl- [3,4 '] bipyridinyl-5-yl) -1- (4-methoxy-benzyl) -1H- Zol-3-yl) -3H-benzoimidazol-5-yl] -methanesulfonamide:
[780] Intermediate 71b was prepared in the same manner as for the preparation of intermediate 7c ' using intermediate 71a and N- (3,4-diaminophenyl) methanesulfonamide in 96% yield: ¹ H NMR (300 MHz, MeOD-d ₄ ) δ8.66 (dd, 2H, J = 4.5, 1.5 Hz), 8.52 (s, 2H), 8.39 (s, 1H), 7.73 (d, 1H, J = 8.7 Hz), 7.47-7.65 (m, 5H), 7.35 (d, 2H, J = 8.7 Hz), 7.17 (br s, 1H), 6.86 (d, 2H, J = 8.7 Hz), 5.72 (s, 2H), 3.73 (s, 3H ), 2.94 (s, 3H), 2.24 (s, 3H).
[781] (c) Compound 71-N- {2- [5- (4-methyl- [3,4 '] bipyridinyl-5-yl) -1H-indazol-3-yl) -3H-benzoimidazole -5-yl] -methanesulfonamide:
[782] Compound 71 was prepared in 35% yield by PBM-deprotecting the intermediate 71b in the same manner as in the preparation of compound 62 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.79 (s, 1H), 13.02 (s, 1H), 9.56 (s, 1H), 8.70 (d, 2H, J = 5.7Hz), 8.54 (s, 1H), 8.47 (d, 2H, J = 7.8Hz), 7.78 (d, 1H , J = 8.7 Hz), 7.49-7.58 (m, 5H), 7.1 O (d, 1H, J = 8.7 Hz), 2.93 (s, 3H), 2.17 (s, 3H). Anal. (C ₂₆ H ₂₁ N ₇ O ₂ S · 1.45 H ₂ O) C, H, N, S. MS (ES) [m + H] / z calc. 496, measured 496.
[783] Example 72: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl} -methanol
[784]
[785] (a) Intermediate 72a-(5-Bromo-4-methyl-pyridin-3-yl) -methanol:
[786] Intermediate 59a (1.5 g, 7.5 mmol) was added to MeOH and stirred at 0 ° C. Sodium borohydride (850 mg, 22.5 mmol) was added in one portion and stirred for 1 hour. The solution was diluted with ethyl acetate and the organics were washed with H ₂ O and brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (80% -100% ethyl acetate / hexanes) gave 1.39 g (92%) of intermediate 72a in the form of a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ8.59 (s, 1H ), 8.38 (s, 1H), 8.43 (s, 1H), 4.75 (d, 1H, J = 5.4 Hz), 2.45 (s, 3H), 2.37 (t, 1H, J = 5.4 Hz).
[787] (b) Intermediate 72b-{5- [3- (1H-Benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1H-indazol-5-yl] -4-methyl -Pyridin-3-yl} -methanol:
[788] Intermediate 72b was prepared in 92% yield using the intermediate 62b and the intermediate 72a in the same manner as the preparation of the intermediate 61c : ¹ H NMR (300 MHz, CDCl ₃ ) δ10.48 (s, 1H), 8.62 (s, 1H), 8.48 (s, H), 8.42 (s, 1H), 7.83 (br s, 1H), 7.45 (d, 2H, J = 8.7Hz), 7.21-7.32 (m, 5H), 6.83 (d, 2H, J = 8.7 Hz), 5.60 (d, 2H, J = 4.5 Hz), 4.80 (s, 2H), 3.76 (s, 3H), 2.25 (s, 3H), 1.94 (br s, 1H).
[789] (c) Compound 72- {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-yl} -methanol:
[790] Compound 72 was prepared in 59% yield by PBM-deprotecting the intermediate 72b in the same manner as in the preparation of compound 62 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.78 (s, 1H), 13.01 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 7.75 (dd, 1H, J = 8.4, 0.6 Hz), 7.68 (d, 1H, J = 7.2 Hz), 7.50 (d, 1H, J = 7.2 Hz), 7.44 (dd, 1H, J = 8.4, 1.5 Hz), 7.15-7.23 (m, 2H), 5.29 (t, 1H, J = 5.4 Hz ), 4.64 (d, 2H, J = 5.4 Hz), 2.22 (s, 3H). _{Anal. (C 2l H l7 N} 5 O · 1.25 H 2 O) C, H, N. MS (ES) [m + H] / z calculated 356, 356 measurements.
[791] Example 73: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -dimethyl-amine
[792]
[793] (a) Compound 73-{5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl} -dimethyl-amine :
[794] Compound 73 was prepared in 36% yield using the compound 72 and dimethylamine in the same manner as the preparation of the intermediate 68b : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.77 (s, 1H), 13.02 (s, 1H), 8.38-8.42 (m, 3H), 7.67-7.76 (m, 2H), 7.50 (d, 1H, J = 7.8 Hz), 7.44 (dd, 1H, J = 8.7, l.5 Hz) , 7.14-7.24 (m, 2H), 3.48 (br s, 2H), 2.28 (s, 3H), 2.21 (s, 6H). Anal. (C ₂₃ H ₂₂ N ₆ .0.8 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 383, found 383.
[795] Example 74: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -ethyl-amine
[796]
[797] (a) Compound 74- {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -ethyl-amine :
[798] Compound 74 was prepared in the same manner as in the preparation of intermediate 68b using compound 72 and ethylamine in 23% yield: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.76 (s, 1H), 13.01 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.74 (d, 1H, J = 8.7 Hz), 7.68 (d, 1H, J = 7.5 Hz) , 7.50 (d, 1H, J = 7.5 Hz), 7.43 (dd, 1H, J = 8.7, l.5 Hz), 7.14-7.23 (m, 2H), 3.81 (s, 2H), 2.65 (q, 2H, J = 7.2 Hz), 2.26 (s, 3H), 1.08 (t, 3H, J = 7.2 Hz). Anal. (C ₂₃ H ₂₂ N ₆ .0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 383. found 383.
[799] Example 75: (3-1H-benzoimidazol-2-yl) -5- (4,5-dimethyl-pyridin-3-yl) -1H-indazole
[800]
[801] (a) Intermediate 75a-5-Bromo-3,4-dimethyl-pyridine:
[802] Intermediate 75a was prepared using the same method as for intermediate 59a using 3,5-dibromo-4-methyl-pyridine and iodinemethane: ¹ H NMR (300 MHz, CDCl ₃ ) δ8.50 ( s, 1H), 8.22 (s, 1H), 2.36 (s, 3H), 2.30 (s, 3H).
[803] (b) Intermediate 75b-3- (1H-benzoimidazol-2-yl) -5- (4,5-dimethyl-pyridin-3-yl) -1- (4-methoxy-benzyl) -1H Indazole:
[804] Intermediate 75b was prepared in the same manner as the preparation of intermediate 61c using the intermediate 62b and the intermediate 75b in 79% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ10.5 (s, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.81-7.85 (m, 1H), 7.4l-7.49 (m, 2H), 7.18-7.27 (m, 5H), 6.81 (d, 2H, J = 4.5 Hz), 5.57 (s, 2H), 3.74 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H).
[805] (c) Compound 75- 3- (1H-benzoimidazol-2-yl) -5- (4,5-dimethyl-pyridin-3-yl) -1 H-indazole:
[806] Compound 75 was prepared in 37% yield by PBM-deprotecting the intermediate 75b in the same manner as in the preparation of compound 62 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.76 (s, 1H), 13,02 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.74 (dd, 1H, J = 8.4, O.6Hz), 7.51-7.69 (m , 2H), 7.44 (dd, 1H, J = 8.7, l.8 Hz), 7.17-7.22 (m, 2H), 2.33 (s, 3H), 2.18 (s, 3H). Anal. (C ₂₁ H ₁₇ N ₅ .1.0 H ₂ O) C, H, N. MS (ES) [m + H] / z 340, found 340.
[807] Example 76: 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-quinoline
[808]
[809] (a) Intermediate 76a- 3- [3- (1H-Benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1 H-indazol-5-yl] -4-methyl- Quinoline:
[810] Intermediate 76a was prepared in the same manner as in the preparation of intermediate 61c using intermediate 62b and 3-bromo-4-methylquinoline (see Kwon et al., Synthesis , 1976, 249) in 86% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ10.24 (s, 1H), 8.94 (s, 1H), 8.78 (s, 1H), 8.25 (dd, 1H, J = 7.8, 0.3Hz), 8.14 (dd , 1H, J = 7.8, 0.3 Hz, 7.75-7.88 (m, 2H), 7.64-7.70 (m, 1H), 7.45-7.57 (m, 3H), 7.27-7.35 (m, 4H), 6.91 ( d, 2H, J = 6.9 Hz, 5.68 (s, 2H), 3.82 (s, 3H), 2.70 (s, 3H). Anal. (C ₃₂ H ₂₅ N ₅ O.0.15 H ₂ O) C, H, N.
[811] (b) compound 76- 3- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-quinoline:
[812] Compound 76 was prepared in 72% yield by PBM-deprotecting the intermediate 76a in the same manner as in the preparation of Compound 62 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.81 (s, 1H), 13.06 (s, 1H), 8.86 (s, 1H), 8.55 (s, 1H), 8.23 (d, 1H, J = 7.8Hz), 8.09 (d, 1H, J = 7.2Hz), 7.68-7.84 (m , 3H), 7.55-7.59 (m, 3H), 7.17-7.23 (m, 2H), 2.66 (s, 3H). Anal. (C ₂₄ H ₁₇ N ₅ .8 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 376, measured 376.
[813] Example 77 5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ol
[814]
[815] (a) Intermediate 77a- 5-Bromo-4-methyl-pyridin-3-ol:
[816] DMF (8 mL) and MeOH (2 mL) containing 3,5-Dibromo-4-methyl-pyridine (2.42 g, 9.64 mmol) and sodium methoxide (3.12 g, 57.8 mmol) in sealed tubes The mixture was added to the mixture and stirred at 180 ° C. for 24 hours. The reaction was cooled and concentrated in vacuo. Purification by silica gel chromatography (100% ethyl acetate) gave 1.10 g (61%) of intermediate 77a in the form of a white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.12 (s, 1 H), 8.04 (s, 1 H), 2.21 (s, 3 H). Anal. (C ₆ H ₆ BrNO) C, H, N.
[817] (b) Intermediate 77b-3-Bromo-5- (4-methoxybenzyloxy) -4-methyl-pyridine:
[818] Intermediate 77a (1.0 g, 5.3 mmol), tetramethylammonium iodine (107 mg, 0.53 mmol) and potassium carbonate (1.47 g, 10.6 mmol) were added to acetone (30 mL) and stirred. P-methoxybenzyl chloride (1.08 mL, 7.98 mmol) was added to the reaction and stirred at 55 ° C. for 8 h. The solution was diluted with ethyl acetate. The organics were washed with H ₂ O and brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (25% ethyl acetate / hexanes) gave 648 mg (40%) of intermediate 77b as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ8.33 (s, 1H), 8.16 (s, 1H), 7.34 (d, 2H, J = 8.7 Hz), 7.93 (d, 2H, J = 8.7 Hz), 5.08 (s, 2H), 3.83 (s, 3H), 2.34 (s, 3H) . Anal. (C ₁₄ H ₁₄ BrNO ₂ ) C, H, N.
[819] (c) Intermediate 77c-5- [3- (1H-Benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1H-indazol-5-yl] -4-methyl- Pyridin-3-ol:
[820] Intermediate 77c was prepared in the same manner as the preparation of intermediate 61c using intermediate 62b and intermediate 77b in 89% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ10.17 (s, 1H), 8.0 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.8l-7.86 (m, 1H), 7.34-7.49 (m, 5H), 7.21-7.29 (m, 4H), 6.95 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H, J = 8.7 Hz), 5.61 (s, 2H), 5.16 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H) , 2.20 (s, 3 H).
[821] (d) Compound 77- 5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ol:
[822] Compound 77 was prepared in 47% yield by PMB-deprotecting the intermediate 77c in the same manner as Compound 62 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.74 (s, 1H), 13.01 (s , 1H), 9.91 (s, 1H), 8.43 (s, 1H), 8.l4 (s, 1H), 7.98 (s, 1H), 7.72 (dd, 1H, J = 8.4, 0.6 Hz), 7.69 ( bs, 1H), 7.51 (bs, 1H), 7.45 (dd, 1H, J = 8.7, l.5 Hz), 7.17-7.22 (m, 2H), 2.09 (s, 3H). Anal. (C ₂₀ H ₁₅ N ₅ O.0.3 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 340, measured 34O.
[823] Example 78: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -isopropyl-amine
[824]
[825] (a) Compound 78- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -isopropyl- Amine:
[826] Intermediate 78 was prepared in 28% yield using compound 72 and isopropylamine in the same manner as for the preparation of intermediate 68b : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.76 (s, 1H) , 13.01 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 7.74 (d, 1H, J = 8.7Hz), 7.68 (d, 1H, J = 7.8 Hz), 7.50 (d, 1H, J = 7.2 Hz), 7.43 (dd, 1H, J = 8.7, 1.5 Hz), 7.15-7.25 (m, 2H), 3.79 (s, 2H), 2.80-2.86 (m , 1H), 2.27 (s, 3H), 1.07 (d, 6H, J = 6.6 Hz). Anal. (C ₂₄ H ₂₄ N ₆ .0.7 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 397, found 397.
[827] Example 79: (5-isoquinolin-4-yl-1 H-indazol-3-ylmethylene) -pyrrol-1-yl-amine
[828]
[829] (a) Intermediate 79a-5-isoquinolin-4-yl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazole-3-carboaldehyde:
[830] Intermediate 79a was prepared by substituting the SEM-protecting group for PMB-protecting group of intermediate 19c in the same manner as intermediate 19f : ¹ H NMR (300 MHz, CDCl ₃ ) δ10.30 (s, 1H), 9.30 (s , 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.08 (dd, 1H, J = 6.6, 2.4 Hz), 7.86 (dd, 1H, J = 6.6, O.6 Hz), 7.81 (dd , 1H, J = 8.7, O.9 Hz), 7.64-7.70 (m, 3H), 5.91 (s, 2H), 3.66 (t, 2H, J = 8.4 Hz), 0.97 (t, 2H, J = 8.4 Hz ), -0.02 (s, 9H).
[831] (b) Intermediate 79b-[5-Isoquinolin-4-yl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-indazol-3-ylmethylene] -pyrrol-1-yl-amine :
[832] Intermediate 79a (400 mg, 0.99 mmol) and 1-aminopyrrole (98 mg, 1.2 mmol) were added to a solution of p-toluenesulfonic acid (10 mg) dissolved in toluene (6 mL) and stirred at 80 ° C. for 2 hours. It was. The solution was concentrated in vacuo and purified by silica gel chromatography (50% ethyl acetate / hexanes) to give 410 mg (89%) of intermediate 79b in the form of a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ9. 31 (s, 1H), 8.77 (s, 1H), 8.58-8.60 (m, 2H), 8.09 (dd, 1H, J = l.2, O.9Hz), 7.92 (d, 1H, J = 7.8Hz ), 7.76 (dd, 1H, J = 8.7, 0.3 Hz), 7.63-7.70 (m, 3H), 7.19 (t, 2H, J = 2.4 Hz), 6.26 (t, 2H, J = 2.4 Hz), 5.85 (s, 2H), 3.66 (t, 2H, J = 8.4 Hz), 0.97 (t, 2H, J = 8.4 Hz), -0.02 (s, 9H).
[833] (c) Compound 79- (5-isoquinolin-4-yl-1H-indazol-3-ylmethylene) -pyrrol-1-yl-amine:
[834] Compound 79 was prepared in 68% yield by SEM-deprotection of intermediate 79b in the same manner as Compound 41 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.82 (s, 1H), 9.38 (s , 1H), 9.09 (s, 1H), 8,52 (s, 1H), 8.41 (s, 1H), 8.24 (dd, 1H, J = 7.2, l.5Hz), 7.71-7.85 (m, 4H) , 7.61 (dd, 1H, J = 8.4, 1.5 Hz), 7.46 (t, 2H, J = 2.4 Hz), 6.15 (t, 2H, J = 2.4 Hz). Anal. (C ₂₁ H ₁₅ N ₅ ) C, H, N. MS (ES) [m + H] / z calc. 338, measured 338.
[835] Example 80: 2- [5- (5-ethylaminomethyl-4-methyl-pyridin-3-yl) -1H-indazol-3- Japanese] -1H-benzoimidazole-4-carboxylic acid methylamide
[836]
[837] (a) Intermediate 80a-(5-Bromo-4-methyl-pyridin-3-ylmethyl) -ethyl-amine:
[838] Intermediate 80a was prepared in the same manner as the preparation of intermediate 68b using intermediate 72a and ethylamine in 95% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ8.59 (s, 1H), 8.37 (s, 1H), 3.83 (s, 2H), 2.73 (q, 2H, J = 7.2 Hz), 2.48 (s, 3H), 1.16 (t, 3H, J = 7.2 Hz).
[839] (b) Intermediate 80b-(5-Bromo-4-methyl-pyridin-3-ylmethyl) -ethyl-carbamic acid dimethyl-ethyl ester:
[840] Intermediate 80a (850 mg, 3.7 mmol) was added to THF (10 mL) and 1N NaOH (10 mL) solution and stirred. Di-tert-butyl dicarbonate (1.09 g, 5 mmol) was added and stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate. The organics were washed with H ₂ O and brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (33% ethyl acetate / hexanes) gave 760 mg (62%) of an intermediate 80b in the form of a clear oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ8.6O (s, 1H), 8.24 (s, 1H), 4.49 (s, 2H), 3.18 (bs, 2H), 2.39 (s, 3H), 1.47 (s, 9H), 1.05 (t, 3H, J = 7.2 Hz).
[841] (c) Intermediate 80c-ethyl- [5- (3-formyl-1H-indazol-5-yl) -4-methyl-pyridin-3-ylmethyl] carbamic acid dimethyl-ethyl ester:
[842] Intermediate 80c was prepared in the same manner as in the preparation of intermediate 61c using intermediate 19e and intermediate 80b in 89% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ10.27 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.49 (dd, 1H, J = 6.7, O.6 Hz), 7.26-7.51 (m, 3H), 6.89 (dd, 2H , J = 6.6, 2.1 Hz), 5.66 (s, 2H), 4.53 (s, 2H), 3.79 (s, 3H), 3.24 (bs, 2H), 2.18 (s, 3H), 1.48 (s, 9H) , 1.10 (t, 3H, J = 7.2 Hz).
[843] (d) Intermediate 80d-Ethyl- {5- [1- (4-methoxy-benzyl) -3- (4-methylcarbamoyl-1H-benzoimidazol-2-yl) -1H-indazole- 5-yl] -4-methyl-pyridin-3-ylmethyl} -carbamic acid dimethyl-ethyl ester:
[844] Intermediate 80d is intermediate 80c and 2-amino-N-methyl-3-nitrobenzamide (Kania, Braganza, et al., Patent application "Compounds and Pharmaceutical Compositions for Inhibiting Protein Kinases, and Methods for Their use, p. 52, line 10, p.53, line 26; and p.59, line 16, p. 60, line 41, US Provisional Application No. 60 / 142,130, filed Jul. 2, 1999, incorporated herein by reference. In the same manner as in the preparation of the intermediate 7c ' , 78% yield was obtained: ¹ H NMR (300 MHz, CDCl ₃ ) δ11.50 (s, 0.3H), 10.21 (s, O.7H), 9.86 (bs, 1H), 8.36-8.57 (m, 3H), 8.18 (dd, O.7H, J = 7.8, 1.2 Hz), 7.97 (dd, O.3H, J = 7.8, 1.2 Hz), 7.63 (dd, O.7H, J = 7.8, 1.2 Hz), 7.24 (m, 5.3H), 6.88 (d, 2H, J = 6.3 Hz), 5.65 (s, 1.4H), 5.63 (s , O.6H), 4.57 (bs, 2H), 3.79 (s, 3H), 3.27 (bs, 2H), 3.12 (d, O.9H, J = 4.8 Hz), 3.06 (d, 2.1H, J = 4.8 Hz), 2.29 (s, 2.1 H), 2.21 (s, 0.1 H), 1.48 (s, 9 H), 1.11 (t, 3 H, J = 6.9 Hz).
[845] (e) Compound 80- 2- [5- (5-ethylaminomethyl-4-methyl-pyridin-3-yl) -1 H- Zol-3-yl] -1 H-benzoimidazole-4-carboxylic acid methylamide:
[846] Compound 80 was prepared in 36% yield by PMB-deprotecting the intermediate 80d in the same manner as compound 62 and purifying by preparative HPLC (0.1% TFA-ACN / 0.1% TFA-H ₂ O): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ14.02 (s, 1H), 13.62 (bs, 1H), 9.72 (bs, 1H), 8.88 (bs, 2H), 8.63 (s, 2H), 8.44 (s, 1H), 7.83-7.88 (m, 2H), 7.72 (d, 1H, J = 7.2 Hz), 7.52 (dd, 1H, J = 8.4, 1.5 Hz), 7.36 (t, 1H, J = 7.8 Hz), 4.33 (bs, 2H), 3.15 (q, 2H, J = 7.2 Hz), 2.90 (d, 3H, J = 4.5 Hz), 2.43 (s, 3H), 1.27 (t, 3H, J = 7.2 Hz). Anal. (C ₂₅ H ₂₅ N ₇ O. 0.3 TFA) C, H, N. MS (ES) [m + H] / z calc. 440, measured 440.
[847] Example 81: ethyl-4- {methyl-5- [3- (4-methylsulfonyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -pyridin-3-ylmethyl } -Amine
[848]
[849] (a) Intermediate 81a- 3-Methylsulfonyl-2-nitro-phenylamine:
[850] 3-chloro-2-nitro-aniline (1.0 g, 5.8 mmol) and potassium carbonate (880 mg, 6.4 mmol) were placed in a tube which could be sealed at 0 ° C., and dried DMF (15 mL) was added thereto and stirred. The solution was bubbled with methanethiol for 4 minutes. The tube was sealed and the reaction stirred at 122 ° C. for 16 hours. The cooled reaction was diluted with H ₂ O and extracted with ethyl acetate. The organics were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (33% ethyl acetate / hexanes) yielded 950 mg (69%) of intermediate 81a in the form of a bright crimson solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ7.21 (t, 1H, J = 8.1 Hz), 6.55 (d, 2H, J = 8.1 Hz), 5.93 (bs, 2H), 2.42 (s, 3H). Anal. (C ₇ H ₈ N ₂ O ₂ S) C, H, N, S.
[851] (b) Intermediate 81b- 3-Methylsulfonyl-benzene-1,2-diamine:
[852] Intermediate 81b was prepared in 96% yield by hydrogenation of intermediate 81a in the same manner as intermediate 9a ' : ¹ H NMR (300 MHz, CDCl ₃ ) δ6.93-6.97 (m, 1H), 6.63-6.70 (m, 2H), 3.71 (bs, 4H), 2.36 (s, 3H). Anal. (C ₇ H ₁₀ N ₂ S) C, H, N, S.
[853] (c) Intermediate 81c-Ethyl- {5- [1- (4-methoxy-benzyl) -3- (4-methylsulfonyl-1H-benzoimidazol-2-yl) -1H-indazole- 5-yl] -4-methyl-pyridin-3-ylmethyl} -carbamic acid dimethyl-ethyl ester:
[854] Intermediate 81c was prepared in the same manner as the preparation of intermediate 7c ' using intermediate 81b and intermediate 80c in 80% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.15 (s, O. 6H), 10.12 (s, O.4H), 8.64 (s, O.4H), 8.59 (s, O.6H), 8.47 (s, 1H), 8.37 (s, 1H), 7.72 (d, O. 6H, J = 7.5Hz), 7.45 (t, 1H, J = 7.2Hz), 7.19-7.34 (m, 5H), 7.10 (d, O.4H, J = 7.5Hz), 6.83-6.89 (m, 2H ), 5.65 (s, 1.2H), 5.61 (s, O.8H), 4.55 (bs, 2H), 3.78 (s, 1.8H), 3.77 (s, 1.2H), 3.26 (bs, 2H), 2.67 (s, 1.2H), 2.57 (s, 1.8H), 2.24 (s, 1.2H), 2.22 (s, 1.8H), 1.49 (s, 9H), 1.12 (t, 3H, J = 6.9 Hz).
[855] (d) Compound 81-ethyl-4- {methyl-5- [3- (4-methylsulfonyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -pyridine-3 -Ylmethyl} -amine:
[856] Compound 81 was prepared in 25% yield by PMB-deprotecting the intermediate 81c in the same manner as Compound 62 : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.78 (s, 1H), 13.10 (s , 1H), 8.48 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 7.75 (d, 1H, J = 8.7 Hz), 7.44 (d, 1H, J = 8.7, 1.8 Hz) , 7.30 (d, 1H, J = 7.8 Hz), 7.19 (t, 1H, J = 7.8 Hz), 6.99 (d, 1H, J = 7.2 Hz), 3.82 (s, 2H), 2.66 (q, 2H, J = 7.2 Hz), 2.56 (s, 3H), 2.28 (s, 3H), 1.08 (t, 3H, J = 7.2 Hz). Anal. (C ₂₄ H ₂₄ N ₆ S. 1.5 H ₂ O] C, H, N, S. MS (ES) [m + H] / z calc. 429, measured 429.
[857] Example 82: N- {2- [5- (5-ethylaminomethyl-4-methyl-pyridin-3-yl) -1H-indazol-3-yl] -1H-benzoimidazol-4-yl} Acetamide
[858]
[859] (a) Intermediate 82a-N- (2,3-diamino-phenyl) -acetamide:
[860] Intermediate 82a is N- (2-amino-3-nitro-phenyl) -acetamide (Harey et al., J. Chem. Soc. Perk. Trans . 1 , 1988, 1939- in the same manner as intermediate 9a ' . 1944) was prepared in 98% yield by ¹ H NMR (300 MHz, CDCl ₃ ) δ9.04 (s, 1H), 6.35-6.49 (m, 3H), 4.38 (bs, 4H), 2.00 (s, 3 H).
[861] (b) Intermediate 82b-{5- [3- (4-acetylamino-1H-benzoimidazol-2-yl) -1- (4-methoxy-benzyl) -1H-indazol-5-yl ] -4-methyl-pyridin-3-ylmethyl} -ethyl-carbamic acid dimethyl-ethyl ester:
[862] Intermediate 82b was prepared in the same manner as the preparation of intermediate 7c ' using intermediate 82a and 80c in 65% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ12.35 (bs, 1H) , 1O.8O (bs, 1H), 7.90-8.85 (m, 4H), 6.76-7.46 (m, 8H), 5.60 (bs, 2H), 4.51 (bs, 2H), 3.78 (s, 3H), 3.61 (bs, 2H), 3.19 (b, 3H), 1.74 (bs, l2H), 1.18 (bs, 3H). MS (ES) [m + H] / z calc'd 660, measured 660.
[863] (c) Compound 82-N- {2- [5- (5-ethylaminomethyl-4-methyl-pyridin-3-yl) -1H-indazol-3-yl] -1H-benzoimidazole-4 -Yl} -acetamide:
[864] Compound 82 was prepared in 6% yield by PMB-deprotection of intermediate 82b in the same manner as Compound 62 : ¹ H NMR (300 MHz, MeOD-d ₄ ) δ8.64 (s, 1H), 8.58 (s , 1H), 8.45 (s, 1H), 7.82 (d, 1H, J = 8.4 Hz), 7.57 (d, 1H, J = 7.2 Hz), 7.50 (d, 2H, J = 7.2 Hz), 7.34 (t , 1H, J = 8.4 Hz, 4.44 (s, 2H), 3.27 (q, 2H, J = 7.5 Hz), 2.43 (s, 3H), 2.22 (s, 3H), 1.41 (t, 3H, J = 7.5 Hz). MS (ES) [m + H] / z calc. 440. found 440.
[865] Example 83: 5- (2,6-difluorophenyl) -3-phenyl-1H-indazole
[866]
[867] (a) Intermediate 83a- 5- (2,6-difluorophenyl) -3-phenyl-1- [2- (trimethylsilanyl) ethoxymethyl] -1 H-indazole:
[868] In the same manner as for intermediate 11e , palladium was coupled to intermediate 11d with 2,6-difluorophenylboronic acid to catalyze to yield 83a (65%) as an intermediate in the form of a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ-0.09 (s, 9H), 0.84 (t, 2H, J = 8.0 Hz), 3.62 (t, 2H, J = 8.0 Hz), 5.86 (s, 2H), 7.24 (dd, 2H, J = 8.1, 8.3 Hz), 7.44 (tt, 1H, J = 1.3, 7.2 Hz), 7.47-7.58 (m, 4H), 7.92 (dd, 1H, J = 0.5, 8.8 Hz), 7.98 (dd, 2H, J = 1.3, 8.2 Hz), 8.14 (d, 1H, J = 0.5 Hz).
[869] (b) Compound 83- 5- (2,6-difluorophenyl) -3-phenyl-1H-indazole:
[870] In the same manner as in compound 7 ' , intermediate 83a and tetrabutylammonium fluoride were treated to give compound 83 (95%) in the form of a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.23 ( dd, 2H, J = 8.1, 8.3 Hz), 7.40 (tt, 1H, J = 1.3, 7.2 Hz), 7.43-7.56 (m, 4H), 7.70 (dd, 1H, J = 0.6, 8.7 Hz), 7.98 (dd, 2H, J = 1.3, 8.4 Hz), 8.11 (d, 1H, J = 0.6 Hz), 13.38 (s, 1H). Anal. (C ₁₉ H ₁₂ N ₂ F ₂ ) C, H, N.
[871] Example 84 5-amino-3- (2-pyrrolyl) -1 H-indazole
[872]
[873] In the same manner as for the intermediate 18c , 5-nitro-3- (2-pyrrolyl) -1H-indazole and intermediate 18b ' in the presence of 10% Pd-C were subjected to hydrogenation to give a beige solid of 5- Amino-3- (2-pyrrolyl) -1 H-indazole, compound 84 (99%) was obtained: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ6.13 (dd, lH, J = 2.4, 2.6 Hz), 6.49 (dd, 1H, J = 1.5, 2.4 Hz), 6.76 (dd, 1H, J = 1.5, 2.6 Hz), 6.79 (dd, 1H, J = 2.1, 8.9 Hz), 7.03 (d, 1H , J = 2.1 Hz, 7.22 (d, 1H, J = 8.9 Hz), 11.16 (s, 1H), 12.45 (s, 1H). Anal. (C ₁₁ H ₁₀ N ₄ .2 ethyl acetate) C, H, N.
[874] Compound 85: 5- (benzylamino) -3- (2-pyrrolyl) -1H-indazole
[875] Benzaldehyde (100 mg, 1 mmol) was added to a solution of 5-amino-3- (2-pyrrolyl) -1H-indazole, compound 84 (100 mg, 0.5 mmol) in EtOH (100 mL). The resulting solution was stirred at ambient temperature for 2 hours and then NaBH ₃ CN (50 mg, 0.8 mmol) solid was added in one portion. After stirring for 2 more hours the crude reaction mixture was poured into H ₂ O (200 mL) and extracted with ethyl acetate (2 × 100 mL). The obtained organic extract was dried over sodium sulfate and concentrated. Purification by silica gel chromatography (60% ethyl acetate / hexanes) gave compound 85 (21%) in the form of a beige solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.33 (s, 2H), 6.11 ( dd, 1H, J = 2.5, 2.6 Hz, 6.38 (dd, 1H, J = 1.5, 2.5 Hz), 6.74 (dd, 1H, J = 1.5, 2.6 Hz), 6.81 (s, 1H), 6.91 (dd , 1H, J = 1.9, 8.9 Hz, 7.17-7.36 (m, 5H), 7.43 (d, 1H, J = 8.9 Hz), 7.45 (d, 1H, J = 1.9 Hz), 11.13 (s, 1H) , 12.48 (s, 1 H). _{Anal. (C 18 H 16 N} 4 · O.33 H 2 O) C, H, N.
[876] Compound 86: 5- (3-methoxymethyl) -3- (phenyl) -1H-indazole
[877]
[878] (a) Intermediate 86a-5- (3-methoxyphenyl) -3-phenyl-1- [2- (trimethylsilanyl) ethoxymethyl] -1 H-indazole:
[879] In the same manner as for intermediate 11e , palladium was coupled to intermediate 11d with 3-methoxyphenylboronic acid to catalyze to yield 86a (46%) as a pale yellow solid: ¹ H NMR (300). MHz, DMSO-d ₆ ) δ-0.10 (s, 9H), 0.84 (t, 2H, J = 8.0 Hz), 3,62 (t, 2H, J = 8.0 Hz), 5.86 (s, 2H), 7.24 -7.34 (m, 4H), 7.38-7.56 (m, 4H), 7.84 (d, 1H, J = 8.3 Hz), 7.91-8.03 (m, 3H).
[880] (b) Compound 86- 5- (3-methoxyphenyl) -3-phenyl-1H-indazole:
[881] In the same manner as in compound 11 , intermediate ( 86a) and tetrabutylammonium fluoride were treated to give 5- (3-methoxyphenyl) -3-phenyl-1H-indazole, compound 86 (65%) in the form of a white solid. Obtained: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ3.83 (s, 3H), 6.93 (dd, 1H, J = 1.9,8.0 Hz), 7.2-7.75 (m, 8H), 8.04 (dd, 2H, J = 1.3, 7.2 Hz), 8.2 O (d, 1H, J = 0.3 Hz), l.27 (s, 1H). Anal. (C ₂₀ H ₁₆ N ₂ O.0.2 H ₂ O) C, H, N.
[882] Example 87: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -isobutyl-amine
[883]
[884] (a) Compound 87- {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -isobutyl- Amine:
[885] Compound 87 was prepared in the same manner as the preparation of intermediate 68b using compound 72 and isobutylamine in 81% yield: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.77 (s, 1H), 13.02 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 7,74 (d, 1H, J = 8.7Hz), 7.68 (d, 1H, J = 7.5 Hz), 7.50 (d, 1H, J = 7.5 Hz), 7.43 (dd, 1H, J = 8.7, 1.5 Hz), 7.14-7.24 (m, 2H), 3.85 (s, 2H), 2.49 (bs, 2H), 2.27 (s, 3H), 1.73-1.79 (m, 1H). 0.90 (d, 6H, J = 6.6 Hz). Anal. (C ₂₅ H ₂₆ N ₆ .0.3 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 411, measured 411.
[886] Compound 88: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -benzyl-amine
[887]
[888] (a) Compound 88- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -benzyl-amine :
[889] Compound 88 was prepared in the same manner as the preparation of the intermediate 68b using compound 72 and benzylamine in 73% yield: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.77 (s, 1H), 13.02 (s, 1H), 8.51 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.74 (d, 1H, J = 8.7 Hz), 7.68 (d, 1H, J = 7.5 Hz) , 7.50 (d, 1H, J = 7.5 Hz), 7.16-7.44 (m, 8H), 3.90 (bs, 4H), 2.23 (s, 3H). Anal. (C ₂₆ H ₂₄ N ₆ 1.2 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 445, measured 445.
[890] Example 89: 2-({5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -amino)- ethanol
[891]
[892] (b) Compound 89-2-({5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl}- Amino) -ethanol:
[893] Compound 89 was prepared in the same manner as in the preparation of intermediate 68b using compound 72 and ethanolamine in 54% yield: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.78 (s, 1H), 13.01 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.42 (s, 1H), 7.75 (d, 1H, J = 8.7 Hz), 7,67 (d, 1H, J = 7.5 Hz), 7.5 l (d, 1H, J = 7.5 Hz), 7.43 (dd, 1H, J = 8.7, 1.5 Hz), 7.15-7.23 (m, 2H), 4.82 (bs, 1H), 4.03 (s, 2H), 3.60 (d, 2H, J = 2.7 Hz), 2.87 (t, 2H, J = 2.7 Hz), 2.29 (s, 3H). Anal. (C ₂₃ H ₂₂ N ₆ O.0.1 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 399, measured 399.
[894] Example 90: {1- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-yl] -ethyl} -methyl-amine
[895]
[896] (a) Intermediate 90a-N- (2-acetyl-6-nitro-phenyl) -acetamide:
[897] A solution of 2,3-dimethyl-7-nitroindole (Acros Organics, 13.55 g, 71.24 mmol) dissolved in dichloromethane (1.0 L) was cooled to an internal temperature of −60 ° C. and treated with ozone gas for 1.5 hours. It was observed that the color of the solution changed from orange to yellow green. The solution was changed to yellow by foaming with argon for one hour. Dimethyl sulfide (10.5 mL, 142.5 mmol) was added and then stirred at −60 ° C. for 1.5 hours. The solution was warmed to room temperature and concentrated to ˜200 mL in vacuo, washed with water (2 × 50 mL), dried over magnesium sulfate, filtered and concentrated and silica gel chromatography (50-100% ethyl acetate / hexanes). Purification) yielded intermediate 90a (11.85g, 75%) in the form of an orange solid: R _f = 0.36 (75% ethyl acetate / hexane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.02 (s, 3H), 2.52 (s, 3H), 7.52 (t, 1H, J = 7.9 Hz), 8.00 (dd, 1H, J = 7.9, 1.5 Hz), 8.05 (dd, 1H, J = 8.1, 1.5 Hz), 10.32 (s, 1H). Anal. (C ₁₀ H ₁₀ N ₂ O ₄ .0.4 H ₂ O) C, H, N.
[898] (b) Intermediate 9Ob- 1- (2-Amino-3-nitro-phenyl) -ethanone:
[899] Concentrated hydrochloric acid (40 mL) was added to a solution of intermediate 90a (4.00 g, 18.0 mmol) dissolved in pure ethanol (4.00 g, 18.0 mmol) and water (40 mL). The mixture was heated to reflux at an internal temperature of 87 ° C. for 1 hour. After cooling the mixture to room temperature, saturated aqueous bicarbonate sodium was added to pH 8. The solution was extracted with ethyl acetate (2x200 mL). The obtained organic extract was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (20-70% ethyl acetate / hexane) to give intermediate 9Ob (2.67g, 82%) in the form of a yellow solid: R _f = 0.45 (50% ethyl acetate / hexane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.62 (s, 3H), 6.74 (t, 1H, J = 8.1 Hz), 8.31 (m. 2H), 8.85 (br s, 2H). Anal. (C ₈ H ₈ N ₂ O ₃ ) C, H, N.
[900] (c) intermediate 90c-l- (2,3-diamino-phenyl) -ethanone:
[901] In the same manner as in compound 9a , intermediate 90b (2.00 g, 11.1 mmol) was added to ethanol to give a hydrogenation reaction to obtain intermediate 90c (1.54 g, 65%) as light yellow crystals: R _f = 0.34 (50%) Ethyl acetate / hexane); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.47 (s, 3H), 4.75 (br s, 2H), 6.40 (dd, 1H, J = 7.5, 8.1 Hz), 6.69 (dd, 1H, J = 7.5, 1.3 Hz), 6.79 (br s, 2H), 7.10 (dd, lH, J = 8.1, 1.3 Hz). Anal. (C ₈ H ₁₀ N ₂ O) C, H, N.
[902] (d) Intermediate 9Od- 1- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1 H-indazol-3-yl] -1 H-benzoimidazole- 4-day} -ethanone:
[903] In the same manner as in compound 19h , aldehyde 19f (2.02 g, 5.13 mmol) and diamine 90c (7.71 mg, 5.13 mmol) were converted to intermediate 90d (1.84 g, 68%) as a light yellow solid in the presence of sulfur: R _f = 0.19 (75% ethyl acetate / hexanes); ¹ H NMR (300 MHz, DMSO-d ₆ ) (some peaks are doubled by tautomeric isomerization) δ 2.72 and 2.87 (2 br s, 3H together), 3.71 (s, 3H), 5.85 (s, 2H), 6.93 (d, 2H, J = 8.7 Hz), 7.34 (m, 3H), 7.75 (m, 5H), 8.07 (m, 2H), 8.25 (d, 1H, J) = 7.5 Hz), 8.56 and 8.80 (2 br s, 2H together), 9.38 (s, 1H), 11.83 (s, 1H), 13.53 (s, 1H).
[904] (e) Intermediate 90e-(l- {2- [5-isoquinolin-4-yl-1- (4-methoxy-benzyl) -1H-indazol-3-yl] -1H-benzoimidazole -4-yl} -ethyl) -methyl-amine:
[905] A solution of methylamine dissolved in methanol at room temperature (2.0 M, 3.02 ml, 6.04 mmol) was added to ketone 90d (527.8 mg, 1.01 mmol), followed by hydrochloric acid (dissolved in 4.0 ml dioxane, 0.504 ml, 2.02 mmol) and methanol. (6.0 mL), and sodium cyanoborohydride (38.0 mg, 0.605 mmol) were added. The suspension was stirred at room temperature for 23 hours, and no reaction was observed by TLC analysis. Anhydrous THF (10 mL) was added to increase the solubility and then stirred for 70 hours. The mixture was partitioned between ethyl acetate and saturated aqueous bicarbonate sodium solution. The organic phase was dried over magnesium sulfate, filtered and concentrated, and then purified by silica gel chromatography (1: 20: 200 aq. NH ₄ OH: ethanol: dichloromethane) to give a yellow foamed intermediate 90e (275.0 mg, 51%). Obtained: R _f = 0.09 (1: 20: 400 aqueous NH ₄ OH: ethanol: dichloromethane); ¹ H NMR (300 MHz, CD ₃ OD) δ 1.53 (d, 3H, J = 6.8 Hz), 2.24 (s, 3H), 3.75 (s, 3H), 4.28 (q, 1H, J = 6.8 Hz) , 5.45 (s, 1H), 5.45 (s, 2H), 6.89 (d, 2H, J = 8.7 Hz), 7.22 (m, 2H), 7.34 (d, 2H, J = 8.7 Hz), 7.52 (d, 1H, J = 7.9 Hz), 7.61 (dd, 1H, J = 8.7, 1.5 Hz), 7.76 (m, 3H), 7.99 (d, 1H, J = 8.3 Hz), 8.20 (dd, 1H, J = 7.2 , 1.7 Hz), 8.48 (s, 1H), 8.70 (s, 1H), 9.27 (s, 1H). Anal. (C ₃₄ H ₃₀ N ₆ O. 1.OH ₂ O) C, H, N,
[906] (f) Compound 90- {l- [2- (5-isoquinolin-4-yl-1H-indazol-3-yl) -1H-benzoimidazol-4-yl] -ethyl} -methyl-amine :
[907] A solution of intermediate 90e (179.7 mg, 0.334 mmol), trifluoromethanesulfonic acid (0.84 mL), and trifluoroacetic acid (3.3 mL) was stirred at 50 ° C. for 2 hours. To the solution was added a mixture of concentrated NH ₄ OH (10 mL) and ethyl acetate (30 mL) with rapid stirring. Extraction and purification in the same manner as in compound 33 , yielded compound 90 (140.9 mg) as an off-white solid. The material was purified by HPLC and ¹ H NMR analysis but found to contain significant impurities in the analysis of the elements. The impurity was dissolved in ethyl acetate (50 mL) and washed with water (10 mL), saturated aqueous bicarbonate sodium solution (10 mL) and saturated aqueous sodium chloride (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to give 90 (49.4 mg, 35%) as a solid in the form of a white solid: ¹ H NMR (300 MHz, CD ₃ OD) δ1.71 (d, 3H, J = 6.8 Hz), 2.45 (s, 3H), 4.66 (q, 1H, J = 7.0 Hz), 7.24 (d, 1H, J = 7.5 Hz), 7.32 (t, 1H, J = 7.7 Hz), 7.61 (dd , 1H, J = 7.9, 1.0 Hz, 7.67 (dd, 1H, J = 8.5, 1.5 Hz), 7.82 (m, 3H), 8.03 (d, 1H, J = 8.3 Hz), 8.24 (d, 1H, J = 7.5 Hz), 8.53 (s, 1 H), 8.71 (s, 1 H), 9.30 (s, 1 H). Anal. (C ₂₆ H ₂₂ N _6. · O ₄ CH ₂ Cl ₂ ) C, H, N.
[908] Example 91: 3- (1H-benzoimidazol-2-yl) -5- (4-methyl-5-morpholin-4-ylmethyl-pyridin-3-yl) -1H-indazole
[909]
[910] (a) Compound 91- 3- (1H-benzoimidazol-2-yl) -5- (4-methyl-5-morpholin-4-ylmethyl-pyridin-3-yl) -1 H-indazole:
[911] Compound 91 was prepared in the same manner as the preparation of the intermediate 68b using compound 72 and morpholine in 68% yield: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.78 (s, 1H), 13.02 (s, 1H), 8.42 (s, 2H), 8.40 (s, 1H), 7.75 (d, 1H, J = 8.7 Hz), 7.59 (br s, 2H), 7.44 (dd, 1H, J = 8.7, l.5 Hz), 7.17-7.22 (m, 2H), 3.58-3.67 (m, 6H), 2.48 (br s, 4H), 2,30 (s, 3H). Anal. (C ₂₅ H ₂₄ N ₆ O.0.7 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 425, measured 425.
[912] Example 92: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -cyclopentyl-amine
[913]
[914] (a) Compound 92- {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -cyclopentyl- Amine:
[915] Compound 92 was prepared in the same manner as the preparation of intermediate 68b using compound 72 and cyclopentylamine in 49% yield: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.49 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 7.73 (d, 1H, J = 8.7 Hz), 7.64 (br s, 2H), 7.45 (d, 1H, J = 8.7 Hz), 7.24-7.28 ( m, 2H), 3.95 (s, 2H), 3.25 (br s, 1H), 2.39 (s, 3H), 1.96-2.02 (m, 2H), 1.71-1.78 (m, 2H), 1.46-1.67 (m (4H). Anal. (C ₂₆ H ₂₆ N ₆ .0.2 H ₂ O) C, H, N. MS (ES) [m + H] / z calc. 423, found 423.
[916] Example 93: {5- [3- (1H-Benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -pyridin-3-yl -Amine
[917]
[918] (a) compound 93- {5- [3- (1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -4-methyl-pyridin-3-ylmethyl} -pyridine-3 -Yl-amine:
[919] Compound 93 was prepared in the same manner as in the preparation of intermediate 68b using compound 72 and 3-amino-pyridine in 68% yield: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.79 (s, 1H ), 13.03 (s, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.75 (d, 1H, J = 8.7 Hz), 7.59 (br s, 2H), 7.45 (d, 1H, J = 8.7 Hz), 7.09-7.22 (m, 4H), 6.55 (br s, 1H), 4.40 (d, 1H, J = 6.0 Hz), 2.28 (s, 3 H). Anal. (C ₂₆ H ₂₁ N ₇ .0.5 H ₂ O) C, H, N. MS (ES) [m + H] / z calculated 432, measured 432.
[920] Biochemical and Biological Evaluation
[921] Cyclin-dependent kinase activity is determined by the time-dependent binding of the radioisotope [ ³² P] ATP or [ ³³ P] ATP, ie, enzyme-catalyzed amount in the protein substrate. To do this, 10 mM HEPES (N- [2-hydroxyethyl] piperazine-N '-[2-ethanesulfonic acid]) (pH 7.4) per reaction, 10 mM MgCl ₂ , 25 μM adenosine triphosphate (ATP), 1 mg / ml ovalbumin (ovalbumin), 5 μg / ml leupeptin, 1 mM dithiothreitol, 10 mM beta-glycerophosphate, 0.1 mM sodium vanadate, 1 mM sodium fluoride sodium fluoride), 2.5 mM ethylene glycol-bis (β-aminoethyl ether) -N, N, N'N'-tetraacetic acid (EGTA), 2% (v / v) dimethylsulfoxide and 0.03-0.4 μCi [ ^{32 / 33} P] ATP was carried out in a 96-co incubator with a total dose of 50 μL and analyzed. The phosphorylated substrate was then captured in nitrocellulose or phosphocellulose using a 96-hole filtration manifold and the unbound radioactive elements were removed by repeated washing with 0.85% phosphoric acid. Radioactivity is the amount exposed to a dry film in a phosphorimager.
[922] Exact K _i values were determined by measuring enzyme activity in the presence of different inhibitor compound concentrations and subtracting background radioactivity measured in the presence of enzymes. Inhibition data fit either equations for competitive inhibition using Kaleidagraph (Synergy Software) or equations for competitive tight-binding inhibition using KineTic software (BioKin, Ltd.). It was.
[923] Inhibition of CDK4 / Cyclin D Retinoblastoma Kinase Activity
[924] Complexes of human CDK4 with cyclin D3 or complexes of human CDK4 with cyclin D3 genetically cleaved (1-264) are similar baculovirus expression vectors (Meijer and Kim, "Chemical Inhibitor of Cyclin-Dependent Kinases", Methods). in insect cells infected with En Enzymol ., vol. 283 (1997), pp. 113-128) using conventional biochemical chromatography techniques. The enzyme complex (5 or 50 nM) was quantified using 0.3-0.5 μg of recombinant retinoblastoma protein fragment (Rb) purified as a substrate. The engineered Rb fragment (386-928 residues of the native retinal blast protein; 62.3 kDa) contains a tag of six histidine residues to facilitate purification as well as the major phosphorylation sites found in the unique 106 kDa protein. Phosphorylated Rb substrates were captured via microfiltration in nitrocellulose membranes and the amounts were measured using the phosphorimager described above. Enzyme complex concentrations were below 5 nM for the measurement of tight inhibitors, and the duration of quantitation was extended to 60 minutes while the time-dependent time of product formation was in line.
[925] Inhibition of CDK2 / Cyclin A Retinoblastoma Kinase Activity
[926] CDK2 is a conventional method known from insect cells infected with baculovirus expression vectors (Rosenblatt et al., "Purification and Crystallization of Human Cyclin-dependent Kinase 2", J. Mol. Biol ., Vol. 230 , 1993, 1317-1319). Cyclin A was purified in E. coli cells expressing full-length recombinant cyclin A and cleaved cyclin A constructs were generated by limited proteolysis and purified by the method described above (Jeffrey et al. , "Mechanism of CDK activation revealed by the structure of a cyclin A-CDK2 complex", Nature , vol. 376 (27 July 1995), pp. 313-320). CDK2 complexes and hydrolyzed cyclin A were prepared by purification by gel filtration. The substrate for this quantification used the same Rb substrate fragment as used in the CDK4 quantification, and the CDK2 / cyclin A and CDK4 / cyclin D3 quantification methods are essentially the same except that CDK2 is present at 150 nM or 5 nM. K _i value was measured by the same method as above.
[927] The promotion of cell proliferation due to VEGF and other growth factors depends on each of the tyrosine kinases of their respective receptors causing an autophosphorylation reaction. Thus, the ability of protein kinase inhibitors to prevent cell proliferation caused by these growth factors is directly linked to the ability of the receptor to block autophosphorylation. The following recombinants are used to determine the protein kinase inhibitory activity of these compounds.
[928] VEGF-R2 Recombinant for Quantification
[929] The recombinant determines the ability of the test compound to inhibit tyrosine kinase activity. The recombinant (VEGF-R2Δ50) of the cytosolic domain of human vascular endothelial growth factor receptor 2 (VEGF-R2) lacking 50 central residues out of 68 residues of the kinase insertion domain is expressed in the baculovirus / insect cell system. do. VEGF-R2Δ50 at 1356 residues of full length VEGF-R2 contains 806-939 and 990-1171 residues, and also a single point mutation (E990V) in the kinase inserts the domain corresponding to wild type VEGF-R2 do. The autophosphorylation of purified recombinants was carried out by incubating the enzyme at a concentration of 4 μM containing 5% glycerol and 5 mM DTT in the presence of 3 mM ATP and 40 mM MgCl ₂ in 100 mM Hepes, pH 7.5 for 2 hours at 4 ° C. After autophosphorylation, the recombinant was shown to have essentially the same catalytic activity as the wild type autophosphorylation kinase domain recombinant. See Parast et al., Biochemistry , 37 , 16788-16801 (1998).
[930] CHK1 Recombinant for Quantification
[931] His-tagged full-length human CHK-1 (FL-CHK1) to the C-terminus was expressed using the baculovirus / insect cell system, and 6 histidine residues (6 x His-tag) at the C-terminus of human CHK1 476 amino acid. ) Is contained. The protein was purified by conventional chromatography techniques.
[932] VEGF-R2 Quantitation
[933] Combined Spectroscopy (FLVK-P) Quantitation
[934] The production of ADP from ATP with phosphate transfer is linked to the oxidation of NADH using phosphoenolpyruvate (PEP), a system containing pyruvate kinase (PK) and lactic acid dehydrogenase (LDH). have. Oxidation of NADH was observed to decrease the absorbance at ₃₄₀ nm (e ₃₄₀ = 6.22 cm ^-1 mM ^-1 ) using a Bechman DU 500 spectrometer. Quantitative conditions of phosphorylated VEGF-R2Δ50 (denoted FLVK-P in the table below) were as follows: 1 mM PEP; 250 μM NADH; 50 units of LDH / ml; 20 units of PK / ml; 5 mM DTT; 20 mM poly (E ₄ Y ₁ ); 3 mM ATP; And 60 mM MgCl ₂ and 2 mM MnCl ₂ in Hepes, pH 7.5. Quantification started with an enzyme of 5-40 nM. K _i values were determined by measuring enzyme activity in the presence of various concentrations of test compound. The data were analyzed using Enzyme Kinetic and Kaleidagraph software.
[935] ELISA quantification
[936] The production of phosphogastrin was observed using biotinylated gastrin peptide (1-17) as the substrate. Biotinylated phosphogastrin was immobilized using a 96-hole microtiter covered with streptavidin and detected using an anti-phosphotyrosine-antibody conjugated with horseradish peroxidase It was. Wasabi peroxidase activity was observed using 2,2'-azino-di- [3-ethylbenzothiazoline sulfonate (6)] diammonium salt (ABTS). Typically the quantitative solution is a 2 μM biotinylated gastrin peptide; 5 mM DTT; 20 μM ATP; 26 mM MgCl ₂ ; And 2 mM MnCl ₂ in 200 mM Hepes, pH 7.5. The quantification started at 0.8 nM phosphorylated VEGF-R2Δ50. Wasabi peroxidase activity was quantified using ABTS 10 mM. Wasabi peroxidase reaction was stopped by addition of (H ₂ SO ₄ ) and read at absorbance 405 nm. K _i values were determined by measuring enzyme activity in the presence of various concentrations of test compound. The data were analyzed using Enzyme Kinetic and Kaleidagraph software.
[937] CHK1 Quantitative
[938] The process of producing ADP from ATP with phosphate transfer to the synthetic substrate peptide Syntide-2 (PLARTLSVAGLPGKK) involves phospho via activity including pyruvate kinase (PK) and lactate dehydrogenase (LDH). Enolpyruvate (PEP) is used to oxidize NADH. Oxidation of NADH was observed to decrease the absorbance at ₃₄₀ nm (ε ₃₄₀ = 6.22 cm ^-1 mM ^-1 ) using an HP8452 spectrometer. Typically the reaction solution is 4 mM PEP; 0.15 mM NADH; 28 units of LDH / ml; 16 units of PK / ml; 3 mM DTT; 0.125 mM Syntide-2; 0.15 mM ATP; 25 mM MgCl ₂ in 50 mM TRIS, pH 7.5 and 400 mM NaCl. Quantification started with 10 nM FL-CHK1. K _i values were determined by measuring enzyme activity in the presence of various concentrations of test compound. The data were analyzed using Enzyme Kinetic and Kaleidagraph software.
[939] Inhibition of Phosphorylated FGF Receptor and LCK Tyrosine Kinase Activity
[940] Cloning, expression and purification of the cytoplasmic domain of three amino acid substituted (L457V, C488A and C584S) FGFR1 tyrosine kinase (amino acids 456-766) is known by Mohammadi, M., Schlessinger, J. & Hubbard, SR (1996), Cell, 86 , 577-587). The domain was expressed in Sf9 insect cells using baculovirus expression vectors, and proteins were purified by conventional techniques in the art. LCK tyrosine kinases were expressed in insect cells starting at amino acid 223 and N-terminally deficient in amino acid 509 at the end of the protein. In addition, the N-terminus of the protein was substituted with two amino acids, P223M and C224D. Kinases were purified using conventional chromatography methods.
[941] Tyrosine kinase activity is transferred to phosphorylated poly (Glu, Tyr; 4: 1) substrates and ADP production via pyruvate kinase-catalysis of phosphate groups with the production of pyruvate from phosphoenolpyruvate to ADP and the modification of ADP Measurements were made using continuous spectrometry quantitation linked to the dosing. The pyruvate preparation is in turn converted from NADH to NAD ⁺ followed by a reduction by lactic acid dehydrogenase-catalysis of pyruvate to produce lactate. Loss of NADH is observed at absorbance 340 nm (see Technikova-Dobrova et al., "Spectrophotometric determination of functional characteristics of protein kinases with coupled enzymatic assay", FEBS Letters , vol. 292 (1991), pp. 69-72) . Enzyme activity was 200 mM HEPES (pH 7.5), 2 mM phosphoenolpyruvate, 0.3 mM NADH, 20 mM MgCl ₂ , 100 μM ATP, 5 mM DTT, 5.1 or 25 mM poly (Glu, Tyr) 4: 1 for P-FGF or P -LCK quantification and measurement in the presence of pyruvate kinase and lactate dehydrogenase of 15 units / ml respectively. Phosphorylated FGF receptor kinase was present at 100 nM and phosphorylated LCK kinase was present at 50 nM. Quantification was carried out at 37 ° C. under initial rate conditions and the rate was adjusted to the background rate measured in the absence of enzyme. Inhibition (%) was calculated corresponding to the control enzyme quantified in the presence of 2% (v / v) DMSO. The results are shown in Table 1.
[942] Combined Spectroscopy (FAK) Quantification
[943] Tyrosine kinase quantification was observed using a Beckman DU 650 spectrometer. The production of ADP has been linked to the process of oxidizing NADH using phosphoenolpyruvate (PEP) through activity including pyruvate kinase (PK) and lactic acid dehydrogenase (LDH). Oxidation of NADH was observed to decrease the absorbance at ₃₄₀ nm (ε ₃₄₀ = 6.22 cm ^-1 mM ^-1 ) using an HP8452 spectrometer. Typically the reaction solution is 1 mM PEP; 250 μM NADH; 50 units of LDH / ml; 20 units of PK / ml; 5 mM DTT; in 200 mM Hepes, pH 7.5 and various concentrations of poly (E ₄ Y ₁ ), ATP and MgCl ₂ . Quantification started with 40 nM cdFGFR1.
[944] The results of the quantification performed with the compounds comprising the specific example compounds described above are shown in Table 1 below. Particularly different descriptions are required, units and quantities used are indicated in the applicable column of the table.
[945] TABLE 1 Kinases and K _i
[946]
[947]
[948]
[949]
[950]
[951] Inhibition of Cell Growth: Evaluation of Cytotoxicity
[952] Inhibition of cell growth was carried out using 3- (4,5-dimethylthiazol-2-yl) -2,5- [2H] -diphenyltetrazolinium bromide (MTT) formazan (Mossman, Journal of Immunological Methods , vol. 65 (1983), pp. 55-58), were measured using tetrazolium salt quantification based on the capacity of cells to grow. The water insoluble purple formazan product was then detected spectrophotometrically. HCT 16 cell lines were cultured in 96-co incubators. Cells were cultured in appropriate medium at a dose of 135 μl / well in McCoy's 5A medium. The plate was incubated for 4 hours before the inhibitor compound was added. Different concentrations of inhibitor compound were added to 0.5% (v / v) dimethylsulfoxide (15 μl / well) and cells were incubated at 37 ° C. (5% CO ₂ ) for 4-6 days (depending on cell morphology). . After incubation, MTT was finally added at a concentration of 0.2 mg / ml and the cells were further incubated at 37 ° C. for 4 hours. The plate was centrifuged before the medium was removed and formazan (dissolved in dimethylsulfoxide) was measured at absorbance 540 nm. The concentration of inhibitor compound that inhibited 50% of growth was determined from the straight portion of the semi-log plot of inhibitor concentration versus percent inhibition. All results were compared to control cells treated with 0.5% (v / v) dimethylsulfoxide only.
[953] TABLE 2
[954]
[955]
[956] This example describes the quantification that is readily performed to determine their activity levels for compounds according to Formulas I and II and various kinase complexes. Such quantification or other conventional quantitation known in the art can be suitably used to select an inhibitor having the required activity level for the selected target.
[957] Exemplary compounds above may be represented in pharmaceutical compositions by the following general formulations.
[958] Parenteral Composition
[959] To prepare safe parenteral pharmaceutical formulations administered by injection, 100 mg of a water soluble salt of the compound of Formula I or II was dissolved in DMSO and mixed with 0.9% sterile saline. The mixture was prepared in the form of a dosage unit that can be safely injected by injection.
[960] Oral Formulations
[961] To provide a pharmaceutical formulation for oral administration, 100 mg of the compound of Formula I or II was mixed with 750 mg of lactose. The mixture was prepared in the form of an oral dosage unit such as hard gelatin capsules to be safe for oral administration.
[962] It is to be understood that the above detailed description is essentially for illustrating and describing the present invention and for illustrating the present invention and preferred embodiments in detail. Thus, it is to be understood that the scope of the present invention is not limited only to the claims and the corresponding parts or those described above.

权利要求:
Claims (24)
[1" claim-type="Currently amended] A compound represented by formula (I)

From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I; Or a prodrug or pharmaceutically active metabolite of Formula (I), or a pharmaceutically acceptable salt of their prodrug or metabolite.
[2" claim-type="Currently amended] The compound of claim 1, wherein in the compound, pharmaceutically acceptable salt, prodrug or pharmaceutically active metabolite:
R ₁ is

Wherein R ₄ is hydrogen; or

Wherein Y is CH or N, and R ₃ is H, substituted or unsubstituted alkyl, aryl, carbocycle, heteroaryl, or heterocycle group; or

Wherein Y is C or N and R ₃ is H, substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle or heterocycle group.
[3" claim-type="Currently amended] Compounds selected from the group described below:


Or their pharmaceutically acceptable salts, prodrugs or pharmaceutically active metabolites, or pharmaceutically acceptable salts of their prodrugs or metabolites.
[4" claim-type="Currently amended] (a) Amount of cell cycle regulator having protein kinase inhibitory effect, wherein the compound represented by the following formula (I) is a cell cycle regulator:

From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I; Or a prodrug or pharmaceutically active metabolite of Formula I, or a pharmaceutically acceptable salt of their prodrug or metabolite; And a pharmaceutically acceptable carrier.
[5" claim-type="Currently amended] A compound represented by formula (I)

From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I; Or inhibiting the kinase complex by administering to a patient in need of treatment of a cell cycle modulator selected from the group consisting of a prodrug or pharmaceutically active metabolite of Formula I, or a pharmaceutically acceptable salt of their prodrug or metabolite The method of treating a disease or disorder adjusted to one.
[6" claim-type="Currently amended] (a) A therapeutically effective amount of a compound represented by formula (I)
(Ⅰ)
From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I;
Or a prodrug or pharmaceutically active metabolite of Formula I, or a pharmaceutically acceptable salt of their prodrug or metabolite; And
(b) a pharmaceutically acceptable carrier, diluent, carrier or excipient thereto;
Pharmaceutical compositions containing.
[7" claim-type="Currently amended] A compound represented by formula (I)

From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I; Or a prodrug or pharmaceutically active metabolite of Formula I, or a pharmaceutically acceptable salt of their prodrug or metabolite;
A method of treating a mammalian disease associated with kinase activity by administering to a mammal in need thereof.
[8" claim-type="Currently amended] 8. The method of claim 7, wherein said mammalian disease is associated with tumor growth, cell proliferation or angiogenesis.
[9" claim-type="Currently amended] A compound represented by formula (I)

From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I; Or a prodrug or pharmaceutically active metabolite of Formula I, or a pharmaceutically acceptable salt of their prodrug or metabolite;
A method for regulating or inhibiting the activity of protein kinases by binding an effective amount of the receptor with a receptor.
[10" claim-type="Currently amended] 10. The method of claim 9, wherein said protein kinase receptor is a CDK complex, VEGF or CHK1.
[11" claim-type="Currently amended] A pharmaceutical composition comprising an effective amount for inhibiting the kinase complex of a cell cycle regulator represented by Formula I:

From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I; Or a pharmaceutically acceptable salt of the prodrug or pharmaceutically active metabolite of Formula I, or their prodrug or metabolite.
[12" claim-type="Currently amended] A compound represented by formula (I)

From here,
R ₁ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group, or
,
Wherein R ₄ is H or lower alkyl and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula I; Or a prodrug or pharmaceutically active metabolite of Formula I, or a pharmaceutically acceptable salt of their prodrug or metabolite;
A method of treating a disease state or disorder associated with abnormal cell proliferation by administering to a patient in need thereof.
[13" claim-type="Currently amended] A compound represented by formula (II)

Wherein R ₁ ′ is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle,
Group,
Wherein R ₄ is individually H or lower alkyl, and X is substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle group; And
R ₂ ′ is substituted or unsubstituted amino, nitro, alkenyl, alkyl, aryl, heteroaryl, carbocycle, or heterocycle,
Group,
Wherein R ₄ is independently H or lower alkyl, and X is a substituted or unsubstituted aryl, heteroaryl, carbocycle, or heterocycle group; or
Pharmaceutically acceptable salts of compounds of formula II; Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt thereof.
[14" claim-type="Currently amended] The method of claim 13,
R ₁ 'is
ego,
Wherein Y is independently CH, CR ₃ or N, and the R ₃ group is independently one or more H, substituted or unsubstituted alkyl, alkenyl, aryl, carbocycle, heteroaryl, heterocycle, The compound, pharmaceutical, characterized in that it is hydroxy, halogen, alkoxy, aryloxy, heteroaryloxy, thioaryl, thioheteroaryl, thioalkyl, thioacyl, or amino and may provide one or more R ₃ groups Acceptable salts, prodrugs or pharmaceutically active metabolites.
[15" claim-type="Currently amended] The compound of claim 14, wherein R ₂ ′ is substituted or unsubstituted nitrogen-containing heteroaryl, and R ₁ ′ is

A compound of formula II characterized in that pharmaceutically acceptable salts thereof;
Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt thereof.
[16" claim-type="Currently amended] 14. A compound of formula II according to claim 13, wherein R ₂ ′ is substituted or unsubstituted nitrogen-containing heteroaryl, their pharmaceutically acceptable salts;
Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt thereof.
[17" claim-type="Currently amended] The compound of claim 13, wherein R ₂ ′ is

A compound of formula II characterized by a substituted or unsubstituted group represented by the above general formula, pharmaceutically acceptable salts thereof;
Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt thereof.
[18" claim-type="Currently amended] The compound of claim 13, wherein R ₂ ′ is

A compound of formula II characterized by a substituted or unsubstituted group represented by the above general formula, pharmaceutically acceptable salts thereof;
Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt thereof.
[19" claim-type="Currently amended] The compound of claim 13, wherein R ₂ ′ is

A compound of formula II characterized by a substituted or unsubstituted group represented by the above general formula, pharmaceutically acceptable salts thereof;
Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt thereof.
[20" claim-type="Currently amended] The compound of claim 14, wherein R ₂ ′ is

A compound of formula II characterized by a substituted or unsubstituted group represented by the above general formula, pharmaceutically acceptable salts thereof;
Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt of the prodrug or metabolite thereof.
[21" claim-type="Currently amended] The compound of claim 13, wherein R ₂ ′ is

A compound of formula II characterized by a substituted or unsubstituted group represented by the above general formula, pharmaceutically acceptable salts thereof;
Or a prodrug or pharmaceutically active metabolite of Formula II, or a pharmaceutically acceptable salt thereof.
[22" claim-type="Currently amended] Compounds selected from the group described below:










Or their pharmaceutically acceptable salts, prodrugs or pharmaceutically active metabolites, or pharmaceutically acceptable salts of their prodrugs or metabolites.
[23" claim-type="Currently amended] Iii) a compound or pharmaceutically acceptable salt, prodrug or pharmaceutically active metabolite of claim 13 or a pharmaceutically acceptable salt of their prodrug or metabolite, and
Ii) pharmaceutically acceptable carriers
Pharmaceutical compositions for treating a disease state associated with abnormal cell proliferation comprising a.
[24" claim-type="Currently amended] Pharmaceutically acceptable salts of compounds of claim 13 or compounds of Formula II; Or prodrugs or pharmaceutically active metabolites of the compounds of Formula II, or pharmaceutically acceptable salts of their prodrugs or metabolites;
A method of treating a disease state or disorder associated with abnormal cell proliferation comprising administering to a patient in need thereof their therapeutically effective amount.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-01-18|Priority to US17648400P

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2000-01-18|Priority to US60/176,484

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2001-01-18|Application filed by 아구론 파마슈티컬스, 인크.

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2001-01-18|Priority to PCT/US2001/001477

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2002-09-26|Publication of KR20020073505A

优先权:

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申请号 | 申请日 | 专利标题

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US17648400P| true| 2000-01-18|2000-01-18|

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US60/176,484|2000-01-18|

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PCT/US2001/001477|WO2001053268A2|2000-01-18|2001-01-18|Indazole compounds, pharmaceutical compositions, and their use for mediating or inhibiting cell proliferation|